At Keystone, HIV vaccine researchers join B-cell experts

When Georgia Tomaras of Duke University Medical Center opened this year’s HIV Vaccines Keystone symposium last night, she said this is the first ever HIV Vaccines meeting that is held jointly with a meeting on B cell development and function. Given the many new antibody-related advances the field has seen in recent years, this is not exactly surprising. “We now have an increasingly detailed map of the vulnerable sites on HIV Envelope, due to an array of newly discovered broadly neutralizing antibodies and the identification of their targets,” said Tomaras, who is the co-organizer of the HIV Vaccines track of the conference. “Research focused on basic B cell biology is the foundation for the development of an HIV vaccine designed to drive the B cell arm of the immune response.” 

But before the discussion turned to vaccines or antibodies, Myron Cohen from the University of North Carolina in Chapel Hill reminded the audience of recent successes in non-vaccine-related prevention approaches such as pre-exposure prophylaxis (PrEP) or test and treat. Such successes, he said, don’t compromise the ability to make a vaccine. “I really don’t think that’s the case,” he said, adding that history has taught us that treatment alone has not been enough to deal with other infectious diseases such as tuberculosis and syphilis. “20 or 30 years ago, we were confronted with treatment for tuberculosis, and we stopped trying to make TB vaccines, because we were going to treat our way out,” he said. “How did that work for us? Not too well.” While it makes sense to treat as many HIV-infected people as possible with antiretroviral drugs, he said, such an approach is not an alternative to a vaccine, but rather a bridge to bring patients closer to a vaccine, to simpler and improved future treatments, or to a cure.

One much-discussed topic in the antibody-related talks today was the observation that bNAbs are only found in a fraction of HIV-infected people, and only after years. That’s because they need to mature and mutate away from their germline precursors, in a process called affinity maturation. Unfortunately, HIV Envelope doesn’t bind to these germline precursors, but only to the final matured bNAbs. This is a problem, because a vaccine that only contains the naturally occurring Envelope, or parts of it, as an immunogen would not be expected to bind and activate B cells in uninfected people; it would, therefore, not be expected to kick start the affinity maturation process towards bNAbs. 

Therefore, researchers have been trying to develop versions of HIV Envelope that can bind the germline precursors of bNAbs, to kick start the affinity maturation process. Today, Andrew McGuire of the non-profit research institute Seattle Biomed reported progress of one such effort. It’s possible, he said, to make a version of Envelope that can not only bind to the germline precursors of the bNAbs VRC01 and NIH 45-46, but that can also activate B cells that express the B cell receptors of these germline precursors. The trick was to make an Envelope protein that lacks a sugar molecule in one position. Next, he said, he and his colleagues will try to see what kind of immune responses the modified Envelope protein can elicit in humanized mice and monkeys.