Tamiflu found to be 99% ineffective against primary flu strain

 

Following up on an initial report last month, The New York Times now says that Tamiflu is 99% of all flu strains 99% ineffective against the dominant flu strain that will strike Americans this season.

Scientists and health officials do not know why. Last winter, roughly 11% of common flu strains patients with the most common flu strain resisted showed resistance to Tamiflu, the leading antiviral drug.

No resistance to Tamiflu has been identified among other circulating viruses, according to the Centers for Disease Control and Prevention and Roche, the manufacturer.

“It’s quite shocking,” Dr. Kent A. Sepkowitz, director of infection control at Memorial Sloan-Kettering Cancer Center, told the Times. “We’ve never lost an antimicrobial this fast. It blew me away.”

So far, it’s not a public-health problem. Officials cite two reasons: the flu season has been below average, and the main strain is susceptible to other antivirals.

January and February are peak months for influenza.

Last month The Wall Street Journal reported that the CDC had alerted doctors about Tamiflu’s apparent ineffectiveness and urged them to prescribe an additional drug.

The Food and Drug Administration has more information about Tamiflu.

WebMD, citing the CDC, reports the first flu-related death of a child this season.

 

Correction: In hastily summarizing the Times article, the effectiveness of Tamiflu was misstated. The headline and text have been corrected. Apologies to all. It’s another reminder of how moving at Internet speed can sometimes kill comprehension…

New Type of Vaccine Delivers Enhanced Immune Response

A new vaccine platform that could bring fundamental changes to vaccine technology is being developed by scientists at the University of Copenhagen. Known as the InVacc platform, it improves upon original DNA vaccines and creates new vaccines with enhanced properties.

The platform consists of a chain of amino acids attached to a gene of the virus being vaccinated against. This “genetic cocktail” is inserted into an appropriate expression vehicle, such as an incapacitated adenovirus, and injected into the body, triggering a broad and aggressive immune response. The chain of 215 amino acids and its insertion into the adenovirus represent the key innovations of this technique.

To date, tests of the vaccine look promising. Researchers were able to provide 100% protection against various lethal strains of flu given to mice. The next phase of development and, ultimately, clinical trials are being planned.

Associate professor Jan Pravsgaard explained, “The platform has proved very effective in our recent tests and could have enormous potential. In principle, vaccines of this type could be used to inoculate against a range of deadly viruses, bacteria, and other diseasecausing agents and even be used to cure certain cancers once they take hold.”

source: Dec. 2008 issue of Ajho

Sanofi Pasteur Wants Liability Protection for Vaccinating Pregnant Women

Sanofi Pasteur Wants Liability Protection for Vaccinating Pregnant Women

By Kelli Ann Davis

Today, during the Institute of Medicine’s (IOM) 2nd National Stakeholder Meeting on the Review of Priorities in the National Vaccine Plan, Stanley Plotkin, Executive Advisor to the CEO of Sanofi Pasteur and Emeritus Professor of Pediatrics at the University of Pennsylvania made a startling revelation: Sanofi Pasteur is lobbying members of the Senate for liability protection.

According to Plotkin, Sanofi Pasteur is concerned about the “legal issue of vaccinating while pregnant” and feels it is “important to keep non-negligence issues” out of the tort system; he stated, “it needs to be addressed” and then went on to say, “I don’t know how it should be done but it needs to be addressed considering what’s happening recently.”

Continued…

Flu Shots Have No Impact on Hospitalizations for Young Children

ROCHESTER, N.Y., Oct. 6 — Immunizations did not reduce emergency department visits or hospitalizations for children younger than five during two recent flu seasons, researchers here reported.

Looking at data from the 2003-2004 and the 2004-2005 flu seasons, there was no evidence that the immunization made any significant difference, although the vaccine was not a good match for circulating flu strains in those years, said Peter G. Szilagyi, M.D., M.P.H., of Strong Memorial Hospital, and colleagues.

 

The case-cohort study, reported in the October issue of Archives of Pediatrics and Adolescent Medicine, compared cases of acute respiratory illnesses in children six months to 59 months treated in hospitals — as inpatients or in the emergency department or outpatient clinic — with a control cluster sample of children treated at pediatric practices.

…The vaccine effectiveness ranged from 7% to 52% across all settings and three age groups (six-23 months, 24-59 months, six-59 months), they said.

…

Earlier studies had suggested that vaccination could reduce hospitalizations or emergency department visits, but those studies were limited by the use of nonspecific endpoints rather than laboratory-confirmed diagnoses or a narrow focus that concentrated on only a single healthcare setting — such as emergency departments — or a single flu season, Dr. Szilagyi wrote.

 

This study, he said, attempted to address those limitations, only to discover other factors that “contributed to the difficulty in demonstrating a positive [vaccine effectiveness].”

 

Chiefly, during the “2003-2004 season, 99% of the strains in these three communities were due to influenza A virus, but only 11% of influenza A specimens across the United States were similar to a strain included in the vaccine.”

 

And a year later, when the flu season was less severe and the vaccine was considered a better match, still “only 36% of the virus isolates were antigenically similar to vaccine strains,” they wrote.

 

Moreover, they acknowledged, the case-cohort design may have been a poor choice since it might be particularly susceptible to bias because parents who have had their children vaccinated might be more likely to seek medical care for their children than other parents.

 

In any case, they said, more studies are needed to adequately “assess the yearly impact of influenza vaccination programs for children.”

Full Article

Vit D and Flu

Something that can explain why flu epidemics also occur both in warm and cold climates is this: During a flu epidemic, wherever it may be, the atmosphere blocks ultraviolet B (UVB) radiation from the Sun. In the temperate zones above latitude 35 degrees North and South, the sun is at a low enough angle in the winter that the ozone layer in the atmosphere absorbs and blocks the short-wavelength (280–315 nanometers) UVB rays. In the tropics during the wet season, thick rain clouds block UVB rays.

Skin contains a cholesterol derivative, 7-dehydrocholesterol. UVB radiation on skin breaks open one of the carbon rings in this molecule to form vitamin D. The activated form of vitamin D (1,25-dihydroxyvitamin D) attaches to receptors on genes that control their expression, which turn protein production on or off. Vitamin D regulates the expression of more than 1,000 genes throughout the body. They include ones in macrophages, cells in the immune system that, among other things, attack and destroy viruses. Vitamin D switches on genes in macrophages that make antimicrobial peptides, antibiotics the body produces. Like antibiotics, these peptides attack and destroy bacteria; but unlike antibiotics, they also attack and destroy viruses.

Vitamin D also expresses genes that stop macrophages from overreacting to an infection and releasing too many inflammatory agents – cytokines – that can damage infected tissue. Vitamin D, for example, down regulates genes that produce interleukin-2 and interferon gamma, two cytokines that prime macrophages and cytotoxic T cells to attack the body’s tissues. In the 1918–19 Spanish flu pandemic that killed 500,000 Americans, young healthy adults would wake up in the morning feeling well, start drowning in their own inflammation as the day wore on, and be dead by midnight, as happened to my 22-year-old grandmother and my wife’s 24-year-old grandmother. Autopsies showed complete destruction of the epithelial cells lining the respiratory tract resulting, researchers now know, from a macrophage-induced severe inflammatory reaction to the virus. In a terribly misguided way, these victims’ own immune system attacked and killed them, not the virus, something in future pandemics vitamin D, in appropriate doses, can prevent.

A creditable hypothesis that explains the seasonal nature of flu is that influenza is a vitamin D deficiency disease. Cannell and colleagues offer this hypothesis in “Epidemic Influenza and Vitamin D” (Epidemiol Infect 2006;134:1129–40). They quote Hippocrates (circa 400 B.C.), who said, “Whoever wishes to investigate medicine properly should proceed thus: in the first place to consider the seasons of the year.” Vitamin D levels in the blood fall to their lowest point during flu seasons. Unable to be protected by the body’s own antibiotics (antimicrobial peptides) that this gene-expresser engineers, a person with a low vitamin D blood level is more vulnerable to contracting colds, influenza, and other respiratory infections (e.g., respiratory syncytial virus).

Studies show that children with rickets, a vitamin D-deficient skeletal disorder, suffer from frequent respiratory infections; and children exposed to sunlight are less likely to get a cold. Given vitamin D’s wide-ranging effects on gene expression, other studies, for example, show that people diagnosed with cancer in the summer have an improved survival compared with those diagnosed in the winter (Int J Cancer 2006;119:1530–36).

A growing body of evidence indicates that rickets in children and osteomalacia in adults (both a softening of bones due to defective bone mineralization) are just the tip of a vitamin D-deficiency iceberg. Tuberculosis and various autoimmune diseases, such as multiple sclerosis, lupus, and type I diabetes have a causal association with low vitamin D blood levels. Vitamin D deficiency plays a causal role in hypertension, coronary artery disease, congestive heart failure, peripheral vascular disease, and stroke. It is also a risk factor for metabolic syndrome and type II diabetes, chronic fatigue, seasonal affective disorder, depression, cataracts, infertility, and osteoporosis. At the bottom of the vitamin D iceberg lies cancer. There is good evidence that vitamin D deficiency is a causal factor in some 15 different common cancers. (NEJM 2007;357:266–81.)

The increased number of deaths that occur in winter, largely from pneumonia and cardiovascular diseases, are much more likely due to vitamin D deficiency than to an increased prevalence of serologically-positive influenza virus (which also results from vitamin D deficiency).

Experts reckon that an optimum blood level of vitamin D (25-hydroxyvitamin D) is 50–99 ng/ml. (Children need a blood level >8 ng/ml to prevent rickets. It takes a concentration >20 to maintain parathyroid hormone levels in a normal range. A level >34 is needed for peak intestinal calcium absorption. And in elderly people neuromuscular performance steadily improves as vitamin D blood levels rise to 50 ng/ml.) The government’s recommended daily allowance (RDA) for vitamin D is 400 IU (international units) a day, an amount sufficient to prevent rickets and osteomalacia but not vitamin D’s other gene-regulating benefits. To achieve all of vitamin D’s benefits one has to take an amount ten times the government’s RDA – 4,000 to 5,000 IU a day.

A light-skinned person will synthesize 20,000 IU of vitamin D in 20 minutes sunbathing on a tropical beach, at which point vitamin D synthesis shuts down for the day (it takes a dark-skinned person 6 to 10 times longer to make this amount). Human breast milk does not contain vitamin D, since, from an evolutionary standpoint, our African ancestors’ infants, reared near the equator, could readily synthesize this gene regulator from sunlight in their skin. Food contains very little vitamin D. (The highest concentrations are in wild salmon, mackerel, sardines, and cod liver oil.) Federal regulations now require that some foods, like milk, be fortified with vitamin D. But one would have to drink 200 glasses of milk to obtain the amount of vitamin D a light-skinned person can make in 20 minutes sunbathing.

The majority of Americans are vitamin D deficient, with a 25-hydroxy D blood level <20 ng/ml, or insufficient, with a level of 20–<30 ng/ml. Cheap vitamin D supplements (D3, not D2) provide the only way most of us can maintain a year-round vitamin D blood levels greater than 50 ng/ml. That requires taking 4–5,000 IU of vitamin D a day (50,000 IU every ten days or 150,000 IU a month).

Taking vitamin D in these doses is safe, far safer than a flu shot with all the bad chemicals it contains. Concerns about vitamin D toxicity are overblown. One can take a 10,000 IU vitamin D supplement on a daily basis without any adverse effects. In healthy persons, long-term consumption of more than 40,000 IU a day is necessary to cause an elevation in the blood calcium level (hypercalcemia), the first manifestation of vitamin D toxicity (Am J Clin Nutr 2006;84:694–97). Check your vitamin D (25-hydroxy D) blood level. People with granulomatous diseases like sarcoidosis should also check their blood level of 1,25-dihydroxyvitamin D, the active form.

Can a shot (or tablets) of vitamin D prevent influenza better than a flu shot? There is good reason to believe that it can.

Doctors in India and Canada give people a once-yearly injection of 600,000 IU of vitamin D (MJA 2005;183:10–12). That would be better, and safer, than having a flu shot. Daily, weekly, or monthly vitamin D tablets work just as well. For more on this subject see my article “Vitamin D in a New Light” and visit Dr. Cannell’s Vitamin D Council website.

Investigators have completed one double-blind, randomized, placebo-controlled trial that shows vitamin D prevents colds and influenza significantly better (P <0.002) than a placebo pill (Epidemiol Infection 2007;135:1095–6). A large multi-center randomized trial conducted over multiple flu seasons comparing vitamin D to a flu shot can show conclusively which is better, and safer. But given the financial stakes underpinning flu shots, and unpatentable vitamin D, who will fund it?

Source

Types of Flu Vaccines

Proper Name: Influenza Virus Vaccine
Tradename: AFLURIA
Manufacturer: CSL Limited, License No. 1764

Indication: For active immunization of adults 18 years of age and older against influenza disease caused by influenza virus subtypes A and type B present in the vaccine
Package insert 

Proper Name: Influenza Virus Vaccine, H5N1
Manufacturer: Sanofi Pasteur Inc, License #1725

Indication: For active immunization of persons 18 through 64 years of age at increased risk of exposure to the H5N1 influenza virus subtype contained in the vaccine

Package Insert

Proper Name: Influenza Virus Vaccine
Tradename: FluLaval
Manufacturer: ID Biomedical Corporation of Quebec, License #1739

Package Insert

Proper Name: Influenza Virus Vaccine Live, Intranasal
Tradename: FluMist
Manufacturer: MedImmune Vaccines, Inc, License #1652

Package Insert

 

Proper Name: Influenza Virus Vaccine
Tradename: Fluarix
Manufacturer: GlaxoSmithKline Biologicals, License #1617

Package Insert

Proper Name: Influenza Virus Vaccine
Tradename: Fluvirin
Manufacturer: Novartis Vaccines and Diagnostics Limited, License #1750

Package Insert 

Proper Name: Influenza Virus Vaccine
Tradename: Fluzone
Manufacturer: Sanofi Pasteur, Inc, License #1725

Package Insert 

Thimerosal(mercury) Amounts:

Fluzone:

Fluzone, a sterile suspension for intramuscular injection, is supplied in four presentations: 

•  Prefilled syringe, 0.25 mL, no preservative, pediatric dose, distinguished by a pink syringe plunger rod
•  Prefilled syringe, 0.5 mL, no preservative
• Single-dose vial, 0.5 mL, no preservative
•  Multi-dose vial, 5 mL, contains thimerosal, a mercury derivative, added as a preservative. Each 0.5 mL dose contains 25 μg mercury.

Fluvirin:

DOSAGE FORMS AND STRENGTHS FLUVIRIN®, a sterile suspension for intramuscular injection, is supplied in two presentations:

•   Prefilled syringe, 0.5-mL. Thimerosal, a mercury derivative used during manufacture, is removed by subsequent purification steps to a trace amount (≤ 1 mcg mercury per 0.5-mL dose).
•   Multidose vial, 5-mL. Contains thimerosal, a mercury derivative (25 mcg mercury per 0.5-mL dose). Thimerosal is added as a preservative.

 Afluria:

AFLURIA®, a sterile suspension for intramuscular injection, is supplied in two presentations:

 

•  0.5 mL preservative-free, single-dose, pre-filled syringe.
•   5 mL multi-dose vial containing ten doses. Thimerosal, a mercury derivative, is added as a preservative; each 0.5 mL dose contains 24.5 micrograms (mcg) of mercury.

Flumist-intranasal and live:

• 0.2 mL pre-filled, single-use intranasal spray (3) Each 0.2 mL dose contains 106.5-7.5 FFU (fluorescent focus units) of live attenuated influenza virus reassortants of each of the three strains for the 2008-2009 season: A/South Dakota/6/2007 (H1N1) (A/Brisbane/59/2007-like), A/Uruguay/716/2007 (H3N2) (A/Brisbane/10/2007-like), and B/Florida/4/2006.

 

Flulaval:

 

•   Thimerosal, a mercury derivative, is added as a preservative. Each 0.5 mL dose contains 25 mcg mercury.

 

Fluarix:

 

• Each 0.5 mL dose also contains octoxynol-10 (TRITON^® X-100) ≤0.120 mg, α-tocopheryl hydrogen succinate ≤0.1 mg, and polysorbate 80 (Tween 80) ≤0.380 mg. The vaccine is formulated without preservatives.
• Thimerosal is used at the early stages of manufacture and is removed by subsequent purification steps to a trace amount (≤1 mcg mercury per dose). Each dose may also contain residual amounts of hydrocortisone ≤0.0016 mcg, gentamicin sulfate ≤0.15 mcg, ovalbumin ≤1 mcg, formaldehyde ≤50 mcg, and sodium deoxycholate ≤50 mcg from the manufacturing process.

Efficacy of Flu Shots in Children

Efficacy of flu shots in children under 2 questioned

Robert Roos   

Feb 25, 2005 (CIDRAP News) – An analysis of 24 studies yielded no clear evidence that influenza vaccines prevent flu in children younger than 2 years old, though they work reasonably well in older children, according to a new report in The Lancet.

Immunization of very young children is not lent support by our findings,” says the report by T. Jefferson of Cochrane Vaccines Field in Alessandria, Italy, and colleagues from there and the University of Oxford in England.

The report comes less than a year after the Centers for Disease Control and Prevention (CDC) recommended that children 6 to 23 months old routinely receive flu shots on grounds that they have an increased risk of flu and its complications.

The CDC says the Lancet analysis left out some important studies showing that flu shots are beneficial for young children. The agency will continue to recommend flu shots for 6- to 23-month-olds, a spokeswoman said.

Jefferson and colleagues combed the worldwide literature up to June 2004 and found 15 randomized controlled trials, eight cohort studies, and one case-control study comparing the effects of flu immunization with placebo or no immunization in children. The researchers looked at the vaccines’ efficacy, defined as prevention of laboratory-confirmed flu; effectiveness in preventing flu-like illness; and effectiveness in reducing hospitalizations, complications, school absences, and secondary transmission.

The authors did separate analyses of studies dealing with live attenuated flu vaccines, which are not used in small children, and those involving inactivated vaccines. The analysis did not include studies assessing children’s immune-system responses to vaccines (serologic studies).

In children under age 2, vaccination yielded 24% efficacy against flu, which was not significantly better than placebo, but this finding was based on one study involving about 800 children, the report says. No data were available on the effectiveness of vaccination for preventing flu-like illness in the under-2 group.

Among children 2 years and older, live attenuated vaccines were 79% efficacious in preventing flu, while inactivated vaccines were 65% efficacious, according to the analysis. The effectiveness of vaccines against flu-like illness was much lower: 38% for live vaccines, 28% for inactivated vaccines.

Differences between efficacy and effectiveness of vaccines are not surprising because influenza vaccines are specifically targeted at influenza viruses and are not designed to prevent other causes of influenza-like illness,” the report states.

The researchers found that immunization reduced long school absences, but they saw little evidence that it reduced hospital admissions and stays, secondary cases, lower-respiratory-tract disease, or acute otitis media.

Although a growing body of evidence shows the effect of influenza on admissions and deaths of children, we recorded no convincing evidence that vaccines can reduce mortality, admissions, serious complications, and community transmission of influenza,” the article concludes.

Kristine Sheedy, a spokeswoman for the CDC’s National Immunization Program in Atlanta, told CIDRAP News that the analysis left out some important evidence on the effects of flu immunization in small children.

The authors “included many important studies, but they did exclude other important studies,” she said. She mentioned a CDC study published in Morbidity and Mortality Weekly Report in August 2004 and a 2001 study by K. M. Neuzil and colleagues, published in the Pediatric Infectious Disease Journal.

A careful review of the Lancet report itself as well as the excluded studies “indicates that influenza vaccination is effective in this population” (6- to 23-month-olds), Sheedy said.

She added that serologic studies of small children have shown a strong immune response to flu vaccine. Also, additional studies soon to be reported by the CDC will provide more support for the effectiveness of flu immunization in preventing hospitalization and outpatient visits in children, she said.

“I hope people will keep in mind the burden of disease in children,” Sheedy said. “When you have a safe and effective vaccine for influenza, why wouldn’t you want to protect the children at greatest risk?”

Jefferson T, Smith S, Demicheli V, et al. Assessment of the efficacy and effectiveness of influenza vaccines in healthy children: systematic review. Lancet 2005;365(Feb 26):773-80 [Abstract]

See also:

Neuzil KM, Dupont WD, Wright PF, et al. Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience. Pediatr Infect Dis J 2001;20(8):733-40 [Abstract]

CDC. Assessment of the effectiveness of the 2003-04 influenza vaccine among children and adults-Colorado, 2003. MMWR 2004 Aug 13;53(31):707-10 [Full text]

Center for Infectious Disease Research & Policy
Academic Health Center — University of Minnesota
Copyright © 2006 Regents of the University of Minnesota

 

Flu

Shedding and immunogenicity of live attenuated influenza vaccine virus in subjects 5-49 years of age

 

Stan L. Block^{a, ,} , Ram Yogev^b, Frederick G. Hayden^{c, 1}, Christopher S. Ambrose^d, Wen Zeng^d and Robert E. Walker^{d a}Kentucky Pediatric and Adult Research, 201 S. 5th Street, Bardstown, KY 40004, United States ^bChildren’s Memorial Hospital, Chicago, IL, United States ^cUniversity of Virginia, Charlottesville, VA, United States ^dMedImmune, Gaithersburg, MD, United States.Received 17 March 2008;  revised 25 June 2008;  accepted 8 July 2008.  Available online 26 July 2008.

 

Abstract-

 

Background

 

 

Live attenuated influenza vaccine (LAIV) is indicated for influenza prevention in persons 2-49 years of age. This study describes the incidence and duration of vaccine virus shedding and serum immune responses after receipt of LAIV.

 

 

Methods

A single open-label dose of trivalent LAIV was administered intranasally to 344 subjects in 3 age cohorts: 5-8, 9-17, and 18-49 years of age. Shedding was determined by culture of nasal swabs (on days 1-7, daily; days 9-25, every other day; and day 28). Immunogenicity was measured as serum strain-specific hemagglutinin inhibition (HAI) titers (days 0, 28).

 

 

Results

 

 

Among subjects aged 5-8 years, 9-17 years, and 18-49 years, 44%, 27%, and 17% of subjects, respectively, shed vaccine virus after vaccination, and the mean number of positive samples per subject was 2.2, 1.8, and 1.5, respectively. Shedding occurred on days 1-11 postvaccination. Shedding incidence peaked on day 2, and maximum observed titers were highest on days 2-3 (<5, <4, and <3 log₁₀ TCID₅₀/mL, respectively, by age group). Despite positive cultures, all titers were <1 log₁₀ TCID₅₀/mL after days 10, 6, and 6, respectively, by age group. Shedding incidence was inversely correlated to age and baseline serum HAI titer. The seroresponse rate (4-fold rise in HAI) to at least 1 strain was 59% (68%, 64%, and 47%, respectively, by age group), and strain-specific rates were higher in baseline seronegative/serosusceptible subjects. Reactogenicity, most commonly runny nose, headache, and sore throat, was not associated with shedding or seroresponse.

 

 

Conclusions

This is the first study to comprehensively evaluate nasal shedding of LAIV in individuals 5-49 years of age. Shedding was generally of short duration and at low titers. Study findings support the current recommendation of the Advisory Committee on Immunization Practices that LAIV recipients should only avoid contact with severely immunosuppressed persons (e.g., hematopoietic stem cell transplant recipients) for 7 days after vaccination.