September 2, 2021 – Over the past decade, advances in HIV treatment have resulted in 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 was it so difficult to make an HIV vaccine?
“The difficulty with vaccine candidates that have been tested in humans so far is that none of them produced broadly neutralizing antibodies (bnAbs) to HIV, which are antibodies made by the host’s immune system that 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 another HIV vaccine candidate, which was targeted at producing non-neutralizing antibodies, was not providing adequate protection against HIV infection in women.
But the tide can turn. IAVI and Scripps Research, together with Moderna and other partners, are starting a clinical phase I study to investigate the ability of the two vaccine candidates, mRNA 1644 and mRNA 1644v2, to safely generate broadly neutralizing antibodies in healthy adults. The study is scheduled to begin recruiting participants in the third week of September.
Can Broadly Neutralizing Antibodies Break the Elusive Spell of HIV?
For four decades, the human immunodeficiency virus (HIV) managed to evade attempts by the immune system to eliminate it. This is due to several factors, including the virus’ ability to evolve quickly to produce new mutations that help it bypass 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 coronavirus, HIV uses env protein tips to attach to host cells, invade host cells, and infect them.
IAVI and Scripps Research may have discovered an important key to cracking the virus’ impenetrable armor. They found a way to develop an immunogen (a type of antigen that elicits an immune response) that both resembles the HIV env structure and can induce specific immature B cells to develop largely neutralizing antibodies before an Person is exposed. It is important that only 10-20% of people infected with HIV develop largely neutralizing antibodies themselves, most often after several years.
The hypothesis that the mRNA 1644 vaccine candidate can activate certain types of immature B cells to specifically produce broadly neutralizing antibodies was first investigated in laboratory and animal studies, and then in humans.
In the human study, 48 healthy, HIV-negative adults received two doses of a scientifically developed, protein-based immunogen, or placebo, 2 months apart. The results, presented earlier this year at HIV Research for Prevention’s annual meeting, provided the “proof of concept” – there were no safety issues and 97% of people who received the vaccine candidate delivered the desired response: 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 given mRNA vaccine 1644, mRNA 1644v2 core antigen, or both. The study will take a step-by-step approach to first activate the immature B cells and then set them on the path to largely neutralizing antibody production against a specific area of the HIV env: the CD4 binding site. In particular, the study uses Moderna’s mRNA platform (the same one used in the manufacture of the COVID-19 vaccine), which will help expedite the process of HIV vaccine discovery and development. The study lasts about 19 months.
A long way to go
Feinberg emphasizes that the research process is still in its infancy and that researchers are hardly close to developing an effective HIV vaccine.
“This is a challenge of unprecedented proportions in vaccine development,” he says. “We pursue specific goals that introduce us [broadly neutralizing antibodies] against different structures on the HIV env glycoprotein. ”
The process of targeting immature B cells with specific properties (which will mature into cells capable of producing multiple broadly neutralizing antibodies) is called “germline targeting” and is intended to target young B cells as part of a first step a possible multi-step vaccination strategy. The aim of the first study is to see how far the initial immunogen goes and use the results to define the steps required to further refine the process of making broadly neutralizing antibodies.
“We know that we ultimately have to induce [broadly neutralizing antibodies] against more than one goal, ”says Feinberg.
Mohammed Sajadi MD, Associate Professor of Medicine at the University of Maryland’s Institute of Human Virology, agrees.
“I find it very innovative, very creative, but very ambitious,” says Sajadi, who was not involved in the study.
“We don’t know how many of these people can get that answer [broadly neutralizing antibody production] with the natural infection, let alone [with] a vaccine, nor do we know how permanent the response is [will be],” he says.
Sajadi also points out the challenge posed by the innate properties of HIV: “The virus is not static; it changes over time. And the body’s reactions to these changes make up these special antibodies. ”
Still, he says he thinks the concept deserves to be tested.
“I think there is a lot to learn about whether they can trigger this process – which looks like the first step – and whether the mRNA platform [is able to] increase the antibody titre or the number of cells that are activated, ”he says.
“The HIV vaccine field is littered with great ideas and very few after all these years. But every time we test something, we learn more and get closer. I hope we can do that with this vaccine, ”says Sajadi.
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