World AIDS Day: AIDS killed 460,000 people in Africa in 2020 — WHO

By Sola Ogundipe

An effective vaccine against the Human Immunodeficiency Virus, HIV, may not be far off, if findings by scientists at Scripps Research, IAVI, the Ragon Institute, and Moderna, Inc., are anything to go by.

Results of the research by the scientists who came together to develop the vaccine, published in Immunity, describe the first steps in a vaccine approach that aims to prompt the creation of broadly neutralizing antibodies (bnAbs) — antibodies broad enough to fight and protect against 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.

William Schief, a Scripps Research professor and executive director of vaccine design at IAVI’s Neutralising Antibody Center at Scripps Research stated:  “Our two studies describe a collaborative effort to genetically and structurally understand bnAbs, and ultimately ‘reverse engineer’ vaccines to elicit these bnAbs.

“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.”

Globally, according to the World Health Organisation, 38.4 million people were living with HIV at the end of 2021. An estimated 0.7 per cent of adults aged 15–49 years worldwide are living with HIV, although the burden of the epidemic continues to vary between countries and regions.

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.

It has been 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.

“To make an effective vaccine, we must first find the precursor antibodies that can eventually become bnAbs, while also seeing if those precursor antibodies are common enough throughout the general population to stimulate,” says the co-first author of both papers Zachary Berndsen, PhD, assistant professor of biochemistry, University of Missouri.

The Scripps Research and IAVI scientists collaborated with the lab of Facundo Batista, PhD, associate director of the Ragon Institute, to show the new immunogen was able to successfully bind to the germline precursor B cells and elicit the desired responses in mice expressing the bnAb germline genes at the same low frequency they appear in humans.

“This is a very important step, as it shows that vaccinating with our immunogen can actually elicit responses from the precursors we were targeting,” adds Willis. “We also showed that vaccinating with an unmodified HIV protein could not elicit those responses, which proves that our affinity engineering was required.”

The antibody responses have the potential to develop into bnAbs that could fight HIV, which the scientists will attempt to achieve in future studies with different boost immunogens that are still in the design stage.

“We and our collaborators are building on this approach, developing and testing immunogens to drive the later stages of bnAb maturation,” says Batista.

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