June 18, 2025

Two-part vaccine strategy generates a stronger, longer-lasting immune boost against HIV Scripps Research scientists' new approach combines two immune-activating molecules known as adjuvants.

June 18, 2025

LA JOLLA, CA In the quest to develop an effective HIV vaccine, scientists from Scripps Research have made a significant leap forward. They found that a two-part delivery strategy can train the immune system to produce a stronger response to HIV, offering new hope in the fight against one of the world's most elusive viruses.

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

Using a dual-adjuvant strategy pulls together the best of both worlds, says senior author Darrell Irvine, a professor of immunology and microbiology at Scripps Research.

Vaccines work by teaching the body to recognize dangerous viruses and bacteria, but HIV has proven to be a particularly challenging target because it mutates rapidly and hides from immune defenses. To explore how to tackle this issue, the research team used an experimental HIV protein called MD39 a type of antigen, or molecule that triggers an immune reaction.

MD39 was designed in a lab to resemble the virus's outer envelope. It's structured to guide the immune system toward generating 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 test which elicited the strongest immune response. One approach used a formulation where MD39 was tagged with phosphoserine (pSer), allowing the protein to anchor to particles of aluminum hydroxide (alum) a widely used adjuvant that enhances immune activity. This formulation enables slow release, prolonging the protein's presence in the body and giving immune cells more time to recognize and react to it.

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

The third and final method which incorporated both alum-pSer and SMNP yielded the best outcomes.

The idea to combine the adjuvants actually came from studying them separately, notes Irvine. The classic adjuvant alum is well known, very safe, but not as potent an adjuvant, whereas SMNP really drives robust activation of the immune system, so it seemed reasonable to explore whether putting the two together would be much more effective.

Results of the dual-adjuvant strategy were striking: B cells multiplied, matured more quickly and became increasingly diverse a critical factor for generating antibodies that can fight multiple variants of HIV. Notably, MD39 remained detectable in lymph nodes for up to four weeks, allowing the protein to accumulate in follicles.

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

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

While the full, two-part vaccine strategy hasn't been tested yet in humans, the SMNP adjuvant is currently under evaluation in a first-in-human clinical trial (HVTN 144).

Its safety profile will probably be comparable to Shingrix, which is a shingles vaccine that has a very potent adjuvant like SMNP, says Irvine. You might get some pain in your arm or flu-like symptoms for a day or so, but nothing much worse than that.

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 of 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 (Koch Institute Core grant), UM1AI144462, AI161818, AI161297, AI125068 and P01AI048240); the National Institutes of Health Fellowship F32 AI164829; the Ragon Institute of Mass General Brigham, MIT, and Harvard; MIT; Harvard; and the Howard Hughes Medical Institute.

Autoimmune Diseases Irvine, Darrell

LINK:	https://www.scripps.edu/news-and-events/press-room/2025/20250618-irvin...
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