Mumps

Posted on April 3, 2011 by crunchymomma

Mumps

Jeryl Lynn strain:

There are more than ten mumps vaccine strains have been used throughout the world, such as Jeryl Lynn, Urabe, Hoshino, Rubini, Leningrad-3, L-Zagreb, Miyahara, Torii, NK M-46, S-12 and RIT 4385. In Japan and Europe, some manufacturers produce a live mumps vaccine containing the Urabe Am9 virus strain. Due to concerns about vaccine-associated meningitis, several countries stopped using Urabe vaccine strain (WER 1992). Some vaccines have a more limited distribution. The mumps vaccines are cultured in various ways. The viruses can be cultured in chick embryo fibroblasts, such as the Jeryl Lynn and Urabe strain containing vaccines, or quail and human embryo fibroblasts are also used for some vaccines.

Vaccines:

MUMPSVAX® (MUMPS VIRUS VACCINE LIVE)

JERYL LYNN™ STRAIN

Package Insert

M-M-R® II (MEASLES, MUMPS, and RUBELLA VIRUS VACCINE LIVE)

Jeryl Lynn** (B level) strain

Package insert

ProQuad® Measles, Mumps, Rubella and Varicella Virus Vaccine Live

MMRV(Measles, Mumps, Rubella, Varicella)

Has been suspended.

ProQuad* is a combined attenuated live virus vaccine containing measles, mumps, rubella, and varicella viruses. ProQuad is a sterile lyophilized preparation of (1) the components of M-M-R*II (Measles, Mumps and Rubella Virus Vaccine Live): Measles Virus Vaccine Live, a more attenuated line of measles virus, derived from Enders’ attenuated Edmonston strain and propagated in chick embryo cell culture; Mumps Virus Vaccine Live, the Jeryl Lynn™ (B level) strain of mumps virus propagated in chick embryo

cell culture; Rubella Virus Vaccine Live, the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts; and (2) Varicella Virus Vaccine Live (Oka/Merck), the Oka/Merck strain of varicella-zoster virus propagated in MRC-5 cells. The cells, virus pools, bovine serum, and human albumin used in manufacturing are all tested to provide assurance that the final product is free of potential adventitious agents.

ProQuad, when reconstituted as directed, is a sterile preparation for subcutaneous administration.

Each 0.5-mL dose contains not less than 3.00 log10 TCID50 (50% tissue culture infectious dose) of measles virus; 4.30 log10 TCID50 of mumps virus; 3.00 log10 TCID50 of rubella virus; and a minimum of 3.99 log10 PFU (plaque-forming units) of Oka/Merck varicella virus.

WHO Position paper on Mumps vaccines

Feb 2007: Mumps vaccines; studies on immune responses, efficacy and effectiveness

Mumps virus strains used for vaccine

At least 10 strains of the mumps virus are in use throughout the world for live attenuated vaccine. The first vaccine strain to be developed, and that most often used, is the Jeryl Lynn strain which was named after the child from whom the virus was isolated. It was developed in the USA by passaging seven times in embryonated hen’s eggs and ten times in chick embryo cell cultures. At the initial level of attenuation, lower than that used in the final vaccine, the Jeryl Lynn strain produced parotid swelling in some vaccinees what was the indicating that the vaccine strain was not suffficiently attenuated. This parotid swelling was not seen after additional passages at the B level of attenuation. Since December 1967, a live attenuated Jeryl Lynn vaccine has been manufactured and distributed by an American company…

In the USSR in the 1950s, the Leningrad-3 strain was developed by Smrodintsev and Klyachko in guinea pig kidney cell culture, with further passages in Japanese quail embryo cultures. Vaccines based on this strain have been used in the former Soviet Union and other countries.

Leningrad-3 mumps virus was further attenuated in Croatia by adaptation and passages on chick embryo fibroblast cell culture. The new mumps strain has been designated L-Zagreb. This strain is used in Croatia and India.

The Urabe strain of live mumps vaccine was first licensed in Japan and thereafter in Belgium, France, and Italy. It is produced either in the amnion of embryonated hen’s eggs or in chick-embryo cell cultures and has been used successfully in Japan and other countries. Its immunogenic properties are similar to those of the Jeryl Lynn strain.

The other strains are used to produce vaccines on a limited local scale. Hoshino, Torii and NKM – 46 strains are said to have characteristics similar to those of the Urabe strain. Mumps vaccine strains have been attenuated on different cell-culture systems and it was originally thought that they are were equally capable of inducing high levels of immunity. Recent observations, however, suggest that some vaccines based on the Rubini strain, approved in 1985 in Switzerland, have lower efficacy than those based on the Jeryl Lynn or Urabe strains. One possible explanation for a low protective efficacy of the Rubini strain may be the high number (> 30) of passages attained during its attenuation process. Vaccines prepared from various strains may differ in their capacity to cause adverse events; meningitis associated with MMR vaccine containing Urabe strains has led to the withdrawal of Urabe-containing vaccine from several countries.

A killed mumps virus vaccine that was licensed in the United States in 1948 and used from 1950 to 1978, found little acceptance because it induced only short-term immunity of low protective efficacy. Since then, live, attenuated mumps virus vaccines have been developed in Japan, the Russian Federation, Switzerland and the United States. The vaccines are scheduled for either one or two doses, the first given at 12–15 months of age and the second at 9–12 years of age. They are available as monovalent, bivalent measles-mumps (MM) vaccines and trivalent measles-mumps-rubella (MMR) vaccines. WHO requirements do not specify the minimum amount of vaccine virus that one human dose should contain. Rather, this is determined by the national control authority of the country where the vaccine is produced. Most of these vaccines contain more than 1000 cell-culture infective doses of attenuated mumps virus per dose…

The incidence of vaccine-associated cases of aseptic meningitis ranges from 0.1–1 per 100 000 doses of the Jeryl Lynn mumps vaccine.The Leningrad-3 vaccine strain developed in the former Soviet Union is propagated in guinea-pig kidney cell culture and further passaged in Japanese quail embryo culture…

Passive surveillance and retrospective reviews indicate an incidence of 20–100 cases of aseptic meningitis per 100 000 doses of MM vaccine based on the Leningrad-3 strain. The Leningrad-3 strain has been further attenuated in Croatia by adaptation to chick embryo fibroblast cell culture. The new strain designated L-Zagreb is used in Croatia,India and Slovenia. Studies of L-Zagreb in Croatia revealed protective properties equivalent to those seen with the Leningrad-3 strain and also the incidence of vaccine associated aseptic meningitis remained largely the same (2–90 per 100 000 doses of MMR).

Live mumps vaccine based on the Urabe strain was first licensed in Japan and then in France, Belgium and Italy. The Urabe strain is produced either in the amnion of embryonated hens’ eggs or in chick embryo cell cultures…

A possible association of the Urabe strain with vaccine-induced meningitis has resulted in its withdrawal from some countries. Studies up to 1993 identified an incidence of approximately 100 cases of aseptic meningitis per 100 000 doses of MMR containing the Urabe mumps strain. However, the rates differed by manufacturer.

The Rubini strain was first licensed in Switzerland in 1985. It was developed by passage in a human diploid cell line, serial passaging in embryonated hens’ eggs and then adapted to the MRC-5 human diploid cell line. Recent observations with the vaccine based on the Rubini strain suggest that this vaccine has lower efficacy than those based on the Jeryl Lynn or Urabe strains. A three-year study in Switzerland showed that the Rubini strain conferred only 6.3% protection whereas the Urabe and Jeryl Lynn based vaccines achieved 73.1% and 61.6% efficacy respectively.In another study the corresponding figures were 12.4%, 75.8% and 64.7%.

An explanation for these poor results may be the high number of passages (>30) resulting in an overly attenuated vaccine strain. Furthermore, the manufacturer of the Rubini strain vaccine now recommends a second dose at four to six years of age. Data on the protective efficacy of this schedule are currently not available. Attenuated mumps virus strains that are used on a limited scale only include the Hoshino, Torii and NKM-46 strains. They are reported to possess immunogenic properties similar to the Urabe strain.

An Evaluation of the Rubini, Urabe AM9, and Jeryl-Lynn Mumps Vaccines, Specifically Concerning Efficacy and Association with Aseptic Meningitis

Comparison of the Neurovirulence of a Vaccine and a Wild-Type Mumps Virus Strain in the Developing Rat Brain Journal of Virology, October 1998, p. 8037-8042, Vol. 72, No. 10

The risk of aseptic meningitis associated with the Leningrad-Zagreb mumps vaccine strain following mass vaccination with measles-mumps-rubella vaccine, Rio Grande do Sul, Brazil, 1997

Abstract

Background Few data are available on the risk of aseptic meningitisfollowing vaccination with the Leningrad-Zagreb (L-Z) strainof mumps vaccine. In 1997 the mumps vaccine was introduced intothe state of Rio Grande do Sul in Brazil through mass vaccinationwith mumps-measles-rubella (MMR), targeting children aged 1–11years. Five municipalities used exclusively MMR vaccine containingthe L-Z strain of mumps. An outbreak of aseptic meningitis wasobserved shortly after the mass campaign.

Methods To estimate the risk of aseptic meningitis associatedwith this strain, we analysed vaccination and meningitis casesurveillance data from the selected municipalities. A case ofvaccine-associated aseptic meningitis was defined as one witha pleocytosis of 10–1500 leukocytes/ml and occurring within15–35 days after vaccine receipt.

Results We estimated a risk of 2.9 cases per 10 000 doses ofL-Z administered, equivalent to 1 case per 3390 doses administered.The overall risk of aseptic meningitis following the campaignwas increased 12.2-fold (95% CI: 6.0–24.7) compared withthe same period in 1995–1996. Following the mass campaign,the incidence of mumps declined 93% during 1998–2000.

Conclusions Vaccination with the L-Z strain of mumps vaccineas part of a mass campaign was associated with a significantlyincreased risk of aseptic meningitis. Decisions about type ofmumps vaccine and mumps vaccination strategies must considervaccine safety issues in addition to other criteria.

Autism Explosion Followed Big Change in MMR Shot

(By Dan Olmsted January 13, 2009)

In 1990, Merck & Co., manufacturer of the mumps-measles-rubella vaccine known as the MMR, made a significant but little-noticed change: It quadrupled the amount of mumps virus in the combination shot, from 5,000 to 20,000 units. Then in 2007 it reversed course, reducing the amount to 12,500 units. Neither the measles nor the rubella (German measles) component of the MMR was changed at all — each remained at 1,000 units throughout.

Merck also makes the single-component mumps shot, and in 1990 it also increased the potency of that shot by the same amount, from 5,000 to 20,000 units. But unlike the MMR shot, the standalone mumps shot’s potency was not scaled back in 2007. It remains at 20,000 units…

Killed Mumps Vaccine:

Mumps virus vaccine. (Calif Med. 1969 November; 111(5): 413–414.)

killedmumpsvaccine

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Rubella Strains

Posted on April 3, 2011 by crunchymomma

Rubella

Global Measles and Rubella Laboratory Network, January 2004-June 2005

Seven genotypes and three additional provisional genotypes of rubella virus are recognized by WHO (Figure 2). These genotypes are classified into two clades (i.e., groups of similar genotypes), designated 1 and 2; clade 2 viruses have not been found circulating in the western hemisphere. Although knowledge concerning the geographic distribution of rubella genotypes has progressed substantially since 2003, the genotypes of rubella viruses present in many countries and regions remain unknown.

rubella2

Global strains of rubella virus

Based on analysis of the viral E1 gene, there are two genotypes of rubella virus: Genotype I is present in Europe, North America, and Asia; Genotype II is present in China, Israel and Korea and appears to co-exist with Genotype I viruses in these countries 14. While these genotypes differ by 7-11% at the nucleotide level, they differ by less than 3% at the amino acid level and are of the same serotype. Therefore, the biological significance of the evolution and maintenance of two genotypes is unclear. Following the widespread use of rubella vaccine in developed countries from the 1970s onward, a change in rubella strains occurred in which an

intercontinental genotype clade of Genotype I present in Europe, North America, and Japan replaced the geographic clades from each continent. There are still large areas of the world from which no rubella virus isolates have been analyzed (Africa, Australia, and most of mainland Asia) and thus there could be additional genotypes as well as unrecognized geographic clades of Genotypes I and II. It will be important to obtain a selection of rubella virus isolates from these regions before or concurrent with widespread introduction of rubella vaccination so that the pre-existing endemic virus genotypes can be identified…(Frey TK, Abernathy ES, Bosma TJ et al. Molecular analysis of rubella virus epidemiology across three continents, North America, Europe, and Asia, 1961-1997. Journal of Infectious Disease 1998;178:642-650).

EVOLUTION AND DISTRIBUTION OF RUBELLA VIRUS GENOTYPES

Rubella virus is a sole member of Rubivirus group of Togaviridae and its genotypes has been classified in 2004 at WHO meeting. They are genotype 1B, 1C, 1D, 1E, 1F , 2A and 2B as confirmed and 1a, 1g and 2c as provisional. They have unique chronological and geographical characteristics. Genotype 1a worldwide distributed in 1960s and 70s, however almost disappeared since 1980. Genotype 1B mainly has distributed in Europe and genotype 1C in North and South American continents. Genotype 1D has distributed mainly in Asia and genotype 1F is restricted in China. Genotype 1E looks to be derived from genotype 1D and recently becomes to be predominant circulating one worldwide since 1997. Genotype 1g looks to be derived from genotype 1B and distributes in Europe and Americas. Genotype 2A was restricted in China and 2B in Eurasia and Africa. Genotype 2c was found in Russia. Molecular epidemiological study of rubella virus genotype could reveal the transportation of rubella virus from a country to another country. It will greatly help to make a effective plan of rubella immunization program to eliminate and eradicate for a certain country.

Ancestor dating analysis resulted in 1942-46 for virus strains in genotype 1 and 1840 for those in genotype 2.

By these analysis shift of major prevailing genotype of rubella virus may happened in the history of this diseases, at least from genotype 2 to genotype 1 and genotype 1a to genotype 1E.

As rubella has no relating animal viruses as far as studied, this evolution and emergence is very curious to be known in the future.

Mapping of Genetic Determinants of Rubella Virus Associated with Growth in Joint Tissue

J Virol. 2000 January; 74(2): 796–804. PMCID: PMC111599

Rubella virus (RV), the etiologic agent of German measles, belongs to the family Togaviridae and is the only member of the genus Rubivirus. Natural infection in childhood causes a systemic illness characterized by a short-lived maculopapular rash and mild fever (50). The disease is generally benign, and infection is often asymptomatic. It is the teratogenic potential of rubella that brought the virus to the forefront of public health interests and provided the impetus for isolation of the virus and subsequent vaccine development (35, 49). The current vaccine strain RA27/3 has been very effective in reducing the incidence of congenital rubella syndrome in North America, where it is given to all children between 12 and 18 months of age. However like the wild-type strains and the earlier vaccine strain, HPV77/DE5, it is reported to be associated with acute and late-onset joint and neurological symptoms (20, 46, 47, 50).

The association of RV with acute, transient joint manifestations, after both natural infection and vaccination, has been recognized for many years (14, 23, 34, 46, 47). Rubella-associated arthritis (RAA) is usually short-lived, although a number of patients go on to develop chronic or recurrent pauci- or polyarticular symptoms which can persist for some time (7, 8, 22, 43, 45, 47). Studies to define the mechanism of pathogenesis of RAA have been limited by the fact that humans are the only natural host for RV and there is presently no animal model of infection. However, the frequency and intensity of clinical symptoms reported for wild-type (wt) and vaccine strains correlate directly with the ability of the infecting strain to propagate in organ cultures of human synovial tissue, suggesting that tropism for joint tissue is a measure of viral arthritogenicity (31). Although RV strains are genetically around 98% homologous, they display striking phenotypic variation in growth characteristics and plaque morphology as well as tropism for joint tissue (9, 31). The wt strains, such as Therien, which have the highest association with persistent joint symptoms (30%) (47), commonly replicate to titers of 10⁶ to 10⁷ PFU/ml in organ cultures of human joint tissue, comparable to the yields from the most permissive cell lines for RV. The vaccine strain RA27/3, which is associated with much lower levels of recurrent arthritis (4%) (47), is severely restricted in these cultures and does not attain titers greater than 10³ PFU/ml. However RA27/3, like the wt Therien strain, was found to persist in joint culture for over 3 months (31). In contrast, no replication of the European vaccine strain, Cendehill, was detected in human joint tissue in this study. Cendehill strain is reported to have a very low association with acute arthritis and none with chronic joint manifestations (4). These results indicate a correlation between the arthrotropism of a specific RV strain and its ability to induce joint symptoms and lends support to the hypothesis that recurrent RAA is triggered by reactivation of virus which has established a persistent infection in the joint.

The Vaccines:

Soon after the rubella virus was first isolated in tissue culture in 1962, several live-attenuated vaccine strains were developed. HPV-77 (duck embryo), HPV-77 (dog kidney) and Cendehill (rabbit kidney) strains were originally licensed in the USA between 1969 and 1970. These vaccines were replaced in 1979 by RA 27/3 (human diploid fibroblast), which produces a strong immune response (similar to natural infection) of 95% or more. While rubella immunity induced by vaccination has been reported to persist for at least 16 years and probably to be lifelong, other recent data indicate that this immunity may wane after 8 years of age. [3] Rubella vaccine is usually offered in combination with measles (MR) or measles and mumps (MMR) vaccines. [1,5] This combination offers the same high levels of immunogenicity and safety as does its individual components. Most of the currently licensed vaccines are based on a live, attenuated strain of rubella virus known as RA 27/3. The vaccines are administered subcutaneously. To avoid interference with possible remaining maternal antibodies the vaccine is usually given at the age of 12-15 months. Attempts to develop killed virus vaccines or sub-component vaccines against rubella have not been successful…

MERUVAX* II

Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts.

(package insert)

BIAVAX® II (Rubella and Mumps Virus Vaccine Live) is a live virus vaccine for immunization against rubella (German measles) and mumps. BIAVAX II is a sterile lyophilized preparation of the Wistar RA 27/3 strain of live attenuated rubella virus grown in human diploid cell (WI-38) culture

PROQUAD -MMRV(Measles, Mumps, Rubella, Varicella)

Has been suspended.

cell culture; Rubella Virus Vaccine Live, the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts; and (2) Varicella Virus Vaccine Live (Oka/Merck), the Oka/Merck strain of varicella-zoster virus propagated in MRC-5 cells. The cells, virus pools, bovine serum, and human albumin used in manufacturing are all tested to provide assurance that the final product is free of potential adventitious agents.

ProQuad, when reconstituted as directed, is a sterile preparation for subcutaneous administration.

M-M-R® II (MEASLES, MUMPS, and RUBELLA VIRUS VACCINE LIVE)

Package insert

Note: “….contains attenuated live measles and mumps viruses propagated in chick embryo cell culture, plus “the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts.”(1) Principal studies published in the American Journal of Diseases of Children and the American Journal of Epidemiology, reveal that the rubella strain was cultured from an aborted human fetus.(2,3) In addition, the growth medium for the three live viruses that are needed to produce the MMR vaccine is a buffered salt solution “supplemented with fetal bovine serum.”(4) Other ingredients include sucrose, phosphate, glutamate, recombinant human albumin, sorbitol, hydrolyzed gelatin stabilizer, and approximately 25 mcg of neomycin (an antibiotic).(5) The MMR vaccine does not contain a preservative. In fact, according to the FDA, MMR-II never contained thimerosal, a potentially dangerous chemical used in some vaccines.(6) However, trace amounts of mercury were detected in an earlier MMR formulation.”

Genomic sequence of the RA27/3 vaccine strain of rubella virus.

Arch Virol. 1997; 142(6):1165-80. PMID: 9229006 [PubMed - indexed for MEDLINE]

The sequence of the genome of the RA27/3 vaccine strain of rubella virus (RUB) was determined. In the process, several discrepancies between the previously reported genomic sequences of two wild RUB strains (Therien and M33) were resolved. The genomes of all three strains contain 9762 nucleotides (nts), exclusive of the 3′ poly A tract. In all three strains, the genome contains (5′ to 3′), a 40 nt 5′ untranslated region (UTR), an open reading frame (ORF) of 6348 nts that encodes nonstructural proteins, a 123 nt UTR between the two genomic ORFs, a 3189 nt ORF that encodes the structural proteins, and a 62 nt 3′ UTR. The 5′ end of the subgenomic RNA was found to correspond to a uridine residue at nt 6436 of the genomic RNA. At the nucleotide level, the sequence of the three strains varied by 1.0 to 2.8%, while at the amino acid level, the sequence varied by 1.1 to 2.4% over both ORFs. The RA27/3 sequence will be of use in identification of the determinants of its attenuation, in vaccine production control and in development of second generation RUB vaccines based on recombinant DNA technology.

A comparative field evaluation of three live, attenuated rubella virus vaccines.

Am J Public Health. 1971 January; 61(1): 152–156.

*Before aborted fetal cell lines were used

rubella-strain

Countries using rubella vaccine, by WHO region, as of December 1999* (pg 69)

Rubella and congenital rubella syndrome: global update

rubella

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Name That Strain

Posted on April 3, 2011 by crunchymomma

Measles

Edmonston strain:

Enders’ attenuated Edmonston strain. Edmonston wild-type (wt) measles virus (Parks et al., 2001). In 1954, the measles virus was isolated from an 11-year old boy from the US, David Edmonston, and adapted and propagated on chick embryo tissue culture (CE). The CE adapted strain, known as Edmonston A, was too virulent for vaccine purposes. The strain was attenuated by means of further passages on CE fibroblasts, resulting in a 2nd generation attenuated virus designated as Edmonston B. Again, the strain was too virulent to be applied on a large scale. Laboratories continued to pass Edmonston B on CE until a 3rd generation of more attenuated strains was developed. These strains, which are known by different names and differ from each other in the number of times the parent strain was passed on CE, provide the seeds for the vaccines now commercially available. The measles vaccines supplied through the World Health Organization’s programme on Immunization in the Americas are prepared from seeds derived from Edmonston B (EPI Newsl., 1980). GenBank Taxonomy No.: 11235

For more information on the various Edmonston strains

Schwarz strain:

Further passages of Edmonston A and B on chicken embryo fibroblasts (CEF) produced the more attenuated Schwarz and Moraten viruses, whose sequences have recently been shown to be identical (Combredet et al., 2003). The Moraten and Schwarz strains are highly genetically related, reflecting their common ancestry and similar passage history, and they are safe and effective for most children. Their use has dramatically reduced the incidence of measles, from over 100 million cases in the prevaccine era to approximately 31 million cases in 1997. However, fatal infections have been documented in immunodeficient children vaccinated with these strains (Valsamakis et al., 1999). GenBank Taxonomy No.: 132487

For more information on the various Schwarz strains

The Measles virus is monotypic, or in other words, there is only one serotype. The genetic differences among the various strains can cause variations in the clinical manifestations of infection. Since the Measles virus is monotypic, immunity against one strain can provide immunity against all strains. Even with various genotypes, the viral genomes have not deviated to produce multiple serotypes.

Vaccines:

The Edmonston strain of measles virus isolated in cell culture in 1954 (7) became the progenitor for many live attenuated measles vaccines such as Moraten, Schwarz, Zagreb and Edmonston B (8). Several measles strains were also used for the development of measles vaccines in other countries such as Russia, China and Japan. All these attenuated strains are used around the world and despite the differences in methods employed for attenuation of the original viruses, which involve various cell culture systems, incubation temperatures, and number of passages, remarkable nucleotide sequence similarity has been found among the strains (9).

A live attenuated vaccine (CAM-70) derived from a Japanese isolate has been used in Brazil since 1982. National vaccination campaigns achieved more than 95% coverage after the Brazilian Measles Eradication Program was established in 1992, although some epidemic outbreaks have occurred after the introduction of the program, mainly in 1997 (2,10)…

CAM-70 vaccine was developed in 1970 from the Tanabe strain in Japan by adaptation to the chorioallantoic membrane (CAM) of chick embryos (12-15). This vaccine has been produced at Bio-Manguinhos/FIOCRUZ since the early eighties by a technology transfer from the Biken Institute, Japan.

Since 1963, when both an inactivated and a live attenuated vaccine (Edmonston B strain) were licensed for use in the United States, both the type of measles vaccine and the recommended age for measles vaccination have changed several times. After 1967 and 1975, the inactivated and the Edmonston B vaccine, respectively, were no longer distributed. A live, further attenuated vaccine (Schwarz strain) was first introduced in 1965, and a similar vaccine (Moraten strain) was licensed in 1968. These further attenuated vaccines cause fewer reactions than the Edmonston B vaccine, yet are equally effective. The Moraten vaccine is the vaccine used currently in the United States.

ROUVAX-Live attenuated vaccine against measles (Schwartz strain)

Each vaccine dose contains:

Lyophilizate:

- Hyperattenuated live measles virus

SCHWARZ strain . . . . . . . . . . . . . . . . . ….. . at least 1000 CCID50*

- Human albumin . . . . . . . . . . . . . . . . . . . . . . . . … q.s. for lyophilization

Solvent:

- Water for injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . q.s. 0.5 ml

*CCID50 = Cell culture infectious dose 50 percent.

This vaccine contains traces of neomycin.

This vaccine also contains lactose.

This vaccine is in conformity with WHO specifications.

M-M-R® II (MEASLES, MUMPS, and RUBELLA VIRUS VACCINE LIVE)

M-M-R* II (Measles, Mumps, and Rubella Virus Vaccine Live) is a live virus vaccine for vaccination against measles (rubeola), mumps, and rubella (German measles).

M-M-R II is a sterile lyophilized preparation of (1) ATTENUVAX* (Measles Virus Vaccine Live), a more attenuated line of measles virus, derived from Enders’ attenuated Edmonston strain and propagated in chick embryo cell culture; (2) MUMPSVAX* (Mumps Virus Vaccine Live), the Jeryl Lynn** (B level) strain of mumps virus propagated in chick embryo cell culture; and (3) MERUVAX* II (Rubella Virus Vaccine Live), the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts.

The growth medium for measles and mumps is Medium 199 (a buffered salt solution containing vitamins and amino acids and supplemented with fetal bovine serum) containing SPGA (sucrose, phosphate, glutamate, and recombinant human albumin) as stabilizer and neomycin.

The reconstituted vaccine is for subcutaneous administration. Each 0.5 mL dose contains not less than 1,000 TCID50 (tissue culture infectious doses) of measles virus; 12,500 TCID50 of mumps virus; and 1,000 TCID50 of rubella virus. Each dose of the vaccine is calculated to contain sorbitol (14.5 mg), sodium phosphate, sucrose (1.9 mg), sodium chloride, hydrolyzed gelatin (14.5 mg), recombinant human albumin (≤0.3 mg), fetal bovine serum (<1 ppm), other buffer and media ingredients and approximately 25 mcg of neomycin. The product contains no preservative.

ATTENUVAX® (MEASLES VIRUS VACCINE LIVE)

ATTENUVAX* (Measles Virus Vaccine Live) is a live virus vaccine for vaccination against measles (rubeola).

ATTENUVAX is a sterile lyophilized preparation of a more attenuated line of measles virus derived from Enders’ attenuated Edmonston strain and propagated in chick embryo cell culture.

The growth medium for measles is Medium 199 (a buffered salt solution containing vitamins and amino acids and supplemented with fetal bovine serum) containing SPGA (sucrose, phosphate, glutamate, and human albumin) as stabilizer and neomycin. The cells, virus pools, fetal bovine serum, and human albumin are all screened for the absence of adventitious agents. Human albumin is processed using the Cohn cold ethanol fractionation procedure.

The reconstituted vaccine is for subcutaneous administration. Each 0.5 mL dose contains not less than 1,000 TCID50 (tissue culture infectious doses) of measles virus. Each dose of the vaccine is calculated to contain sorbitol (14.5 mg), sodium phosphate, sucrose (1.9 mg), sodium chloride, hydrolyzed gelatin (14.5 mg), human albumin (0.3 mg), fetal bovine serum (<1 ppm), other buffer and media ingredients and approximately 25 mcg of neomycin. The product contains no preservative.

ProQuad® Measles, Mumps, Rubella and Varicella Virus Vaccine Live

MMRV(Measles, Mumps, Rubella, Varicella)

Has been suspended.

ProQuad, when reconstituted as directed, is a sterile preparation for subcutaneous administration.

Killed Measles Vaccine (no longer used)

Severe local reactions to live measles virus vaccine following an immunization program.

Am J Public Health. 1983 August; 73(8): 899–900.

killedmeaslesversion

Edmonston-Zagreb (high-titer vaccine)

“In an experiment to find out of they could give high-potency Edmonston Zagreb (EZ) measles vaccine to babies as young as four months old [completing disregarding developmental neurology and lack of myelinization in the nervous system of babies] in order to overwhelm their natural maternal antibodies and replace them with vaccine-induced antibodies, medical “researchers” at the CDC and Johns Hopkins University injected thousands of babies in the Third World with the experimental vaccine that reportedly caused chronic immune suppression and the deaths of an unknown number of babies. Also, in the United States, with the help of Kaiser Permanente, more than 1500 six-month old black and Hispanic babies in inner city Los Angeles were “enrolled” in the experiment starting in June 1990. [ During the administration of president and ex-CIA director George Bush.] The study was halted in October 1991, after more than one year of genocidal activity, after repeated reports from vaccine trial sites in Africa that girl babies were dying in higher than expected numbers six months to three years after injection. [A less-than-admirable population control effort.] “–Leading Edge http://www.cco.net/~trufax/vaccine/0696.html Based on NVIC Vaccine Report 0696 Rec 9/3/96

Also see: MEASLES VACCINE EXPERIMENTS ON MINORITY CHILDREN TURN DEADLY

CDC Admits Informed Consent Violations – CDC director David Satcher admitted in a June 17 Los Angeles Times article that a National Institutes of Health (NIH) investigation of the 1990-91 Los Angeles study found that informed consent regulations had been violated because the parents were not told their babies would be injected with an experimental vaccine that had never been licensed by the FDA for use in America. Both Kaiser and the CDC have denied that any of the Los Angeles babies were harmed by the high potency EZ vaccine but did admit that one child, who received a standard potency EZ vaccine, died from a bacterial infection they maintain is unrelated to the vaccination.

The high potency EZ measles experiments began at four major sites in the mid-1980′s including Haiti, the Senegal, Guinea Bissau and Mexico. Other trials followed in Cameroon, Gambia, Bangladesh, Togo, Iran, New Guinea, Peru, Rwanda, Sudan, South Africa, Egypt, Philippines, Uzbekistan, Thailand, Zaire and Los Angeles. Primary funding came from the U.S. Agency for International Development (USAID) and the World Health Organization (WHO). In Haiti, infants were given the experimental vaccine at 10 to 500 times the usual dose levels. In a June 1996 article in Journal of Infectious Diseases, Johns Hopkins researchers report that infants with the highest antibody responses to high titer measles vaccine have the most profound immune suppression.

Warnings Ignored - The measles vaccine experiment was only stopped two years after the director of one of the African sites warned the WHO and CDC experiment leaders in April 1990 that African mortality data raised a red flag about the high titer EZ vaccine. His reports were first ignored and then discounted and he was replaced as a principal investigator. After his mortality data was dismissed as incorrect for more than a year, with support from colleagues at Harvard, he published the mortality data in The Lancet in October 1991. WHO then called for all the sites to submit mortality data for independent analysis. The CDC has stated that enrollment for the LA study was halted in October 1991.

outrage1

outrage2

EDMONSTON-ZAGREB MEASLES VACCINE PROJECT

Studies comparing Edmonston-Zagreb (EZ) measles vaccine with Schwartz measles vaccine in young infants (four to nine months of age) have been conducted in several developing countries, including Guinea-Bissau, Senegal, Haiti, Gambia, Togo, and the Philippines.

These studies revealed high seroconversion rates with EZ vaccine even in the presence of high maternal measles antibody. Several of these studies that used high-dose (4.84 In TCID50) EZ measles vaccine found increased mortality predominantly or exclusively among African female infants immunized with high-dose EZ measles vaccine. In these cases, death occurred approximately one year after vaccination. The causes of these deaths are common causes of infant and child mortality in Third World settings, e.g., respiratory infections, diarrhea and dehydration. Data from these, as well as other studies which did not find higher mortality post-vaccination, were reviewed during a two-day meeting organized by the Expanded Programme on Immunization (EPI), World Health Organization (WHO), in February 1991. Principal investigators of the major clinical trials of EZ vaccine and an international panel of experts attended the meeting and reviewed the data. The panel felt that the probability that the higher mortality was due to the vaccine was very low. Among the reasons cited was the lack of biologic plausibility, particularly in reference to the sex-specific findings.

DIPLOVAX HDC 4.0 -Freeze-dried measles vaccine produced from the Edmonston-Zagreb strain which has been further attenuated in human diploid cells.

The vaccine contains live, attentuated measles virus of the Edmonston-Zagreb strain, propagated in human diploid cells. Each dose of 0.5 mL contains at least 104 CCID50 (cell culture infective doses) of live measles virus. The vaccine is stabilized with a 10% gelatin-sorbitol stabiliser. The freeze-dried vaccine is reconstituted with 0,5 mL Sterile Water for Injections per dose.

TRESIVAC™

…is prepared from live attenuated strains of Edmonston-Zagreb Measles virus propagated on human diploid cell culture, L-Zagreb Mumps virus propagated on chick embryo fibroblast cells and Wistar RA 27/3 Rubella virus propagated on human diploid cell culture.

The reconstituted vaccine contains, in single dose of 0.5 ml. not less than
1000 CCID₅₀ of Measles virus
5000 CCID₅₀ of Mumps virus
1000 CCID₅₀ of Rubella virus.
Diluent : Sterile water for injection.
The vaccine meets the requirements of USP and WHO when tested by the methods outlined in USP and WHO, TRS 840 (1994).

Measles virus are divided into 21 genotypes

Review of the temporal and geographical distribution of measles virus genotypes in the prevaccine and postvaccine eras (Virology Journal 2005, 2:87)

Although measles virus (MV) is serologically monotypic, the genetic characterization of wild-type viruses has identified eight clades (A – H), which have been divided into 22 genotypes and one proposed genotype. Clades B, C, D, G and H each contain multiple genotypes (B1 – 3, C1 – 2, D1 – 10, G1 – 3, H1 – 2) while clades A, E and F each contain a single genotype (A, E, F) [1,2]. The sequences of the vaccine strains indicate that the wild type viruses from which they were derived were all members of genotype A. All measles genotypes can be neutralized by serum from vaccinated persons in vitro, although with varying efficiency [3,4]. There are no known biological differences between viruses of different genotypes. Specific measles genotypes are not associated with differences in severity of disease, likelihood of developing severe sequela such as subacute sclerosing panencephalitis or inclusion body encephalitis, or variability in sensitivity of laboratory diagnosis.

Review of the temporal and geographical distribution of measles virus genotypes 1951 – 2004

Although measles virus (MV) is serologically monotypic, the genetic characterization of wild-type viruses has identified eight clades (A – H), which have been divided into 22 genotypes and one proposed genotype. Clades B, C, D, G and H each contain multiple genotypes (B1 – 3, C1 – 2, D1 – 10, G1 – 3, H1 – 2) while clades A, E and F each contain a single genotype (A, E, F). The sequences of the vaccine strains indicate that the wild type viruses from which they were derived were all members of genotype A.
There are no known biological differences between viruses of different genotypes. Specific measles genotypes are not associated with differences in severity of disease, likelihood of developing severe sequela such as subacute sclerosing panencephalitis or inclusion body encephalitis, or variability in sensitivity of laboratory diagnosis.

Analysis of the variability in the nucleotide sequences of wild-type MVs has enabled the use of molecular epidemiologic techniques for measles surveillance. Genetic characterization of viral isolates or RT-PCR products is the only laboratory test that can differentiate between vaccine-associated cases and wild-type infection.

In 1998, the World Health Organization (WHO) recommended a standard protocol for the designation of measles genotypes. The minimum amount of sequence data required to assign a virus to a genotype are the 450 nucleotides encoding the carboxy terminus of the N protein. The entire sequence of the coding region of the H gene should be obtained from representative isolates.

The purpose of this summary is to collate all available reports of MV genotypes and to standardize the published genotype nomenclature, according to the current WHO criteria, with the aim of giving a comprehensive overview of the distribution of MV genotypes in the prevaccine and postvaccine eras.

Summary of distribution of MV genotypes from the prevaccine era to 2004

Genetic Diversity of Wild-Type Measles Viruses: Implications for Global Measles Elimination Programs

Figure 4. Change in genetic groups of measles viruses associated with U.S. cases and outbreaks between 1988 and September 1997. Arrows indicate sources of virus, if known.

Filed under: Measles | Tagged: strains | Comments Off

Pneumococcal

Posted on April 3, 2011 by crunchymomma

Pneumococcal

Pneumococcal is also known as S. pneumoniae or pneumococcal meningitis.

Staphylococcus aureus is a common commensal of humans and its primary habitat is the moist squamous epithelium of the anterior nares (1). About 20% of the population are always colonized with S. aureus, 60% are intermittent carriers, and 20% never carry the organism. As there is considerable evidence that carriage is an important risk factor for invasive infection (1, 2), it is surprising that so little is known about the bacterial factors that promote colonization of squamous epithelial surfaces and the host factors that determine whether an individual can be colonized or not.

Healthy individuals have a small but finite risk of contracting an invasive infection caused by S. aureus, and this risk is increased among carriers. Hospital patients who are catheterized or who have been treated surgically have a significantly higher rate of infection. In some, but not all, developed countries, many nosocomial infections are caused by S. aureus strains that are multiply resistant to antibiotics — known as methicillin-resistant Staphylococcus aureus (MRSA) (3, 4) — although the acronym MRSA is somewhat misleading because the semisynthetic β-lactam methicillin is no longer used to treat S. aureus infections….

…only Staphylococcus aureus and Staphylococcus epidermidis are significant in their interactions with humans. S. aureus colonizes mainly the nasal passages, but it may be found regularly in most other anatomical locales, including the the skin, oral cavity and gastrointestinal tract. S epidermidis is an inhabitant of the skin.

Vaccines:

For Adults:

There are more than 90 different types of pneumococcus bacteria-23 of these are covered in the current vaccination. The vaccine is injected into the body to stimulate the normal immune system to produce antibodies that are directed against pneumococcus bacteria. Pneumococcal vaccination does not protect against pneumonia caused by microbes other than pneumococcus bacteria, nor does it protect against pneumococcal bacteria strains not included in the vaccine…

PNEUMOVAX^® 23 (PNEUMOCOCCAL VACCINE POLYVALENT)

Pneumococcal 23-valent polysaccharide vaccine is used in adults and selected children 24 months or older to stimulate active immunity to infection caused by the serotypes of S. pneumoniae contained in the vaccine.¹⁰⁰ ¹⁰² ¹¹⁵ ¹²⁹ The vaccine commercially available in the US contains 23 capsular antigens that represent at least 85–90% of the serotypes that cause invasive pneumococcal infection in adults and children in the US.¹¹⁵

BRIEFING DOCUMENT Pneumococcal Adult Vaccine OPEN SESSION VRBPAC Meeting November 17th 2005

For Children:

The heptavalent pneumococcal conjugate vaccine (PCV7) is recommended for use in children 23 months of age and younger. Although other pneumococcal vaccines are available, PCV7 represents the first pneumococcal vaccine approved for use in children younger than age 2.

Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein) Prevnar^®
FOR PEDIATRIC USE ONLY

PCV7 protects against seven pneumococcal capsular types (serotypes)—4, 6B, 9V, 14, 18C, 19F, and 23F

Licensed or In Development:

Potential Impact of Conjugate Pneumococcal Vaccines on Pediatric Pneumococcal Diseases

GSK’s paediatric pneumococcal candidate vaccine Synflorix™ receives positive opinion in Europe

Synflorix™

The paediatric vaccine is proposed to be indicated for active immunisation against invasive pneumococcal disease (IPD) and middle ear infections (acute otitis media) caused by Streptococcus pneumoniae in infants and children from 6 weeks up to 2 years. The European Marketing Authorisation for the vaccine is expected to be granted in the coming months. 10-valent pneumococcal vaccine. Of these strains, serotypes 1 and 7F are on the rise in several Europe an countries and in many other parts of the world.^6,7,8,9 The 10 serotypes included in GSK’s candidate vaccine are responsible for up to 90% of IPD in young children, and are responsible for a significant proportion of IPD globally.

Synflorix™ GSK’s candidate vaccine is a 10-valent, pneumococcal conjugate vaccine. It was designed with polysaccharides derived from 10 different strains of pneumococcus. Eight are linked to a novel carrier protein ‘D’ derived from a second major paediatric pathogen – non-typeable Haemophilus influenzae (NTHi)¹³. This novel carrier protein is intended to minimise the possibility of immune interference when co-administered with other vaccines.¹⁴ GSK’s robust clinical development programme includes trials in Europe, as well as Africa, Asia and Latin America. Antibody responses to co-administered paediatric vaccines are similar to those observed when the vaccine is given alone, indicating that the candidate vaccine does not interfere with these co-administered paediatric vaccines.¹⁵

A prototype 11-valent pneumococcal vaccine formulation, which used the same novel approach in conjugation technology and contained the 10 serotypes covered by the current candidate vaccine (along with another serotype for which efficacy was not demonstrated), offered 33.6 % reduction of clinical acute otitis media in a European trial.¹⁶

GSK’s pneumococcal candidate vaccine is expected to deliver broad public health benefit by offering coverage against three additional pneumococcal strains (serotypes 1, 5 and 7F) on top of the seven serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) which are covered in the existing paediatric pneumococcal vaccine.¹ Serotypes 1, 5 and 7F are responsible for a significant burden of disease, accounting for 5-25% of all IPD cases.⁴

Synflorix;

Streptorix; Pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine; PHiD-CV; Streptococcus pnuemoniae capsular antigens–Haemophilus influenzae protein D conjugates vaccine.

5th International Symposium on Pneumococci and Pneumococcal Diseases

Public health potential of a 13vPnC vaccine for immunization of adults in the US PO4.07

Hackell, JG, Paradiso, PR, Siber, G

Wyeth Vaccines Research, Pearl River, NY, USA

The 13-valent pneumococcal conjugate (13vPnC) vaccine covers fewer serotypes than the 23-valent polysaccharide (23vPS) vaccine, but potentially has the additional benefits of a conjugate vaccine. This includes the ability to extend protection throughout the high-risk period by allowing revaccination, if necessary, without risk of induction of hyporesponsiveness (blunting of subsequent immune response).

Fry et al1 at CDC developed a model to look at the relative potential public health impact of various pneumococcal conjugate formulations, as compared to the currently available 23vPS vaccine in adults >65 years of age. The authors found a significant benefit of the conjugate vaccines based on the potential for more durable immunity and perhaps higher efficacy. We updated this model, using the rate of invasive pneumococcal disease (IPD) observed in 2004 (significantly lower than the 1998 data used in Fry et al). We also expanded the analysis to include 50-64 year olds. We assumed that 13vPnC had the same level of efficacy for the serotypes in the vaccine as 23vPS, but a longer duration of immunity, that could be sustained either through the induction of memory or through re-immunization, if needed.

We assumed vaccine uptake to be 60%, comparable to the current estimates for 23vPS uptake in >65 year olds. Similar to the original Fry et al estimates, the model predicts that more cases of IPD could be prevented with the 13vPnC vaccine compared to the cases currently prevented with the 23vPS vaccine (5544 vs 2979). The same is true for deaths due to IPD (895 vs 489). This is due in

part to the ability to extend the age of initial vaccination down to 50 years of age without the risk of diminished immune responsiveness later in life, and in part due to the ability to maintain immunity throughout the entire high-risk period.

(1Fry AM et al. Comparing potential benefits of new pneumococcal vaccines with the current polysaccharide vaccine in the elderly. Vaccine 2002; 21:303-311.)

Study Evaluating 13-Valent Pneumococcal Conjugate Vaccine In Healthy Infants

*in development

PCV13 includes the 13 most prevalent pneumococcal serotypes associated with serious PD. Seven of these (4, 6B, 9V, 14, 18C, 19F and 23F) are included in Prevenar* (Pneumococcal saccharide conjugated vaccine, adsorbed) — the current global standard in PD prevention in infants and young children. The six additional serotypes (1, 3, 5, 6A, 7F and 19A) are associated with the greatest burden of remaining invasive disease. Both Prevenar (also known as PCV7) and PCV13 use CRM197 — an immunological carrier protein with a 20-year history of use in pediatric vaccines.

Earlier this year, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to PCV13 for infants and toddlers. Fast Track designation is designed to facilitate review of products for serious or life-threatening conditions for which there is an unmet medical need. The Company expects to complete its U.S. filing for pediatric use of the vaccine in the first quarter of 2009, while initiating other pediatric filings in the near term. PCV13 is also being studied in global Phase 3 clinical trials in adults, with regulatory filings expected in 2010.

Update on Investigational 13-Valent Pneumococcal Conjugate Vaccine Dr. Peter Paradiso. Wyeth Vaccines (ACIP meeting 10/23/08)

Dr. Paradiso presented an update on investigational 13-valent pneumococcal conjugate vaccine. The current 7-valent vaccine, PREVNAR®, contains the serotypes that were the most prevalent in the US at the time this vaccine was launched (e.g., 4, 6B, 9V, 14,18C, 19F, and 23F). The 13-valent vaccine, PCV13, includes those seven serotypes and an additional six new conjugate vaccines covering serotypes 1, 3, 5, 6A, 7F, and 19A. The seven components that

are common within the vaccine are essentially identical in dosage and form to those found in PREVNAR® (e.g., 2 μg of each of those serotypes, except for 6B which is 4 μg). The six new serotypes are all conjugates of the same carrier protein as the original seven types in PREVNAR® (e.g., CRM197), using the same chemistry of reductive amination to the polysaccharide and in a dosage of 2 μg of each of those serotypes. Thus, the 13-valent vaccine essentially takes the PREVNAR® vaccine in its dosage form and adds the six new serotypes that make 13 all together. It is important to point this out, particularly as it relates to the seven original types, because the transition anticipated from 7-valent to 13-valent will be facilitated by the fact that those seven types are common and it should be possible to switch to the 13-valent at any point in the immunization program.

When considering the assessment of a new conjugate vaccine, the situation is different from that of developing PREVNAR®, given that PREVNAR® is now on the market. Thus immunogenicity must be considered as the correlate or the way to assess the new vaccine. Wyeth has had some assistance in that consideration from many groups, particularly the World Health Organization, who have reviewed the data regarding efficacy and immune response for

PREVNAR® and established criteria by which they can consider comparing a new vaccine to an old vaccine. Weyth’s clinical trials are set up to compare the 13-valent vaccine to the standard of care, the 7-valent vaccine. The serological criteria used to assess PCV13 immunogenicity for the common serotypes in PREVNAR® and PCV13 are to examine non-inferiority to PCV7 in the percentage of children achieving > 0.35 ug/ml anticapsular antibody, and the non-inferiority toPCV7 types in geometric mean antibody concentration. For the six additional serotypes in PCV13, a comparison is made to the original types to examine non-inferiority in the percentage of children achieving 0.35 ug/ml anticapsular antibody compared to the lowest responses in PCV7, and non-inferiority in geometric mean anticapsular antibody concentration compared to the lowest responses in PCV7. In considering the entire immune response, good functional antibody that correlates with overall immunogenicity is an important parameter, given that it is

essential to show that a functional response is induced with the six new types and that this response correlates with the overall antibody response. For the immunization program and long-term immunity, boostability in the second year of life is also examined within a schedule that has been used for many conjugate vaccines over the years. There are additional predetermined analyses that may be examined should the primary criteria not be met. Wyeth is currently completing their Phase 3 Clinical Pediatric Program, which is extensive and global.

Wyeth is also in a Phase 3 program examining PCV13 for adults with the goals of studying the indication for the prevention of pneumococcal disease in adults; induction of a functional immune response in individuals >18 yrs of age that is non-inferior / superior to the polysaccharide; induction of immunological memory that allows periodic boosting of immunity; demonstration of no hyporesponsiveness; and ability to overcome hyporesponsiveness induced

by the polysaccharide. Unfortunately, the preliminary data show that those who have had the polysaccharide vaccine are hyporesponsive not only to another polysaccharide vaccine, but also to a conjugate vaccine. Therefore, a component of the program will be to examine whether that hyporesponsiveness can be overcome with a dose of the conjugate vaccine and be set up for a future booster of that response. This study is particularly focused on adults 58 years of age and older, but will go down to 18 years of age. This study will also include a large-scale effectiveness trial that just began in the Netherlands.

6th International Symposium on Pneumococci and Pneumococcal Diseases 8–12 June 2008, Reykjavik, Iceland

(pg 13)…The success and failure of pneumococcal clones depends on host, environmental and bacterial factors. Important host and environmental factors are immunity, heredity and antibiotic use. The widespread use of antibiotics and vaccination of children with a conjugated pneumococcal vaccine has provided an unprecedented selective pressure on pneumococci. Before the introduction of the 7-valent Prevnar vaccine in the United States in the year 2000, penicillin non-susceptible pneumococci had become 26% of all invasive isolates, but decreased following vaccination to 22% (2004, all ages). At the same time the proportion of clones belonging to serotype 19A increased from 2.5% to 36% (children ≤5 years old). Drastic changes in prevalence may also be unrelated to vaccination and antibiotic

use. Pneumococcal clones can spread in an epidemic fashion, apparently unrelated to external factors. A multidrug-resistant clone of serotype 19A increased markedly in the Bedouin population of southern Israel in the absence of vaccination, and the multidrugresistant clone Spain6B-ST90 spread fast and reached 19% of pneumococci carried by

healthy children in an Icelandic community with limited antimicrobial use. The bacterial factors related to successful spread are not known but surface pili could be important….

S10-KS2 Towards a protein-based vaccine against Streptococcus pneumoniae (pg.22)

…The existing conjugated 7-valent Prevnar vaccine (PCV7) is effective against bacteremia and meningitis, when caused by the seven CPS serotypes included in the vaccine. However the pneumococcal serotype distribution changes dramatically from region to region, and in some developing countries PCV7 covers less than one third of disease causing strains. Furthermore, few years after the introduction of PCV7 in the US, phenomena of serotype replacement have been clearly demonstrated, thus limiting the overall effectiveness of the vaccine also in developed countries. Second-generation extended coverage glycoconjugate are in late stage of development, however, they will only partially address the unmet serotype coverage needs…

S12-KS1 Pneumococcal carriage and transmission (pg 27)

The pneumooccus is a normal component of nasopharyngeal flora and carriage is the reservoir of bacteria transmitted to others and a source of disease causing pneumococci in the host.

The prevalence of colonization varies greatly globally, by age and by serotype. The main reasons for this are the differences in the exposure and the host immunity. The exposure is affected by several factors like family size, day care attendance and viral infections. Transmission of pneumococci is characterised by microepidemics within families and day care facilities….

…Pneumococcal carriage induces production of antibodies to pneumocccal protein and polysaccharide antigens, but the role of these ’natural’ antibodies in prevention subsequent acquisition has been addressed in only few studies. These studies suggest that antipolysaccharide antibodies, at least to certain serotypes, can be associated with the risk of

subsequent colonization. Epidemiological studies among Israeli children suggest that previous colonization can prevent homotypic colonization, while a study among Bangladeshi infants could not show homotypic but showed heterotypic protection. A study using human colonization model found association of anti-protein antibodies, but not of antipolysaccharide antibodies and type 23F pneumococcal colonization. Animal studies suggest that CD4 T cells rather than antibodies offer the main mechanism for protection against colonization. Finally, studies on human mucosal T cells and cytokine production suggest that cell mediated immunity has a role in prevention and termination of pneumococcal carriage.

P1-017 Population-based strain surveillance of invasive serotype 19A pneumococci recovered in the United States: 2006 (pg 96)

Background: Pneumococcal serotype 19A has increased in frequency as a cause of invasive

disease since introduction of the 7 valent pneumococcal conjugate vaccine (PCV7) in the

U.S. in 2000. Serotype 19A isolates have become increasingly resistant, primarily because of

the rapid emergence of clonal complex (CC) 320 isolates highly related to multi-resistant

clone Taiwan19F-14, but also through the emergence of other strains.We assessed all available invasive isolates and predicted 19A disease rates from areas under continuous surveillance from1999 -2006 through CDC’s Active Bacterial Core surveillance (ABCs, about 18 million persons)…

Results: Serotype 19A incidence has been incrementally increasing annually. Between 1999 and 2005 incidence increased more than 3-fold in children < 5 years (from 2.6 cases/100,000 to 8.9 cases/100,000). Incidence of serotype 19A disease in this age group further increased to 10.7 cases/100,000 during 2006. Between 1999 and 2005, the proportion of 19A isolates from all age groups that were penicillin-resistant (MICs > 2 ug/ml) increased from 6.7% to 35% and further increased to 36.2% during 2006. The CC320 complex increased from 21% of type 19A during 2005 isolates to 24% during 2006. Other 19A strains that appear to be derived from major PCV7-serotype strains increased during 2006 relative to 2005.

Conclusions: These updated results indicate that serotype 19A continues to increase as a cause of invasive disease and resistant infections. While most of the increase in resistant infections is related to a single CC, multiple strains are contributing to the problem.

5th International Symposium on Pneumococci and Pneumococcal Diseases

pneumvax5

5th International Symposium on Pneumococci and Pneumococcal Diseases (pg 260)

pnemovax4

5th International Symposium on Pneumococci and Pneumococcal Diseases (pg 269)

pneumvax51

Pneumococcal Resistance

…pneumococcal strains with decreased susceptibility to penicillin were identified in Australia and New Guinea in the 1960s and in South Africa in the 1970s. Isolates nonsusceptible (minimal inhibitory concentration [MIC] ≥0.1 µg/mL) or resistant (MIC ≥2.0 µg/mL) to penicillin and other antimicrobial agents became increasingly prevalent in many other countries during the 1980s. Drug-resistant strains were relatively uncommon in the United States (US) throughout the 1980s and penicillin remained the drug of choice for empiric treatment of life-threatening pneumococcal infections. However, a rapid increase in the prevalence of isolates nonsusceptible or resistant to penicillin occurred in the US during the late 1980s and early 1990s (Figure 1). In some parts of the US, over 35% of pneumococcal isolates are now nonsusceptible to penicillin. Concomitant with the emergence of penicillin-resistant strains, pneumococci with decreased susceptibility to other classes of antimicrobial agents also became more prevalent, making selection of therapy difficult. Strains susceptible only to vancomycin have been isolated…

Vaccine Escape Recombinants Emerge after Pneumococcal Vaccination in the United States

The Centers for Disease Control and Prevention (CDC) has been monitoring invasive pneumococcal disease since 1995 through the Active Bacterial Core (ABC) surveillance program [6,14,30] and as a result, the post-vaccination increase in nonvaccine serotype 19A disease in the US was quickly detected. Serotype 19A strains collected by the CDC through 2005 were genotyped by MLST, which revealed that vaccine escape strains had begun to emerge in 2003 [14,15]. These strains possessed an MLST genotype, ST695, that had always been associated with vaccine serotype 4 (ST695⁴), but now expressed a serotype 19A capsule (ST695^19A). These strains were detected only 3 y after vaccine implementation, but rapidly increased in prevalence. The first three strains were detected in 2003; two strains were detected in 2004; and 32 strains were detected in 2005, some of which had evolved further. Moreover, in 2005, two new types of serotype 19A vaccine escape strains emerged, ST2365^19A (n = 4) and ST899^19A (n = 1); these appeared to represent new recombinational events that also occurred between serotype 4 recipients and serotype 19A donors. The aim of this study was to sequence the regions upstream and downstream of the capsular locus, including both PBPs, to identify the putative recombinational event(s) that resulted in these vaccine escape strains.

Filed under: Pneumococcal | Comments Off

Haemophilus Influenzae

Posted on April 3, 2011 by crunchymomma

Haemophilus Influenzae

The HIB vaccine is solely for capsulated Haemophilus B, not non encapsulated Hib. The HIB vaccine is solely for invasive Hib disease caused by capsular Hib. It has no effect on any other type of Hib disease. You can’t make a Hib vaccine for non-encapsular HIB. Due to the recommended and rountine use of Hib conjugate vaccine, at least half of invasive H influenzae infections are now caused by the nonencapsulated strains.

There are six strains of H. influenzae that have been classified (types a through f) and other non-typeable strains. Type b is responsible for 95 percent of all strains causing invasive disease. Invasive Hib disease usually manifests itself clinically as meningitis, accounting for 50 to 65 percent of all cases.

HIB vaccines are available as a single vaccine or in combination vaccines and four conjugate Hib vaccines are currently available:

Monovalent Hib vaccines:

PedvaxHIB® [Merck] [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] PedvaxHIB* [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] is a highly purified capsular polysaccharide (polyribosylribitol phosphate or PRP) of Haemophilusinfluenzae type b (Haemophilus b, Ross strain) that is covalently bound to an outer membrane protein complex (OMPC) of the B11 strain of Neisseria meningitidis serogroup B. Each 0.5 mL dose of Liquid PedvaxHIB is a sterile product formulated to contain: 7.5 mcg of Haemophilus b PRP, 125 mcg of Neisseria meningitidis OMPC and 225 mcg of aluminum as amorphous aluminum hydroxyphosphate sulfate (previously referred to as aluminum hydroxide), in 0.9% sodium chloride, but does not contain lactose or thimerosal.

ActHib [sanofi pasteur] The vaccine consists of the Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP), a high molecular weight polymer prepared from the Haemophilus influenzae type b (HiB) strain 1482 grown in a semi-synthetic medium, covalently bound to tetanus toxoid.1 The lyophilized ActHIB vaccine powder and saline diluent contain no preservative. The tetanus toxoid is prepared by extraction, ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium.

Combination vaccines:

COMVAX® (Hib/hepatitis B vaccine) [Merck] [HAEMOPHILUS b CONJUGATE (MENINGOCOCCAL PROTEIN CONJUGATE) and HEPATITIS B (RECOMBINANT) VACCINE]

COMVAX* [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine] is a sterile bivalent vaccine made of the antigenic components used in producing PedvaxHIB* [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] and RECOMBIVAX HB* [Hepatitis B Vaccine (Recombinant)]. These components are the Haemophilus influenzae type b capsular polysaccharide [polyribosylribitol phosphate (PRP)] that is covalently bound to

an outer membrane protein complex (OMPC) of Neisseria meningitidis and hepatitis B surface antigen (HBsAg) from recombinant yeast cultures. Haemophilus influenzae type b and Neisseria meningitidis serogroup B are grown in complex

fermentation media.

The PRP-OMPC conjugate is prepared by the chemical coupling of the highly purified PRP (polyribosylribitol phosphate) of Haemophilus influenzae type b (Haemophilus b, Ross strain) to an OMPC of the B11 strain of Neisseria meningitidis serogroup B. The coupling of the PRP to the OMPC is necessary for enhanced immunogenicity of the PRP. This coupling is confirmed by analysis of the components of the conjugate following chemical treatment which yields a unique amino acid. After conjugation, the aqueous bulk is then adsorbed onto an amorphous aluminum hydroxyphosphate sulfate adjuvant (previously referred to as aluminum hydroxide).

TriHIBit® (diphtheria and tetanus toxoids and acellular pertussis [DTaP]/Hib vaccine) [sanofi pasteur]

When Tripedia vaccine is used to reconstitute ActHIB® [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)

manufactured by Aventis Pasteur SA] the combination vaccine is TriHIBit®. Each single 0.5 mL dose of TriHIBit vaccine for the

fourth dose only, is formulated to contain 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid (both toxoids induce at least 2 units

of antitoxin per mL in the guinea pig potency test), 46.8 μg of pertussis antigens (approximately 23.4 μg of inactivated PT and

23.4 μg of FHA), 10 μg of purified Haemophilus influenzae type b capsular polysaccharide conjugated to 24 μg of inactivated tetanus toxoid, and 8.5% sucrose. (Refer to ActHIB vaccine package insert.)

HibTITER HAEMOPHILUS b CONJUGATE VACCINE (Diphtheria CRM197 Protein Conjugate)

Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) HibTITER is a sterile solution of a conjugate of oligosaccharides of the capsular antigen of Haemophilus influenzae type b (Haemophilus b) and diphtheria CRM197 protein (CRM197) dissolved in 0.9% sodium chloride. The oligosaccharides are derived from highly purified capsular polysaccharide,

polyribosylribitol phosphate, isolated from Haemophilus b strain Eagan grown in a chemically defined medium (a mixture of mineral salts, amino acids, and cofactors).

Three conjugate Hib vaccines are licensed for use in infants as young as 6 weeks of age (see below). All three vaccines

utilize different carrier proteins. Two combination vaccines that contain Hib conjugate vaccine are also available.

hibbrands1

hibbrands2

HIB Vaccine Timeline and History Tidbits:

1970-1^st hib vaccine

1980’s Conjugate vaccine for hib

1985-polysaccharide vaccine

Provoked Hib in rats (by causing transient immune suppression for 7 – 14 days) and also in humans.
The polysaccharide vaccine was quietly swept under the rug. It continued to be used after 1987, but was rapidly replaced with the conjugate vaccine.

In 1985, the first Hib polysaccharide vaccines were licensed for use in the United States. These vaccines contained purified polyribosylribitol phosphate (PRP) capsular material from the type b serovar. Antibody against PRP was shown to be the primary component of serum bactericidal activity against the organism. PRP vaccines were ineffective in children less than 18 months of age because of the T-cell-independent nature of the immune response to PRP polysaccharide.

Conjugation of the PRP polysaccharide with protein carriers confers T-cell-dependent characteristics to the vaccine and substantially enhances the immunologic response to the PRP antigen. In 1989, the first Hib conjugate vaccines were licensed for use among children 15 months of age or older. In 1990, two new vaccines were approved for use among infants.

Haemophilus influenzae type b Polysaccharide-Protein Conjugate Vaccines

Conjugation is the process of chemically bonding a polysaccharide (a somewhat ineffective antigen) to a protein “carrier,” which is a more effective antigen. This process changes the polysaccharide from a T-independent to a T-dependent antigen and greatly improves immunogenicity, particularly in young children. In addition, repeat doses of Hib conjugate vaccines elicit booster responses and allow maturation of class-specific immunity with predominance of IgG antibody. The Hib conjugates also cause carrier priming and elicit antibody to “useful” carrier protein. The first Hib conjugate vaccine (PRP-D, ProHIBIT) was licensed in December 1987. This vaccine was not consistently immunogenic in children younger than 18 months of age.

PRP-D is no longer available in the United States.

Haemophilus influenzae is a small, nonmotile Gram-negative bacterium in the family Pasteurellaceae, on the level with the Vibrionaceae and the Enterobacteriaceae. The family also includes Pasteurella and Actinobacillus, two other genera of bacteria that are parasites of animals. Encapsulated strains of Haemophilus influenzae isolated from cerebrospinal fluid are coccobacilli, 0.2 to 0.3 to 0.5 to 0.8 um, similar in morphology to Bordetella pertussis, the agent of whooping cough. Non encapsulated organisms from sputum are pleomorphic and often exhibit long threads and filaments. The organism may appear Gram-positive unless the Gram stain procedure is very carefully carried out. Furthermore, elongated forms from sputum may exhibit bipolar staining, leading to an erroneous diagnosis of Streptococcus pneumoniae.

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Seven serotypes of the bacterium have been identified on the basis of capsular polysaccharides. Until the implementation of widespread vaccination programs, type b H. influenzae was the most common cause of meningitis in children between the ages of 6 months and 2 years (see Figure 4 below), resulting in 12,000 to 20,000 cases annually in the U.S. It would be interesting to view comparative data since the era of vaccination against H. influenzae meningitis, which began in 1985. Certainly, there are fewer than 100 cases annually of bacterial meningitis caused by H. influenzae type b.

*bloggers note..type g has since been identified.

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Two variants among Haemophilus influenzae serotype b strains with distinct bcs4, hcsA and hcsB genes display differences in expression of the polysaccharide capsule

Background

Despite nearly complete vaccine coverage, a small number of fully vaccinated children in the Netherlands have experienced invasive disease caused by Haemophilus influenzae serotype b (Hib). This increase started in 2002, nine years after the introduction of nationwide vaccination in the Netherlands. The capsular polysaccharide of Hib is used as a conjugate vaccine to protect against Hib disease. To evaluate the possible rise of escape variants, explaining the increased number of vaccine failures we analyzed the composition of the capsular genes and the expressed polysaccharide of Dutch Hib strains collected before and after the introduction of Hib vaccination.

Differences in Genetic and Transcriptional Organization of the glpTQ Operons between Haemophilus influenzae Type b and Nontypeable Strains

Haemophilus influenzae is a common pathogen, especially among children,but the clinical manifestations are largely type specific. Theencapsulated H. influenzae serotype b (Hib) usually causes invasiveinfections, such as meningitis and septicemia (2), whereas themuch more common nonencapsulated, or nontypeable, H. influenzae(NTHi) is a major cause of otitis media, sinusitis, and pneumonia (8).General vaccination against Hib has reduced the incidence ofHib infection to a near minimum (10), while attempts to constructa vaccine against the costly NTHi infections have as yet beenunsuccessful due to a high genetic heterogeneity among NTHi strains.

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Meningococcal Meningitis Strains

Posted on April 3, 2011 by crunchymomma

N. meningitidis strains are grouped on the basis of their capsular polysaccharides. There are at least 13 serogroups, some of which are subdivided according to the presence of outer membrane protein and lipopolysaccharide antigens.

Meningococcal capsular polysaccharides provide the basis for grouping the organism. Twelve serogroups have been identified (A, B, C, H, I, K, L, X, Y, Z, 29E, and W135). The most important serogroups associated with disease in humans are A, B, C, Y, and W135. The chemical composition of these capsular polysaccharides is known. The prominent outer membrane proteins of N. meningitidis have been designated class 1 through class 5. The class 2 and 3 proteins function as porins and are analogous to gonococcal Por. The class 4 and 5 proteins are analogous to gonococcal Rmp and Opa, respectively. Serogroup B and C meningococci have been further subdivided on the basis of serotype determinants located on the class 2 and 3 proteins. A handful of serotypes are associated with most cases of meningococcal disease, whereas other serotypes within the same serogroup rarely cause disease. All known group A strains have the same protein serotype antigens in the outer membrane. Another serotyping system exists based on the antigenic diversity of meningococcal LOS (lipooligopolysaccharide).

Infection with N. meningitidiscan present in two ways. Either as meningococcemia, characterized by skin lesions, or as acute bacterial meningitis.

Five predominant strains or serogroups of N. meningitidis account for most cases of meningococcal disease. These are A, B, C, Y, and W-135. The currently available capsular polysaccharide vaccines are available for four of the five strains (A, C, Y, and W-135) No vaccine is available for widespread vaccination against serogroup B.

The group B capsular polysaccharide is a homopolymer of sialic acid which is not immunogenic in humans. A group B meningococcal vaccine consisting of outer membrane protein antigens has been developed, but is not licensed in the United States. Polysaccharide vaccines are ineffective in young children. In children under 1 year old, antibody levels decline rapidly after immunization.The duration of protection is also limited in children vaccinated at 1 to 4 years of age. Routine vaccination is not currently recommended due to the risk of infection as being classified as low.

There are two vaccines against N. meningitidis available in the U.S.

Meningococcal polysaccharide vaccine (MPSV4 or Menomune^®) has been approved by the Food and Drug Administration (FDA) and available since 1981.

Meningococcal conjugate vaccine (MCV4 or MenactraT) was licensed in 2005. Both vaccines can prevent 4 types of meningococcal disease, including 2 of the 3 types most common in the U.S. (serogroup C, Y, and W-135) and a type that causes epidemics in Africa (serogroup A).

Meningococcal vaccines cannot prevent all types of the disease.

MCV4 is recommended for all children at their routine preadolescent visit (11 to 12 years of age). MCV4 is the preferred vaccine for people 11 to 55 years of age in these risk groups, but MPSV4 can be used if MCV4 is not available. MPSV4 should be used for children 2 to 10 years old and adults over 55, who are at risk.

MPSV4: Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined

Menomune® – A/C/Y/W-135

Menomune® – A/C/Y/W-135, Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined, for subcutaneous use, is a freeze-dried preparation of the group-specific polysaccharide antigens from Neisseria meningitidis, Group A, Group C, Group Y and Group W-135. N meningitidis are cultivated with Mueller Hinton agar1 and Watson Scherp2 media. The purified polysaccharide is extracted from the Neisseria meningitidis cells and separated from the media by procedures which include centrifugation, detergent precipitation, alcohol precipitation, solvent or organic extraction and diafiltration. No preservative is added during manufacture.

The 0.78 mL vial of diluent contains sterile, preservative-free, pyrogen-free distilled water and is used for reconstitution of product supplied in 1 mL vials. The 6 mL vial of diluent contains sterile, pyrogen-free distilled water to which thimerosal (mercury derivative) 1:10,000 is added as a preservative. The 6 mL vial is for reconstitution of product supplied in 10 mL vials.

After reconstitution with diluent as indicated on the label, the 0.5 mL dose is formulated to contain 50 μg of “isolated product” from each of Groups A, C, Y and W-135 in an isotonic sodium chloride solution.

MCV4: Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine Menactra®

Menactra®, Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine, is a sterile, intramuscularly administered vaccine that contains Neisseria meningitidis serogroup A, C, Y and W-135 capsular polysaccharide antigens individually conjugated to diphtheria toxoid protein. N meningitidis A, C, Y and W-135 strains are cultured on Mueller Hinton agar1 and grown in Watson Scherp2 media. The polysaccharides are extracted from the N meningitidis cells and purified by centrifugation, detergent precipitation, alcohol precipitation, solvent extraction and diafiltration. To prepare the polysaccharides for conjugation, they are depolymerized, derivatized, and purified by diafiltration. Corynebacterium diphtheriae cultures are grown in a modified Mueller and Miller medium3 and detoxified with formaldehyde. The diphtheria toxoid protein is purified by ammonium sulfate fractionation and diafiltration. The derivatized polysaccharides are covalently linked to diphtheria toxoid and purified by serial diafiltration. The four meningococcal components, present as individual serogroupspecific glycoconjugates, compose the final formulated vaccine. No preservative or adjuvant is added during manufacture.

Potency of Menactra vaccine is determined by quantifying the amount of each polysaccharide antigen that is conjugated to diphtheria toxoid protein and the amount of unconjugated polysaccharide present.

Menactra vaccine is manufactured as a sterile, clear to slightly turbid liquid. Each 0.5 mL dose of vaccine is formulated in sodium phosphate buffered isotonic sodium chloride solution to contain 4 μg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 μg of diphtheria toxoid protein carrier.

Advantages of Meningococcal Conjugate Vaccines (ACIP meeting May 27, 2005 / 54(RR07); 1-21)

Bacterial polysaccharides, including those comprising the capsule of N. meningitdis, are T-cell–independent antigens. T-cell–independent antigens do not elicit a memory response; they stimulate mature B-lymphocytes but not T-lymphocytes, thus inducing a response that is neither long-lasting nor characterized by an anamnestic response after subsequent challenge with the same polysaccharide antigen (72). Thus, meningococcal polysaccharide vaccines have inherent limitations. The serogroup C polysaccharide is poorly immunogenic among children aged <2 years (73–75). The A polysaccharide induces antibody response in infants, but vaccine efficacy declines rapidly (64). Meningococcal polysaccharide vaccines do not confer long-lasting immunity (61,64); they also do not cause a sustainable reduction of nasopharyngeal carriage of N. meningitdis (76,77) and therefore do not substantially interrupt transmission to elicit herd immunity. Finally, multiple doses of serogroup A and C polysaccharide vaccine might cause immunologic hyporesponsiveness to the group A (56,57) and C (58,59) polysaccharide, although clinical implications of this phenomenon are unknown.

Conjugation (i.e., covalent coupling) of polysaccharide to a protein carrier that contains T-cell epitopes changes the nature of immune response to polysaccharide from T-cell–independent to T-cell–dependent, leading to a substantial primary response among infants and a strong anamnestic response at re-exposure (78). Both conjugate Hib and conjugate S. pneumoniae vaccines (introduced for mass infant immunization in the United States in 1990 and 2000, respectively) have reduced incidence of disease caused by vaccine-preventable serotypes (1,79). In addition, both vaccines reduce asymptomatic carriage of respective bacteria (80–82), thus protecting unvaccinated persons through a herd immunity effect (1).

What was said in 1990 in regards to polysaccharide vaccine:

Notice to Readers Availability of Meningococcal Vaccine in Single-Dose Vials for Travelers and High-Risk Persons (MMWR Weekly October 26, 1990 / 39(42);763)

The Food and Drug Administration has approved a single-dose vial of quadrivalent polysaccharide vaccine against Neisseria meningitidis serogroups A, C, Y, and W135. The single-dose vial replaces the previously available 10-dose vial, which, once reconstituted, has a 5-day shelf life. This limitation is obviated by the single-dose vial and should facilitate administration to persons at high risk.

Immunization is recommended for persons with anatomic or functional asplenia and deficiencies of the terminal components of the complement system. Additionally, travelers to areas with hyperendemic or epidemic meningococcal disease should be immunized (1). Updated travel advisories can be obtained from travelers’ clinics, county and state health departments, and CDC.

The vaccine is not recommended for routine use in the United States for three reasons: 1) meningococcal disease is infrequent (approximately 3000 cases per year); 2) no vaccine exists for serogroup B, which accounts for about 50% of cases in the United States; and 3) vaccine is not efficacious against group C disease in children less than 2 years of age (2). This age group accounts for 28% of the group C cases in the United States (CDC, unpublished data).

In adults, the protective efficacy of the vaccine is 85%-95% for disease caused by serogroups A or C (3, 4). Efficacy data are not available for serogroups Y and W135, but the vaccine is immunogenic for both of these serogroups (5-7). Side effects of the vaccine are mild and infrequent, consisting primarily of erythema and induration at the site of injection and low-grade fever. Protective immunity is achieved 10-14 days after vaccination.

Meningococcal lipopolysaccharides: virulence factor and potential vaccine component. (Microbiol Rev. 1993 March; 57(1): 34–49. PMCID: PMC372900)

meningitsstarins

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ChickenPox/Shingles Strains

Posted on April 3, 2011 by crunchymomma

Identification of Five Major and Two Minor Genotypes of Varicella-Zoster Virus Strains: a Practical Two-Amplicon Approach Used To Genotype Clinical Isolates in Australia and New Zealand

Whole genome phylogenetic analysis in this study resolved a total of five major genotypes among the 22 varicella-zoster virus (VZV) strains or isolates for which complete genomic sequences are available.

cpstarins2

Acquiring one strain can result in immunity to all strains of the virus. In some cases, however, complete immunity is not attained and an individual can become re-infected.

Shingles, or herpes zoster, this is a later reactivation of latent virus. It can occur any time after the initial infection. Usually, it occurs years later, and is activated by stress or an unbalanced immune system.

Varicella Zoster Virus

VZV is a member of the herpes virus group or (alpha) herpes virus 3, and it is a DNA virus. VZV can persist as a latent infection in dorsal root or extra medullary cranial ganglia.

Toward Universal Varicella-Zoster Virus (VZV) Genotyping: Diversity of VZV Strains from France and Spain

…wild-type varicella-zoster virus (VZV) strainsto seven genotypes: A1, A2, J1, B1, B2, C, and C1. VZV isolatesidentified as E (ORF22 method) had the genetic signature ofgenotype C VZV strains, M1 strains were A1, and M2 were A2.No J strains were detected, but parental Oka and vaccine Oka(genotype J) corresponded to genotype J1. M4 isolates (B) sharethe SNP array observed for M1 and E viruses, and probably representrecombinants between African-Asian (M1) and European (E) viruses.The two genotyping methods, using entirely different genomictargets, produced identical clusters for the strains examined,suggesting robust phylogenetic linkages among VZV strains circulatingin Europe.

cpstarins

pOka is the parental Oka strain from which varicella vaccine was derived. Sequence positions are based on the published genomic sequence for the Dumas strain. Green cells indicate European genotype (E) markers; yellow cells are Japanese genotype (J) markers, rose cells are markers unique to various M genotype variants, and uncolored cells reflect markers that are consistent across genotypes. ND, not determined.

The Immunological Basis for Immunization Series Module 10: Varicella

VZV is a member of the herpesvirus family. It has 71 genes, all of which are expressed in lytic infection and seven of which are expressed in latent infection (5). Only neurons support latent infection. There is one serotype, but several genotypes are known, with small differences in their DNAs, classified as European, Japanese, and Mosaic (6). Recently, 3% of VZV strains circulating in the United States of America have been identified as Japanese type (7).

VZV was successfully attenuated by Takahashi and colleagues in 1974, by serial passage of a clinical isolate from an otherwise healthy boy with chickenpox (13).

Attenuation was achieved by passage 11 times at 34ºC in human embryonic lung fibroblasts (HELF), 12 passages at 37ºC in guinea-pig fibroblasts, and 5 to 6 passages in MRC -5 human fibroblasts at 37ºC. Infected cell suspensions were sonicated to obtain cell-free VZV.Standard safety-testing after injection into small mammals was also performed, and did not identify any adventitious agents.

Varicella vaccines contain a mixture of Oka and parental strains (14-16). Sequencing of the Dumas strain of wild-type VZV, and the Oka strain, has shown that there are 42 differing bases, over one third of which are in gene 62.Three fixed mutations have been identified in Oka strains present in skin rashes of vaccinees, all located in gene 62 (15,17,18). Although the genetic basis for attenuation is still unknown, it is possible to differentiate Oka from wild-type VZV by PCR in clinical specimens (8).

Monovalent varicella vaccine is produced in the United States (VarivaxTM; Merck & Co., Inc.), the Kingdom of Belgium (VarilrixTM; GlaxoSmithKline), and Japan (OKAVAX™; Biken, distributed by Aventis Pasteur). These vaccines vary slightly in passage number in human diploid cells, antibiotics for sterility, stabilizers and minor constituents. Each preparation guarantees 1350 plaque forming units (PFU) per 0.5 ml at expiration; doses at release vary from 3 000 to 17 000 PFU.

Combination vaccines for measles-mumps-rubella-varicella (MMRV) are produced by Merck (ProQuadTM)and GSK (Priorix-TetraTM). MMRV vaccines are licensed for children 12 months to 12 years old. They contain the same measlesmumps-rubella (MMR) components as MMR vaccine, but have a higher concentration of Oka varicella vaccine (~ 10 000 PFU at expiration) than monovalent varicella vaccines.

A formulation of the Oka strain containing~ 17 000 PFU (ZostavaxTM), is used for prevention of zoster when administered to healthy adults above the age of 60 years.

VARIVAX® Varicella Virus Vaccine Live

VARIVAX* [Varicella Virus Vaccine Live] is a preparation of the Oka/Merck strain of live, attenuated varicella virus. The virus was initially obtained from a child with natural varicella, then introduced into human embryonic lung cell cultures, adapted to and propagated in embryonic guinea pig cell cultures and finally propagated in human diploid cell cultures (WI-38). Further passage of the virus for varicella vaccine was performed at Merck Research Laboratories (MRL) in human diploid cell cultures (MRC-5) that were free of adventitious agents. This live, attenuated varicella vaccine is a lyophilized preparation containing sucrose, phosphate, glutamate, and processed gelatin as stabilizers.

ZOSTAVAX® Zoster Vaccine Live

ZOSTAVAX is a lyophilized preparation of live, attenuated varicella-zoster virus (Oka/Merck) to be reconstituted with sterile diluent to give a single dose suspension with a minimum of 19,400 PFU (plaque forming units) when stored at room temperature for up to 30 minutes.

ProQuad® Measles, Mumps, Rubella and Varicella Virus Vaccine Live

(no longer available until further notice)

ProQuad* is a combined attenuated live virus vaccine containing measles, mumps, rubella, and varicella viruses. ProQuad is a sterile lyophilized preparation of (1) the components of M-M-R*II (Measles, Mumps and Rubella Virus Vaccine Live): Measles Virus Vaccine Live, a more attenuated line of measles virus, derived from Enders’ attenuated Edmonston strain and propagated in chick embryo cell culture; Mumps Virus Vaccine Live, the Jeryl Lynn™ (B level) strain of mumps virus propagated in chick embryo cell culture; Rubella Virus Vaccine Live, the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts; and (2) Varicella Virus Vaccine Live (Oka/Merck), the Oka/Merck strain of varicella-zoster virus propagated in MRC-5 cells. The cells, virus pools, bovine serum, and human albumin used in manufacturing are all tested to provide assurance that the final product is free of potential adventitious agents.

ProQuad, when reconstituted as directed, is a sterile preparation for subcutaneous administration. Each 0.5-mL dose contains not less than 3.00 log10 TCID50 (50% tissue culture infectious dose) of measles virus; 4.30 log10 TCID50 of mumps virus; 3.00 log10 TCID50 of rubella virus; and a minimum of 3.99 log10 PFU (plaque-forming units) of Oka/Merck varicella virus.

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Rotavirus Strains

Posted on April 3, 2011 by crunchymomma

Rotavirus-Synopses

The major antigenic properties of rotaviruses—group, subgroup, and serotype—are determined by the viral capsid proteins. Rotavirus has seven major groups (A-G); most human strains belong to group A, although groups B and C have occasionally been associated with human illness. The product of the 6th gene of group A rotaviruses encodes VP6, the most abundant viral protein, which is the major determinant of group reactivity, the target of common diagnostic assays, and contains the antigen used to further classify rotaviruses into subgroups I and II. The outer capsid proteins, VP7, the glycoprotein or G-protein (encoded by gene 7, 8, or 9, depending on the strain), and VP4, the protease-cleaved or P-protein (encoded by gene segment 4), determine the serotype specificity and form the basis of the binary classification (G and P type) of rotaviruses. Both G and P proteins induce neutralizing antibodies and may be involved in protective immunity.

Fourteen G serotypes of rotavirus, 10 of which occur in humans, have been defined by cross-neutralization studies with polyclonal animal serum samples; these serotypes correlate with antigenic specificities of the VP7 glycoprotein. The characterization of P serotypes has been difficult because adequate reagents are not available. Eight P serotypes of human rotaviruses have been characterized. Additional VP4 gene variants have been identified, so ultimately the number of P serotypes may exceed 20. Theoretically, 80 different strains of rotavirus could result from various combinations of the known 10 G and 8 P serotypes of human rotaviruses. For vaccine development purposes, it is fortunate that only four common strains (P[8]G1; P[8]G3; P[8]G4; and P[4]G2) of rotavirus predominate globally (Figure 4) (11). However, the prevalence of rotavirus strains varies considerably from one geographic area to another, and unusual strains are common in several developing countries (e.g., unusual P[6] strains, including those with serotype G9 specificity, accounted for 9.5% of all rotaviruses from a multicenter collection in India)

In infants and young children, neutralizing antibodies directed primarily against the G serotype of the infecting strain (homotypic response) develop after primary infection with rotavirus (18). Repeat rotavirus infections elicit both a homotypic and heterotypic (against strains with different G serotypes) antibody response. Protection against rotavirus diarrhea correlates with serum antibody titers following natural infection of young children, and infected children are more protected against reinfection with similar rather than different G serotypes. A protective role of placentally transferred maternal antibody among infants < 3 months of age has also been speculated since rotavirus disease is uncommon in this age group. However, serum neutralizing antibody responses among vaccine recipients have sometimes correlated poorly with protection from disease; therefore, the exact role of serum antibody in protection against disease remains unclear.

Genome Variability

Rotavirus is a highly variable virus even within the subset of those that are infective to humans. [4] Rotaviruses are usually categorized into seven groups A-G, with subgroups I and II based on the VP6 protein. [8] Within these groups, A, B, and C are infective to Humans. [19]

Rotavirus is further categorized into G and P serotypes. The G serotype is specified by the glycoprotein VP7 of the outer capsid, which is coded by viral genes 7, 8, and 9. [8] The P serotype is specified by protein VP4, also on the outer capsid. It is a protease cleaved protein coded by gene 4 of the virus genome. [8] The most common G serotypes currently are G1, G2, G3, G4, and G9, with G1 being most prevalent and G9 the fastest emerging worldwide. [7] [8] [10] [12] Common P serotypes are P1a, P1b, and P8. [13] [6] [4]

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Rotavirus Vaccines:

Monovalent “Jennerian” Vaccines

Initial development of rotavirus vaccines was based on the Jennerian approach, which involved the use of a live, attenuated, antigenically related virus derived from a nonhuman host (21). This approach was prompted by studies indicating that animal and human rotaviruses shared a common group antigen and that experimental animals immunized with animal strains of rotavirus had a significantly lower risk for illness and viral shedding when subsequently challenged with human rotaviruses. Furthermore, neutralizing antibodies to human rotavirus serotypes in the animal models indicated the potential for cross-protection.

Bovine Vaccines

The first two Jennerian vaccines were developed with bovine rotavirus strains RIT4237 and WC3. The WC3 strain was passaged in cell culture less than RIT4237 and was developed because of concern that excessive passaging of the RIT vaccine might cause overattenuation and diminished efficacy. RIT4237 and WC3 were nonreactogenic and immunogenic when administered to infants 2 to 18 months of age. However, the protection conferred by both vaccines varied greatly in efficacy studies, 0% to 76% against any rotavirus diarrhea and 0% to 100% against severe disease (22-32). A well-defined correlate of protection was not identified, and reasons for the variable efficacy were unknown, although late age at vaccination, timing of vaccination with respect to the onset of the rotavirus season, and variations in the strength and number of doses of the vaccine were proposed as contributing factors. Both vaccines performed less well in developing than in industrialized countries, possibly because of interference by other enteropathogens or inadequate surveillance during follow-up.

Rhesus Vaccine

The third Jennerian vaccine was developed with rhesus rotavirus strain MMU18006, which shares neutralization specificity with human rotavirus G3 strains. Besides sharing antigenic specificity with an epidemiologically important human rotavirus serotype, MMU18006 was suitable for vaccine development because it grew efficiently in cell culture. As in the bovine rotavirus-based vaccines, MMU18006 was safe and immunogenic, although in some trials, one third of infants became febrile 3 to 4 days after vaccination. The reactogenicity of MMU18006 was particularly high in two studies in Finland and Sweden in which 64% and 79% of infants, respectively, became febrile. Most children with febrile responses were >5 months of age; lack of passively transferred maternal antibody might have contributed to the high reactogenicity of the vaccine. As in the RIT4237 and WC3 vaccines, the protective efficacy of MMU18006 in field trials was quite variable, 0% to 60% against any rotavirus diarrhea and 0% to 85% against severe rotavirus diarrhea (33-39).

Reassortant “Modified Jennerian” Vaccines

The greatest efficacy of MMU18006 was observed in a Venezuelan trial in which the rotavirus strain circulating in the community (G3) was the same serotype as the vaccine strain, which suggested that serotype-specific immunity against each of the epidemiologically important strains of human rotaviruses may be required for maximum protection. Similar observations in vaccine challenge cross-protection studies in animals initiated the development of vaccines that used a modified Jennerian approach in which animal-human reassortants expressing VP7 proteins of serotypes 1 through 4 were used as the immunogens.

Rhesus-Human Reassortant Vaccines

Rhesus-human reassortants were generated by coinfecting cell cultures with rhesus rotavirus (RRV) strain MMU18006 (G serotype 3) and human rotavirus strains D (G serotype 1), DS-1 (G serotype 2), and ST3 (G serotype 4). Selection pressure (induced by the addition of neutralizing antibody to VP7 of RRV) produced reassortant strains D x RRV, DS-1 x RRV, and ST3 x RRV, each of which possessed the VP7 gene from HRV serotype 1, 2, or 4 and the other 10 genes from RRV (Figure 6) (40). Because vaccines made from the individual reassortants were safe and immunogenic, RRV-TV was developed incorporating each of the three reassortants and MMU18006 to provide coverage against the four common VP7 serotypes of rotavirus.

RRV-TV testing was initiated at an inoculum of 10⁴ PFU of each of the four viruses (i.e., at 4 x 10⁴ PFU) and completed at 10⁵ PFU, the dose submitted for licensure (i.e., at 4 x 10⁵ PFU). In most trials, vaccine was administered orally in three doses separated by at least 3 weeks to optimize the immune response to the component antigens; immunization was completed by the age of 6 to 7 months. Because the vaccine virus strains are acid labile, they are administered with 2.5 ml of citrate-bicarbonate buffer.

Bovine-Human Reassortant Vaccines

Bovine-human reassortant rotavirus vaccines include a tetravalent WC3 rotavirus reassortant vaccine with genes coding for the VP7 of three major serotypes of rotavirus (G1, G2, and G3) and W179-4, a human VP4 reassortant with P[8] specificity. Theoretically, this vaccine should induce antibodies broadly reactive to the three common serotypes of rotavirus sharing P [8] specificity, thereby increasing the protective efficacy of this vaccine. In an efficacy trial of a three-dose regimen of the WC3 reassortant vaccine, protection was 67% against all rotavirus diarrhea and 69% against severe rotavirus diarrhea (48).

Other Candidate Vaccines

In clinical trials, no Jennerian vaccine has provided complete protection against rotavirus diarrhea; as a result, several non-Jennerian candidate vaccines are being developed. Vaccines based on neonatal, cold-adapted, and attenuated human strains of rotavirus are under evaluation (49). Other approaches, such as the use of baculovirus-expressed viruslike particles or naked DNA vaccines, are also being used to develop candidate rotavirus vaccines (50,51).

The Ever-Changing Landscape of Rotavirus Serotypes

(The Pediatric Infectious Disease Journal:Volume 28(3) Supplement March 2009pp S60-S62)

Abstract:

Rotavirus is a double-stranded RNA virus that is characterized by substantial genetic diversity. The various serotypes of rotavirus have been determined by the presence of neutralizing epitopes on the outer capsid of the protein shell. At present, 5 rotavirus serotypes (G1, G2, G3, G4, G9) are the predominant circulating strains, accounting for approximately 95% of strains worldwide, although there is considerable geographic variability. Incidence rates for various serotypes also vary temporally with seasonal and year-to-year fluctuations. Unusual serotypes are generally uncommon, but new serotypes can emerge. In particular, G9[P8], a reassortment virus, was first identified in 1983 and in the last 10 to 15 years has become widely distributed worldwide. Indeed, G9[P8] has become highly prevalent in many countries in Europe and Australia, with somewhat lower incidence rates in South America, Africa, and Asia. The heterogeneity and ever-changing epidemiology of rotavirus underscores the need for continued surveillance to ensure that vaccination programs provide optimal protection.

Three oral RV vaccines are currently licensed, a human monovalent live attenuated RV strain, RotarixTM, a pentavalent live bovine-human reassortant vaccine, RotaTeqTM, and a lamb-derived monovalent live attenuated strain, LLR, which is only being used in China.

ROTARIX^®(Rotavirus Vaccine, Live, Oral)

ROTARIX is a vaccine indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4, and G9) in infants and children.

ROTARIX (Rotavirus Vaccine, Live, Oral), for oral administration, is a live, attenuated rotavirus vaccine derived from the human 89-12 strain which belongs to G1P [8] type. The rotavirus strain is propagated on Vero cells. After reconstitution, the final formulation (1 mL) contains at least 10^6.0median Cell Culture Infective Dose (CCID₅₀) of live, attenuated rotavirus.

RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) Oral Solution

RotaTeq is indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the G1, G2, G3 and G4 serotypes contained in the vaccine.

RotaTeq, 2 mL for oral use, is a ready-to-use solution of live reassortant rotaviruses, containing G1,G2, G3, G4 and P1A[8] which contains a minimum of 2.0 – 2.8 x 106 infectious units (IU) per individual reassortant dose, depending on the serotype, and not greater than 116 x 106 IU per aggregate dose.

RotaTeq is a live, oral pentavalent vaccine that contains 5 live reassortant rotaviruses. The rotavirus parent strains of the reassortants were isolated from human and bovine hosts. Four reassortant rotaviruses express one of the outer capsid proteins (G1, G2, G3, or G4) from the human rotavirus parent strain and the attachment protein (serotype P7) from the bovine rotavirus parent strain. The fifth reassortant virus expresses the attachment protein, P1A (genotype P[8]), herein referred to as serotype P1A[8], from the human rotavirus parent strain and the outer capsid protein of serotype G6 from the bovine rotavirus parent strain…

Monovalent Lamb Vaccine

The only vaccine that is currently licensed is in use in China. Developed by Zhi-Sheng Bai at the Lanzhou Institute, the attenuated monovalent vaccine is based on a strain of lamb rotavirus. Similar to Rotarix^®, the lamb rotavirus strain was attenuated by passage in cell culture.

The lamb vaccine is classified as serotype P[10], G12. It is delivered as a single dose, between the ages of 2-24 months.

The vaccine has been proven to be safe and immunogenic (with 61% of vaccinees developing neutralizing antibody responses), but efficacy results of the Phase II trails have yet to be published.[6]

Additional Information about the vaccines:

Live attenuated RV strains

The first RV vaccines to be tested in humans were the live bovine strains RIT4237 (P[1]-G6) and WC3 (P[5]-G6), and the live simian strain RRV (P[3]-G3), which are attenuated for humans and could be administered by the oral route. The three strains induced neutralizing antibodies in a majority of infants but showed inconstant capacity to protect against RV disease.

In China, a lamb-derived monovalent (P[12]-G10) live-attenuated, 3-dose oral vaccine, was developed by the Lanzhou Institute of Biomedical Products and is used in the private sector. The vaccine is reported to induce neutralizing antibody responses in 60% of vaccinees but its efficacy is not precisely known since it was not tested against placebo in a controlled Phase III trial [135] .

A human P[8]-G1 RV strain, RIX 4414, which was isolated from the stools of a sick 15-month old boy in the USA, was attenuated by multiple passages in cell culture, plaque-purified and passaged again in Vero cells. The strain was developed as a 2-dose monovalent oral vaccine by AVANT Immunotherapeutics then licensed to GlaxoSmithKline Biologicals. The vaccine (RotarixTM) showed 70%-85% protective efficacy against severe disease, including that due non-G1 serotypes [149, 150]. It now has been tested in more than 60 countries in Latin America, Africa, Asia and Europe. A large, multicentered safety trial on 63 225 infants between 6 and 14 weeks of age in Latin America and Finland confirmed the initial safety data and indicated no increased attributable risk of intussusceptions (IS) in the high-risk period up to 30 days post any dose [151]. The vaccine was first licensed in 2004 in Mexico and the Dominican Republic and has now been licensed in many countries worldwide. It also has been prequalified by WHO for procurement by UNICEF and the UN Vaccine Fund. Additional Phase IIb and III trials are in progress in South Africa, Malawi and Bangladesh to determine if the vaccine will work well in children from poor settings in developing countries, if it can be administered with the oral polio vaccine without interference, and whether it can safely be administered to HIV positive infants. Final results are due in 2009.

Another human RV strain, RV3 (P2[6]-G3), isolated from newborns at the Royal Hospital in Melbourne, Australia [152] is also developed as a candidate live oral vaccine. A small Phase II study with three doses of 105 pfu of the vaccine indicated relatively low immunogenicity in infants as measured by serum IgA levels [153] . However, the vaccine recipients who developed an immune response were protected against clinical disease in the following year. Strategies to increase the potency of the vaccine are under study with a vaccine producer in Indonesia.

6.3.2 Live reassortant RV strains

Efforts also were made to develop human-animal reassortant RV strains containing the VP7 or VP4 RNA segment from a human RV strain to provide the required antigenicity and the other 10 RNA segments from a simian or a bovine strain to provide the attenuated phenotype [154, 155].

A tetravalent rhesus-human reassortant RV vaccine, RRV-TV, was initially developed at the NIH, Bethesda, using the simian RRV strain (G3) mixed with three human-simian reassortant strains of G types 1, 2, and 4, respectively. The vaccine (RotaShieldTM, Wyeth-Lederle Vaccines, USA) was shown to provide 48–68% protection against any RV disease and 64–91% protection against severe disease [156] . It was introduced in August 1998 on the market in the USA and administered in a three dose schedule to over 600 000 infants within the following year, until an unexpected adverse event, intussusception (IS), was found to occur in a significant number of cases within two weeks after administration of the first two doses of vaccine, leading to its eventual withdrawal [157] . The risk of IS, initially targeted at 1 in 2500 children immunized, has now been reassessed as 1 in 10 000. Its occurrence led to a very thorough safety assessment of the following generation of live oral RV vaccines (viz RotarixTM and RotaTeqTM), with sample sizes in excess of 60 000 subjects. The original RotashieldTM vaccine has now been licensed to a biotech company, BIOVIRx Inc., USA.

A pentavalent human-bovine reassortant vaccine, RotaTeqTM, was prepared by Merck Research Co., Pennsylvania, by reassortment between the naturally attenuated bovine RV strain WC3 and five different human RV strains of serotypes G1, G2, G3, G4 and P[8], respectively. The live-attenuated, 3-dose oral vaccine, was tested in a large safety and efficacy trial in Finland and the USA on more than 70 000 children who were carefully monitored for 2 weeks after each immunization for risks of IS. The vaccine was found to be totally safe and to elicit 74% protection against any G1-G4 RV gastroenteritis through the first RV season after vaccination [158]. Vaccination reduced doctor visits for RV diarrhoea by 86% and hospitalizations and emergency department visits by 94.5%. The vaccine was shown not to interfere with the immunogenicity of a combined Hib, DTP, HepB, conjugated pneumococcal and inactivated polio vaccine, nor with concomitant administration of the oral polio vaccine [159]. RotaTeqTM was licensed in February 2006 in the USA and subsequently in many countries worldwide. It officially was recommended for the routine immunization of children in the USA after active surveillance showed only three cases of IS among more than 100 000 vaccinated infants. It also has been included into national vaccination programs in several countries. A Phase III trial is ongoing in African countries (Mali, Ghana, and Kenya). Results are expected end of 2009.

An alternative multivalent bovine-human reassortant oral vaccine was developed by the National Institute of Allergy and Infectious Diseases (NIAID, NIH, Bethesda), based on the attenuated bovine strain UK reassorted with the five most common RV serotypes in humans, G1-G4, G8 and G9 [156] . Phase II data showed a good immune response and no adverse interference with concomitantly administered childhood vaccines. A non-exclusive license for production of the vaccine has been granted to vaccine producers in Brazil, China and India.

Finally, a naturally occurring human–bovine, neonate-derived RV strain, 116E (P[10]-G9), which was isolated from a nosocomial outbreak of asymptomatic infection in New-Delhi, is under development by Bharat Biotech Ltd in India [148, 160]. A similar strain, I321 (P[11]-G10), was found not to be immunogenic [161] .

6.3.3 Other RV vaccine approaches

New RV vaccine approaches include an inactivated virus vaccine [162] , DNA vaccines [163] , a VP6 subunit vaccine [164, 165] and virus-like particles (VLPs) expressed in a baculovirus system [166-168]. Depending on the number of viral proteins expressed, the complexity of the VLPs can vary from mono-layered (VP2-VLPs) to double-layered (VP2/6 VLPs) or triple- layered VLPs (VP2/6/7/4 VLPs).

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HPV Strains

Posted on April 3, 2011 by crunchymomma

HPV

The Human Papilloma Virus (HPV) is the cause of both genital and non-genital warts. This is a very common family of viruses. There are actually more than 100 different strains of HPV. Of these, approximately 30 exist in the genital area and can cause genital warts (condyloma acuminata). These 30 strains can be further broken down to “high” and “low” risk strains.

High risk strains may show up in a Pap smear and may rarely develop into cancer. There are approximately 13 high-risk strains of HPV. Two strains (16 & 18) are believed to cause about 70% of all cervical cancer.

Low risk strains can sometimes cause changes in a Pap smear, but do not progress to cancer. Two of the low risk-risk strains (6 and 11) are most likely to cause genital warts.

There are 40 strains of HPV that can affect the anal and genital tracts and these are further divided into low risk and high risk strains.

Thirteen strains are considered high risk, or more likely to progress to high grade lesions (HSIL, CIN 2 or 3) and possibly cancer, if not cleared by the immune system. These strains are: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Strains 16 and 18 are by far the most common types, and one or both are present in approximately 70% of cervical cancers worldwide. Despite this strong link, only a very small percentage of high risk HPV infections will ever become invasive cancer (estimated at 2%). The time between initial exposure and the development of cancer can vary from months to years, but the average time is thought to be 15 years. Unfortunately, the high risk HPV strains do not usually cause any symptoms to alert someone that they have the infection. The low risk strains are not considered a risk for cervical cancer, but they can cause low grade lesions (CIN 1) and several of these strains can cause genital warts.

GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant]

GARDASIL is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine:

Cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18

Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:

Cervical intraepithelial neoplasia (CIN) grade 2/3 and Cervical adenocarcinoma in situ (AIS)

Cervical intraepithelial neoplasia (CIN) grade 1

Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3

Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3

GARDASIL, Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant, is a non-infectious recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include

vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final

purification buffer.

GARDASIL is a sterile suspension for intramuscular administration. Each 0.5-mL dose contains approximately 20 mcg of HPV 6 L1 protein, 40 mcg of HPV 11 L1 protein, 40 mcg of HPV 16 L1 protein, and 20 mcg of HPV 18 L1 protein.

Each 0.5-mL dose of the vaccine contains approximately 225 mcg of aluminum (as Amorphous Aluminum Hydroxyphosphate Sulfate adjuvant), 9.56 mg of sodium chloride, 0.78 mg of L-histidine, 50 mcg of polysorbate 80, 35 mcg of sodium borate, < 7 mcg yeast protein/dose, and water for injection.

The product does not contain a preservative or antibiotics.

CERVARIX® PRODUCT INFORMATION Human Papillomavirus Vaccine Types 16 and 18

(Recombinant, AS04 adjuvanted)

CERVARIX contains recombinant C-terminally truncated L1 proteins from human papillomavirus (HPV) type-16 and type-18 each assembled as virus-like particles (VLPs)…

The HPV-16 and HPV-18 L1 antigens are prepared by recombinant DNA technology using a Baculovirus expression system in Trichoplusnia ni cells.

HPV-16 and HPV-18 L1 antigens in CERVARIX are adjuvanted with AS04. This AS04 adjuvant system comprises aluminium hydroxide (Al(OH)3) and 3-O-desacyl-4’-monophosphoryl lipid A (MPL). The MPL within AS04 enhances the initiation of the immune response through the activation of innate immunity, leading to an improved cellular and humoral adaptive immune response.

Each 0.5ml dose of CERVARIX contains 20 micrograms each of HPV-16 L1 and HPV-18 L1 proteins, 0.5 milligrams of Al(OH)3 and 50 micrograms of MPL. CERVARIX also contains sodium chloride (NaCl) 4.4 mg, sodium phosphate – monobasic (NaH2PO4.2 H2O) 624 micrograms and water for injection as excipients. CERVARIX does not contain a preservative.

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Rotavirus Strains

Posted on April 3, 2011 by crunchymomma

Rotavirus

Rotavirus-Synopses

Genome Variability

rotastarins

Rotavirus Vaccines:

Monovalent “Jennerian” Vaccines

Bovine Vaccines

Rhesus Vaccine

Reassortant “Modified Jennerian” Vaccines

Rhesus-Human Reassortant Vaccines

Bovine-Human Reassortant Vaccines

Other Candidate Vaccines

The Ever-Changing Landscape of Rotavirus Serotypes

(The Pediatric Infectious Disease Journal:Volume 28(3) Supplement March 2009pp S60-S62)

Abstract:

ROTARIX^®(Rotavirus Vaccine, Live, Oral)

ROTARIX is a vaccine indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4, and G9) in infants and children.

RotaTeq (Rotavirus Vaccine, Live, Oral, Pentavalent) Oral Solution

RotaTeq is indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the G1, G2, G3 and G4 serotypes contained in the vaccine.

Monovalent Lamb Vaccine

The lamb vaccine is classified as serotype P[10], G12. It is delivered as a single dose, between the ages of 2-24 months.

The vaccine has been proven to be safe and immunogenic (with 61% of vaccinees developing neutralizing antibody responses), but efficacy results of the Phase II trails have yet to be published.[6]

Additional Information about the vaccines:

Live attenuated RV strains

6.3.2 Live reassortant RV strains

6.3.3 Other RV vaccine approaches

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Hepatitis A Strains

Posted on April 3, 2011 by crunchymomma

Hepatitis A

The pathogen and the disease

HAV is a member of the Picornaviridae family that includes both the enteroviruses and rhinoviruses of humans. Being the only species member, it constitutes its own genus named hepatovirus. HAV is a non-enveloped (naked) virus of 27–28 nm diameter without morphological features differentiating it from other picornaviruses. Four structural proteins encapsulate the RNA genome. Neutralization sites for anti-HAV antibodies are mainly contained in two of these proteins. Although six genotypes of HAV have been identified, there appears to be no variation detectable by serology in these neutralization sites. The virus is relatively stable at low pH and moderate temperatures, but is inactivated by high temperature (almost instantly at 85°C/185°F), and by formalin or chlorine. HAV itself is not cytopathic and the liver-cell damage is caused by the cell-mediated immune response.

The clinical course of acute hepatitis A is indistinguishable from other types of acute viral hepatitis. Symptoms typically include fever, malaise, anorexia, nausea and abdominal discomfort, followed by dark urine and jaundice. The severity of disease and mortality increases in older age groups. The convalescence following hepatitis A may be slow, and is characterized by fatigue, nausea and lack of appetite. Complications of hepatitis A include relapsing hepatitis, cholestatic hepatitis and fulminant hepatitis. Fulminant hepatitis occurs in approximately 0.01% of clinical infections and is characterized by rapid deterioration in liver function and a very high fatality rate. Chronic infection with HAV does not occur. No specific antiviral therapy is currently available.

The aetiological diagnosis is made by the demonstration of IgM antibodies to HAV (IgM anti-HAV) in serum. Detection of the virus or viral antigens in the stool is of limited value for routine diagnosis.

Strains

Only one serotype of HAV has been identified and a single infection confers lifelong immunity. However, genetic heterogeneity between HAV isolates from different parts of the world has enabled the classification of HAV strains into seven different genotypes, designated I to VII. Four of these have been associated with human disease, I, II, III, and VII. Most human HAV strains belong to genotypes I and III, with 80% of them being genotype I. Genotypes I and III are further divided into subtypes A and B. Genotypes II and VII are represented only by one human strain each, and genotypes IV, V, and VI include strains recovered from simians (Arauz-Ruiz et al., 2001). Genotype IA appears to be the agent responsible for the majority of hepatitis A cases worldwide and has been isolated from all parts of the world. Genotype IB appears to occur in the Mediterranean region, whereas genotype III viruses have been isolated from diverse sources such as Panamanian owl monkeys, drug abusers in Sweden and patients from India and Nepal. Single representatives of genotype II and VII were isolated from individual patients from Sierra Leone and France (Lu et al., 2004). Several studies have indicated that HAV strains in North America mainly belong to subtype IA (Arauz-Ruiz et al., 2001).

Variant(s): (Click link to the list of all the variant strains)

Hepatitis A vaccines

Techniques for growing HAV in cell culture have made it possible to generate sufficient amounts of virus for vaccine production. Several inactivated or live attenuated vaccines against hepatitis A have been developed, but only four inactivated hepatitis A vaccines are currently available internationally. All four vaccines are similar in terms of efficacy and side-effect profile. The vaccines are given parenterally, as a two-dose series, 6-18 months apart. The dose of vaccine, vaccination schedule, ages for which the vaccine is licensed, and whether there is a paediatric and adult formulation varies from manufacturer to manufacturer. No vaccine is licensed for children younger than one year of age.

Three vaccines are manufactured from cell-culture-adapted HAV propagated in human fibroblasts. Following purification from cell lysates, the HAV preparation is formalin-inactivated and adsorbed to an aluminium hydroxide adjuvant. One vaccine is formulated without preservative; the other two are prepared with 2-phenoxyethanol as a preservative. The fourth vaccine is manufactured from HAV purified from infected human diploid cell cultures and inactivated with formalin. This preparation is adsorbed to biodegradable, 150 nm phospholipid vesicles spiked with influenza haemagglutinin and neuramidase. These virosomes are thought to directly target influenza-primed antibody-presenting cells as well as macrophages, thus stimulating a rapid vaccine-induced B-cell and T-cell proliferation in the majority of vaccinees. A combination vaccine containing inactivated hepatitis A and recombinant hepatitis B vaccines has been licensed since 1996 for use in children aged one year or older in several countries. The combination vaccine is given as a three-dose series, using a 0, 1, 6 month schedule.

The Vaccines Available:

TWINRIX® [Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine]

TWINRIX® [Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine] is a sterile bivalent vaccine containing the antigenic components used in producing HAVRIX® (Hepatitis A Vaccine, Inactivated) and ENGERIX-B® [Hepatitis B Vaccine (Recombinant)]. TWINRIX is a sterile suspension of inactivated hepatitis A virus (strain HM175) propagated in MRC-5 cells, and combined with purified surface antigen of the hepatitis B virus. The purified hepatitis B surface antigen (HBsAg) is obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus, in synthetic media containing inorganic salts, amino acids, dextrose, and vitamins. Bulk preparations of each antigen are adsorbed separately onto aluminum salts and then pooled during formulation.

A 1.0-mL dose of vaccine contains 720 ELISA Units of inactivated hepatitis A virus and 20 mcg of recombinant HBsAg protein. One dose of vaccine also contains 0.45 mg of aluminum in the form of aluminum phosphate and aluminum hydroxide as adjuvants, amino acids, sodium chloride, phosphate buffer, polysorbate 20, Water for Injection, traces of formalin (not more than 0.1 mg), and residual MRC-5 cellular proteins (not more than 2.5 mcg). Neomycin sulfate, an aminoglycoside antibiotic, is included in the cell growth media; only trace amounts (not more than 20 ng) remain following purification. The manufacturing procedures used to manufacture TWINRIX result in a product that contains no more than 5% yeast protein.

VAQTA® (HEPATITIS A VACCINE, INACTIVATED)

VAQTA* [Hepatitis A Vaccine, Inactivated] is an inactivated whole virus vaccine derived from hepatitis A virus (HAV) grown in cell culture in human MRC-5 diploid fibroblasts. It contains inactivated virus of a strain which was originally derived by further serial passage of a proven attenuated strain. The virus is grown, harvested, purified by a combination of physical and high performance liquid chromatographic techniques developed at the Merck Research Laboratories, formalin inactivated, and then adsorbed onto amorphous aluminum hydroxyphosphate sulfate. One milliliter of the vaccine contains approximately 50 units (U) of hepatitis A virus antigen, which is purified and formulated without a preservative. Within the limits of current assay variability, the 50U dose of VAQTA contains less than 0.1 mcg of non-viral protein, less than 4 x 10–6 mcg of DNA, less than 10–4 mcg of bovine albumin, and less than 0.8 mcg of formaldehyde. Other process chemical residuals are less than 10 parts per billion (ppb).

Pediatric/Adolescent Formulation (12 Months Through 18 Years of Age): each 0.5 mL dose contains approximately 25U of hepatitis A virus antigen adsorbed onto approximately 0.225 mg of aluminum provided as amorphous aluminum hydroxyphosphate sulfate, and 35 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride.

Adult Formulation (19 Years of Age and Older): each 1 mL dose contains approximately 50U of hepatitis A virus antigen adsorbed onto approximately 0.45 mg of aluminum provided as amorphous aluminum hydroxyphosphate sulfate, and 70 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride.

HAVRIX ^®(Hepatitis A Vaccine)

HAVRIX (Hepatitis A Vaccine) is a sterile suspension of inactivated virus for intramuscular administration. The virus (strain HM175) is propagated in MRC-5 human diploid cells. After removal of the cell culture medium, the cells are lysed to form a suspension. This suspension is purified through ultrafiltration and gel permeation chromatography procedures. Treatment of this lysate with formalin ensures viral inactivation. Viral antigen activity is referenced to a standard using an enzyme linked immunosorbent assay (ELISA), and is therefore expressed in terms of ELISA Units (EL.U.).

Each 1-mL adult dose of vaccine consists of 1440 EL.U. of viral antigen, adsorbed on 0.5 mg of aluminum as aluminum hydroxide.

Each 0.5-mL pediatric dose of vaccine consists of 720 EL.U. of viral antigen, adsorbed onto 0.25 mg of aluminum as aluminum hydroxide.

HAVRIX contains the following excipients: Amino acid supplement (0.3% w/v) in a phosphate-buffered saline solution and polysorbate 20 (0.05 mg/mL). From the manufacturing process, HAVRIX also contains residual MRC-5 cellular proteins (not more than 5 mcg/mL), formalin (not more than 0.1 mg/mL), and neomycin sulfate (not more than 40 ng/mL), an aminoglycoside antibiotic included in the cell growth media.

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Hepatitis B Strains

Posted on April 3, 2011 by crunchymomma

Hepatitis B Strains

HBV is a mostly double-stranded DNA virus in the Hepadnaviridae family. HBV causes hepatitis in human and related virus in this family cause hepatitis in ducks, ground squirrels and woodchucks. The HBV genome has four genes: pol, env, pre-core and X that respectively encode the viral DNA-polymerase, envelope protein, pre-core protein (which is processed to viral capsid) and protein X. The function of protein X is not clear but it may be involved in the activation of host cell genes and the development of cancer.

Organization of the HBV Genome

The genomes of more than a dozen isolates of hepatitis B virus have been cloned and the complete nucleotide sequences determined. Analysis of the coding potential of the genome reveals four open reading frames (ORFs) which are conserved between all of these isolates.

The first ORF encodes the various forms of the surface protein and contains three in-frame methionine codons which are used for initiation of translation. A second promoter is located upstream of the pre-S1 initiation codon. This directs the synthesis of a 2.4 kb mRNA which is co-terminal with the other surface messages and is translated to yield the large (pre-S1) surface proteins.

The core open reading frame also has two in-phase initiation codons. The “precore” region is highly conserved, has the properties of a signal sequence and is responsible for the secretion of HBeAg.

The third ORF, which is the largest and overlaps the other three, encodes the viral polymerase. This protein appears to be another translation product of the 3.5 kb RNA, and is synthesized apparently following internal initiation of the ribosome.

The amino terminal domain is believed to be the protein primer for minus strand synthesis. There is then a spacer region followed by the (RNA and DNA-dependent) DNA polymerase.

The fourth ORF was designated “x” because the function of its small gene product was not known. However, “x” has now been demonstrated to be a transcriptional transactivator.

…The discovery of variation in the epitopes presented on the surface of the virions and subviral particles identified several subtypes of HBV which differ in their geographical distribution. All isolates of the virus share a common epitope, a, which is a domain of the major surface protein which is believed to protrude as a double loop from the surface of the particle. Two other pairs of mutually exclusive antigenic determinants, d or y and w or r, are also present on the major surface protein. These variations have been correlated with single nucleotide changes in the surface ORF which lead to variation in single amino acids in the protein. Four principal subtypes of HBV are recognized: adw, adr, ayw and ayr. Subtype adw predominates in northern Europe, the Americas and Australasia and also is found in Africa and Asia. Subtype ayw is found in the Mediterranean region, eastern Europe, northern and western Africa, the near East and the Indian subcontinent. In the Far East, adr predominates. But the rarer ayr occasionally may be found in Japan and Papua New Guinea.

The major response of recipients of hepatitis B vaccine is to the common a epitope with consequent protection against all subtypes of the virus. First generation vaccines were prepared from 22 nm HBsAg particles purified from plasma donations from chronic carriers. These preparations are safe and immunogenic but have been superseded in some countries by recombinant vaccines produced by the expression of HBsAg in yeast cells. The expression plasmid contains only the 3′ portion of the HBV surface ORF and only the major surface protein, without pre-S epitopes, is produced. Vaccines containing pre-S2 and pre-S1, as well as the major surface proteins expressed by recombinant DNA technology, are undergoing clinical trials.

Types of HBV Genomes

The following is a list of the major types of HBV genomes found in the human population:

1993: Genetic relatedness of hepatitis B viral strains of diverse geographical origin and natural variations in the primary structure of the surface antigen.
1995: Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene.
1998: Antigenic diversity of hepatitis B virus strains of genotype F in Amerindians and other population groups from Venezuela.

6 Genotypes (A,B,C,D,E,F) [PMID: 8336122]

Group A – Orig – N. Europe – Sub-Saharan Africa
Group B – Confined to – Eastern Asia (China)
Group C – Far East (Japan)
Group D – Mediterranean – Near, Mid East, South Asia
Group E – W. Sub-Saharan Africa, south to Angola
Group F – New World – Brazil, N. + S. America

121 Strains Exist as Quasispecies

There are four serotypes which are based on subtypes of the hepatitis B surface antigen (HBsAg). These are defined by two mutually exclusive determinant pairs d/y and w/r with a common determinant ‘a’. These subtypes are adw, ayw, adr, and ayr.

Four genomic groups of HBV were later referred as genotypes designated with A-D. Sequencing of the S-gene of HBV is the molecular basis for the assessment of the serological variations of HBsAg within the major four subtypes. Two new genotypes of HBV are designated with E and F. The F genotype diverges from other HBV genomes sequenced by 14%. So far, it is the most divergent HBV genome. Worldwide molecular epidemiology of HBV is based on the variability of the S-gene. The E and F strains appear to originate from aboriginal populations of Africa in the New World.

Characterization of genotype H hepatitis B virus strain identified for the first time from a Japanese blood donor by nucleic acid amplification test

Hepatitis B virus (HBV) has been classified into seven genotypesA–G. However, recently genotype H, which is phylogeneticallyclosely related to genotype F, has been reported (Arauz-Ruizet al., 2002 ). These genotypes of HBV show a distinctive geographicaldistribution and a relevance to clinical severity (Mayert etal., 1999 ; Kobayashi et al., 2002 ; Locarnini, 2002)

Possible New Hepatitis B Virus Genotype, Southeast Asia

(Emerging Infectious Diseases Volume 14, Number 11–November 2008)

Abstract
We conducted a phylogenetic analysis of 19 hepatitis B virus strains from Laos that belonged to 2 subgenotypes of a new genotype I. This emerging new genotype likely developed outside Southeast Asia and is now found in mixed infections and in recombinations with local strains in a geographically confined region.

Hepatitis B Vaccines:

COMVAX® [HAEMOPHILUS b CONJUGATE (MENINGOCOCCAL PROTEIN CONJUGATE) and HEPATITIS B (RECOMBINANT) VACCINE]

HBsAg is produced in recombinant yeast cells. A portion of the hepatitis B virus gene, coding for HBsAg, is cloned into yeast, and the vaccine for hepatitis B is produced from cultures of this recombinant yeast strain according to methods developed in the Merck Research Laboratories. The antigen is harvested and purified from fermentation cultures of a recombinant strain of the yeast Saccharomyces cerevisiae containing the gene for the adw subtype of HBsAg. The fermentation process involves growth of Saccharomyces cerevisiae on a complex fermentation medium which consists of an extract of yeast, soy peptone, dextrose, amino acids and mineral salts.

The HBsAg protein is released from the yeast cells by mechanical cell disruption and detergent

extraction, and purified by a series of physical and chemical methods, which includes ion and hydrophobic chromatography, and diafiltration. The purified protein is treated in phosphate buffer with formaldehyde and then coprecipitated with alum (potassium aluminum sulfate) to form bulk vaccine adjuvanted with amorphous aluminum hydroxyphosphate sulfate. The vaccine contains no detectable yeast DNA, and 1% or less of the protein is of yeast origin.

The individual PRP-OMPC and HBsAg adjuvanted bulks are combined to produce COMVAX. Each 0.5 mL dose of COMVAX is formulated to contain 7.5 mcg PRP conjugated to approximately 125 mcg OMPC, 5 mcg HBsAg, approximately 225 mcg aluminum as amorphous aluminum hydroxyphosphate sulfate, and 35 mcg sodium borate (decahydrate) as a pH stabilizer, in 0.9% sodium chloride. The vaccine contains not more than 0.0004% (w/v) residual formaldehyde.

The potency of the PRP-OMPC component is measured by quantitating the polysaccharide

concentration by an HPLC method. The potency of the HBsAg component is measured relative to a standard by an in vitro immunoassay.

ENGERIX-B^®[Hepatitis B Vaccine (Recombinant)]

ENGERIX-B [Hepatitis B Vaccine (Recombinant)] is a noninfectious recombinant DNA hepatitis B vaccine developed and manufactured by GlaxoSmithKline Biologicals. It contains purified surface antigen of the virus obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus. The surface antigen expressed in Saccharomyces cerevisiae cells is purified by several physicochemical steps and formulated as a suspension of the antigen adsorbed on aluminum hydroxide. The procedures used to manufacture ENGERIX-B result in a product that contains no more than 5% yeast protein. No substances of human origin are used in its manufacture.

Pediatric/Adolescent: Each 0.5-mL dose contains 10 mcg of hepatitis B surface antigen adsorbed on 0.25 mg aluminum as aluminum hydroxide. The pediatric formulation contains sodium chloride (9 mg/mL) and phosphate buffers (disodium phosphate dihydrate, 0.98 mg/mL; sodium dihydrogen phosphate dihydrate, 0.71 mg/mL).

Adult: Each 1-mL adult dose contains 20 mcg of hepatitis B surface antigen adsorbed on 0.5 mg aluminum as aluminum hydroxide. The adult formulation contains sodium chloride (9 mg/mL) and phosphate buffers (disodium phosphate dihydrate, 0.98 mg/mL; sodium dihydrogen phosphate dihydrate, 0.71 mg/mL).

PEDIARIX^®[Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined]

It contains diphtheria and tetanus toxoids, 3 pertussis antigens (inactivated pertussis toxin [PT] and formaldehyde-treated filamentous hemagglutinin [FHA] and pertactin [69 kiloDalton outer membrane protein]), hepatitis B surface antigen, plus poliovirus Type 1 (Mahoney), Type 2 (MEF-1), and Type 3 (Saukett). The diphtheria toxoid, tetanus toxoid, and pertussis antigens are the same as those in

INFANRIX^®(Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed). The hepatitis B surface antigen is the same as that in ENGERIX-B^®[Hepatitis B Vaccine (Recombinant)].

…The hepatitis B surface antigen (HBsAg) is obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus, in synthetic medium. The surface antigen expressed in the S. cerevisiae cells is purified by several physiochemical steps, which include precipitation, ion exchange chromatography, and ultrafiltration.

…The diphtheria, tetanus, and pertussis antigens are individually adsorbed onto aluminum hydroxide; hepatitis B component is adsorbed onto aluminum phosphate. All antigens are then diluted and combined to produce the final formulated vaccine. Each 0.5-mL dose is formulated to contain 25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 mcg of inactivated PT, 25 mcg of FHA, 8 mcg of pertactin, 10 mcg of HBsAg, 40 D-antigen Units (DU) of Type 1 poliovirus, 8 DU of Type 2 poliovirus, and 32 DU of Type 3 poliovirus.

TWINRIX® [Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine]

TWINRIX® [Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine] is a sterile bivalent vaccine containing the antigenic components used in producing HAVRIX® (Hepatitis A Vaccine, Inactivated) and ENGERIX-B® [Hepatitis B Vaccine (Recombinant)].

The purified hepatitis B surface antigen (HBsAg) is obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus, in synthetic media containing inorganic salts, amino acids, dextrose, and vitamins. Bulk preparations of each antigen are adsorbed separately onto aluminum salts and then pooled during formulation.

RECOMBIVAX HB® HEPATITIS B VACCINE (RECOMBINANT)

RECOMBIVAX HB* Hepatitis B Vaccine (Recombinant) is a non-infectious subunit viral vaccine

derived from hepatitis B surface antigen (HBsAg) produced in yeast cells. A portion of the hepatitis B virus gene, coding for HBsAg, is cloned into yeast, and the vaccine for hepatitis B is produced from cultures of this recombinant yeast strain according to methods developed in the Merck Research Laboratories.

The antigen is harvested and purified from fermentation cultures of a recombinant strain of the yeast Saccharomyces cerevisiae containing the gene for the adw subtype of HBsAg. The fermentation process involves growth of Saccharomyces cerevisiae on a complex fermentation medium which consists of an extract of yeast, soy peptone, dextrose, amino acids and mineral salts. The HBsAg protein is released from the yeast cells by cell disruption and purified by a series of physical and chemical methods. The purified protein is treated in phosphate buffer with formaldehyde and then coprecipitated with alum (potassium aluminum sulfate) to form bulk vaccine adjuvanted with amorphous aluminum

hydroxyphosphate sulfate. The vaccine contains no detectable yeast DNA but may contain not more than 1% yeast protein. The vaccine produced by the Merck method has been shown to be comparable to the plasma-derived vaccine in terms of animal potency (mouse, monkey, and chimpanzee) and protective efficacy (chimpanzee and human).

Pediatric/Adolescent Formulation (Without Preservative), 10 mcg/mL: each 0.5 mL dose contains 5 mcg of hepatitis B surface antigen.

Adult Formulation (Without Preservative), 10 mcg/mL: each 1 mL dose contains 10 mcg of

hepatitis B surface antigen.

Dialysis Formulation (Without Preservative), 40 mcg/mL: each 1 mL dose contains 40 mcg of hepatitis B surface antigen.

All formulations contain approximately 0.5 mg of aluminum (provided as amorphous aluminum

hydroxyphosphate sulfate, previously referred to as aluminum hydroxide) per mL of vaccine. In each formulation, hepatitis B surface antigen is adsorbed onto approximately 0.5 mg of aluminum (provided as amorphous aluminum hydroxyphosphate sulfate) per mL of vaccine. The vaccine is of the adw subtype.

RECOMBIVAX HB is indicated for vaccination of persons at risk of infection from hepatitis B virus

including all known subtypes. RECOMBIVAX HB Dialysis Formulation is indicated for vaccination of adult predialysis and dialysis patients against infection caused by all known subtypes of hepatitis B virus.

Nabi-HB® Hepatitis B Immune Globulin (Human)

DESCRIPTION

Hepatitis B Immune Globulin (Human), Nabi-HB, is a sterile solution of immunoglobulin (5 ± 1%

protein) containing antibodies to hepatitis B surface antigen (anti-HBs). It is prepared from plasma

donated by individuals with high titers of anti-HBs. The plasma is processed using a modified

Cohn 6 / Oncley 9 cold-alcohol fractionation process1,2 with two added viral reduction steps

described below. Nabi-HB is formulated in 0.075 M sodium chloride, 0.15 M glycine, and 0.01%

polysorbate 80, at pH 6.2. The product is supplied as a nonturbid sterile liquid in single dose

vials and appears as clear to opalescent. It contains no preservative and is intended for single

use by the intramuscular route only.

The manufacturing steps for Nabi-HB are designed to reduce the risk of transmission of viral disease.

The solvent/detergent treatment step, using tri-n-butyl phosphate and Triton® X-100, is

effective in inactivating known enveloped viruses such as hepatitis B virus (HBV), hepatitis C

virus (HCV), and human immunodeficiency virus (HIV) 3. Virus filtration, using a Planova® 35

nm Virus Filter, is effective in reducing some known enveloped and non-enveloped viruses4. The

inactivation and reduction of known enveloped and non-enveloped model viruses were validated

in laboratory studies as summarized in the following table…

BayHepB Immune Globulin (Human)

Filed under: Hepatitis B | Comments Off

Pertussis and Transmission

Posted on April 3, 2011 by crunchymomma

Pertussis and Transmission

I’m sure we’ve all seen the campaign ads called “Do it for your baby”. If not, here is an example. There is also a website.

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More recently, J. Lo was recruited by Sanofi Pasteur and the March of Dimes to jump on the bandwagon and promote Pertussis vaccines for adolescents and adults.

Let’s take a look at the issue of Pertussis transmission and what the vaccine really does or doesn’t do.

Pertussis Infection in Fully Vaccinated Children in Day-Care Centers, Israel (Emerging Infectious Diseases (Vol. 6, No. 5, September–October 2000)

Conclusions

The effects of whole-cell pertussis vaccine wane after 5 to 10 years, and infection in a vaccinated person causes nonspecific symptoms (3-7). Vaccinated adolescents and adults may serve as reservoirs for silent infection and become potential transmitters to unprotected infants (3-11). The whole-cell vaccine for pertussis is protective only against clinical disease, not against infection (15-17). Therefore, even young, recently vaccinated children may serve as reservoirs and potential transmitters of infection.

…We found that immunity does not even persist into early childhood in some cases. We also observed that DPT vaccine does not fully protect children against the level of clinical disease defined by WHO. Our results indicate that children ages 5-6 years and possibly younger, ages 2-3 years, play a role as silent reservoirs in the transmission of pertussis in the community. More studies are needed to find the immunologic basis of protection against infection and colonization and thus an effective way to eradicate pertussis.

Also See:

Characterization of Bactericidal Immune Responses following Vaccination with Acellular Pertussis Vaccines in Adults

…booster immunization of adults with acellular pertussisvaccines was not found to increase bactericidal activity overpreimmunization levels. Identifying ways to promote bactericidalimmune responses might improve the efficacy of acellular pertussisvaccines.

Informal consultation on the control of pertussis with whole cell and acellular vaccines

Dr Cherry pointed out in the 1999 WHO meeting, that even with a return to high vaccination coverage in Japan, pertussis incidence in children less than three months of age, had not declined substantially.

Pertussis toxin inhibits neutrophil recruitment to delay antibody-mediated clearance of Bordetella pertussis

…However, their efficacy against subclinical infection is doubtful, as the majority of vaccinated populations test positive for subsequent infection (10, 17), suggesting that the bacterium successfully infects immune and/or vaccinated individuals.

The Pertussis vaccines do not prevent transmission or infection. It simply prevents or suppresses the symptoms, or causes subclinical infection. The reason the vaccines do not prevent transmission is because they do not kill the bacteria that cause the disease. The vaccines only make the body able to resist the toxin that the bacteria release. The toxin is what makes a person sick and causes clinical disease. That is the reason behind the claim that being vaccinated will make a clinical case of Pertussis ‘milder’. Even if you don’t get the full effect of the vaccine, you might get partial blockage of the toxin which might cause you to cough less, etc.

What is also worth noting is the small print of an advertisement for Adacel, a DTaP booster:

“It is unknown whether immunizing adolescents and adults against pertussis will reduce the risk of transmission to infants.”

At least there was some honesty there. The adolescent or adult booster helps one person, the person who receives it! Why doesn’t the campaign advertisement just say “Do it for you!” They don’t because time as shown repeatedly that the majority of adults will not do booster vaccines. But, if they use infants or children as a reason, it works.

Read on…

Acellular Pertussis Vaccines and Complement Killing of Bordetella pertussis

At least one of the antigens in the acellular pertussis vaccine appears to be able to serve as a target for complement-mediated bactericidal activity. However, in this study and other studies (19, 21), improved bactericidal responses after immunization were rarely observed, possibly due to induction of antibodies that fail to fix complement. The absence of vaccine-induced bactericidal activity in vitro is consistent with the observation that the pertussis vaccine is effective at preventing severe disease, likely due to pertussis toxin neutralization and blocking attachment to reduce bacterial colonization, but it is less effective at producing a sterilizing immune response (5, 18). Despite high vaccination rates, the number of reported cases of pertussis in the United States has increased steadily since the 1980s (22). Developing a pertussis vaccine with a greater potential to elicit bactericidal activity could reduce bacterial carriage and reduce the incidence of disease.

According to this study, some were less likely to be protected, and the majorities were no more likely to be protected from infection than they were before the vaccine. To boot, the vaccine made them more susceptible to infection. There was a level of protection from severe disease due to the toxoid in the vaccine. This study alone shows that the vaccine doesn’t reduce carriage of the bacteria. Therefore, marketing the vaccines solely to protect infants isn’t being entirely truthful. It simply does not work that way. The vaccine can’t stop you from being infected, nor stop you from spreading the bacteria to infants, the immuno-compromised, the unvaccinated or vaccinated.

It is also acknowledged that the whole-cell pertussis vaccine was more efficacious, but also more reactive, hence why we now use the DTaP.

Use of Pertussis Vaccines in Outbreaks

Estimates of the efficacy of immunization with pertussis vaccines are subject to wide variation due to variation in study design, including factors such as case definition, case ascertainment, and duration of follow up. A recent study of reported cases in the United States in 1992 – 1994 estimated the effectiveness of whole-cell vaccine against culture proven pertussis; the effectiveness of three doses among children aged 7-18 months was 79% and the effectiveness of 4 doses among children aged 19-47 months was 90%.2

Estimates are also available from recent field trials that compared the efficacy of acellular and whole-cell pertussis vaccines. In these trials, the efficacy of three doses of whole cell pertussis vaccines from different manufacturers ranged from 83% to 98%, although the DTP vaccine from one manufacturer had a low efficacy in two trials (35% to 48%). In the field trials, the efficacy of the four licensed acellular vaccines ranged from 71% to 89%.

When is a true case a case… or not? How does case definition come into play?

The Science and Fiction of Pertussis Vaccines (PEDIATRICS Vol. 104 No. 6 December 1999, pp. 1381-1383)

Case definition has been particularly problematic in all of the recent DTaP vaccine efficacy trials. For uniform comparative purposes a case definition was suggested by a WHO expert committee. This definition required 21 days of paroxysmal cough plus laboratory confirmation of pertussis in the subject or household contact. There are 2 problems with this definition. The first is that a substantial number of B pertussis infections in unvaccinated children are mild and would not meet the case definition. The second is that all pertussis vaccines tend to modify duration and severity of disease rather than completely preventing illness. Therefore, the WHO definition has made all vaccines look better than they are and it has tended to obscure differences between vaccines.

Easily Missed?

Whooping cough is a common respiratory infection caused by thebacterium Bordetella pertussis. It should be considered as apossible diagnosis in any adolescent or adult with an acutecough of more than two weeks’ duration, even if they havebeen fully immunised.

Whooping cough in school age children with persistent cough: prospective cohort study in primary care

…Studies in the United States report a 20% incidence of Bordetella pertussis infection among adults with a persistent cough.² Despite data showing that neither infection nor immunisation results in lifelong immunity, whooping cough is seldom diagnosed in primary care because of the lack of specificity of clinical symptoms and signs. Whooping cough is perceived as a disease of very young children who have not been immunised and who have classic features such as whoop…

…General practitioners should be alert to a potential diagnosis of whooping cough in any child who presents with a persistent cough. We found that children with pertussis cough for a median of 16 weeks. Little evidence indicates that administering erythromycin to children with pertussis two weeks after they have contracted the infection either reduces symptoms or prevents transmission.^10…

Acellular Pertussis Vaccines and Complement Killing of Bordetella pertussis

When examined individually, the pre- versus postimmunization bactericidal activity was not significantly different at any dilution tested for 8 of the 15 acellular vaccine recipients. The individuals in the group with unchanged activity after immunization included an individual with undetectable preimmunization activity against the wild-type strain (individual 32-60), and the individual with the highest preimmunization activity (individual 26-47) (Fig. 2). These results suggest that the level of preimmunization bactericidal activity does not necessarily influence the ability to generate a postimmunization response.

However, statistically significant differences between pre- and post immunization bactericidal activity were observed (P < 0.05) using the paired t test for at least one serum dilution for 7 of the 15 acellular vaccine recipients. Furthermore, evidence of both improved bactericidal activity and reduced bactericidal activity after immunization was found in these seven serum samples. Four individuals displayed improved bactericidal activity after immunization when serum was added at lower concentrations (1.0 or 0.10%) but not at 10% (Fig. 3). However, in addition to enhanced bactericidal activity, individuals 4-43 and 20-55 displayed evidence of blocking activity, since fewer bacteria were killed when serum was added at 10% than when serum was added at 1%. Blocking activity could occur when antibodies that do not fix complement compete with complement-fixing antibodies for access to antigen. More definitive evidence of blocking was demonstrated in three other individuals (Fig. 4). For these individuals, the post immunization serum samples had significantly less bactericidal activity than the pre immunization serum samples at a serum concentration of 10%.

However, in this study and other studies (19, 21), improved bactericidal responses after immunization were rarely observed, possibly due to induction of antibodies that fail to fix complement. The absence of vaccine-induced bactericidal activity in vitro is consistent with the observation that the pertussis vaccine is effective at preventing severe disease, likely due to pertussis toxin neutralization and blocking attachment to reduce bacterial colonization, but it is less effective at producing a sterilizing immune response (5, 18).

In various studies, vaccinated children do not fit the case definition of pertussis, yet they test positive. They exhibit atypical or mild symptoms. This shows the vaccine may protect against clinical disease, but not against infection. Vaccinated children and adults are still serving as asymptomatic reservoirs and transmit infection. A reduction in colonization, without any kind of sterilizing immune response, is the most you will get. There should be an enhanced bacterial clearance in the vaccinated, but studies have proved there isn’t. What is even worse is, serology states that more than half of are catching pertussis every 2 1/2 years. If humans did not transmit pertussis easily, or could clear it easier, we wouldn’t have it so much. The vaccine has not changed that. Vaccinated or not, you can and do, carry and transmit the disease.

Other Studies:

Cell-mediated immune responses to antigens of Bordetella pertussis and protection against pertussis in school children (Pediatric Infection Disease Journal 1999; 18: 366-370)

Abstract

Background. Increasing evidence suggests that cell-mediated immunity (CMI) is involved in immune response against Bordetella pertussis. However, there are practically no studies evaluating the significance of pertussis-specific CMI in relation to protection against clinical pertussis.

On pg. 366: “The immunologic mechanisms of protection against clinical pertussis are poorly understood. Although several studies have suggested that antibodies to some pertussis antigens may be predictive of protection against pertussis, there is no generally accepted laboratory measure of immunity. Further in clinical efficacy trials of acellular vaccines, no clear correlation has been found between serum antibody values and protection.“

…”In the present study, no clear association was found between serum antibody values and clinical outcome.”

Pertussis toxin: the cause of the harmful effects and prolonged immunity of whooping cough. A hypothesis. (Rev Infect Dis. ;1 (3):401-12 233166)

The nature of the pathogenesis and of the prolonged immunity of whooping cough has not been clearly defined. The literature of Bordetella pertussis indicated that only the antigen that induces histamine sensitization, lymphocytosis, and other biological reactions in mice is the cause of the harmful effects and prolonged immunity of whooping cough. This antigen has the general characteristics of bacterial protein exotoxins that cause the harmful effects of infectious diseases such as diphtheria and tetanus. It is proposed that this antigen, which is histamine-sensitizing, lymphocyte-leukocyte-promoting, and islets-activating (HSF-LPF-IAP), be designated pertussis toxin. Agglutinogen, hemagglutinin, and heat-labile (at 56 C) and heat-stable (at 100 C) toxins are no doubt interrelated with the immunologic and/or toxic reactions of whooping cough. It appears that the first defense against the disease is the antibody that prevents adhesion of the bacteria to the cilia of the respiratory epithelium and that the second defense is the antitoxin against pertussis toxin (HSF-LPF-IAP).

Those who have been vaccinated are still considered susceptible, unless they have had a natural case of Pertussis, because a natural case can protect them at a higher rate than the vaccine. A vaccine may give them a less severe case with exposure, but it has been shown repeatedly that it does not prevent transmission. The vaccine for adolescents and adults is solely to prevent them from getting a clinical case and passing it on the infant. But overall, it just extends the length of time before they do/can get it.

The vaccine can provide some ‘herd immunity’. How? It can postpone, suppress the disease, or make a less severe case. But herd immunity is limited. The chance of catching pertussis at some point in ones life is inevitable. People can also get Pertussis more than once. This natural cycle of the disease also provides herd immunity. Pertussis has virulent cycles of every 2-5 years and vaccines have not changed its natural virulence cycle.

Underreporting of Pertussis has been acknowledged repeatedly. How does this correlate to the reduced disease burden? Simply put-It is only a guess.

Reemergence of Pertussis: Methods

Data from pertussis reporting (required by law since 1976) were obtained from 1976 to 1998 from the Inspectorate of Health. A case definition, introduced in 1988, included clinical symptoms and laboratory confirmation (or close contact with a person with laboratory-confirmed pertussis).

…From 1988 to April 1997, laboratory confirmation was defined as either a positive culture of B. pertussis (or B. parapertussis) or positive two-point serology, in turn defined as a significant rise of immunoglobulin (Ig) G antibodies against pertussis toxin or IgA antibodies against B. pertussis in paired sera. In April 1997, a positive polymerase chain reaction (PCR) and positive one-point serology were also accepted as laboratory confirmation. Positive one-point serology was defined as high IgG or IgA antibody titers in a single serum sample…

Pertussis in Adults

…In the prevaccine era, reported pertussis was a cyclic disease,with epidemic peaks every 2 to 5 years [9]. When pertussis wasbrought under control by vaccination of children in the 1960sin the United States and England and Wales, it was noted thatthe 2- to 5-year cyclic pattern continued…Failure of the pertussiscycle to lengthen led to Fine and Clarkson’s suggestion [11]that immunization controlled the disease in children but didnot disrupt circulation of the organism. This observation andthe knowledge that adults were a common source of disease ininfants led our group and others to study the epidemiology ofadult pertussis.

…contrast with our findings in the UCLA students (94% of whomhad been vaccinated in childhood), we found that German adults(most of whom had not been vaccinated during childhood) weremore likely to have typical pertussis with whooping and post-tussivevomiting [12]. Twenty-six percent of these adults had had pertussisduring childhood.

Immunoglobulin A antibodies to B. pertussis antigens usuallyresult from infection, not immunization. With this fact in mind,we examined the prevalence and degree of IgA antibody to fourB. pertussis antigens in young adults in the United States andGermany [18]. We found that the mean titers and the prevalenceof antibody to the four antigens were similar, suggesting thatthe circulation of B. pertussis in adults in the two countrieswas similar even though pertussis was epidemic in Germany andrare in the United States. In another study [19], in which weobtained serum samples yearly for 5 years from 51 persons, 90%of these persons had serologic evidence of at least one caseof pertussis [19].

Essential Problems in Pertussis (Am J Public Health, Apr 1939; 29: 337 – 340).

…It would seem reasonable to expect that the case fatality of pertussis might have been favorably affected bv the better home hygiene, antirachitic and other nutritional advances in the dietaries of children, more general and skilled home nursing of patients during isolation, and other factors which we see applied for the benefit of children under 5 years of age, but there are, I believe, no studies to confirm these general impressions.

…Second, one finds a very considerable incompleteness of reporting, the extent of which varies widely according to the interest and adequacy of the local health and medical services of the community, from approximate completeness to about 5 per cent of estimated cases.

Third, one finds that routine departmental procedure in establishing the diagnosis and recording the presumed susceptibility, exposure, and subsequent history of infection in households where other children than the reported patient are living, is neither uniform nor adequate to permit study of the relative merits of isolation periods of different lengths, of inoculations intended to prevent, or of therapy designed to modify the course of the disease.

Pertussis surveillance

…Surveillance is carried out in some countries, but is not done in any meaningful way in three quarters of the world. Surveillance data and coverage data are both unreliable. Reliable surveillance data are needed to check coverage and vaccine efficacy; both surveillance and coverage data are needed to monitor immunization programmes…

… There are two principal methods of estimating burden: the natural history method and the proportional mortality method. The general approach used by WHO to estimate disease burden is to start with an expert consultative process in order to develop a sound approach. The methodology should aim to use the best data available and seek to validate results with existing data. Sensitivity analysis and continuous critical review are the only guarantees that the approach is as sound as it can be.

The estimates continue to be refined as new information becomes available. The final product is a database of cases and deaths by age, sex, country and year, as well as a careful documentation of methods, assumptions, and data sources. The process should result in recommendations on how to improve the precision, robustness and usefulness of the estimates.

Factors that affect the estimates are epidemiologic, demographic and programmatic, as well as co-factors such as HIV prevalence and nutritional status. Other practical issues include the quality and generalizability of the input data. Validation of the estimates is always important. The process is often messy since reliable data may be lacking, broad extrapolations or generalizations are made, or there is a heavy reliance on “expert opinion”.

Prevention of Pertussis among Adolescents by Vaccination: Taking Action on What We Know and Acknowledging What We Do Not Know

…But there is much that is not known about pertussis. It is unclear whether the recent increases in reported disease are real or are artifacts of increased recognition; the increase in reported cases among young infants, coupled with relatively stable rates of reported disease among older infants and preschool-aged children, suggests that there may be a real increase in the circulation of Bordetella pertussis in some age groups [1]. But there is no doubt that ascertainment of pertussis is variable and incomplete in most age groups. Physicians may not consider the diagnosis, especially in adolescents and adults, because of a lack of clinical awareness that pertussis occurs in these age groups. Diagnostic testing is imperfect, and some tests have not been well standardized. Culture of B. pertussis remains the gold standard by which other assays are judged, but unless the diagnosis is considered early in the course of illness and before administration of antimicrobial therapy, isolation of the bacterium is unlikely. Serological testing, once standardized, may facilitate diagnosis, but it remains unavailable in most areas, and assays based on PCR are variable in sensitivity and specificity [2]. Thus, our knowledge of the burden of pertussis is far from complete.

There is also much that we do not know about the dynamics of B. pertussis transmission. It is unclear what impact vaccinating young adolescents would have on disease incidence in other age groups. Do middle and high schools, with their high contact rates and susceptible populations, amplify B. pertussis circulation in the community? If routine vaccination of young adolescents prevented those outbreaks but immunity was not long lasting, would outbreaks then occur among young adults? Would transmission to young infants—the group with the highest morbidity and mortality due to pertussis—decrease or increase following implementation of an adolescent pertussis vaccination program? Mathematical modeling suggests that the impact of routine adult pertussis vaccination on the incidence of pertussis in young children may be relatively modest [3].

Because of these and other uncertainties, estimating the impact of pertussis vaccination of adolescents and adults on disease burden requires many assumptions….

Epidemiology of pertussis

…In the majority of countries where pertussis is a notifiable disease, a case-based national surveillance system is in place. However, different case definitions, methods of diagnosis and reporting and surveillance systems make direct intercountry comparisons difficult, and pertussis is not a statutory notifiable disease in every country. Nevertheless the general consensus is that reported incidences are probably considerably lower than the actual incidence of pertussis; underreporting is common. Prolonged cough may be the only clinical feature in adolescents or adults, who may present for diagnosis late (precluding laboratory confirmation) or not at all. When they do present, their condition is often misdiagnosed because, in part, clinicians continue to perceive pertussis as a childhood disease.Despite underreporting, an increased incidence of infant, adolescent and adult pertussis has been observed worldwide since the introduction of widespread vaccination…

Also See: Failure of Physicians to Consider the Diagnosis of Pertussis in Children

More on Adacel (11-64 years):

Clinical Studies;

The efficacy of the tetanus toxoid and diphtheria toxoid used in Adacel vaccine was based on the immune response to these antigens compared to a US licensed Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) vaccine manufactured by Sanofi Pasteur Inc., Swiftwater, PA.

The protective efficacy against mild pertussis (defined as at least one day of cough with laboratory-confirmed B pertussis infection) was 77.9% (95% CI: 72.6%, 82.2%). (8) (9) In addition, the ability of Adacel vaccine to elicit a booster response to the pertussis antigens following vaccination was evaluated. The acellular pertussis formulations for Adacel and DAPTACEL vaccines differ only in the amount of detoxified PT (2.5 μg in Adacel vaccine versus 10 μg in DAPTACEL vaccine).

The primary measures of immunogenicity were (a) the percentage of participants attaining an antibody level of at least 0.1 IU/mL and (b) the percentage of participants achieving a rise in antibody concentration after vaccination (booster response). The demonstration of a booster response depended on the antibody concentration to each antigen prior to immunization.

Threshold or “cut-off” values for antibody concentrations to each antigen were established based on the 95th percentile of the pre-vaccination antibody concentrations observed in previous clinical trials. A booster response was defined as a four-fold rise in antibody concentration if the pre-vaccination concentration was equal to or below the cut-off value and a two-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value.

The efficacy of the pertussis antigens used in Adacel vaccine was inferred based on a comparison of pertussis antibody levels achieved in recipients of a single booster dose of Adacel vaccine with those obtained in infants after three doses of DAPTACEL vaccine. In the Sweden I Efficacy Trial, three doses of DAPTACEL vaccine were shown to confer a protective efficacy of 84.9% (95% CI: 80.1%, 88.6%) against WHO defined pertussis (21 days of paroxysmal cough with laboratory-confirmed B pertussis infection or epidemiological link to a confirmed case).

…Pregnancy Category C

Animal reproduction studies have not been conducted with Adacel vaccine. It is also not known whether Adacel vaccine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Adacel vaccine should be given to a pregnant woman only if clearly needed…

Nursing Mothers

It is not known whether Adacel vaccine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Adacel vaccine is given to a nursing woman.

…The safety and effectiveness of concomitant administration of Adacel vaccine with other vaccines has not been evaluated.

Boostrix (10-18years)

Prevention of Pertussis, Tetanus, and Diphtheria Among Pregnant and Postpartum Women and Their Infants

In 2006, ACIP recommended routine administration of Tdap for postpartum women who were not vaccinated previously with Tdap to provide personal protection and reduce the risk for transmitting pertussis to their infants (1,2) . After careful consideration, in June 2006, ACIP voted to reaffirm its recommendation for use of Td in pregnant women who have urgent indication for tetanus toxoid or diphtheria toxoid vaccination to prevent maternal or neonatal tetanus, or to prevent diphtheria. Pregnant women not vaccinated previously with Tdap will receive a measure of protection against pertussis by ensuring that children in the household are up-to-date with recommended doses of pediatric diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP)* (21–23) and that adult and adolescent household contacts have received a dose of Tdap (Table 2) (1,2). Health-care providers can monitor pregnant women who have not received a dose of Tdap for exposures to pertussis or to respiratory illness consistent with pertussis, and they can administer antimicrobials for postexposure prophylaxis or treatment of pertussis, if needed, to reduce the risk for transmitting pertussis to their infants.

This report provides the background and rationale for routine administration of Tdap in postpartum women who were not vaccinated previously with Tdap and for maintaining the previous recommendation for use of Td in pregnant women if indicated. The safety and efficacy of using Tdap in pregnant women has not been demonstrated, and Tdap is not recommended for use in pregnant women in any country. No evidence exists of excess morbidity or any fatality among pregnant women ascribed to pertussis. No evidence exists demonstrating whether

Tdap in pregnant women harms the fetus or increases risk for adverse pregnancy outcomes,

transplacental antibody induced by Tdap administered during pregnancy will protect infants against pertussis, or

Tdap-induced transplacental maternal antibody will have a negative impact on an infant’s protective immune response to later-administered routine pediatric DTaP or to conjugate vaccines containing tetanus toxoid or diphtheria toxoid.

…Health-care providers should weigh the theoretical risks and benefits before choosing to administer Tdap vaccine to a pregnant woman…

…The specific issues for pertussis differ from those for tetanus and diphtheria. Important among these is the limited understanding of immunity and correlates of protection for pertussis. In addition, data supporting the safety of vaccinating pregnant women with Tdap to prevent pertussis are scarce for women, their fetuses, and pregnancy outcomes. Whether transplacental maternal antibody exerts an inhibitory or other effect on the infant-protective immune response to active immunization with pediatric DTaP or conjugate vaccines containing tetanus toxoid or diphtheria toxoid has not been studied. Protection against infant pertussis through Tdap-induced transplacental maternal antibody has not been demonstrated. Until additional information is available, the majority view of the working group held that Tdap administered to women in the immediate postpartum period, in addition to ensuring pertussis vaccination of close contacts, would likely provide a measure of protection for mother and infant.

Vaccinating Pregnant Women against Pertussis

Tdap:

No prelicensure studies were conducted with Tdap in pregnant women. In 2005, to increase understanding of the safety of Tdap in relationship to pregnancy, both Tdap manufacturers established registries to solicit voluntary reports of pregnant women who received Tdap during pregnancy or who received Tdap and were determined subsequently to be pregnant (212,213). The main utility of the registries is to signal the possibility and nature of any risk (214). All women who are vaccinated with Tdap at any time during pregnancy should be reported to the registry as early as possible during the pregnancy. Information from pregnancy registries differs from surveillance reports, which are used to evaluate outcomes among women when an adverse outcome of pregnancy already might have occurred (e.g., an infant born with a birth defect) (214).

Also see: Guidelines for Vaccinating Pregnant Women (ACIP Guidelines May 2008)

…Pregnancy is not a contraindication for use of Tdap. Data on safety, immunogenicity and the outcomes of pregnancy are not available for pregnant women who receive Tdap. When Tdap is administered during pregnancy, transplacental maternal antibodies might protect the infant against pertussis in early life. They also could interfere with the infant’s immune response to infant doses of DTaP, and leave the infant less well protected against pertussis. 11

ACIP recommends Td when tetanus and diphtheria protection is required during pregnancy. In some situations*, healthcare providers can choose to administer Tdap instead of Td to add protection against pertussis. When Td or Tdap is administered during pregnancy, the second or third trimester is preferred. 11

Providers who choose to administer Tdap to pregnant women should discuss the lack of data with the pregnant women and are encouraged to report Tdap administrations regardless of the trimester, to the appropriate manufacturer’s pregnancy registry: for Boostrix® to GlaxoSmithKline Biologicals at 1-888-825-5249, or for Adacel®, to sanofi pasteur at 800-822-2463. 11

It appears there is much they ‘don’t know’. But that isn’t stopping them. Vaccinating Post-partum Mothers before leaving the hospital with Tdap, even if they are breastfeeding, has been increasing.

Investigators in Houston have successfully implemented a novel vaccination strategy – vaccinating women who have just given birth to prevent them transmitting pertussis (whooping cough) to their young infants. This study took place in a medically underserved and underinsured population. Study investigators gave tetanus, diphtheria and acellular pertussis (Tdap) vaccine to over 1000 mothers at Ben Taub General Hospital, a county hospital that serves a predominantly Hispanic population in Houston, over a 3 month period. Approximately 75% of women who were offered Tdap received the vaccine and when Tdap was not administered it was usually because mothers had received a recent tetanus vaccine (a relative precaution to receiving Tdap vaccine). This program is, to our knowledge, the first to implement and track on a large scale the 2006 Centers for Disease Control and Prevention (CDC) recommendation that women receive Tdap before they leave the hospital after delivery.

Also see: Forrest General gives recommended vaccine for new mothers

Filed under: Pertussis | Comments Off

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Comparison of the Neurovirulence of a Vaccine and a Wild-Type Mumps Virus Strain in the Developing Rat Brain Journal of Virology, October 1998, p. 8037-8042, Vol. 72, No. 10

Figure 4. Change in genetic groups of measles viruses associated with U.S. cases and outbreaks between 1988 and September 1997. Arrows indicate sources of virus, if known.

Figure 4. Change in genetic groups of measles viruses associated with U.S. cases and outbreaks between 1988 and September 1997. Arrows indicate sources of virus, if known.

Varicella Zoster Virus

Monovalent “Jennerian” Vaccines

Bovine Vaccines

Rhesus Vaccine

Reassortant “Modified Jennerian” Vaccines

Rhesus-Human Reassortant Vaccines

Bovine-Human Reassortant Vaccines

Other Candidate Vaccines

Abstract:

Monovalent “Jennerian” Vaccines

Bovine Vaccines

Rhesus Vaccine

Reassortant “Modified Jennerian” Vaccines

Rhesus-Human Reassortant Vaccines

Bovine-Human Reassortant Vaccines

Other Candidate Vaccines

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