Broadly Neutralizing Antibodies Against HIV and Novel Vaccine Approaches to Generate Them

A large and diverse body of evidence indicates that vaccine-mediated protection against HIV infection will require the induction, in vaccinated individuals, of antibody responses that are able to potently neutralize the ability of diverse genetic variants of HIV to establish infection in host target cells. Such broadly neutralizing monoclonal antibodies (HIV bnAbs) have been isolated from HIV infected individuals and their interactions with specific regions of the HIV Envelope glycoprotein (EnV) mapped in exquisite detail. In addition, the unusual structural features of the HIV bnAbs themselves are now well understood. Further, the pathways of evolution of HIV bnAbs within infected individuals over the course of their infections has been described for a number of HIV bnAb families. Collectively, these data have provided detailed insights into why induction of HIV bnAbs by a wide range of HIV vaccine candidates represents an unprecedentedly complex challenge and why it has not been achieved by any HIV vaccine candidates evaluated in clinical trials to date. A recent clinical trial (the “AMP study”) has provided direct evidence that a HIV bnAb can protect individuals at high risk of HIV infection from becoming infected, and also helped define a potential threshold for bnAb potency, breadth of recognition and in vivo levels needed to confer protection. Despite the biological challenges in inducing HIV bnAb responses by vaccination, the combination of contemporary structural and computational biology approaches, combined with high resolution immunologic analyses have helped frame a rational hypothesis for how HIV bnAbs may be generated by vaccination, and an initial experimental medicine trial (IAVI G001) has provided important foundational evidence to support this concept. This presentation will summarize progress made to date in HIV bnAb-focused vaccine efforts and describe ongoing work to further accelerate progress to achieve this long-elusive goal.