Their research and continuous scientific discoveries have led to taking new, more advanced approaches that bring us closer towards developing an optimal HIV vaccine regimen.
decades of successful ongoing research
commited lead scientists and investigators
We discovered prototype broadly neutralizing antibodies (bnAbs) which are able to neutralize global isolates from well-curated panels. Many bnAbs have long or short complementarity-determining regions, extensive somatic hypermutation, indels and other features that allow them to overcome steric restrictions imposed on antibody recognition.
Passive transfer studies demonstrate that bnAbs can provide sterilizing immunity against HIV exposure, providing further evidence that a bnAb-based vaccine has the potential to be a highly effective HIV vaccine. Moreover, results from passive administration of HIV nAbs provide a proof of concept that Env protein-based vaccination strategies can indeed protect against hard-to-neutralize viral strains by inducing Tier 2 nAbs, provided that appropriate nAb titers can be reached and maintained.
We made major advances with a soluble recombinant stabilized trimer that has many antigenic and molecular properties characteristic of the native Env trimer. It also provided the first molecular insights into why some currently used Env constructs aren’t leading to a successful vaccine.
We’ve been advancing rational immunogen design to make breakthroughs in several areas, including Germline Targeting (GT) immunogen design, which seeks to enable B cells to mutate and produce bnAbs that more effectively bind to targeted epitope sites on HIV Envelope. This is accomplished by using GT priming immunogens to activate appropriate B-cell precursors, followed by structure-guided boost immunogens to shepherd and polish the response along a pathway to bnAbs. The can be done against 2-3 different Env sites to provide the most effective coverage against the diversity of virus strains.
To drive the vaccine response from naïve antibodies to bnAbs, we need to learn how to drive affinity maturation along a course to nAbs and bnAbs. Insights into the biology of T “follicular” helper (Tfh) cells and germinal centers (GCs) will help to optimize B cell responses to immunogens designed to generate HIV bnAbs. We can now track antigen-specific GC Tfh cells seek to understanding what signals from Tfh cells are most important to recruit rare bnAb precursor B cells into the vaccine-elicited responses.
Testing of immunogens in small animal models will narrow the focus of human clinical trials. We have established a method for generating knock-in (KI) mice as a surrogate for human germline bnAb induction. Combining KI mouse models with our expertise in B cell biology will help identify specific immunogens which elicit desired immune responses in humans.
During the past 7+ years, we pursued designs to induce bnAbs against 5 major Env bnAb sites. We now have a clinical trial starting for an immunogen targeting one of the bnAb sites, GMP manufacturing initiated for immunogens targeting two additional sites, and promising product designs for the final two.
STRATEGIES AND PROTOCOLS
In our research, we heavily invested in Env trimer design and immunogenicity studies. This enabled us to leverage computational design and mammalian display directed evolution, and led us to develop the MD39 trimer platform as a substantially modified SOSIP design. Platform Env trimer immunogen BG505 MD39, with key stabilizing mutations highlighted in magenta. Green: Gp120 Grey: Gp41. Gold: Glycans.
BUILDING TOWARDS SUCCESS
As we proved in various experiments conducted on animal models, the process of targeting multiple bnAb sites is more likely to achieve a comprehensive neutralization coverage, and that could reduce the chances of vaccine failure when it comes to translating the process into humans.
BnAbs typically only arise during natural infection (left panel) after many years when the immune system has encountered a large diversity of different viral Envs and wandered from target to target. However, a more efficient route to the induction of bnAbs lies through a sequential multi-immunogen vaccination process (right panel), where specifically designed immunogens can guide the immune response along a more direct path to development of bnAbs.
We’ve shown that one of the most effective routes to developing a successful HIV vaccine is the formation of a sequential multi-immunogen vaccination process. Our research demonstrates that a designed sequential immunization strategy leads to elicitation of bnAbs to multiple sites on HIV Env. A desirable HIV vaccine should induce bnAbs in a much shorter period with a manageable number of immunogens.