New double adjuvant vaccine strategy offers hope in the fight against HIV

New double adjuvant vaccine strategy offers hope in the fight against HIV

Scientists at Scripps Research have made a significant leap forward in the search for an effective HIV vaccine. They found that a two-part delivery strategy can train the immune system to mount a stronger response to HIV and offer new hope in the fight against one of the world's most elusive viruses.

The approach described inScience Translational MedicineOn June 18, 2025, a mouse model was used to test two types of adjuvants: immune-boosting molecules that improve vaccine response. One of the adjuvants helped the HIV protein last longer in the body and another amplified immune activation. When combined, the adjuvants produced stronger and more effective antibody responses than either one alone.

Using a dual adjuvant strategy brings together the best of both worlds. “

Darrell Irvine, senior author, professor of immunology and microbiology at Scripps Research

Vaccines work by teaching the body to recognize dangerous viruses and bacteria, but HIV has proven a particularly challenging target because it mutates quickly and hides from immune defenses. To study how to address this problem, the research team used an experimental HIV protein called the MD39-A antigen type, or molecule, that triggers an immune response.

MD39 was developed in a laboratory to resemble the outer envelope of the virus. It is structured to direct the immune system to produce broadly neutralizing antibodies (BNABs): rare immune proteins that can recognize and block a wide range of HIV variants.

The antigen was paired with three different adjuvant strategies to elicit the strongest immune response. One approach used a formulation in which MD39 was labeled with phosphosposerine (pSER), which anchored the protein to particles of aluminum hydroxide (Alum)—a widely used adjuvant that enhances immune activity. This formulation allows for slow release, prolonging the protein's presence in the body and giving immune cells more time to recognize and respond to it.

A second strategy used saponin/MPLA nanoparticles (SMNP). This adjuvant contains saponins, natural compounds found in plants that stimulate the immune system. To enhance immune response, SMNP delivers vaccine components to key immune sites such as lymph node follicle regions where immune training occurs. These follicles are rich in B cells: white blood cells that, when mature, can produce high-quality antibodies such as BNABs.

The third and final method, which integrated both Alum-Pser and SMNP, achieved the best results.

“The idea of ​​actually combining the adjuvants actually came from studying them separately,” notes Irvine. "The classic adjuvant alum is known to be very safe, but not as strong an adjuvant, while SMNP really drives robust activation of the immune system. So it seemed prudent to investigate whether putting the two together would be much more effective."

The results of the dual adjuvant strategy were striking: B cells multiplied, matured faster, and became more diverse—a critical factor for generating antibodies that can combat multiple HIV variants. Remarkably, MD39 remained detectable in lymph nodes for up to four weeks, allowing the protein to accumulate in follicles.

“The intact antigen assembly contributed to the significant effects we observed,” says first author Yiming “Jason” Zhang, a postdoctoral fellow at the Massachusetts Institute of Technology (MIT), where Irvine previously led his laboratory. “This suggests that other techniques that achieve this type of follicular buildup may also result in a strong immune response.”

The researchers compared their results with previous data from non-human primates that received the same protein and adjuvants. Encouragingly, the combination approach resulted in similarly strong and diverse immune responses.

While the full, two-part vaccine strategy has not yet been tested in humans, the SMNP adjuvant is currently being evaluated in a first-in-human clinical trial (HVTN 144).

“Its safety profile will likely be comparable to Shingrix, a shingle that has a very strong adjuvant like SMNP,” says Irvine. “You might have pain in your arm or flu-like symptoms for a day, but not much worse.”

In addition to Irvine and Zhang, authors of the study, "Vaccines combining slow release and follicle targeting of antigens increase germinal center B cell diversity and clonal expansion," are Kristen A. Rodrigues, Aereas Aung, Anna Romanov, Laura Maiorino, Parisa Yousefpour, Grace Gibson, Gabriel Ozorowski, Justin R. Gregory, Parastoo Amlashi, Maureen Buckley, Andrew B. Ward and William R. Schief from Scripps research; and Jonathan Lam, Duncan M. Morgan, Richard Van, and J. Christopher Love of MIT.

This work was supported by funding from the National Institutes of Health (grants P30-CA14051 (Kern Grant Koch Institute), UM1AI144462, AI161818, AI161297, AI125068, and P01AI048240). the National Institutes of Health Fellowship F32 AI164829; the Ragon Institute of Mass General Brigham, MIT and Harvard; WITH; Harvard; and the Howard Hughes Medical Institute.

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