May 15, 2025

Two HIV vaccine trials show proof of concept for pathway to broadly neutralizing antibodies North American and African clinical trials led by Scripps Research, IAVI and additional collaborators across the U.S. and Africa mark progress toward an effective HIV vaccine.

May 15, 2025

LA JOLLA, CA and NEW YORK, NY A decades-long scientific challenge in HIV vaccine development has been finding a way to train the immune system to produce antibodies that can target many variants of the virus. Traditional approaches haven't worked largely because HIV mutates rapidly and hides key parts of itself from the immune system.

Now, a new study combining data from two separate phase 1 clinical trials shows that a targeted vaccine strategy can successfully activate early immune responses relevant to HIV, and, in one trial, further advance them a key step toward a long-sought goal in vaccine development. Conducted by an international team led by scientists at IAVI and Scripps Research, the trials included nearly 80 participants from both North America and Africa, laying essential groundwork for a future HIV vaccine with global potential. The study was published in Science on May 15, 2025.

One of the trials tested a stepwise vaccination strategy, in which a priming dose and a distinct booster dose were given sequentially to guide the immune system through stages of antibody development. That trial demonstrated that administering this combination a technique known as heterologous boosting could further advance the immune response in humans. The second trial focused on the priming stage and showed that an initial vaccine dose could successfully activate the desired immune cells in African participants, supporting the use of this approach in regions most affected by HIV. In both trials, the vaccines were delivered using an mRNA-based vaccine platform similar to the technology used in the COVID-19 vaccines which enabled faster production and clinical testing, and provided strong immune responses.

We've now shown in humans that we can initiate the desired immune response with one shot and then drive the response further forward with a different second shot. We've also shown that the first shot can work well in African populations, says senior author William Schief, a professor of immunology and microbiology at Scripps Research; vice president for protein design in infectious disease research at Moderna, Inc.; and executive director of vaccine design at IAVI's Neutralizing Antibody Center. These trials provide proof of concept for a stepwise approach to elicit custom-tailored responses not just for our vaccine, but for the vaccine field at large, including non-HIV vaccines.

These remarkable results validate the rational vaccine design that underpins this approach, adds Mark Feinberg, President and CEO of IAVI. A vaccine would be a tremendous step forward for global health and could help bring an end to the HIV pandemic. This effort has been made possible by a phenomenal collaboration of scientific research institutions, funders, private sector and government and is a testament to the power of partnership-driven scientific inquiry.

Broadly neutralizing antibodies, or bnAbs, are a rare type of immune defense that can recognize and block a wide range of HIV variants. Unlike standard antibodies, which often only recognize a specific variant of the virus, bnAbs target parts of HIV that stay the same even as the virus mutates. Scientists have long viewed bnAbs as the immune system's best shot at preventing HIV infection.

The first step in helping the body produce bnAbs is through what's known as a priming vaccine an initial dose designed to activate rare, na ve B cells with the potential to eventually produce bnAbs. This approach is called germline targeting. B cells are a type of white blood cell that play a central role in the immune system by making antibodies that recognize and fight off viruses and other threats. Later vaccine doses, known as boosters, guide those cells through a process of maturation toward producing HIV-targeting antibodies. Even though these trials weren't intended to generate bnAbs themselves, they demonstrated that the vaccine strategy to deliver a series of different shots to guide the immune system to produce bnAbs has great promise.

Targeting the right cells at the right time

This work builds on two key lines of earlier research emerging from Schief's lab: results published in 2022 from the IAVI G001 clinical trial, which showed how a protein-based vaccine could successfully activate the rare immune cells needed to initiate bnAb development, and a series of four preclinical studies published in 2024 that demonstrated how a multi-step vaccination strategy could guide the immune system toward producing protective antibodies.

The new study analyzed data from two distinct phase 1 clinical trials: the IAVI G002 trial, conducted in North America, and the IAVI G003 trial, conducted specifically in South Africa and Rwanda countries that are among the most affected by HIV in sub-Saharan Africa. G002 enrolled 60 participants, while G003 enrolled 18. Both trials used germline targeting.

In G002, participants received either the priming vaccine alone or the priming vaccine followed by a slightly different booster the latter being the heterologous boosting strategy. This two-step process is designed to guide the immune response further along the path toward bnAb development by generating VRC01-class antibodies early immune defenses with key features of bnAbs. Named after a well-studied bnAb that neutralizes a wide range of HIV variants, VRC01-class antibodies block HIV from binding to a host cell's entry receptor by targeting a region of HIV that rarely changes, despite the virus's rapid mutation. Thus, these antibodies are considered among the m

LINK:	https://www.scripps.edu/news-and-events/press-room/2025/20250515-schie...
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