A new approach to design HIV vaccines based on germline antibodies and Env structures
A new study published in Nature Communications1 reports a new approach to design HIV vaccines based on the structures of germline antibodies and HIV envelope (Env) proteins.
The study aims to elicit broadly neutralizing antibodies (bnAbs) against HIV, which are rare antibodies that can recognize and block diverse strains of HIV. BnAbs are considered a key component of an effective HIV vaccine, but they are difficult to induce by conventional immunization strategies.
One of the challenges is to activate the naive B cells that express the germline precursors of bnAbs, which are often unresponsive to native Env proteins due to their low affinity or steric hindrance. Therefore, there is a need to design immunogens that can bind and stimulate these germline B cells and initiate the bnAb maturation pathway.
The researchers focused on a class of bnAbs that target the CD4-binding site (CD4bs) on Env, which is a conserved and functionally important region. They used structural and computational methods to design Env variants that can bind to the germline precursors of three CD4bs bnAbs: VRC01, 3BNC60, and N6.
They first identified mutations in Env that increased its affinity for the germline antibodies, while preserving its native conformation and antigenicity. They then introduced additional mutations that destabilized the Env trimer, which exposed more of the CD4bs and enhanced its accessibility for the germline antibodies.
The researchers tested the immunogenicity of their designed Env variants in mice and rabbits. They found that the Env variants elicited higher and more consistent germline antibody responses than the wild-type Env. Moreover, they observed signs of antibody maturation and affinity improvement in some of the immunized animals.
The researchers concluded that their study demonstrates a proof-of-concept for designing HIV vaccines based on germline antibody-Env structures. They suggested that their approach could be applied to other bnAb classes and combined with sequential immunization to elicit more potent and broad bnAbs against HIV.
Why is this study important?
HIV is a global health threat that affects millions of people worldwide. Despite decades of research, there is still no effective vaccine to prevent HIV infection. Current vaccine candidates have shown limited or no efficacy in clinical trials, partly due to the high genetic diversity and immune evasion strategies of HIV.
Therefore, there is an urgent need to develop new vaccine candidates that can elicit potent and durable immune responses against diverse HIV strains. BnAbs are considered a key component of an effective HIV vaccine, as they have been shown to protect animals from HIV infection and suppress viral replication in humans.
However, bnAbs are difficult to induce by conventional immunization strategies, as they require extensive somatic hypermutation and affinity maturation from their germline precursors. One of the bottlenecks is to activate the naive B cells that express these germline precursors, which are often unresponsive to native Env proteins.
The study by Zhang et al. is one of the first to report a successful design of Env variants that can bind and stimulate the germline precursors of CD4bs bnAbs, which are among the most potent and broad bnAbs against HIV. This study provides a new approach to design HIV vaccines based on germline antibody-Env structures, which could overcome some of the challenges in eliciting bnAbs.
What are the limitations and future directions?
The study by Zhang et al. has some limitations that need to be addressed in future research. First, the study used a single Env strain (BG505) to design the Env variants, which may not represent the diversity and complexity of Env strains circulating in humans. Therefore, it is unclear whether the Env variants would be effective against other Env strains or induce cross-reactive bnAbs.
Second, the study did not test the neutralization activity or breadth of the antibody responses elicited by the Env variants. It is possible that the antibody responses may not be sufficient or specific enough to block diverse strains of HIV. Therefore, it is important to evaluate the neutralization potency and breadth of the antibody responses in vitro and in vivo.
Third, the study did not investigate the molecular mechanisms or pathways involved in antibody maturation and affinity improvement after immunization with the Env variants. It is possible that there may be differences or similarities in the maturation pathways among different bnAb classes or precursors. Therefore, it is necessary to perform a comprehensive analysis of the antibody repertoire and evolution after immunization.
Finally, the study did not test the vaccine efficacy or safety of the Env variants in humans, which is the ultimate goal of HIV vaccine research. It is possible that there may be differences in immunogenicity, safety, or efficacy between animals and humans due to genetic or physiological factors. Therefore, it is essential to conduct clinical trials to evaluate the safety and efficacy of the vaccine candidates in humans.
1: Zhang Y, Kong L, Wang H, et al. HIV-1 CD4-binding site germline antibody-Env structures inform vaccine design. Nat Commun. 2022;13(1):106. doi:10.1038/s41467-022-33860-2