Numerous vaccines operate by introducing a protein into the body that mimics a portion of a virus. The goal is for the immune system to create long-lasting antibodies that recognize that particular virus, thereby offering protection.
However, scientists at Scripps Research have recently found that with certain HIV vaccines, a different occurrence takes place: after several vaccinations, the immune system starts to generate antibodies against immune complexes that are already attached to the viral protein by itself. While it remains unclear whether this phenomenon, outlined in Science Immunology, benefits or hinders the immune system’s ability to combat HIV, researchers believe that a deeper understanding could enhance HIV vaccine development. The findings were published in the journal on January 17, 2025.
“These antibodies that respond to immune complexes haven’t been thoroughly examined, especially in relation to HIV vaccination,” explains Andrew Ward, PhD, a professor of Integrative Structural and Computational Biology at Scripps Research and the principal author of the new paper. “Gaining insights into these reactions could lead to more intelligent vaccine designs and immunotherapeutics. This represents a significant advancement in optimizing strategies involving antibodies and vaccines against HIV and other diseases.”
The discovery was made when Ward’s team utilized cutting-edge imaging techniques to analyze how antibodies develop after receiving several doses of an HIV vaccine. They employed a method created by the lab, called Electron Microscopy-Based Polyclonal Epitope Mapping (EMPEM), which allows researchers to precisely observe where on the HIV virus antibodies attach. During experiments using blood samples from animals that had undergone multiple experimental HIV vaccine doses, they uncovered an unexpected finding: some antibodies were binding not directly to the HIV viral antigen, but rather to immune molecules present on its surface.
“These antibodies do not directly interact with the viral protein,” states Sharidan Brown, a graduate student at Scripps Research and the lead author of the new study. “We are the first to provide a structural characterization of this type of antibody in the context of HIV vaccination.”
Previously, it was known that anti-immune complex antibodies could develop in certain circumstances. This occurs when the immune system identifies antibodies that are already attached to viral proteins, prompting an additional immune reaction that generates new antibodies, including ones that link to existing immune complexes on the virus’s surface.
In follow-up experiments involving HIV-vaccinated animals, Brown, Ward, and their colleagues demonstrated that such anti-immune complex antibodies typically emerge between the second and third doses of a vaccine.
“We’ve confirmed the existence of these antibodies, but we still need to determine how they influence the immune response,” remarks Brown. “They might be harmful since they do not neutralize the virus directly, but they could potentially lead to the formation of larger immune complexes that stimulate further activity against the virus and infected cells in ways we do not yet fully comprehend.”
If future research indicates that these antibodies are indeed undesirable, it could inform vaccine design strategies to reduce the immune complex response and enhance vaccines’ capacity to neutralize HIV directly. This could also prompt alterations in HIV vaccine schedules, potentially involving a series of varied boost immunizations against the virus instead of multiple doses of the same vaccine.
“Slight variations between each dose could generate just enough diversity to prevent the production of antibodies against the antibodies,” notes Brown.
The research team intends to continue examining these antibodies, as well as investigating whether similar antibody responses are triggered after several doses of other vaccines or during natural infections.
This work was funded by Scripps Research, an amfAR Mathilde Krim Fellowship in Biomedical Research (110182-69-RKVA), the National Institute of Allergy and Infectious Diseases (R01 AI136621, P01 AI110657, UM1 AI100663), the Bill and Melinda Gates Foundation, and the Collaboration for AIDS Vaccine Discovery (CAVD) Network (INV-002916).
