Genotype III-Based Japanese Encephalitis Vaccines Exhibit Diminished Neutralizing Response to Re-emerging Genotype V

Japanese encephalitis (JE) has been predominantly controlled through vaccination. However, the isolation of JE virus (JEV) genotype V (GV) in China in 2009, and the subsequent alarming increase in JE cases in the Republic of Korea since 2010, present a new challenge. Serum samples from individuals vaccinated with genotype III (GIII)-based JE vaccines were analyzed for neutralizing seroresponse to GV isolates. Serum from immunocompromised pediatric patients vaccinated with an inactivated JE vaccine showed higher 50% plaque reduction neutralization test (PRNT50) geometric mean titer (GMT) against GIII Nakayama (11,358; 95% CI = 1,790, 29,658), but lower GMTs against GV isolates: GV Muar (499; 95% CI = 0, 2,437), GV 43279 (308; 95% CI = 159, 582), and GV 43413 (231; 95% CI = 108, 738). Similarly, 32 healthy volunteers receiving a live attenuated JE vaccine achieved 100% seroprotection against GIII Nakayama with GMT of 338 (95% CI = 304, 651) at 1 month post-vaccination. However, GMTs against GV isolates were 123 (95% CI = 102, 446) for GV Muar, 81 (95% CI = 63, 168) for GV 43279, and 107 (95% CI = 100, 322) for GV 43413, not achieving 100% seroprotection against these isolates. At 6 months post-vaccination, GMT against Nakayama increased to 696 (95% CI = 409, 2,353), while remaining similar for GV isolates. Our study underscores that current GIII-based vaccines do not provide comparable protection against GV JEVs, impacting individuals in both current and potential endemic regions, as well as travelers to these regions.