Scripps Research scientists receive NIH grant to unlock long-term HIV protection

Nearly 40 years after HIV was first identified, the virus continues its devastating march across the globe. Today, 38 million people live with HIV, and each year brings 1.5 million new infections and 650,000 more deaths-while nearly 10 million people still lack access to life-saving medicines. Despite decades of intensive research and remarkable progress in treatment, one goal remains frustratingly out of reach: a vaccine that provides lasting protection.

Now, a team of scientists at Scripps Research has been awarded a $6.9 million five-year grant from the National Institutes of Health (NIH) to address this specific challenge. Led by Bryan Briney, associate professor of the Department of Immunology and Microbiology, the collaborative project will combine the expertise of researchers across specialties. Collaborators on the project include Renan de Carvalho, assistant professor in the Department of Immunology and Microbiology; Andrew Ward, professor in the Department of Integrative Structural and Computational Biology; and Darrell Irvine, professor and vice chair of the Department of Immunology and Microbiology.

We've learned how to generate strong initial immune responses in patients, but we haven't cracked the code for making them durable enough to treat HIV. This project is about identifying the specific recipe-the right ingredients, the right amounts, the right timing-that creates protection lasting years or decades rather than months."

Bryan Briney, Associate Professor, Department of Immunology and Microbiology, Scripps Research Institute

Following immune 'breadcrumbs'

One key component is leveraging a novel mouse model from de Carvalho's lab that allows scientists to tag immune cells as they respond to a vaccine and then use those tags to follow the cells' journeys over months. While some vaccine-activated cells fizzle out quickly, others transform into long-lived plasma cells (LLPCs)-the immune system's dedicated antibody factories that can provide protection against viruses for years or even decades.

"We can now timestamp these cells with incredible precision, knowing exactly when they originate and tracking what becomes of them," explains de Carvalho. "It's like leaving breadcrumbs through the immune system-we can see which vaccine approaches lead cells down the path to long-term protection."

Identifying the right ingredients

Beyond tracking immune cells, Briney and his lab will focus on analyzing how individual cells protect against the virus. The team will use an advanced technique called single-cell multi-omics, which analyzes multiple layers of cell activity to provide a more complete picture of how each cell functions.

This approach is crucial for understanding complex biological processes, diseases and therapeutic effects that researchers' may have otherwise missed. By profiling thousands of cells and integrating multiple types of data, Briney's group will identify the molecular signatures that predict which vaccine-activated cells are destined to become LLPCs and provide sustained protection against HIV.

Building on their ability to closely profile immune cells, Ward and his team will use an imaging technique called electron microscopy polyclonal epitope mapping (EMPEM), which rapidly reveals how certain antibodies bind to the virus and whether they are able to provide protection.

"We're not just measuring antibody levels anymore," says Ward. "We're seeing the structural details of what the immune system builds in response to each vaccine design. That level of insight is exciting."

Meanwhile, Irvine's team will address ways to improve and extend vaccine protection by studying how LLPCs are formed. A key focus is on adjuvants, vaccine additives that can enhance the immune response. Not all vaccines require them, but the team aims to determine how adjuvants may boost LLPC production and improve vaccine durability.

"Understanding how LLPCs can support protection against HIV will unlock new insights into how to develop better vaccines," says Irvine. "Identifying the potential role of adjuvants in improving a vaccine could bring us closer to finding the perfect ingredients."

Building for the future

This project's implications reach far beyond HIV: Improving vaccine durability could accelerate efforts against influenza, malaria and other diseases where lasting protection remains elusive. By systematically connecting vaccine designs to long-term immune outcomes, the team hopes to create a roadmap that transforms how vaccines are built-not just for HIV, but for any disease where protection needs to go the distance.

"Finding an effective, long-lasting vaccine could significantly improve global public health outcomes," says Briney. "We're excited to work across disciplines to find a path toward this goal."