WebMD – Updated for October 2021

Author: Liz Scherer

Over the past decade, advances in HIV treatment have yielded new drug combinations, once-daily dosing, and, most recently, the introduction of long-acting injectables for pre- and post-exposure prevention and treatment.

But why has it been so difficult to make an HIV vaccine?

“The difficulties of vaccine candidates that have been tested in people so far is that none of them produced broadly neutralizing antibodies (bnAbs) against HIV, which are antibodies produced by the host immune system that have the ability to block HIV in target cells,” explains Mark Feinberg, MD, president and CEO of the International AIDS Vaccine Initiative (IAVI).

Just this week, the National Institutes of Health announced that yet another HIV vaccine candidate, which was aimed at producing non-neutralizing antibodies, failed to provide sufficient protection against HIV infection in women.

But the tide may be turning. IAVI and Scripps Research, along with Moderna and other partners, are about to launch a phase I clinical study that will assess the ability of two vaccine candidates mRNA 1644 and mRNA 1644v2 to safely generate broadly neutralizing antibodies in healthy adults. The study is set to begin recruiting participants the third week of September.

Can Broadly Neutralizing Antibodies Break HIV’s Elusive Spell?

For four decades, the human immunodeficiency virus (HIV) has managed to elude the immune system’s attempts to eliminate it. This is due to several factors, including the virus’s ability to rapidly evolve to produce new mutations that help it evade antibodies. The virus has also found a way to camouflage its outer layer (the HIV envelope glycoprotein, or HIV env) with the same sugar chains found on human proteins, so that it remains hidden from attack. Like the coronavirus, HIV env uses protein spikes to attach to and enter host cells and infect them.

IAVI and Scripps Research may have discovered an important key to crack the virus’s impenetrable armor. They’ve come up with a way to engineer an immunogen (a type of antigen that elicits an immune response) that both looks like the HIV env structure and can induce specific immature B cells to develop broadly neutralizing antibodies before a person is exposed. Importantly, only 10%-20% of people infected with HIV develop broadly neutralizing antibodies on their own, most commonly after several years.

The hypothesis that the mRNA-1644 vaccine candidate can activate certain types of immature B cells to produce targeted broadly neutralizing antibodies was first explored in laboratory and animal studies, and then in human subjects.

In the human study, 48 healthy, HIV-negative adults received two doses of a scientifically engineered, protein-based immunogen or placebo 2 months apart. The findings, which were presented earlier this year at the HIV Research for Prevention annual meeting, provided the “proof of concept” — no safety issues emerged, and 97% of people who got the vaccine candidate produced the desired response: the production of specific immature B cells.

In the upcoming study, 56 adults between the ages of 18 and 50 will be divided into four groups and receive the mRNA vaccine 1644, the mRNA 1644v2-core antigen, or both. The study will use a stepwise approach, first to activate the immature B cells and then to guide them along the path to broadly neutralizing antibodies production against one specific area on the HIV env: the CD 4 binding site. Notably, the trial is using Moderna’s mRNA platform (the same used in the production of the COVID-19 vaccine), which will help accelerate the process of HIV vaccine discovery and development. The study will run for roughly 19 months.

A Long Road Ahead

Feinberg emphasizes that it’s early in the research process, and researchers are hardly close to developing an effective HIV vaccine.

“This is a challenge of unprecedented magnitude in vaccine development,” he says. “We’re going after specific targets introducing [broadly neutralizing antibodies] against different structures on the HIV env glycoprotein.”

The process of targeting immature B cells with specific properties (that mature into cells capable of generating multiple broadly neutralizing antibodies) ) is called “germline targeting” and is intended to “prime” young B cells as part of a first step of an eventual multi-step vaccine strategy. The goal of the first study is to see how far down the path the initial immunogen goes and use the findings to define the steps needed to further refine the process of making broadly neutralizing antibodies.

“We know that ultimately, we are going to have to induce [broadly neutralizing antibodies] against more than one target,” Feinberg says.

Mohammed Sajadi MD, an associate professor of medicine at University of Maryland’s Institute of Human Virology, agrees.

“I think that it’s very innovative, very creative, but very ambitious,” says Sajadi, who was not involved in the study.

“We don’t know how many of these individuals can get this response [broadly neutralizing antibody production] with the natural infection, let alone [with] a vaccine, nor do we know how durable the response [will be],” he says.

Sajadi also points out the challenge that HIV’s innate properties pose: “The virus isn’t static; it changes with time. And the body’s responses against those changes is what makes these special antibodies.”

Still, he says that he believes the concept deserves to be tested.

“I think that there’s a lot to be learned from whether they can trigger this process — which it looks like they did in the first step — and if the mRNA platform [is able to] increase antibody titers or the number of cells that get activated,” he says.

“The field of HIV vaccines has been littered with great ideas, and very little show after all these years. But every time we do test something, we learn more and get closer. I am hoping that we can do that with this vaccine,” Sajadi says.

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