First in-human HIV vaccine to induce virus-specific neutralizing antibodies

Researchers at Fred Hutchinson Cancer Center, led by Dr. Julie McElrath, Director of the Vaccine and Infectious Disease Division, have found a new way to train our immune system to make antibodies that could prevent HIV infection. The work, recently published in the Journal of Experimental Medicine, builds on past efforts to generate antibodies that recognize the HIV envelope (Env) proteins on the virus particle’s outer surface. Their new paper describes the results of a human trial with a new HIV vaccine formulation—dual stimuli plus HIV Env protein complex—to induce in humans the first-ever neutralizing antibodies to a vaccine matching the HIV envelope of a strain isolated from a human HIV infection.

Vaccines activate our immune system to fight a viral infection by producing neutralizing antibodies that bind and prevent a virus from infecting our cells. Vaccines contain two key ingredients: a viral protein or “immunogen” that the antibodies will recognize and an “adjuvant” that will stimulate the immune system to make the immunogen-specific antibodies. To date, candidate HIV vaccines typically contain Env protein as the immunogen paired with one or more standard adjuvants shown to be effective in other vaccines. The researchers in the McElrath lab made important modifications to the vaccine formulation against HIV in their recent work. “This is the first description of a new class of vaccine adjuvants (3M-052-AF) combined with a newer class of candidate HIV recombinant protein immunogen ("Env trimers"). Env trimers have been engineered to mimic the native structure of the HIV Env on the surface of the HIV virion,” shared first author Dr. William Hahn, a Clinical Assistant Professor at the University of Washington, Department of Medicine (Division of Allergy and Infectious Disease). Most other HIV vaccine formulations use a single HIV Env protein as the immunogen which has different surfaces available that can distract the immune system from making antibodies binding the Env trimer—the native arrangement.

For a vaccine to produce a strong antibody response it requires an effective adjuvant. A study conducted in 2022 showed that antibodies can bind to the base of the Env trimer—a site with less glycosylation masking that is normally occluded by the host membrane and therefore isn't a target for neutralizing antibodies—when the vaccine formulation includes the Env trimer and the aluminum hydroxide (alum) adjuvant. However, despite achieving binding to the trimer base, the antibody response elicited was insufficient to neutralize HIV in this context. The McElrath group wanted the vaccine to prime and boost the antibody neutralizing activity against HIV away from the Env base with high titers. Vaccine studies in monkeys demonstrated that using a novel adjuvant, a synthetic imidazoquinolinone 3M-052, was able to boost the production of target specific, neutralizing antibodies. “The 3M-052-AF adjuvant signals via toll-like receptor 7 and 8 (TLR7/TLR8) and our study is the first report of using this adjuvant in healthy volunteers in clinical trials (“first-in-human”),” commented Dr. Hahn. “The adjuvant was safe and the 5 microgram dose of 3M-052-AF/Alum induced antibodies capable of neutralizing a wild-type HIV matched to the vaccine.” Intriguingly, the dual adjuvant vaccine changed the antibody target site on the Env trimer from the base of the trimer to the trimer apex. “Unfortunately, the types of neutralizing antibodies the vaccine induced were relatively narrowly matched to the vaccine and ultimately the vaccine will need to neutralize additional circulating HIV strains that cause clinical infection,” explained Dr. Hahn. Therefore, this study marks a new HIV vaccine platform for which continued optimization is needed and planned to elicit broadly neutralizing antibodies for protection against circulating HIV strains.

While this vaccine formulation is not yet optimized, it demonstrates two significant advancements. Foremost, Dr. Hahn shared that “this is the first report of such [HIV neutralizing] antibodies induced by a vaccine in humans.” Even vaccine studies using similar Env trimers and alum adjuvant alone did not produce neutralizing antibodies. “Our findings suggest that adjuvant may play a key role in the quality of the immune response and directs the immune response to different areas of the Env trimer,” stated Dr. Hahn. Yet, “additional work will need to be done to identify vaccine regimens capable of inducing such broadly neutralizing antibodies.”

The spotlighted research was funded by the National Institutes of Health and the Gates Foundation.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Holly Janes, Stephen De Rosa, Lawrence Corey, Ollivier Hyrien, and M Juliana McElrath contributed to this work.

Hahn WO, Parks KR, Shen M, Ozorowski G, Janes H, Ballweber-Fleming L, Woodward Davis AS, Duplessis C, Tomai M, Dey AK, Sagawa ZK, De Rosa SC, Seese A, Kallur Siddaramaiah L, Stamatatos L, Lee WH, Sewall LM, Karlinsey D, Turner HL, Rubin V, Furth S, MacPhee K, Duff M, Corey L, Keefer MC, Edupuganti S, Frank I, Maenza J, Baden LR, Hyrien O, Sanders RW, Moore JP, Ward AB, Tomaras GD, Montefiori DC, Rouphael N, McElrath MJ. 2024. Use of 3M-052-AF with Alum adjuvant in HIV trimer vaccine induces human autologous neutralizing antibodies. J Exp Med. 221(10):e20240604.