Live attenuated SA 14-14-2 Japanese encephalitis (JE) vaccine

During the June 2013 meeting of GACVS the safety profiles of 1 live attenuated and 2 inactivated Japanese encephalitis (JE) vaccines based on the SA 14-14-2 strain were considered, and the Committee concluded that there were no significant concerns regarding the safety profile of these vaccines.³ During the December 2013 meeting GACVS considered the safety profile of a novel chimeric JE vaccine (Imojev). This vaccine is a live vaccine construct using the yellow fever (YF) 17D and JE SA-14-14-2 vaccines strains. Construction of the vaccine involves insertion of the nucleic acid sequences encoding the envelope proteins (prM and E) of the JE SA 14-14-2 strain into the YF17D backbone, resulting in a chimeric vaccine virus which is attenuated and lacks neurotropic properties.

Pre-licensure and post-licensure safety and immunogenicity data for Imojev were presented. This vaccine is currently licensed in Australia, Malaysia, the Philippines and Thailand. Pre-licensure data are available for 2486 adults and 2248 children (9–18 months, at first dose). The vaccine is immunogenic and immunogenicity does not appear to be affected by concomitant administration of the measles/mumps/rubella (MMR) vaccine. Short-term safety data for injection site and systemic reactions (reported by >10% of vaccine recipients) were presented and showed that in the adult population, adverse reaction rates were significantly lower with Imojev than with a mouse brain-derived vaccine.⁴ There is limited post-licensure safety experience with Imojev, with approximately 49 000 doses administered to date, and a larger safety database will be necessary to evaluate the risk of rare adverse events.

GACVS expressed interest in receiving additional information about potential environmental safety issues relative to the use of a chimeric vaccine. These include the theoretical risk of reversion or genetic reassortment with wild-type JE viruses or other circulating flaviviruses that could result in the vaccine virus acquiring neurotropic and/or infectivity properties, and vaccine virus transmission through mosquito hosts. However the biological plausibility of this is remote, given the short duration of viraemia post vaccination and the limited potential for virus vaccine replication and dissemination within the mosquito.

Post-licensure studies are essential in countries were widespread use of a JE chimeric vaccine is planned or is currently implemented. In particular, post-licensure studies and surveillance should include active surveillance of cases of encephalitis along with a laboratory determination of the aetiology of the encephalitis. Safety data on JE vaccines (including but not limited to the chimeric vaccine) administered to immunocompromised persons and pregnant and lactating women are limited.

³ See No. 88, 2013, pp. 301-312.

⁴ Torresi J, McCarthy K, Feroldi E, et al. Immunogenicity, safety and tolerability in adults of a new single-dose, live-attenuated vaccine against Japanese encephalitis: randomised controlled phase 3 trials. Vaccine. 2010; 28:7993-8000.

Full report of GACVS meeting of 11-12 December 2013, published in the WHO Weekly Epidemiological Record on 14 February 2014

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.

Full report of GACVS meeting of 12-13 June 2013, published in the WHO Weekly Epidemiological Record on 19 July 2013

GACVS reviewed an updated report on the frequency and severity of AEFI reported with the use of live Japanese encephalitis vaccine (JEV) in the Republic of Korea, where it was introduced in 2002 but is used only in the private sector. The recommended schedule is 2 doses administered 12 months apart in children aged 1–2 years and a booster at 6 years of age. Inactivated mouse-brain JEV is used in the national immunization programme. Since the private sector is not linked to AEFI surveillance, no safety data are available on the >1.7 million doses of live JEV distributed since 2002. The national requirement for the introduction of new drugs is to investigate adverse events in detail in 600 subjects. Among 673 children followed up after a dose of live JEV, 318 events were reported in 163 subjects; most AEFI reported were relatively minor, non-neurological and indistinguishable from common childhood illnesses. The review of the safety of live JEV will be finalized in 2008.

GACVS also reviewed a study on co-administration of measles vaccine (MV) with live JEV conducted in the Philippines. Three groups of 223–228 infants (aged 9–11 months) were given either JEV followed by MV a month later, MV followed by JEV a month later or both given simultaneously. The design was to examine non-inferiority of response to MV when co-administered. One month after vaccination, although overall sero-protection was very high in all 3 groups, in the group in which the vaccines were co-administered, the proportion of infants who achieved sero-protection following MV (96%) was slightly lower than in the MV-only group (100%); [difference = –4%, 95% confidence interval, –1, –6]). In addition, the antibody titres were significantly lower in the co-administration group than in those who had received only MV.

These results indicate some interference of live JEV on MV response. Among those who had sero-converted by 1 month, at 1-year follow-up the geometric mean antibody titres were similar in both groups, suggesting that the interference is only temporary and that co-administration of live JEV and MV is acceptable.

Based on earlier reviews and the information from the above studies, GACVS concluded that the short-term safety profile of live JEV appears satisfactory and the vaccine could safely be administered with measles vaccine as of 9 months of age. More investigations are needed to confirm that low-frequency adverse events (especially neurological) do not occur. Since live JEV is currently used in “catch-up” campaigns on many millions of children in Asian countries, the opportunity should be taken to examine if the vaccine-safety profile remains valid in large study populations. Further studies to check if MV effectiveness remains undiminished should be encouraged.

Full report of GACVS meeting of 12-13 December 2007, published in the WHO Weekly Epidemiological Record on 25 January 2008

GACVS considered recent data on the safety profile of live attenuated SA 14-14-2 JE vaccine, provided in a number of expert presentations to the Committee. Live attenuated SA 14-14-2 JE vaccine constitutes more than 50% of the global production of all JE vaccines. The anticipated global demand for JE vaccine in 2012 is expected to exceed the present requirement twofold. Even though several new vaccine candidates are in development, their production and distribution remain uncertain for the time being.

The current production of live attenuated SA 14-14-2 vaccine exceeds 50 million doses annually, most of which are used in China. Neuroattenuation of the virulent JE SA 14-14-2 strain is reported to be based on 57 nucleotide changes and 24 amino acid substitutions, suggesting that reversion to neurovirulence of the vaccine strain would be highly unlikely. Vaccine production is in accordance with WHO technical specifications, including detailed screening for adventitious viruses. Data reported from several studies have shown vaccine efficacy to be between 80% and 99% following single-dose vaccination and 98% or greater with 2 doses of the vaccine. In a comparative observational study of approximately 26 000 subjects in China undergoing routine immunization with JE vaccine, the most common reactions were fever, rash and vomiting. There was no increased risk of serious adverse events within 30 days of vaccination. Data presented to GACVS, covering a 20-year period from 1979 to 1998, contained no reported cases of vaccine-associated JE. Preliminary data on co-administration of the SA-14-14-2 JE vaccine with measles vaccine have been reassuring.

Information is available from both passive and active post-marketing surveillance in the Republic of Korea, where the SA 14-14-2 vaccine was first licensed in 2001. Of 522 vaccinated children actively monitored for adverse events for 4 weeks after vaccination, approximately 10% developed fever higher than 38 °C and a cough. Redness and swelling at the site of injection were observed in less than 1%. These findings are consistent with those reported from China.

GACVS took note of the work of the Program for Appropriate Technology in Health (PATH) – Japanese Encephalitis Project (JE Project), conducted in collaboration with WHO and other partners, in accelerating availability of a safe, effective and affordable JE vaccine in endemic countries in Asia. The SA 14-14-2 vaccine is especially important in this regard. GACVS noted that studies planned in collaboration with the PATH JE Project aim at addressing short- and long-term efficacy and safety, with special reference to co-administration with measles vaccine and evaluating the degree of viraemia in vaccinees.

GACVS acknowledged the excellent safety and efficacy profile of the SA 14-14-2 vaccine but nonetheless recommended more detailed study of the following: the safety profile in special risk groups including immunocompromised people and pregnant women; whether viral shedding occurs in vaccinees and the potential implications of such shedding; further analysis of sequential or co-administration of JE and measles vaccines; the interchangeability of inactivated and live JE vaccines; the safety of vaccine administration to infants aged under 1 year; and the implications for the efficacy and safety of the vaccine in infants with maternal antibodies against JE virus.

Full report of GACVS meeting of 9-10 June 2005, published in the WHO Weekly Epidemiological Record on 15 July 2005

Safety of Japanese encephalitis vaccination in India

GACVS considered the report from an Indian expert panel that assessed the reported cases of serious adverse events following immunization campaigns with the live, attenuated SA 14-14-2 Japanese encephalitis vaccine in 4 Indian states during the summer of 2006. These campaigns reached >9.3 million children aged between 1 year and 15 years. A total of 65 serious adverse events were reported, 22 of which were fatal. Most serious adverse events were considered to be unrelated to the vaccine. A total of 2 clusters of encephalitis-like syndromes were identified after immunization, 1 probably representing cases of natural Japanese encephalitis and another classified as acute encephalopathy syndrome of unknown etiology; thorough investigation into possible alternative etiologies has not been conducted.

The Committee considered that the overall number of reported serious adverse events appeared low for the target population and that the type of clustering of encephalopathy and encephalitis cases made it unlikely that they were related to the vaccine. However, a better definition of cases of serious adverse events, using standard case classifications, such as the Brighton Collaboration definitions, and more active case investigation would be valuable. GACVS recommended that future immunization campaigns should be accompanied by strengthened AEFI monitoring and investigation activities.

Full report of GACVS meeting of 29-30 November 2006, published in the WHO Weekly Epidemiological Record on 19 January 2007