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.
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…
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
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.
PCV7 protects against seven pneumococcal capsular types (serotypes)—4, 6B, 9V, 14, 18C, 19F, and 23F
Licensed or In Development:
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
Streptorix; Pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine; PHiD-CV; Streptococcus pnuemoniae capsular antigens–Haemophilus influenzae protein D conjugates vaccine.
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.)
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.
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.
…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…
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 (ST69519A). 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, ST236519A (n = 4) and ST89919A (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.
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