Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies

Area of Science:

• Immunology
• Vaccinology
• Virology

Background:

• Inducing broadly neutralizing antibodies (bnAbs) is a critical objective for effective HIV vaccine design.
• VRC01-class bnAbs represent promising vaccine candidates due to the prevalence of their precursor B cells in humans.
• Previous studies showed an engineered immunogen could initiate a bnAb response, but maturation remained unproven.

Purpose of the Study:

• To develop boosting immunogens that promote the genetic and functional maturation of VRC01-class bnAb precursors.
• To assess the efficacy of sequential immunization strategies in guiding bnAb development.

Main Methods:

• Engineered priming and boosting immunogens were designed to target VRC01-class B cell precursors.
• A transgenic mouse model expressing germline VRC01 heavy chains was utilized.
• Neutralization breadth and antibody genetic/functional characteristics were analyzed.

Main Results:

• Boosting immunogens successfully induced broad neutralization of near-native HIV isolates (N276A) and weak neutralization of fully native HIV.
• The resulting antibodies exhibited characteristics of partially mature VRC01-class antibodies.
• These antibodies were positioned on a maturation pathway toward fully developed bnAbs.

Conclusions:

• Reductionist sequential immunization strategies can effectively guide the maturation of HIV bnAb responses.
• This approach demonstrates a viable method for developing VRC01-class bnAbs for HIV vaccine candidates.
• Further research can build upon these findings to optimize bnAb induction for HIV prevention.