Innovating towards an HIV vaccine

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HIV: A Tricky Virus

Making an HIV vaccine is a difficult and complex task that has eluded scientists for more than 35 years.

Conventional vaccines such as live attenuated and killed virus fail against the highly variable and evasive HIV. Our approach is based on the induction of broadly neutralizing antibodies (bnAbs) to the envelope trimer (green) on the surface of the virus.

HIV: A Tricky Virus

HIV Envelope Trimer (Env)

Env houses the machinery that allows HIV to infect cells; it is the sole target of bnAbs.

At the heart of difficulty in eliciting bnAbs is the nature of Env, which is a compact protein structure highly decorated with sugars (purple) and difficult for Abs to recognize. We have determined the molecular structure Env and have defined the sites on Env recognized by bnAbs in molecular detail. These studies have facilitated the precise design of our vaccine candidates.

bnAbs and Our Approach

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 encounter with many different viruses (immunogens) antibodies evolve to recognize a variety of shapes exhibited by distinct viral strains.

What are bnAbs?

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.

The bnAb challenge

CHAVI-ID Iterative Rational Approach to HIV Vaccine Design

CHAVI-ID Iterative Rational Approach to HIV Vaccine Design

We propose a rational vaccine design strategy in which a small number of well-designed immunogens are used in sequence. Immunogens are designed based on molecular level understanding of the interaction of bnAbs with the virus and on the biology of Ab responses.

Equally important is the optimization of immunization strategies. We vigorously pursue novel immunogens and immunization strategies in pre-clinical models with the aim of bringing them into the clinic as soon as possible to yield an HIV vaccine.

Our Philosophy

We enter the clinic only with immunogens for which we have convincing evidence in preclinical animal models that they behave according to design.

Additionally, we emphasize that each immunogen that enters clinical studies should test key hypotheses in our overall strategy.

  • Natural infection: lineage-based design
  • Reductionist design

Our Accomplishments

Immunogens (grey) entering the clinic (eOD-GT8 and BG505 SOSIP) and initiating GMP manufacturing (N332-GT5 and MT145K) in 2018 and their targets (black) on HIV Env.

Our first three immunogens (top) are currently entering manufacturing or Phase I clinical trials, each targeted to a different bnAb site on Env.

Who We Are

The CHAVI-ID has 19 Principal Investigators working on different aspects of designing and evaluating an HIV vaccine across the US and the World. The CHAVI-ID is led by Dr Dennis Burton at The Scripps Research Institute in La Jola, California.

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Joint Publications and Partnerships

We have worked together extremely well as a team, as evidenced by our 142 high-profile joint manuscripts, but also by our successful collaborations. Those collaborations and partnerships facilitate the staged process during which we proceed from Ab and Env discoveries through immunogen design to animal testing and ultimately to the clinic.

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Vaccine Product Concept Pipeline

We have a rich pipeline of highly innovative vaccine concepts that progress through early laboratory design, preclinical testing, iterative design, GMP manufacturing, and eventually human Phase I trials. We continuously prioritize and re-evaluate our candidates, discarding designs that fail at critical junctures, and advancing only the best-in-class vaccine product candidate with convincing preclinical evidence.

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Looking Back and Forward

EM mapping of Ab responses to vaccination

Our advances in basic science, HIV vaccine development and vaccine biology have been substantial. We take pride in our innovation and contributions to:

  • HIV bnAb generation
  • Trimer structure determination
  • CryoEM
  • Glycobiology
  • Tfh and germinal center (GC) cell biology
  • Immunogen design and immunization schedules
  • Adjuvants
  • Genetically engineered animal models for immunogen evaluation
  • CD4+ T cell assays
  • BCR sequencing
  • Antigen-specific (Ag) human naive B cell isolation
  • Immune monitoring approaches such as fine needle aspiration

While we have made fundamental scientific advances, we still maintain our focus on delivering an HIV vaccine.