tuberculosis2This animation shows HIV’s outermost Envelope protein, known as the trimer (in gray), cycling through different conformations. The trimer is densely coated with sugar molecules (in purple) that do not trigger an immune response. Most of the surface of the trimer that is not covered in sugars is highly variable (in red and yellow), making it difficult for the immune system to generate antibodies that are capable of neutralizing multiple strains of HIV. Photo credit: Sergey Menis, IAVI

There are numerous scientific challenges to developing an HIV vaccine. The unprecedented genetic variability of the virus, its ability to quickly establish a persistent lifelong infection, and the fact that not a single person has cleared HIV on their own are just some of the obstacles researchers must face in trying to understand how to induce protective immunity against the virus.

Given the complexity of combatting HIV, traditional approaches to vaccine development that led to many of the licensed vaccines in use today are either impractical, or have so far failed to be widely effective in protecting against HIV infection.

Instead, IAVI’s scientists and their collaborators are pursuing innovative strategies to design vaccine immunogens capable of activating both arms of the adaptive immune response, antibodies and T cells, to induce durable immunity against HIV.

B-cell Immunogens 

After more than a decade of concerted effort, new and improved HIV vaccine candidates carrying immunogens that are designed to stimulate B cells to generate broadly neutralizing antibodies (bnAbs) against the virus are now in clinical trials.

Two scientific advances led to this point. The first was the identification of more potent bnAbs from large cohorts of HIV-infected individuals. Isolation of these antibodies set off a new era of HIV vaccine development. By analyzing how these antibodies interact with the virus, scientists pinpointed several spots of vulnerability on HIV. They then used this information to design vaccine immunogens. This approach is referred to as structure-based vaccine design.

The first of these engineered immunogens (eOD-GT8 60mer) developed by IAVI and its partners is now in a Phase I clinical trial. Scientists are testing whether this approach will stimulate the human immune system to initiate the long and complicated process required to make bnAbs.

The other scientific development fueling the design of immunogens to induce bnAbs was obtaining a clearer understanding of the structure of HIV’s outermost protein known as HIV Envelope, which is the target of all broadly neutralizing antibodies. For decades scientists were hindered by their inability to capture the precise structure of this notoriously unstable trimeric protein, but recent advances have allowed them to both stabilize and understand HIV Envelope in unprecedented detail. Now researchers are developing and testing engineered vaccine immunogens that are meant to look like the actual structure of HIV Envelope. IAVI is supporting the development and clinical evaluation of some of these so-called native-like trimers as another way to stimulate production of HIV-specific bnAbs. One such candidate, BG505 SOSIP.664 gp140, adjuvanted, is being evaluated in a Phase I clinical trial at two locations in the US and one in Kenya.

The goal of the immunogen design work is to refine and improve these vaccine candidates until they are able to induce bnAbs that can protect against HIV infection.

Read more about this new generation of HIV vaccine candidates.

T-cell Immunogens 

IAVI is also supporting the development of vaccine approaches that are intended to primarily elicit broadly reactive, potent antiviral T-cell responses against the virus. Some of the most promising T-cell immunogens in development are specifically designed to address the global diversity of HIV. IAVI is supporting the clinical development of one of these approaches, a so-called conserved HIV immunogen, which combines portions of the virus, or viral epitopes, that are consistent across most of the genetically distinct variants of HIV currently in circulation.

Through its African-led science initiative known as VISTA, IAVI and its clinical research partners are also helping to guide the design and assessment of next-generation T-cell immunogens. The VISTA consortia are also involved in efforts to identify the types of T-cell responses that are associated with the spontaneous control of HIV infection that occurs among a certain subset of infected individuals known as elite controllers.