Research from the IAVI Neutralizing Antibody Center and partners provides additional evidence for germline-targeting strategy of HIV vaccine development

New research published May 30 in two papers in Nature Immunology demonstrates that vaccination can induce broadly neutralizing antibody (bnAb) precursors to HIV glycoprotein 41 (gp41), an important potential vaccination target, in mice and non-human primates. Results from both studies, which focus on membrane-proximal external region (MPER) antibodies, provide additional evidence supporting and guiding the germline-targeting strategy of HIV vaccine development.

Many scientists think that for wide vaccine-induced protection against HIV, and other antigenically diverse viruses like influenza, bnAbs will need to be elicited. IAVI’s research and development program designed to elicit broadly neutralizing antibodies to HIV is based on a strategy called germline targeting. This approach relies on carefully sequenced vaccinations designed to coach naïve B cells to produce bnAbs. Study results from the IAVI G001 Phase 1 clinical trial demonstrated that it is possible to prime B cells as a first step toward their maturation to produce bnAbs, an important proof-of-principle for this approach. IAVI G001 elicited VRC01 class bnAb precursors specifically. While this was an exciting step forward, it will be necessary to develop an HIV vaccine that elicits multiple classes of bnAbs to achieve broad immunity to HIV. It is assumed that for bnAbs to be effective, they must possess both the breadth to block a wide variety of circulating viruses and the potency to successfully ward off infection.

The study described in Schiffner et al. provides another important finding supporting the potential of the germline-targeting approach. Glycoproteins on the outside of HIV are important antibody targets for future vaccines. MPER-targeting bnAbs, such as bnAb 10E8, are of particular interest for scientists because of their high neutralizing breadth; however, 10E8 class bnAbs have specific, challenging physical requirements to enable binding to the targeted glycoprotein on HIV.

Many of the lead researchers for this study are from IAVI’s Neutralizing Antibody Consortium (NAC). IAVI authors include Jeong Hyun Lee, Claudia Flynn, Katherine McKenney, Oleksandr Kalyuzhniy, Alessia Liguori, Yumiko Adachi, Elise Landais, Devin Sok, and Bill Schief. They demonstrated that it is possible to engineer nanoparticles that produce bnAb-precursor responses to HIV gp41. These protein nanoparticles induced bnAb precursor responses in stringent mouse models and rhesus macaques, and mRNA-coded nanoparticles induced similar responses in mice.

A second study, led by Rashimi Ray of the Ragon Institute of Mass General, MIT and Harvard, with important contributions from researchers at the IAVI NAC, Scripps Research, and the La Jolla Institute for Immunology, examined whether a series of germline-targeting immunogens similar to those used in the Schiffner et al. study could drive MPER-specific precursors toward bnAbs in mice. The study found that recruitment of 10E8 precursors to germinal centers (GCs), a critical step required for B cell maturation, required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief. Study authors did identify one MPER precursor clonotype, MPER-HuGL18, able to close the affinity gap in the GC, leading the paper authors to suggest that a precursor-competitor affinity gap may regulate B-cell residency in the GC.

These important findings continue to support the potential of the germline-targeting strategy for HIV vaccine development. This strategy was also progressed by a series of preclinical research findings published in Science earlier this month. To learn more, please refer to the full articles available in Nature Immunology here and here, and please read the perspective article from Rogier Sanders and John Moore published in Science.