Immunology, virology, and epidemiology of flaviviruses and other emerging viruses

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

IMPROVED CORRELATES OF PROTECTION AGAINST DENGUE Sequential infection with two distinct dengue virus serotypes is likely how protective immunity is achieved naturally. Further, existing dengue vaccines are effective in individuals who have had dengue virus previously but can increase risk of disease in those without prior dengue. Binding and neutralizing antibodies measured using standard assays can be associated with enhanced disease or protection, depending on the titers. However, these assays do not measure antibody quality. The most potently neutralizing monoclonal antibodies are known to bind quaternary epitopes across envelope protein dimers and can neutralize fully mature forms of dengue virions, while low quality, enhancing antibodies do not. It was not known whether mature neutralizing antibodies could serve as correlates of protection, and which epitope broadly neutralizing antibodies targeted. We collaborated with a team at the University of the Philippines Manila who had conducted an observational cohort of 2,996 children in Cebu, Philippines who either received one dose of Dengvaxia or remained unvaccinated (cohort closed in 2022). Among the unvaccinated participants at baseline, high ‘standard’ neutralizing antibody titers, measured using partially immature virions, and titers measured using mature virus were both associated with reduction in dengue compared to naïve individuals. However, the mature titers were more specific to the next infecting serotype and required a lower threshold for protection than the standard titers. Further, the mature neutralization assay had similar ability to predict breakthrough infection as measurements of type-specific antibodies, considered the ideal correlate of vaccine protection but which is a much more difficult assay (Odio…Katzelnick, Nature Communications 2025). • Odio CD, Daag JV, Crisostomo MV, Voirin CJ, Coello Escoto A, Adams C, Dahora Hein L, Aogo RA, Mpingabo PI, Raimundi Rodriguez G, Firdous S, Abad Fernandez M, White LJ, Agrupis KA, Deen J, de Silva AM, Ylade M, Katzelnick LC. Dengue virus IgG and neutralizing antibody titers measured with standard and mature viruses are protective. Nature Communications. 2025; 16(1): 191. In the same cohort, we evaluated whether natural infection and vaccination induced a class of broadly neutralizing antibodies targeting the envelope dimer epitope (EDE), measured using a blockade-of-binding assay we developed to stabilized dengue virus envelope protein dimers. EDE-like antibodies were mostly absent in those with primary dengue virus immunity but were prevalent among those with secondary immunity and increased with neutralization of more mature dengue virus serotypes. EDE-like antibodies were also associated with protection against dengue caused by multiple serotypes as well as more severe disease and explained the protective effect of mature neutralizing and binding antibodies, suggesting they measure a key cross-reactive, protective component of the serum repertoire (Mpingabo…Katzelnick, Science Translational Medicine 2025). • Mpingabo PI, Ylade M, Aogo RA, Crisostomo MV, Thiono DJ, Daag JV, Agrupis K-A, Coello Escoto A, Raimundi-Rodriguez GL, Odio CD, Abad Fernandez M, White L, de Silva AM, Deen J, Katzelnick LC. Envelope-dimer epitope-like broadly protective antibodies against dengue in children following natural infection and vaccination. Science Translational Medicine. 2025; 17(808): eadq0571. CROSS-REACTIVITY BETWEEN DENGUE AND OTHER FLAVIVIRUSES Serological testing is important for determining suitability for using dengue vaccines. We evaluated the PanBio IgG ELISA against the plaque reduction neutralization test in a cohort of 770 children ages 2-9 in Cambodia. The dengue IgG ELISA had a lower specificity than previously reported, as compared to a PRNT to DENV1-4 (58% vs. 93-100%). Of those with false positive DENV IgG results, 46% had detectable neutralizing antibodies against other flaviviruses including 14% against West Nile virus. A higher IgG cut-point identified using receiver-operating characteristic curve improved the test accuracy in this population. Our work on immunological cross-reactivity to Zika and other flaviviruses, including West Nile, in places where it is not known to circulate, highlight the difficulty of interpreting dengue virus serological data in a real-world setting and point to the need for improved serological tools to identify populations that would most benefit from dengue vaccines. • Odio CD, Yek C, Hasund CH, Man S, Ly P, Nhek S, Chea S, Lon C, Voirin C, Rekol Huy R, Leang R, Huch C, Lamirande E, Whitehead SS, Oliveira LF, Manning JE, Katzelnick LC*. Immunity to non-dengue flaviviruses impacts indirect IgG ELISA specificity in Cambodia. The Journal of Infectious Diseases. 2025; 231(2): e337. There are still no licensed vaccines or therapeutics to prevent the severe manifestations of Zika, including congenital abnormalities. We helped write a perspective on research and development for Zika vaccines and monoclonal antibodies. Specifically, we contributed sections on whether Zika virus infection or vaccination could increase risk of more severe dengue virus infection and highlighted vaccine and monoclonal antibody-based strategies that may overcome these risks. • Ostrowsky JT, Katzelnick LC, Bourne N, Barrett ADT, Thomas SJ, Diamond MS, Beasley DWC, Harris E, Wilder-Smith A, Leighton T, Mehr AJ, Moua NM, Ulrich AK, Cehovin A, Fay PC, Golding JP, Moore KA, Osterholm MT, Lackritz EM. Zika virus vaccines and monoclonal antibodies: a priority agenda for research and development. The Lancet Infectious Diseases. 2025, epub ahead of print. Dengue is an emerging cause of severe disease in Mali. We were co-authors on a manuscript describing the genotypes of dengue virus serotypes 1 and 3 during a recent outbreak of severe disease, providing guidance on interpretation of dengue molecular epidemiology results. • Kane F, Cissoko Y, Collins J, Diallo D, Diarra B, Kone A, Dabitao DK, Sako O, Coulibaly TA, Keita D, Togo ACG, Coulibaly G, Tangara CO, Diakite M, Konate I, Lu XJ, Briese T, Lipkin WI, Odio DC, Katzelnick LC, Aboulhab J, Akpa E, Fouth-Tchos K, Neal AT, Shaw-Saliba K, Dao S, Chen RY, Wickiser JK, Doumbia S. Analyzing Transmission Patterns of Two Dengue Virus Serotypes during the 2023 Outbreak in Mali, West Africa. Am J Trop Med Hyg. 2025; 113(2): 374-377.