Researchers at MIT and the Scripps Research Institute have shown that they can generate a strong immune response to HIV with just one vaccine dose, by adding two powerful adjuvants — materials that help stimulate the immune system.
In a study of mice, the researchers showed that this approach produced a much wider diversity of antibodies against an HIV antigen, compared to the vaccine given on its own or with just one of the adjuvants. The dual-adjuvant vaccine accumulated in the lymph nodes and remained there for up to a month, allowing the immune system to build up a much greater number of antibodies against the HIV protein.
This strategy could lead to the development of vaccines that only need to be given once, for infectious diseases including HIV or SARS-CoV-2, the researchers say.
“This approach is compatible with many protein-based vaccines, so it offers the opportunity to engineer new formulations for these types of vaccines across a wide range of different diseases, such as influenza, SARS-CoV-2, or other pandemic outbreaks,” says J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at MIT, and a member of the Koch Institute for Integrative Cancer Research and the Ragon Institute of MGH, MIT, and Harvard.
Love and Darrell Irvine, a professor of immunology and microbiology at the Scripps Research Institute, are the senior authors of the study, which appears today in Science Translational Medicine. Kristen Rodrigues PhD ’23 and Yiming Zhang PhD ’25 are the lead authors of the paper.
More powerful vaccines
Most vaccines are delivered along with adjuvants, which help to stimulate a stronger immune response to the antigen. One adjuvant commonly used with protein-based vaccines, including those for hepatitis A and B, is aluminum hydroxide, also known as alum. This adjuvant works by activating the innate immune response, helping the body to form a stronger memory of the vaccine antigen.
Several years ago, Irvine developed another adjuvant based on saponin, an FDA-approved adjuvant derived from the bark of the Chilean soapbark tree. His work showed that nanoparticles containing both saponin and a molecule called MPLA, which promotes inflammation, worked better than saponin on its own. That nanoparticle, known as SMNP, is now being used as an adjuvant for an HIV vaccine that is currently in clinical trials.
Irvine and Love then tried combining alum and SMNP and showed that vaccines containing both of those adjuvants could generate even more powerful immune responses against either HIV or SARS-CoV-2.
In the new paper, the researchers wanted to explore why these two adjuvants work so well together to boost the immune response, specifically the B cell response. B cells produce antibodies that can circulate in the bloodstream and recognize a pathogen if the body is exposed to it again.
For this study, the researchers used an HIV protein called MD39 as their vaccine antigen, and anchored dozens of these proteins to each alum particle, along with SMNP.
After vaccinating mice with these particles, the researchers found that the vaccine accumulated in the lymph nodes — structures where B cells encounter antigens and undergo rapid mutations that generate antibodies with high affinity for a particular antigen. This process takes place within clusters of cells known as germinal centers.
The researchers showed that SMNP and alum helped the HIV antigen to penetrate through the protective layer of cells surrounding the lymph nodes without being broken down into fragments. The adjuvants also helped the antigens to remain intact in the lymph nodes for up to 28 days.
“As a result, the B cells that are cycling in the lymph nodes are constantly being exposed to the antigen over that time period, and they get the chance to refine their solution to the antigen,” Love says.
This approach may mimic what occurs during a natural infection, when antigens can remain in the lymph nodes for weeks, giving the body time to build up an immune response.
Antibody diversity
Single-cell RNA sequencing of B cells from the vaccinated mice revealed that the vaccine containing both adjuvants generated a much more diverse repertoire of B cells and antibodies. Mice that received the dual-adjuvant vaccine produced two to three times more unique B cells than mice that received just one of the adjuvants.
That increase in B cell number and diversity boosts the chances that the vaccine could generate broadly neutralizing antibodies — antibodies that can recognize a variety of strains of a given virus, such as HIV.
“When you think about the immune system sampling all of the possible solutions, the more chances we give it to identify an effective solution, the better,” Love says. “Generating broadly neutralizing antibodies is something that likely requires both the kind of approach that we showed here, to get that strong and diversified response, as well as antigen design to get the right part of the immunogen shown.”
Using these two adjuvants together could also contribute to the development of more potent vaccines against other infectious diseases, with just a single dose.
“What’s potentially powerful about this approach is that you can achieve long-term exposures based on a combination of adjuvants that are already reasonably well-understood, so it doesn’t require a different technology. It’s just combining features of these adjuvants to enable low-dose or potentially even single-dose treatments,” Love says.
The research was funded by the National Institutes of Health; the Koch Institute Support (core) Grant from the National Cancer Institute; the Ragon Institute of MGH, MIT, and Harvard; and the Howard Hughes Medical Institute.
