Vaccines for preventing Japanese encephalitis
Vaccination is recognized as the only practical measure for preventing Japanese encephalitis. Production shortage, costs, and issues of licensure impair vaccination programmes in many affected countries. Concerns over vaccine effectiveness and safety also have a negative impact on acceptance and uptake.
To evaluate vaccines for preventing Japanese encephalitis in terms of effectiveness, adverse events, and immunogenicity.
In March 2007, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2007, Issue 1), MEDLINE, EMBASE, LILACS, BIOSIS, and reference lists. We also attempted to contact corresponding authors and vaccine companies.
Randomized controlled trials (RCTs), including cluster‐RCTs, comparing Japanese encephalitis vaccines with placebo (inert agent or unrelated vaccine), no intervention, or alternative Japanese encephalitis vaccine.
Data collection and analysis
Authors independently extracted data and assessed methodological quality. Dichotomous data were compared with risk ratios and a 95% confidence interval (CI), and converted into percentage vaccine efficacy.
Eight RCTs involving 358,750 participants were included. These trials investigated two available and three pre‐licensure vaccines. Two RCTs assessing efficacy of the commercially available inactivated Nakayama vaccine were identified. A two‐dose schedule of the licensed vaccine provided significant protection of 95% (95% CI 10% to 100%) for one year only, while two doses of an unpurified precursor vaccine protected children by 81% (95% CI 45% to 94%) in year one and by 59% (95% CI 2% to 83%) in year two. Serious adverse events were not observed. Mild and moderate episodes of injection site soreness, fever, headache, and nausea were reported in less than 6% of children receiving inactivated vaccine compared to 0.6% of unvaccinated controls. One cluster‐RCT compared the live‐attenuated SA14‐14‐2 vaccine (widely used in China) with no intervention measuring adverse events. Fever was reported in 2.7% of vaccinees compared to 3.1% of controls, while 0.1% of both groups suffered diarrhoea or seizures. Four small pre‐licensure RCTs assessing a genetically engineered vaccine and two cell culture‐derived inactivated vaccines revealed high immunogenicity and relative safety.
Only one of the three currently used vaccines has been assessed for efficacy in a RCT. Other RCTs have assessed their safety, however, and they appear to cause only occasional mild or moderate adverse events. Further trials of effectiveness and safety are needed for the currently used vaccines, especially concerning dose levels and schedules. Trials investigating several new vaccines are planned or in progress.
23 April 2019
Studies awaiting assessment
The CIDG is currently examining a new search conducted in April 2019 for potentially relevant studies. These studies have not yet been incorporated into this Cochrane Review.
Karin L Schiøler, Miny Samuel, Khin Lay Wai
Plain language summary
Two doses of an inactivated vaccine can help prevent Japanese encephalitis disease for at least one year; however, comparisons with other widely used vaccines are not available
Japanese encephalitis is a viral disease of the central nervous system with general symptoms of headache, fever, vomiting, and diarrhoea. Most people recover within a week without further complications, but approximately 1 in 300 suffers additional and severe symptoms such as disorientation, seizures, paralysis, and coma. Around thirty per cent of the severe cases are fatal and most survivors are left with serious and often chronic disabilities such as mental impairment, limb paralysis, and blindness. In this review of randomized controlled trials, a commercially available inactivated vaccine given in two doses was shown to provide disease protection for at least one year after vaccination, but with some adverse events. Disease protection by two vaccines, widely used in China but presently commercially unavailable, has not been investigated in randomized controlled trials. Further research is needed on all currently used as well as newly developed vaccines.
Karin L Schiøler, Miny Samuel, Khin Lay Wai
Implications for practice
Vaccines in current use
It is not possible to compare the effectiveness of currently used vaccines in preventing clinical disease as only one of three vaccines have been directly investigated for effectiveness in a RCT. Available evidence shows that two doses of the currently used inactivated Nakayama vaccine is over 95% protective for the first year with subsequent decline in the second year. Protection after two years has not been investigated. Mild and moderate events such as arm soreness, fever, and headache occurred in less than 6% of vaccinees receiving an inactivated vaccine. Safety data for the live‐attenuated SA14‐14‐2 vaccine show a range of mild and moderate adverse events of which fever is the most common (less than 3% of vaccinees) when compared to no intervention.
Large‐scale investigations of effectiveness, duration, and safety are awaited for all vaccine candidates. The recombinant ChimeriVax‐JE vaccine has caused no serious adverse events at the investigated dose levels in early trials. Mild and moderate adverse events are frequent but mostly at lower or similar rates to that of control vaccines. A Vero cell‐derived Beijing‐1 vaccine has been associated with a few mild and moderate events but not with serious episodes. Cell culture‐derived inactivated IC51 (JE‐PIV) vaccine was not associated with serious adverse events at the investigated dose levels, but mild and moderate adverse events were frequent.
Implications for research
Data from RCTs that assess the long‐term effectiveness and safety of currently used and prospective vaccines are needed. The timing and effects of booster doses should also be analysed in these trials. Such trials should aim to demonstrate the superior performance (in terms of effectiveness and safety) of the tested vaccine to that of approved Japanese encephalitis vaccines. A comparison with placebo would be unethical in endemic settings given the demonstrated effectiveness of the current vaccines.
Vaccine immunogenicity may represent an effective surrogate measure for vaccine protection, but the protective level of neutralizing antibodies in humans has to be verified in clinical studies. The role of cellular immunity should also be evaluated as a potential component in a surrogate assay of vaccine effectiveness. Once proven, a standard immunogenicity assay should be developed. Standardized trial formats (eg length of follow‐up period) and standard methods for reporting of outcomes such as disease activity, immunogenicity, and adverse events are also recommended for future trials.- - Finally, differences in strain and genotype cross protection should be assessed in order to detail expected vaccine effectiveness in various geographic settings. Potential differences in the type and rate of outcomes between children and adults should also be investigated.