First Study Results of Passive Antibody Transfer Spur Future Planning

Following positive initial results from Phase I safety trials evaluating direct administration of VRC01, an HIV-specific antibody that is able to neutralize a broad variety of HIV strains, the National Institute of Allergy and Infectious Diseases (NIAID) is preparing for a series of further studies to see if this broadly neutralizing antibody is effective in preventing transmission of HIV from mothers to their infants, as well as among high-risk adults. The researchers are also doing experiments on the antibody to see if they can boost its potency and lengthen the time the antibody lasts in the body, with an eye to reducing the eventual dosage that patients would need if this approach is successful.

The initial adult trials will likely involve a group of 64 volunteers who will receive different doses of the VRC01 antibody, isolated at NIAID’s Vaccine Research Center (VRC), administered either intravenously or via injection under the skin. The study, to be coordinated with the HIV Vaccine Trials Network, will include healthy, HIV-uninfected adults from age 18 to 50 monitored over a period of six months, with 12 weeks of follow-up after the final dose.

Researchers will use this study to further evaluate safety and examine the pharmacokinetics—in this case, the length of time an effective amount of antibody remains in the bloodstream—of the antibody using this approach, which is called passive transfer. One group of 20 volunteers will get an initial dose of 40 milligrams of antibody per kilogram of weight, then 20 milligrams every month; the second group will get the same initial dose followed by a 40 milligram dose every other month; a third group will get the 40 milligram starting dose and then subcutaneous injections of 5 milligrams per kilo of weight every two weeks. A small fourth group will get placebo injections.

Researchers will look to see if the different doses generate different VRC01 antibody levels in the body over time, and whether these levels reach the threshold level that is needed to neutralize HIV. To stop HIV from transmitting from one person to another, says immunologist and VRC senior investigator Barney Graham, you need much lower antibody coverage than you would need to actually treat or cure HIV. Developing a vaccine that can induce this level of antibodies remains the ultimate goal, but Graham says studies such as these may help define a threshold level of neutralization that would be a guideline or target for a future candidate vaccine.

Results of intravenous and subcutaneous antibody injections to both HIV-infected and uninfected adults in the Phase I safety trials, known as VRC 601 and VRC 602, are now being examined by researchers, Graham says; so far some volunteers have taken more than 80 doses and have shown no signs of serious side effects. Analysis is ongoing but, for example, in dose levels of 20 milligrams per kilo of body weight, antibody levels are staying above the 40 microgram per milliliter threshold for as long as 28 days later.

Thinking ahead, Graham says, making the antibody levels last longer would make it much more likely for people to want to use it—a new mother is busy, and if she has to get injections every week it might be hard to comply. This is especially true in Africa, where Graham is attending this week’s HIV R4P congress in Cape Town. It would be hard enough for a mother to come in every other week from the sprawling Cape Flats suburbs; reaching moms in rural Tanzania would take some doing.

So researchers continue to work with VRC01 to see if they can improve both its potency and lengthen its lifespan, both of which would have the effect of reducing the necessary dosage in passive transfer studies. So far, VRC scientists have manipulated the VRC01 antibody’s amino acid structure and experimented with mutations, producing new antibody variants that show promise. VRC07-523, for instance, is more potent and has a greater neutralization breadth than VRC01, Graham says. Another mutated antibody is retained in monkey epithelial cells—especially in the gastro-intestinal tract—which could mean that the body would start producing, or at least recycling, the neutralizing antibody on its own. Since HIV is essentially a disease of the gut, this would be a good place for that to happen.

The ongoing safety trials of VRC01 should also lead to a new set of trials to study prevention of mother-to-child HIV transmission. NIAID would team up with IMPAACT—the International Maternal, Pediatric, Adolescent AIDS Clinical Trial Network—to conduct studies involving 13 volunteers, some in the US and then a few in Africa, Graham says. Each would get a single dose of VRC01 in order to evaluate safety. From there on studies would look at efficacy of HIV prevention and volunteers would get antibody doses in addition to antiretroviral treatment.

“The idea is that a long-acting product may significantly improve the overall efficacy of that approach,” Graham says. – Michael Dumiak