Dengue annually infects millions of people from a regionally and seasonally varying dengue virus population circulating as four distinct serotypes. Effective protection against
dengue infection and disease requires
tetravalent vaccine formulations to stimulate a balanced protective immune response to all four serotypes. However, this has been a challenge to achieve, and several clinical trials with different leading
vaccine candidates have demonstrated unbalanced replication and interference of interindividual serotype components, leading to low efficacy and enhanced disease severity for
dengue-naïve populations. Production of serotype-specific
neutralizing antibodies is largely viewed as a correlate of protection against
severe dengue disease. However, the underlying mechanisms that lead to these protective immune responses are not clearly elucidated. In this work, using a stochastic model of B cell affinity maturation, we tested different live-
attenuated vaccine constructs with varied viral replication rates and contrasted the initiation and progress of adaptive immune responses during tetravalent vaccination and after dengue virus challenge. Comparison of our model simulations across different disease-severity levels suggested that individual production of high levels of serotype-specific
antibodies together with a lower cross-reactive antibody are better correlates for protection. Furthermore, evolution of these serotype-specific
antibodies was dependent on the percent of viral attenuation in the
vaccine, and production of initial B cell and T cell populations pre- and post-secondary
dengue infection was crucial in providing protective immunity for
dengue-naïve populations. Furthermore, contrasting disease severity with respect to different
dengue serotypes, our model simulations showed that
tetravalent vaccines fare better against DENV-4 serotype when compared to other serotypes.