In a significant advancement for HIV vaccine development, researchers have demonstrated that a vaccine candidate can successfully generate broadly neutralizing antibodies (bNAbs) against HIV in humans, according to findings published in the journal Cell. This NIAID-supported early-stage clinical trial represents a critical proof-of-concept that could potentially lead to an effective HIV prevention strategy.
The trial enrolled 24 participants, with 20 receiving the vaccine and four receiving placebo injections. Among vaccine recipients, 13 generated early-stage antibodies targeting the membrane proximal external region (MPER) of an HIV surface protein after just two doses. More remarkably, among five participants who received three doses, two developed antibodies capable of neutralizing many common globally circulating HIV strains in laboratory tests.
"This study provided the proof of concept that a vaccine can induce bNAbs in people, which is a key question being pursued in the HIV vaccine research field," noted trial investigators. "Moreover, bNAbs were detected within weeks, which is much faster than the antibody response in people with HIV."
Overcoming HIV's Genetic Diversity Challenge
HIV's extensive genetic diversity has long been a major obstacle to vaccine development. Broadly neutralizing antibodies are considered crucial to overcoming this hurdle because they bind to relatively stable parts of the virus that remain constant despite mutations.
The vaccine specifically targeted the MPER region of HIV's surface protein. In one participant who received three doses, B cells showed signs of maturing in a way that would enable them to produce MPER-directed bNAbs with further stimulation. Another participant had already begun producing these specialized antibodies.
The trial also documented evidence of CD4+ T cell activity, which plays a vital role in enabling antibody development. However, the study was halted after one participant experienced anaphylaxis, a rare allergic reaction that was promptly managed and resolved. Investigators determined this was likely caused by an additive used to stabilize the vaccine contents.
Complementary Animal Studies Show Promise
In parallel research published in Nature Immunology, scientists have made additional progress using a different approach. NIH-funded researchers successfully stimulated animals' immune systems to induce rare precursor B cells that could develop into cells producing a class of bNAbs called 10E8, which is particularly promising for HIV vaccine development due to its ability to neutralize a broad range of HIV variants.
The researchers engineered immunogens on nanoparticles that mimic a specific part of gp41, a glycoprotein on HIV's surface involved in cell entry. When rhesus macaques and mice were vaccinated with these immunogens, their immune systems produced specific responses from 10E8 B cell precursors and induced antibodies showing signs of maturing into bNAbs capable of reaching a hidden region of gp41.
"Using a combination of cutting-edge immunologic technologies, researchers have successfully stimulated animals' immune systems to induce rare precursor B cells of a class of HIV broadly neutralizing antibodies," the research team reported. Similar responses were observed when mRNA-encoded nanoparticles were used in mice.
Implications for Human Vaccine Development
The animal study also revealed that the same immunogens produced B cells that could mature to generate an additional type of gp41-directed bNAb called LN01. Laboratory analysis of human blood samples found that 10E8-class bNAb precursors occur naturally in people without HIV, and the engineered immunogens successfully bound to and isolated naïve human B cells with 10E8-like features.
These findings suggest that the promising immunization data from animal models has potential for translation to humans. According to the researchers, these results support the development of the immunogens as the first part of a multi-step vaccine regimen for humans.
Path Forward for HIV Vaccine Research
While these results mark an important milestone, researchers acknowledge that an effective vaccine will likely need to build on and amplify the immune response observed in these studies. Based on the clinical trial findings, a new vaccine candidate is being developed with enhanced safety and efficacy profiles.
The research was sponsored by NIAID, co-funded by the Bill & Melinda Gates Foundation, and conducted by the Duke Consortium for HIV/AIDS Vaccine Development in collaboration with the NIAID-funded HIV Vaccine Trials Network. The animal studies were conducted by the Scripps Consortium for HIV/AIDS Vaccine Development, also supported by NIAID.
These complementary approaches represent significant progress toward the ultimate goal of developing an HIV vaccine that generates multiple classes of broadly neutralizing antibodies capable of preventing HIV infection despite the virus's genetic diversity.
