Project 2: Tetravalent live attenuated dengue virus vaccines: Linkage of vaccine-induced human B cell and antibody response to protective or dengue disease-enhancing immunity

University Of California Berkeley, Berkeley CA

Investigators

Linked publications & trials

Abstract

Project 2: Tetravalent Live Attenuated Dengue Virus Vaccines: Linkage of vaccine-induced human B cell and antibody response to protective or dengue disease-enhancing immunity (UNC). SUMMARY The four-dengue virus (DENV) serotypes carried by mosquitoes infect several hundred million people each year. While effective vaccines have been developed for some flaviviruses, dengue vaccines have been challenging because antibodies to one serotype can protect or enhance viral replication and disease by another serotype, necessitating development of tetravalent (TV) vaccines. The overall objective of Project 2 is to study clinical samples from individuals in dengue vaccine studies to reveal mechanisms of vaccine- mediated protection, vaccine failure and vaccine-enhanced dengue disease. Central to this renewal application is a bio-archive of >15,000 samples collected from an actively monitored cohort of children in the Philippines who received Dengvaxia®, a TV live attenuated DENV vaccine (TV-DLAV). In Aim 1, we define the landscape of DENV neutralizing antibodies (nAbs) and mechanisms of vaccine breakthrough infections in baseline seronegative vaccinees. We will determine if DENV serotype-specific (TS) Abs are a better correlate of protection than the current standard of total nAbs (Aim 1.1). We will also test if TV-DLAVs stimulate a TS nAb response that is narrower in breadth, allowing breakthrough infections with variant genotypes, compared to WT primary (1°) DENV infections, in collaboration with Project 1 (Aim 1.2). In clinical trials thus far, TV-DLAV have performed better in baseline DENV-seropositive individuals compared to seronegative individuals. We propose that the strong vaccine performance in seropositive individuals is due to the ability of even one replicating vaccine component to activate pre-existing memory B and T cells and stimulate a strong, broad, and durable “secondary” cross-protective response. In Aim 2, we will test this hypothesis using samples collected from baseline DENV-seropositive children who received a single dose of Dengvaxia® (DENV4- biased) vaccine before 5 years of active monitoring. In the original Dengvaxia® clinical trial, seronegative subjects who received the vaccine were at a greater risk of developing dengue disease and/or being hospitalized compared to unvaccinated controls. In Aim 3, we will analyze samples from subjects enrolled in our Dengvaxia® cohort who subsequently experienced asymptomatic, mild or severe (hospitalized) DENV infections to define Ab features, both at the level of antigen-specificity and Fc structure/function, correlated with vaccine-enhanced WT infections. This Aim parallels Project 1 Aim 3. Project 2 studies are highly interconnected with Project 1 (Ab and B cells in WT DENV infections) and Project 3 (T cell responses to DENV infections and vaccines), sharing samples and comparing datasets. The proposed experiments and data analysis rely on extensive interactions with Core B (Viral Assays), Core D (Antibodyomics) and Core C (Clinical, Data Management, and Statistical Modeling). Completion of these aims will fill critical gaps in DENV immunology and support evaluation of vaccines in the current pipeline and design of 2nd generation vaccines.