Optimal sequence-based design for multi-antigen HIV-1 vaccines using minimally distant antigens

The immense global diversity of HIV-1 is a significant obstacle to developing a safe and effective vaccine. We recently showed that infections established with multiple founder variants are associated with the development of neutralization breadth years later. We propose a novel vaccine design strategy that integrates the variability observed in acute HIV-1 infections with multiple founder variants. We developed a probabilistic model to simulate this variability, yielding a set of sequences that present the minimal diversity seen in an infection with multiple founders. We applied this model to a subtype C consensus sequence for the Envelope (Env) (used as input) and showed that the simulated Env sequences mimic the mutational landscape of an infection with multiple founder variants, including diversity at antibody epitopes. The derived set of multi-founder-variant-like, minimally distant antigens is designed to be used as a vaccine cocktail specific to a HIV-1 subtype or circulating recombinant form and is expected to promote the development of broadly neutralizing antibodies.