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Global Advisory Committee on Safety (GACVS)

Report on GACVS meeting

16-17 June 2010

Peter G. Smith

1 | GACVS June 2010 report– SAGE November 2010 Safety of pandemic A (H1N1)

 >30 pandemic (H1N1) 2009 vaccines licensed worldwide.

 >350 million doses of pandemic influenza vaccines administered (as of June 2010).

 Passive surveillance data from North America, EU, Japan and China reviewed

2 | GACVS June 2010 report– SAGE November 2010 Safety of pandemic influenza A (H1N1) vaccines – GACVS advice

 To date, the safety data of pandemic (H1N1) 2009 vaccines are reassuring - no unexpected safety concerns have been identified.  Risk of GBS, if any, has been no more than reported previously for some seasonal trivalent inactivated - the committee is waiting results of ongoing studies.  So far there are no safety signals among those vaccinated during and their offspring.  Prospectively agreed upon case definitions for adverse events (e.g., anaphylaxis, GBS, convulsion) facilitate global comparisons of the safety profiles of vaccines used in different countries.

3 | GACVS June 2010 report– SAGE November 2010 Febrile seizures following seasonal influenza vaccine in Australia

 Increased number of reports of fever and febrile convulsions in children <5 years of age following receipt of the 2010 seasonal inactivated influenza vaccine (Fluvax) made by CSL.

 Seasonal influenza vaccine suspended for children <5 years of age.

GACVS advice:

 Not aware of reports of increased fever or febrile convulsions with other 2010 seasonal vaccines.

 Recommends review data on the use of 2010 seasonal vaccines elsewhere.

4 | GACVS June 2010 report– SAGE November 2010 Adventitious agent in vaccines

 Review of Rotarix and RotaTeq following the 25 March 2010 review of Rotarix with respect to PCV (porcine circo-virus).

 Neither PCV1 nor PCV2 is known to infect, or cause disease in, humans.

 Pre- and post- serum samples from 40 infants who participated in clinical trials reveals no evidence of serologic response to PCV1.

 More than 69 million doses of Rotarix and 37 million doses of RotaTeq had been distributed (as of June 2010).

GACVS advice:

 Given the extensive clinical data supporting the safety of both Rotarix and RotaTeq and the benefits of rotavirus vaccination for children, GACVS considers that the benefits of vaccination far outweigh any currently known risk associated with use of either .

5 | GACVS June 2010 report– SAGE November 2010 Live attenuated A vaccine

 >10 million doses of H2 and L-A-1 vaccine used annually in China national programme since 2007.  Epidemiologic correspondence between widespread use of HAV vaccines and decrease in disease incidence.  Limited data about H2 vaccine reactions during clinical trials and, for both vaccines, through passive surveillance did not identify any significant safety issues. GACVS advice:  In view of the huge volume of use of live HAV vaccines in China and their potential usefulness outside China, carefully collected and validated data on several aspects of vaccine safety and efficacy will be of great value.  Also examine shedding and secondary in contacts.  Of particular interest will be molecular markers of attenuation and genetic stability of attenuation markers after human passage.

6 | GACVS June 2010 report– SAGE November 2010 Updated clinical safety profile of meningococcal A

 Seven clinical trials in Phase I-III.  4614 vaccinees followed up for serious adverse events (SAEs) up to at least one year after vaccination.  237 reported SAE (including 16 deaths), only 2 classified as related to the study vaccines: – Hypersensitive reaction (facial edema) in 10 months old infant. – Simple febrile convulsion in 17 months child (also received ).  15 reported shortly after administration of the vaccine in two studies. GACVS advice:  Latest data available provide further indication of the safety of this vaccine.  Careful post marketing surveillance needed to further understand the safety profile and immunogenicity. Additional information should be sought on need for a booster dose, effect on carriage, interactions with other EPI vaccines, possible effect on serotype replacement and effects of the vaccine on high risk groups including pregnant women.

7 | GACVS June 2010 report– SAGE November 2010 and

 3 breastfeeding infants developed encephalitis as a result of infection with yellow fever vaccine virus transmitted to them from their recently vaccinated mothers. GACVS advice:  Further research needed to determine and quantify the potential risk of transmission of yellow fever vaccine virus from vaccinated mothers to breastfeeding infants.  Might include: – Testing breast milk. – Testing infants for evidence of to vaccine virus. – Assess risk of potential transmission with respect to prior vaccination status.  In endemic areas or during outbreaks, the committee believes that the benefits of vaccinating nursing mothers outweigh the risk of potential transmission to their breastfeeding infants, and that the benefits of breastfeeding outweigh the alternatives for infant feeding.  Nursing mothers who are considering travel to endemic areas should be counseled regarding the benefits and potential risks. If travel cannot be avoided or postponed, vaccination is recommended.

8 | GACVS June 2010 report– SAGE November 2010 Urgent issue – 22 September 2010 statement Rotavirus vaccines and intussusception

 Preliminary analyses of PMS data (CDC/PATH/PAHO/MoH study) identified a clustering of 18 cases of intussusception (none fatal) in the period 1 to 7 days after the first dose in Mexico, corresponding to a risk about 4-5 times higher than in later periods after vaccination, after adjusting for age.  GSK study (different population) in Mexico also found a increased risk of intussusception of about 1.7-fold after first dose the first 30 days after vaccination, with clustering of cases in the first week after vaccination.  No clustering observed after the first dose in Brazil. Data from U.S. (Rotateq and more limited data on Rotarix) do not confirm the association but number of vaccinees under active surveillance not large enough to rule out an effect of the size observed.

 If confirmed, this corresponds to excess risk of about one to two additional intussusception hospitalizations per 100 000 vaccinees.

9 | GACVS June 2010 report– SAGE November 2010 Rotavirus vaccines and intussusception GACVS advice

 Possibility of an increased risk of intussusception shortly after the first dose of rotavirus vaccination in some populations.

 If confirmed, the level of risk observed in these post-marketing studies is substantially lower than the risk of one case of intussusception in 5 000-10 000 vaccinees identified after Rotashield vaccination.

 In Mexico, nationwide use of Rotarix vaccine would prevent approximately 12 000 hospitalizations and 700 deaths from each year, a benefit that greatly outweighs the possible risk of vaccine-associated intussusception found in this preliminary analysis of around 20-40 cases.

10 | GACVS June 2010 report– SAGE November 2010 Urgent issue – 27 August 2010 statement vaccine and cases of narcolepsy

 Reports of narcolepsy in Sweden and allegedly related to with Pandemrix®, an adjuvanted 2009 influenza A (H1N1) vaccine produced by GSK. GACVS not had access to the data.

 European Medicines Agency (EMA) has concluded available evidence insufficient to establish link - launched a review to look carefully at all of the available data.

 Pending the outcome of the ongoing reviews, Pandemrix® remains licensed for use by the EMA and prequalified by WHO. Given that the benefits of 2009 influenza A (H1N1) vaccines are established, WHO recommendations to immunize vulnerable populations remain unchanged.

11 | GACVS June 2010 report– SAGE November 2010 Next GACVS meeting: 8-9 December 2010

Specific issues Generic issues

 Update on pandemic and  Background rates of vaccines seasonal influenza vaccines. adverse events.

 Yellow fever vaccines and HIV  Classification for vaccine safety infection. causality assessment.

 Rotavirus vaccines and intussusception.

 Meningococcus A conjugate vaccine safety profile.

12 | GACVS June 2010 report– SAGE November 2010