Durability and mechanisms of dengue vaccine and infection mediated immunity

Dengue virus (DV) is a global pandemic causing 400 million infections annually; many veterans are exposed to dengue while serving in endemic areas. There are 4 co-circulating viruses, severe disease is most commonly seen with 2nd infections and caused by low-titer antibodies from first infection mediating enhanced viremia/disease on 2nd infection (ADE). To date there are no therapies or vaccines safe in all people, however TDV/TAK003, a live attenuated tetravalent vaccine, has shown good safety and protection up to 4.5 years post vaccination, and just received its first approval. This is the first dengue vaccine safe and protective in a DV seronegative population. TDV/TAK003 induces type-specific neutralizing antibodies to DV2, and mostly cross- reactive antibodies to DV1,3, and 4. TDV/TAK003 includes CD4+ and CD8+ T cell epitopes, unlike the earlier Dengvaxia, which caused increased disease in DV seronegatives, did not. We have shown that TDV/TAK003 induces durable type-specific CD4+ and C8+ T cell responses, still detectable 10 years post vaccination, while a single natural infection does not. Further, TDV/TAK003 induces multifunctional cytotoxic CD4+ T cells, which are not seen after first infection but are seen after 2nd infection, per our data and reported by others. We hypothesize that TDV/TAK003 induces a durable immune phenotype comparable to immunity after 2 DV infections, the current best model of protection in humans. Since TDV/TAK003 may receive wide approval in the next year, it is vital to better understand the type, specificity, and durability of post vaccination immunity in seronegatives and how this compares with seropositive vaccinees (who have stronger and broader protection) and immunity after 2nd infection. Durability of immunity is key after vaccination, especially in dengue, given the risk of severe disease as immunity wanes. We have an ongoing study with multiple stored serum and PBMC samples from TDV/TAK003 vaccinees and infected veterans, and collaborators in Puerto Rico and Colombia will provide us with samples from seropositive vaccinees and people with post 2nd infection immunity. We hypothesize that durable protective immunity after TDV/TAK003 vaccination in seropositives and seronegatives is mediated by multiple mechanisms, including durable type-specific polyfunctional CD4+ cytotoxic T cells (CTLs), memory B cell secreted antibodies (MBCs) and Fc-mediated antibody cytotoxicity (ADCC) in addition to better studied type-specific neutralizing antibodies. We hypothesize that vaccine immunity is broader and more sustained than immunity after 1st DV infection, and closer to immunity after 2nd infection. We hypothesize that TDV/TAK003 immunity is durable and protects from DV disease in an adoptive transfer murine model up to 10 years after vaccination. To challenge our hypotheses, we will Aim 1: Determine the specificity and functionality of durable B cell immunity in seronegative and seropositive TDV/TAK003 vaccinees compared with people recovered from 1st and 2nd DV infections. Aim 2: Determine if multifunctional type-specific CD4+ CTLs seen after 2nd infections (thus associated with protection) are uniquely induced by vaccination and 2nd but not 1st infection, and kill DV+ target cells. Aim 3: Determine if durable seronegative immunity after TDV/TAK003 vaccination inhibits DV replication/disease in an adoptive transfer murine model, and if this inhibition is comparable in strength and breadth to seropositive TDV/TAK003 vaccinees and 2nd infections.