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Scientists at Scripps Research, IAVI, the Ragon Institute and Moderna, Inc., have come together to make critical advances in developing an effective vaccine against human immunodeficiency virus (HIV).

The findings were published on September 29, 2022, in Immunity in two individual papers. The research describes the first steps in a vaccine approach that aims to prompt the creation of broadly neutralizing antibodies (bnAbs) — antibodies that are broad enough to fight and protect against many different variants of a virus. By identifying the most promising bnAbs and the human genes needed to make them — as well as designing protein and mRNA vaccine candidates to begin bnAb creation and verifying the vaccine candidates — the team is paving the way to create an effective HIV vaccine.

“Our two studies describe a collaborative effort to genetically and structurally understand bnAbs, and ultimately ‘reverse engineer’ vaccines to elicit these bnAbs,” says senior author William Schief, ciproxin flebo PhD, a Scripps Research professor and executive director of vaccine design at IAVI’s Neutralizing Antibody Center at Scripps Research. “HIV has remained one of the most difficult viruses to protect against because of its natural ability to quickly mutate and evade capture from the immune system. Working closely together across scientific disciplines and institutions, our team’s findings mark a crucial step forward in overcoming these historic hurdles and creating an effective HIV vaccine.”

Building Backwards

Researchers have long studied how a small percentage of infected individuals with HIV are able to make bnAbs. Even when bnAbs do develop during infection in these cases, they arise too late to help block the virus. However, researchers have demonstrated that bnAbs can protect against the virus if they are present before a person gets infected with HIV. This observation has led scientists to try to develop vaccines that induce bnAbs in healthy individuals, but designing such vaccines has proved difficult.

The new work at Scripps Research, IAVI and Ragon aims to break the logjam by carefully choosing the bnAbs to elicit, and then designing custom vaccines that coax the immune system to produce the target bnAbs in a stepwise manner. The team focused on bnAbs that bind to the apex of the HIV spike protein (analogous to the spike protein of SARS-CoV-2). These apex bnAbs employ extremely long loops (called HCDR3 loops) to pierce the spike protein like a spear. By binding to the apex of the HIV spike, the bnAbs prevent HIV from infecting human cells.

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