Decades into the HIV epidemic, there is as yet no effective vaccine to prevent new cases. In a recent Nature Immunology article (Ray et al.), the Batista lab of the Ragon Institute has preclinically validated a new HIV immunogen design approach from the Scripps Institute’s Schief lab targeting an unexplored site on the HIV-1 Envelope protein (Env).

Most human vaccines fight infection by calling up an antibody response. While it has been observed for decades that some patients develop broadly neutralizing antibodies (bnAbs) against HIV, obtaining a protective response through vaccination has proven immensely challenging. Antibodies are secreted by B cells: when an infectious invader first enters the body, some B cells are capable of binding to parts of the invader—its antigens. These B cells may then immediately start secreting high levels of antibody or enter into a reaction called the germinal center, where B cells compete with each other for limited amounts of antigen and get selected for better and better binding, allowing them to make better and better antibodies. HIV bnAbs present challenges at every stage: in their naïve, pre-infection state, referred to as “germline,” the B cells that might be capable of eventually producing bnAbs make up a small fraction of the whole B cell repertoire, and generally do not bind well to HIV before they have undergone a long, complex process of B cell receptor (BCR) modification in the germinal centers. To correct for this, researchers have pursued a vaccine concept called “germline targeting” (GT): researchers first identify B cells which may be capable of producing bnAbs after substantial modification, and then design immunogens to activate those B cells to enter the germinal centers.

The MPER GT immunogens tested here and in the simultaneously published by the Scripps team (Schiffner et al., Nature Immunology) represent a first for this site on the HIV Envelope. “MPER-targeting bnAbs are great from a vaccinology perspective: they neutralize a diverse range of HIV variants, and the MPER site itself is well conserved, so the virus is less likely to escape by mutating. But it’s also a hard target; previous attempts to generate mouse models for MPER-targeting bnAbs, for one, just couldn’t get off the ground because B cells expressing their precursors self-deleted,” says Facundo D. Batista, PhD, Associate and Scientific Director of the Ragon Institute and PI of the lab in which the mouse studies were conducted. “This required really major innovations from both labs—for our collaborators at Scripps, developing immunogens capable of reaching this tricky, recessed, site, and for us, generating models where those immunogens could actually be tested.”

Rashmi Ray, PhD, who led both mouse model development and the in vivo immunogen testing process in those models, emphasized the importance of the feedback process between the immunogen design team and the B cell biology group. “The model development could not have happened without the [immunogen design] Scripp’s groups insights into the shapes of the antibodies required to bind the MPER sites, and in turn, we were able to use the outputs in those models to help guide their design of increasingly immunogenic nanoparticles. I’ll admit I was most excited about the underlying biology, however; as we fine-tuned immunogen delivery, we were also able to observe how B cells competed with each other in the germinal centers. The role of the affinity gap—the difference in the strength of BCR binding to the antigen between B cell lines—as opposed to absolute affinity was critical here, and that concept was the key to what was happening in terms of B cell maturation. Ultimately, that understanding of how B cells win or lose out in germinal centers can be applied to vaccine development beyond HIV.”