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

BACKGROUND

In India, two inactivated Japanese encephalitis (JE) vaccines, JENVAC and JEEV, are used in childhood immunization program as a two-dose schedule. Vaccine supply interruptions and population mobility can result in children receiving different products for their first and second doses. We assessed immunogenicity and safety of mixed-product vaccine schedules.

METHODS

In this multicentric, open-label, phase 4, non-inferiority randomized trial conducted during November 11, 2023-September 2, 2025, infants aged 9-12 months were assigned (1:1:1:1) to JENVAC-JEEV, JENVAC-JENVAC, JEEV-JENVAC, or JEEV-JEEV. Second dose was given at the age of 16-24 months. The primary outcome was seroconversion assessed by 50% plaque reduction neutralization test titer against wild-type JE virus 28 days after dose-2. The secondary outcomes included frequency of solicited and unsolicited adverse events, and serious adverse events following JE vaccine schedules. Non-inferiority was concluded if the lower bound of the 95% CI for difference in seroconversion proportion between the mixed and same-product vaccine schedule exceeded -10% and was less than 0%. Registered with Clinical Trials Registry-India (CTRI/2023/07/055155).

FINDINGS: Between November 11, 2023, and June 8, 2024, 911 infants were randomly assigned (1:1:1:1) to JENVAC-JEEV (n = 228), JENVAC-JENVAC (n = 228), JEEV-JENVAC (n = 227), and JEEV-JEEV (n = 228). In modified intention-to-treat analysis, seroconversion after second dose was 89.8% (194/216), 90.2% (184/204), 90.9% (189/208), and 89.2% (190/213) respectively. The difference in seroconversion between mixed-product and same-product vaccine schedules was -0.38% (95% CI -6.1 to 5.4) among JENVAC-primed and 1.66% (-4.1 to 7.4) among JEEV-primed infants. The corresponding estimates in per-protocol analysis were -1.11% (95% CI -6.7 to 4.5) and 0.89% (-4.9 to 6.6) respectively. Solicited adverse events occurred in 35.5-37.9% infants across the study groups. None of the serious adverse events was vaccine related.

INTERPRETATION: Mixed-product JENVAC and JEEV schedules were non-inferior to same-product schedules for short-term neutralizing antibody seroconversion and showed no safety signals. These findings support programme flexibility when children cannot complete JE vaccination with the same-product.

FUNDING: The trial was funded by Indian Council of Medical Research, New Delhi, India.