Sequential immunizations with a panel of HIV-1 Env virus-like particles coach immune system to make broadly neutralizing antibodies

Broadly neutralizing antibodies (bnAbs) are correlated with passive HIV/SHIV protection and are desirable components of a HIV protective immunity. In the current study, we have designed a sequential-immunization strategy with a panel of envelope glycoprotein (Env)-enriched virus-like particles (VLPs) from various HIV-1 clades (A-E) to elicit bnAbs with high breadth and potency of neutralization in rabbits. We have compared this regimen with repetitive immunizations of individual Env (subtype B) VLPs or a mixture of various Env VLPs. Our results demonstrate that the sequential immunization group of animals induced significantly higher IgG endpoint titers against respective HIV Env (autologous) antigen than other control groups. Animals vaccinated sequentially showed an increase in the antibody endpoint titers and IgG antibody secreting cells (ASCs) against Con-S Env protein. Sequential immunizations with various Env VLPs promoted antibody avidity indices and enhanced bnAb responses against a panel of HIV pseudotyped virions including some of the tier 3 pseudostrains. Sequential immunizations with various VLPs displaying “native-like” HIV-1 Envs elicited bnAb responses with increased breadth and potency of neutralization.