A stochastic B cell affinity maturation model to characterize mechanisms of protection for tetravalent dengue vaccine constructs.

ABSTRACT

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.