Japanese encephalitis is a mosquito-borne viral encephalitis caused by a flavivirus transmitted predominantly by Culex mosquitoes, and it remains the leading vaccine-preventable cause of viral encephalitis in the Asia-Pacific region. An estimated 3 billion people living in 24 countries are at risk of infection. In 2019, an estimated 57,000 cases and 20,642 deaths occurred globally, with India contributing the largest share of the burden at 39.1 percent, followed by Bangladesh and China. Although most infections are asymptomatic, roughly one in 250 infected people develop severe neuroinvasive disease. Among those who develop encephalitis, case fatality rates range between 20 and 30 percent, and 30 to 50 percent of survivors are left with long-term neurological, cognitive, or psychiatric sequelae. Childhood vaccination therefore remains the cornerstone of prevention in endemic countries.

India’s Universal Immunization Programme relies on two inactivated Vero cell-derived vaccines. JENVAC, manufactured by Bharat Biotech, is derived from an Indian JE virus strain known as Kolar-821564XY, while JEEV, produced by Biological E, is based on the SA 14-14-2 strain that underpins several internationally used JE vaccines. Both are administered as a two-dose intramuscular schedule, with the first dose given at 9 to 12 months of age and the second at 16 to 24 months. Although individual states generally receive a single vaccine type for routine immunization, programmatic realities mean that some children inevitably receive a second dose of a different product. Until now, no trial had evaluated such mixed-product schedules under India’s routine two-dose program, and previous studies of JE vaccine interchangeability had mostly examined other vaccine platforms or shorter dosing intervals.

The trial was conducted between November 2023 and September 2025 at hospitals in Kolkata, Wardha, Bhubaneswar, Bibinagar, and Patna. Healthy infants aged 9 to 12 months attending immunization clinics were eligible, while those with severe malnutrition, systemic disorders, neurological conditions, or prior JE vaccination were excluded. A total of 937 infants were screened and 911 were randomly assigned in equal proportions to one of four schedules: JENVAC followed by JEEV, JENVAC followed by JENVAC, JEEV followed by JENVAC, or JEEV followed by JEEV. Randomization was performed centrally using a computer-generated permuted block sequence, and although the study was open-label, laboratory staff performing the immunogenicity assays were masked to treatment allocation. The trial was funded by the Indian Council of Medical Research, which had no role in the design, analysis, or reporting.

The vaccines themselves differ subtly in composition. Each 0.5 milliliter dose of JENVAC contained 5 micrograms of purified inactivated JE virus protein from the Kolar strain, adsorbed onto 0.25 milligrams of aluminum hydroxide with thiomersal as a preservative, whereas each dose of JEEV contained 3 micrograms of inactivated virus from the SA 14-14-2 strain with aluminum hydroxide. Participants received their assigned vaccine in the thigh alongside the routine vaccines scheduled at the same visits, including measles-rubella vaccine, fractional inactivated polio vaccine, and pneumococcal conjugate vaccine at the first visit, and measles-rubella and DPT booster at the second. Blood samples were collected before vaccination, after the first dose, before the second dose, and 28 days after the second dose.

The primary outcome was seroconversion, measured by the 50 percent plaque reduction neutralization test, or PRNT50, against a wild-type JE virus strain isolated during a large 2005 outbreak in Uttar Pradesh. Seroconversion was defined as a rise in antibody titer from below 1:10 to at least 1:10, or a four-fold or greater rise among children with detectable baseline antibodies. In the modified intention-to-treat analysis of 841 children with evaluable samples, seroconversion 28 days after the second dose reached 89.8 percent in the JENVAC-JEEV group, 90.2 percent in the JENVAC-JENVAC group, 90.9 percent in the JEEV-JENVAC group, and 89.2 percent in the JEEV-JEEV group. The differences between mixed and same-product schedules were small and their confidence intervals fell entirely above the prespecified non-inferiority margin of minus 10 percentage points, in both the intention-to-treat and per-protocol analyses.

Geometric mean neutralizing antibody titers followed the same pattern, climbing from around 2 before vaccination to between roughly 68 and 74 after the second dose across all four groups, with no meaningful separation between mixed and same-product schedules. Among children who were seronegative at baseline, seroconversion rates after two doses ranged from about 92 to 95 percent. Among the smaller subset who were seropositive at baseline, fewer met the strict four-fold rise criterion, but the overwhelming majority nonetheless remained seroprotected. In a randomly selected subset, responses were also tested against the two vaccine-homologous strains, and titers were generally higher against these than against the wild-type strain, particularly after the first dose, a pattern consistent with the strain-specific bias that earlier trials using homologous assays may have introduced.

Safety results were reassuring. Roughly 36 percent of children in each group reported at least one solicited adverse event within seven days of vaccination, with fever the most common, followed by runny nose and cough. The vast majority of events were mild and resolved without sequelae. Twenty participants experienced 23 serious adverse events during follow-up, but none was assessed as related to vaccination according to the World Health Organization causality assessment algorithm. A Data and Safety Monitoring Board oversaw participant safety throughout the trial, and written informed consent was obtained from a parent or legal guardian of every enrolled child.

One finding warrants attention: only about a third of children, between 34 and 41 percent, remained seroconverted just before receiving the second dose, roughly seven months after the first. This suggests a possible window of reduced antibody-mediated protection in the second year of life. Surveillance data from India’s Virus Research and Diagnostic Laboratory Network indicate that children aged 12 to 24 months accounted for 3.4 to 6.5 percent of JE cases diagnosed annually between 2014 and 2025, without an apparent increasing trend, but the trial’s authors note that age-specific incidence data are needed to determine whether the longer dosing interval increases risk. They emphasize that timely completion of both doses remains essential.

The public health implications extend well beyond immunology. In large-scale programs, children may not always receive the same product for both doses because of migration, stock availability, procurement cycles, or supply changes, and in the absence of interchangeability evidence, program managers might defer or withhold second doses unnecessarily. By showing that JENVAC and JEEV can be swapped without sacrificing short-term immunogenicity or safety, the trial removes a barrier to maintaining high two-dose coverage in endemic districts. The authors caution that immune responses were assessed only one month after the second dose, leaving the durability of protection after the extended-interval schedule an open question, and that cell-mediated immunity, which may contribute to protection, was not measured. Still, for the hundreds of millions of children living in JE-endemic Asia, the message from this trial is straightforward: whichever of the two licensed inactivated vaccines is available when the second dose falls due, it can be given with confidence.

Subject of Research: Interchangeability of two inactivated Japanese encephalitis vaccines in India's childhood immunization schedule

Article Title: Immunogenicity and safety of an interchangeable vaccination schedule of two inactivated Japanese encephalitis vaccines: a multicentric, phase IV, open-label, randomized controlled trial

Article References: Vivian Thangaraj, J. W., Reddy, H., Sapkal, G. N., Velusamy, S. K., Jain, M. A., Dwibedi, B., Kanungo, S., Kundapur, R., Pandey, S., Deshpande, G. R., Saritha, A., Kadavath, V., Kanagasabai, K., Maliye, C., Parida, S. P., Majumdar, A., Reddy, M., Singh, C., Lade, A. R., … Murhekar, M. V. (2026). Immunogenicity and safety of an interchangeable vaccination schedule of two inactivated Japanese encephalitis vaccines: a multicentric, phase IV, open-label, randomized controlled trial. eClinicalMedicine, 100, Article 104235. https://doi.org/10.1016/j.eclinm.2026.104235

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104235

Keywords: Japanese encephalitis, JENVAC, JEEV, vaccine interchangeability, immunogenicity, PRNT50, non-inferiority trial, India, Universal Immunization Programme, flavivirus, childhood vaccination, vaccine safety

The review was designed to answer a narrower and more operational question than previous syntheses: not whether rainfall matters, but whether the published evidence can support approximate rainfall ranges, lag periods and disease-specific patterns that could inform climate-informed disease surveillance. Previous reviews had typically treated the rainfall-disease relationship qualitatively or within single-disease and single-country frames, leaving uncertainty about whether pooled effect sizes, dose-response patterns and typical delays between rainfall and peak incidence could be quantified. The researchers registered their protocol prospectively with PROSPERO, followed the PRISMA 2020 reporting guidelines, and screened 2,739 records after duplicate removal, assessing 312 full-text articles against PECO-structured eligibility criteria with substantial inter-rater agreement of kappa equal to 0.82.

Eligible studies were required to report quantitative associations between rainfall-related exposures and human disease outcomes that were laboratory-confirmed or linked to recognised surveillance definitions, a deliberate choice intended to reduce misclassification from non-specific febrile illness, a common problem in climate-health research. Studies reporting only undifferentiated fever, entomological indices without human disease data, or temperature-only exposures were excluded. Because rainfall metrics varied widely across the literature, from percentile-based contrasts such as rainfall above the 75th or 90th percentile to flooding events and continuous millimetre measurements, the team harmonised exposures carefully and graded the quality of meteorological inputs using a six-criterion framework covering data source documentation, temporal completeness, spatial representativeness, cross-validation, calibration and uncertainty reporting.

The headline result was a pooled relative risk of 1.74 for vector-borne disease incidence during elevated rainfall or flooding, but the authors emphasise that the 95 percent prediction interval ranged from 1.12 to 2.71, meaning the true effect in a comparable future setting could be considerably smaller or larger. Between-study heterogeneity was substantial, with an I-squared value of 78 percent. Disease-specific analyses showed the strongest association for dengue, with a relative risk of 1.89, followed by Japanese encephalitis at 1.67, malaria at 1.58 and chikungunya at 1.45, although the Japanese encephalitis estimate rested on only three studies and must be treated as imprecise. Geographic contrasts were striking: Bangladesh showed the highest pooled estimate at 2.13, India an intermediate 1.68, and Sri Lanka the lowest at 1.42, with statistically significant between-country differences confirmed by meta-regression.

The dose-response analyses, conducted using restricted cubic splines with three knots positioned at the 10th, 50th and 90th percentiles of the pooled rainfall distribution, suggested that risk remains relatively stable below approximately 100 millimetres of monthly rainfall and increases above that level. For dengue, the curve indicated rising risk above roughly 100 millimetres per month with an apparent peak near 200 millimetres, where the estimated relative risk reached approximately 2.3 compared with the reference level, before plateauing or declining above 400 millimetres, though confidence intervals widened considerably at the extremes of the rainfall distribution where few studies contributed data. For malaria, the spline model suggested an apparent double-peak pattern, with elevations near 125 and 350 millimetres per month, a shape that could reflect distinct hydrological mechanisms, moderate rainfall supporting temporary Anopheles breeding pools while heavier rainfall first flushes habitats and later creates post-flood transmission opportunities, but which was also sensitive to knot placement and model specification.

The authors are careful to stress that these threshold-like patterns are exploratory signals rather than fixed biological cut-points. Sensitivity analyses using alternative reference points at 50, 75, 125 and 150 millimetres per month, and four- and five-knot spline models, produced variation in curve shape, particularly for malaria, and the team interpreted such instability as evidence of uncertainty rather than stable operational thresholds. Chikungunya showed a gradual increase in risk across the rainfall range without a clear threshold pattern, limited by the small number of contributing studies. The biologically plausible mechanisms differ by disease: Aedes mosquitoes that transmit dengue and chikungunya breed in artificial containers, water-storage vessels and peri-domestic habitats replenished by moderate rainfall, whereas Japanese encephalitis transmission is more closely tied to rice agriculture, pig-rearing ecology and Culex mosquito habitats in rural settings.

One of the most operationally useful findings concerns lag periods. Across 67 studies reporting lag analyses, the pooled delay between rainfall exposure and peak disease incidence was 2.4 months, with a 95 percent confidence interval of 2.1 to 2.7 months. Disease-specific estimates were 2.2 months for dengue, 2.8 months for malaria and 1.9 months for chikungunya, differences consistent with variation in vector development rates, pathogen extrinsic incubation periods and disease-reporting dynamics. Meta-regression suggested that lag periods lengthened with latitude, increasing by 0.08 months per degree, and geographic patterns ran opposite to the effect sizes: Bangladesh showed the shortest mean lag at 2.1 months, India an intermediate 2.5 months, and Sri Lanka the longest at 2.7 months. This means country context alters both the magnitude of the rainfall signal and the warning time it may offer public health authorities.

The review also detected a temporal trend: pooled relative risks rose from 1.52 in studies covering 1990 to 2004, to 1.67 for 2005 to 2014, and to 1.91 for 2015 to 2024, with a meta-regression coefficient of 0.018 per year corresponding to an approximate 26 percent increase in the rainfall-disease association between the earliest and latest periods. The authors interpret this cautiously. A rising effect size could reflect genuine increasing vulnerability driven by urban expansion, informal settlements, drainage pressure and climate variability, but it could equally reflect improved surveillance, better diagnostics, changing publication patterns or residual confounding. Notably, when the analysis was restricted to time-series studies with comprehensive temporal adjustment, the temporal coefficient was attenuated and no longer statistically significant, suggesting that methodological differences between older and newer studies may partly explain the apparent trend.

Methodological rigour and its limits are central to the paper’s conclusions. Restricting the analysis to studies with comprehensive confounding control, defined as adjustment for four or more confounding categories, attenuated the pooled estimate to 1.62, and further restriction to high-quality studies produced a relative risk of 1.58, indicating that confounding may inflate part of the association without fully accounting for it. Publication bias analyses using Egger’s regression test and trim-and-fill adjustment suggested modest small-study effects, lowering the pooled estimate from 1.74 to 1.67, while leave-one-out and influence diagnostics showed that heterogeneity was distributed across the evidence base rather than driven by any single study. Flooding events produced larger pooled effects than heavy rainfall alone, a relative risk of 2.31 versus 1.67, which the authors attribute to the compound nature of flooding as an environmental and social exposure involving water stagnation, disrupted sanitation, displacement and altered healthcare access.

The practical message for public health is that rainfall can support early warning systems but should never be used alone, and that universal rainfall thresholds are not justified by the current evidence. The approximate 100 millimetre monthly signal and the two-to-three-month lag window may serve as useful starting points for local model development, but they require prospective validation against independent surveillance data, with estimation of sensitivity, specificity, positive predictive value, false-alarm rates and lead time before operational deployment. In resource-constrained health systems, repeated false alarms can waste limited response capacity and erode trust in early warning. The authors recommend combining rainfall monitoring with disease surveillance, temperature and humidity data, flood extent and drainage indicators, vector indices, population vulnerability measures and health-system readiness, and they call for stronger evidence from under-represented countries such as Pakistan, Nepal, Bhutan, the Maldives and Afghanistan, more studies of chikungunya and Japanese encephalitis, and sub-national and intra-urban research capable of resolving the street-level and household-level processes that country-level pooling inevitably averages away.

Subject of Research: Rainfall thresholds and temporal trends in vector-borne disease transmission in India, Bangladesh and Sri Lanka

Article Title: Rainfall thresholds and temporal trends in vector-borne disease transmission in India, Bangladesh and Sri Lanka: a systematic review and meta-analysis

Article References: Asaga, P. M., Kadukatti, V., Arsha, L., & Kroeger, A. (2026). Rainfall thresholds and temporal trends in vector-borne disease transmission in India, Bangladesh and Sri Lanka: a systematic review and meta-analysis. Environmental Challenges, 25, Article 101655. https://doi.org/10.1016/j.envc.2026.101655

Image Credits: AI Generated

DOI: Not provided

Keywords: vector-borne disease, dengue, malaria, chikungunya, Japanese encephalitis, rainfall, flooding, South Asia, meta-analysis, early warning systems, climate sensitivity, monsoon