Well-designed immunogens are crucial to our rational approach to HIV vaccine design, but equally important is the optimization of immunization strategies.
Broadly Neutralizing Antibodies (bnAbs)
What are bnAbs?
They are antibodies able to neutralize (inactivate) a large proportion of global circulating HIV strains. They arise in some HIV-infected individuals, usually after several years of infection. Through exposure to many different viruses (immunogens), antibodies evolve to recognize a variety of shapes exhibited by distinct viral strains.
The bnAb Challenge
The challenge, and essence of the bnAb approach to HIV vaccine design, is then to generate bnAbs in HIV- uninfected humans. We do not have the luxury of presenting many different immunogens over several years. In vaccination, we must present a manageable number of immunogens over a limited time period.
Develop a sequential vaccine regimen that induces sustained protective levels of broadly neutralizing antibodies in humans.
Broadly neutralizing antibodies or bnAbs are antibodies that have the ability to neutralize multiple viral strains of HIV. bnAbs are very efficient due to the fact that they can successfully target vulnerability sites on the Env, and because humans themselves have the potential to generate potent HIV bnAbs.
When we talk about focusing our research around a sequential vaccine regimen, we mean that the key aspect of a successful HIV vaccine lies in training the immune system with a set of different immunogens, as opposed to a classical vaccine protocol that involves multiple administrations of the same immunogen.
Well-designed immunogens are crucial to our rational approach to HIV vaccine design, but equally important is the optimization of immunization strategies. We have demonstrated impressive improvements in nAb responses in NHPs by utilizing novel vaccine delivery approaches designed to enhance germinal center responses. We will further optimize these approaches using preclinical models and then proceed to validate their utility in human clinical trials.
Env vulnerability sites targeted by bnAbs
HIV ENV TRIMER
Three features make HIV Env trimer an evasive machine that can escape nAbs - a dense glycan shield, rapid sequence variation of the protein surface and significant structural flexibility.
glycans per molecule on surface
5 key vulnerability sites
ROLE OF BNABS
Support for bnAbs in HIV vaccine protection comes from experiments conducted by us and other research groups. They show that bnAbs, administered passively or through vaccination, provide sterilizing immunity against a robust, clinically relevant virus challenge in appropriate animal models.
When compared to immunization with corresponding soluble proteins, immunization with proteins expressed on particles is shown to result in enhanced antibody responses.
NATIVE-LIKE TRIMER IMMUNOGENS
NATIVE-LIKE TRIMER IMMUNOGENS
Colored spheres represent mutated residues that stabilize the native-like NFL trimers — BG505 Trimer Derived residues transferred to other Env sequences, helix-breaking glycine and proline substitutions in gp41 and substitutions in the highly dynamic V3 and fusion peptide regions of the Env. Together, these alterations provide a general means to generate well-ordered trimers from multiple Envs.