Two years ago, at the HIV Prevention Research Conference (HIVR4P) in Madrid , Professor Lynn Morris of the South African National Institute of Communicable Diseases made a prediction about the AMP (Antibody-Mediated Protection) studies . These two studies are the first large-scale trials to use bimonthly injections of a broadly neutralizing antibody (bNAb) called VRC01 as a drug to prevent infections.
Morris said: "There is currently a lot of debate about whether an antibody will be enough to do the job."
At yesterday 's virtual HIVR4P conference , originally planned for Cape Town but now taking place on computer screens worldwide, that debate was answered. VRC01 simply wasn't enough. The overall reduction in HIV infections, compared to the placebo, was 19%, and this reduction wasn't statistically significant, so scientifically speaking, it wasn't considered a reduction at all. This result confirmed Lynn Morris's concerns, but it was more disappointing than expected.
So why were the AMP studies still hailed as a "game changer"? The VRC01 antibody produced a 75% reduction in the number of infections with the type of virus most sensitive to this particular bNAb. Since these represent less than a third of circulating viral strains, VRC01 cannot be used as a preventative drug on its own.
But for the first time, scientists have a very precise threshold for its effectiveness and know that it will contribute to prevention regimens that use combinations of bNAbs, combinations that are currently undergoing trials.
Broadly neutralizing antibodies are unusual antibodies that develop in a minority of people chronically infected with HIV and have characteristics that elude the strategies HIV uses to ignore the body's natural antibody response.
The two AMP studies randomly assigned a total of 4,600 people to receive one of two doses of VRC01 or a placebo. The HVTN 704 trial involved 2,700 gay and bisexual men and transgender women in the Americas, and HVTN 703 recruited 1,900 cisgender women in sub-Saharan Africa.
The potency of antibodies is measured in what are called titers, which are the concentration of antibodies in the blood needed to reduce the infectivity of a particular viral strain, in this case, by 80% (the so-called IC80 ). The higher the titer, the wider the range of viruses inhibited by the antibody.
At the start of the AMP trials, researchers expected that HIV strains with an IC80 of less than 10 micrograms per milliliter would be neutralized by VRC01. This would represent 65 to 81% of circulating viral variants, as measured by so-called 'panels' of different viruses taken from patients in different parts of the world.
However, in this case, a significant difference in infections was only observed between those who received VRC01 and those who received placebo in patients infected with viruses with an IC80 below 1 microgram per milliliter. This represents only the 30% most "sensitive" viral variants.
Because the proportion of susceptible viruses differed between the two studies, this meant that the efficacy of VRC01 was different: it prevented 26.6% of infections in the HVTN704 trial in gay men, but only 8.8% of infections in the HVTN703 trial in women. On average, the overall efficacy was 19.25%, and this was not statistically significant.
As noted, although the AMP results were disappointing, they still represent progress.
Lead researcher Professor Larry Corey told aidsmap.com : “We now have a success marker for the use of bNAbs as preventative measures, and it confirms that we will need cocktails of these antibodies, rather than individual ones, to neutralize most viral isolates.
“Yes, it would have been good if VRC01 had been more potent on its own. But it was only the first of many bNAbs to be characterized, and we are already conducting a clinical trial with three of these antibodies. We are also looking for longer-lasting formulations of these antibodies.”
"The VRC01 antibody produced a 75% reduction in the number of infections in the most sensitive viruses."
Until now, the search for and purification of these rare antibodies, which have so much potential as components of new HIV treatment and prevention combinations, has been a matter of chance. Their production has been a complex business, involving the extraction of these antibodies from mixtures, which entails significant expense.
Another study presented at the HIVR4P opening press conference has found a way to get the immune system's B cells, the ones that produce antibodies, to produce bNAbs in larger quantities and of greater purity than before.
Dr. Emilie Seydoux, from the Fred Hutchinson Research Center in Seattle, presented her team's work on so-called 'anti-idiotypic monoclonal antibodies' (AI-mABs) that bind to B cells themselves. They can be 'tuned' to stimulate the proliferation of highly specific B cells that produce only one type of antibody. In mouse experiments, using a combination of two of these antibodies, they were able to induce the proliferation of VRC-01-producing B cells. These AI-mABs could also be used as a vaccine to induce a finely tuned response to HIV. References
Corey L et al. VRC01 Antibody HIV Prevention. HIVR4P Virtual Conference, abstract HY01.01LB, 2021.
Seydoux E et al. Development of a novel germline immunogen targeting the VRC01 class derived from anti-idiotypic antibodies . HIVR4P Virtual Conference, abstract OA08.05LB, 2021.
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