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. Author summary Diverse HIV-1 populations are generally thought to promote neutralizing responses. Current leading HIV-1 vaccine design strategies maximize the distance between antigens to attempt to cover global HIV-1 diversity or serialize immunizations to recapitulate the temporal evolution of HIV-1 during infection. To date, no vaccine has elicited broadly neutralizing antibodies. As we recently demonstrated that infection with multiple HIV-1 founder variants is predictive of neutralization breadth, we propose a novel strategy that endeavors to promote the development of broadly neutralizing antibodies by replicating the diversity of multi-founder variant acute infections. By training an HIV-1 Env consensus sequence on the diversity from acute infections with multiple founders, we derived in silico a set of minimally distant antigens that is representative of the diversity seen in a multi-founder acute infection. As the model is particular to the input sequence, it can produce antigens specific to any HIV-1 subtype or circulating recombinant form (CRF). We applied this to HIV-1 subtype C and obtained a set of minimally distant antigens that can be used as a vaccine cocktail.

Automated summary

The immense diversity of HIV-1 poses a challenge for vaccine development. Researchers propose a novel strategy that aims to promote the development of broadly neutralizing antibodies by replicating the diversity of multi-founder variant acute infections. They developed a probabilistic model to simulate the variability observed in these infections, generating a set of minimally distant antigens that can be used as a vaccine cocktail.