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VACCINE SAFETY: YELLOW FEVER VACCINE SAFETY DURING MASS IMMUNIZATION CAMPAIGNS

Sunday, 21st of July 2013

• YELLOW FEVER VACCINE SAFETY DURING MASS IMMUNIZATION CAMPAIGNS IN SUB-SAHARAN AFRICA

The introduction of the yellow fever 17D vaccine in the 1930s provided an effective preventive measure resulting in a significant decline of the disease. However, there has been a resurgence of yellow fever resulting from changes in population dynamics, urbanization, deforestation coupled with other agricultural and developmental activities, climate changes and a decline in population immunity. In 2006, the Yellow Fever Initiative led by the WHO in partnership with UNICEF and GAVI was launched to control this resurgence in order to reduce the risk of epidemics in sub-Saharan Africa. This entailed a mass preventive vaccination campaign against the backdrop of other WHO-UNICEF yellow fever control strategies.

The recent (2007–2010) preventive yellow fever (YF) vaccination campaigns in West and Central African countries provided an opportunity for surveillance of AEFIs, thus further characterizing the safety of the vaccine. Nine countries were involved – Benin, Burkina Faso, Cameroun, Guinea, Liberia, Mali, Senegal, SierraLeone and Togo. GACVS reviewed the recently published findings of surveillance of AEFIs conducted during those campaigns. In all, 38 million doses of the vaccine were administered, and 3116 AEFIs were observed(2952 non-serious and 164 serious). Of the serious AEFIs, 22 were classified as related to the YF vaccine and 142 were not related; of the 22, 6 clinical cases resembled acute neurotropic disease (YEL-AND), 5 clinical cases resembled acute viscerotropic disease (YEL-AVD) and a further 11 involved hypersensitivity reactions.

The attack rates per 100 000 vaccinated people obtained from the study therefore were 0.016, 0.013 and 0.029 for YEL-AND, YEL-AVD and hypersensitivity reactions respectively. These rates were lower than those seen with recipients of a first dose of YF vaccine in more developed settings. The median time to onset

(days) was observed as 8 (YEL-AND), 4 (YEL-AVD) and 1.8 (hypersensitivity reactions). Vaccine virus identification, however, was not successful for acute cases.

The authors noted the challenges and limitations of the study to account for a relatively low specificity and sensitivity of active case findings due to many coincidental cases, operational issues with inadequate collection, storage and transportation of specimens, poor laboratory and investigation facilities, cultural practices hindering post-mortem examination, misclassification of cases, and inadequate prioritization of pharmacovigilance, amongst others. Despite the limitations, the authors concluded that the study has had impact on the countries in ensuring a proactive surveillance system as well as reinforcing the safety profile of YF vaccine in this particular setting.

GACVS noted the enormous challenges of conducting a pharmacovigilance study in a resource-limited setting. The committee suggested that enhanced vaccine safety monitoring, including additional resources to provide adequate capacity and expertise, should be included in planning vaccination campaigns. It observed that the criteria for case definition were very strict and difficult to apply appropriately in such settings. It therefore suggested that more operational criteria could be proposed that would be adapted to local clinical practice or that additional dedicated efforts be conducted to meet existing criteria. There is also a need to put standard operating procedures or tiered instructions in place to strengthen pharmacovigilance and address technical and logistic issues. GACVS also recommended that clinical and laboratory findings even if limited be more systematically correlated with post-mortem examinations.

Safety profile of Japanese encephalitis vaccines GACVS considered recent data on the safety profiles of a cell culture based on live attenuated and 2 inactivated Japanese encephalitis (JE) vaccines. The live attenuated SA 14-14-2 JE vaccine manufactured by the Chengdu Institute of Biological Products was licensed 25 years ago and is now in routine use in several countries including China, where it is given routinely at 8 months and 2 years. Worldwide, >400 million doses of the vaccine have been administered. GACVS previously reviewed this vaccine and found it to be generally safe.

The Committee recommended studies in special populations, on viraemia, and post-marketing surveillance.3 Subsequently, studies on a few hundred children in the Philippines and Sri Lanka examined the safety of the SA-14-14-2 and found that the vaccine produces only mild local and systemic reactions. A study in India on 19 adults previously unexposed to Japanese encephalitis found no evidence of viraemia up to 2 weeks after SA-14-14-2 administration.

Post-marketing surveillance carried out by the Chinese Centre for Drug Evaluation during 2009–2012 reported 6024 AEFI of which 70 were considered severe. The severe events included a range of disorders including febrile convulsions, thrombocytopenic purpura and encephalitic/meningitic illness. Of the 9 encephalitis cases, one was considered vaccine related while the others were classified as coincidental illnesses. There were 4 recorded deaths, none of which were considered related to vaccination on expert review. The GACVS reviewed these data and noted that although there was no evidence of a safety signal, the number of events

recorded in the AEFI reporting system was low given that >70 million doses of vaccine have been administered. Limited data demonstrating safety in HIV-infected individuals were available for the inactivated mouse-brain vaccine, which was marketed as either Biken® or JE-Vax®. The production and distribution of this vaccine has ceased, and the last lots of the vaccine expired in May 2011. GAVCS recommended that studies in immunocompromised populations, particularly individuals with HIV, should be carried out with the new inactivated vaccines, starting with those with CD4 T-cell counts >200. Additional data on the recently licensed inactivated vaccines, Ixiaro®, made by Intercell SA, and Jeev®, made by Biological E Ltd, in India were presented by the manufacturers. Those vaccines are based on inactivation of the SA 14-14-2 strain. Both vaccines were licensed on the basis of serologic correlates and have not been evaluated against disease. Ixiaro® was evaluated in 1869 children from 2 months to 18 years in a Phase III trial in the Philippines, a JE-endemic area.

Study participants received either full (6 μg) or half (3 μg) doses of Ixiaro® (2 doses 1 month apart), Havrix® hepatitis A vaccine for children > 1year or Prevnar® 7-valent pneumococcal conjugate vaccine for children aged <1 year. The safety profile was generally comparable with the age-specific control vaccines. In children aged <1 year, the dominant local reaction was redness; in the older ages pain and tenderness were most common.

The predominant systemic reaction was fever, mostly ≤39.3 °C. Immunogenicity and safety of Ixiaro® compared to JenceVac® (a mouse brain inactivated vaccine made by Korean Green Cross) were investigated in 60 healthy Indian children aged 1 to 3 years. No difference was seen in the safety profiles of these vaccines.

Overall, GAVCS noted that the live attenuated and the inactivated vaccines based on SA-14-14-2 appear to have an excellent safety profiles. The Committee emphasized the need for building post-marketing surveillance systems in countries where disease is endemic and vaccines are used, and currently only limited data are collected post-licensure. GACVS recommended more detailed study of the safety profile of those vaccines in pregnant women, on viral shedding of the live vaccine, and the implications for the efficacy and safety of the vaccine in infants with high maternal antibodies against JE virus. inactivation of the SA 14-14-2 strain. Both vaccines were licensed on the basis of serologic correlates and have not been evaluated against disease. Ixiaro® was evaluated in 1869 children from 2 months to 18 years in a Phase III trial in the Philippines, a JE-endemic area.

Study participants received either full (6 μg) or half (3 μg) doses of Ixiaro® (2 doses 1 month apart), Havrix® hepatitis A vaccine for children > 1year or Prevnar® 7-valent pneumococcal conjugate vaccine for children aged <1 year. The safety profile was generally comparable with the age-specific control vaccines. In children aged <1 year, the dominant local reaction was redness; in the older ages pain and tenderness were most common.

The predominant systemic reaction was fever, mostly ≤39.3 °C. Immunogenicity and safety of Ixiaro® compared to JenceVac® (a mouse brain inactivated vaccine made by Korean Green Cross) were investigated in 60 healthy Indian children aged 1 to 3 years. No difference was seen in the safety profiles of these vaccines.

Overall, GAVCS noted that the live attenuated and the inactivated vaccines based on SA-14-14-2 appear to have an excellent safety profiles. The Committee emphasized the need for building post-marketing surveillance systems in countries where disease is endemic and vaccines are used, and currently only limited data are collected post-licensure. GACVS recommended more detailed study of the safety profile of those vaccines in pregnant women, on viral shedding of the live vaccine, and the implications for the efficacy and safety of the vaccine in infants with high maternal antibodies against JE virus.