Mutation-guided vaccine design: A process for developing boosting immunogens for HIV broadly neutralizing antibody...

Area of Science:

• Immunology
• Vaccinology
• Virology

Background:

• Developing an effective HIV-1 vaccine requires inducing broadly neutralizing antibodies (bnAbs).
• Initiating bnAb B cell lineages is achievable, but designing boosting immunogens to select for necessary improbable mutations for bnAb affinity maturation remains a significant hurdle.
• The V3-glycan bnAb B cell lineage is a key target for vaccine development.

Purpose of the Study:

• To demonstrate a process for designing boosting immunogens targeting a specific V3-glycan bnAb B cell lineage.
• To evaluate the efficacy of both protein and mRNA-based immunogens in selecting for improbable mutations essential for bnAb development.
• To assess the potential of these immunogens in advancing HIV-1 vaccine research.

Main Methods:

• Designed novel boosting immunogens for a V3-glycan bnAb B cell lineage.
• Utilized bnAb precursor knockin mice to test immunogen efficacy.
• Employed nucleoside-modified mRNA-encoded HIV-1 envelope trimer immunogens for prime-boost strategies.

Main Results:

• The designed immunogens successfully induced affinity-matured antibodies by selecting for functional improbable mutations.
• Both protein and mRNA prime-boost immunizations showed success in selecting for these critical mutations.
• mRNA immunogens demonstrated improved selection of improbable mutations crucial for bnAb binding to key HIV envelope glycans.

Conclusions:

• Protein and mRNA prime-boost immunogens can effectively select rare B cell lineage intermediates with neutralizing breadth.
• This study represents a key proof of concept and milestone for HIV-1 vaccine development.
• The findings pave the way for designing more effective immunogens to elicit bnAbs against HIV-1.