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. 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.
3 See No. 4, 2008, pp. 37-44.