To Build A Viable HIV Vaccine, Start from the Molecule Up

AN HIV DIAGNOSIS is a nightmare, but it is no longer a death sentence. Someday, vaccines might bat the virus out of your system without you ever knowing you’d...

AN HIV DIAGNOSIS is a nightmare, but it is no longer a death sentence. Someday, vaccines might bat the virus out of your system without you ever knowing you’d been exposed. If successful, such a vaccine would effectively cure AIDS. Someday, maybe. So scientists are working on it. Like yesterday: Researchers published results to a promising study on primates infected with SIV, a monkey version of HIV. The study, published in Nature, used a special drug to awaken the virus, which made it easier for their novel vaccine to detect and snuff it out. This study is part of a new wave of HIV-focused vaccinology powered by troves of genetic data and atomic-scale engineering.

More than two million people get HIV each year. In developed countries, antiretroviral drugs can keep the infection in control. But roughly half of all HIV/AIDS patients simply don’t have access. Which is why a vaccine—which patients would only need to get once, or perhaps with a few boosters—would be so transformative to global health.

A Molecular Revolution

Compared to methodical do-no-harm modern medicine, historical vaccinologists were cowboys. They used coarse methods that only let them see results at the end of their research. And they took a lot of risks with their patients’ health. And now—though patient safety standards are better, and biologists know more about the immune system—vaccines are basically developed using the same old primitive methods devised by pioneers like Edward Jenner and Jonas Salk. In order to trigger an immune system response, they use a weakened, dead, or deconstructed version of the virus.

But now the field is starting to move away from empirical gunslinging, and towards rational drug design. Rather than use old viruses, biologists practicing rational design create their own vaccines from scratch, designing molecules after images they glean from advanced microscopes and intricate modeling software. “We’ve got a sort of new revolution going on now,” says Dr. Barney Graham, the Deputy Director of the Vaccine Research Center at the National Institute of Health. “It involves the ability to not just design antigens at the atomic level but to also conceive of novel ways to deliver them. Vaccinologists before studied viruses. Today they are more structural biologists, protein biochemists and immunologists.”

Driving these changes is a stark reality: Biologists have already figured most of the easy vaccines—measles, smallpox, polio. HIV is way more tricky and tenacious. “If you think of it in terms of a sports analogy, the score is 76 million to zero.” says Carl Dieffenbach, Director of the AIDS Division at the NIH. “Even some people survive Ebola. But humans have no natural immunity to HIV. So we’re having to engineer an immune response that doesn’t exist anywhere in a human body.” That kind of difficulty has forced vaccinologists to think creatively about their adversary.

But new technologies are what really let the scientists put their creativity to work. Single cell sequencing lets scientists figure out exactly how immune system cells—usually a B lymphocyte, a type of white blood cell that produces antibodies—memorize foreign pathogens. Once they know which genes make different antibodies, they can make them artificially. Then they use a technique called cryo-electron tomography to make 3D models of each antibody. Unlike other imaging techniques (like plain old electron microscopy) that destroy molecular folds and crannies, the plunge-freezing process preserves cellular structures. Scientists need to see minuscule sites like receptors up close to figure out how antibody molecules fit inside and bind to them. Because that binding is what creates immunity.

“It’s fundamentally a shape problem,” says Dennis Burton, a longtime HIV/AIDS researcher at The Scripps Research Institute. “All the shapes these antibodies recognize are parts of proteins on the surface of the virus. If we can study these antibodies in molecular terms then we can reconstruct these shapes and put them into people. If we do everything right, they’ll react to those shapes, make the right antibodies and be protected against HIV.”

Neutralization, Broadly

But nothing with HIV is so simple. While humans don’t have full-blown immunity to the virus, about twenty percent of HIV-infected individuals do develop something called broadly neutralizing antibodies. Most antibodies work by binding to an antigen, thereby flagging it for destruction by a white blood cell. Broadly neutralizing antibodies bind to an antigen, and block its biological effects. The end result is the same (virus can’t go viral), but broadly neutralizing antibodies don’t need white blood cells to do the system-wide body cleansing. Which is a big deal with HIV, since white blood cells are its primary target.

Burton is one of a handful of researchers dedicated to developing a vaccine approach using these broadly neutralizing antibodies. In the early 90s, Burton was the first to show that broadly neutralizing antibodies could protect macaque monkeys from SIV. But he says breakthroughs have only really been happening in the past few years. “There’s been a real explosion of activity in making these antibodies,” he says. “For a long time we only had four different kinds, and now we’ve got hundreds. That enabled us to understand exactly how they recognize the spike protein on the surface of the virus, which led to the design of many new proteins that are really good candidates for vaccines that could induce broad immune responses.”

In April, the HIV Vaccine Trial Network and its partner the HIV Prevention Trial Network began enrolling participantsin two phase 2b clinical trials to evaluate the safety and efficacy of a broadly neutralizing antibody called VRC01. The first will enroll 2700 men or transgender persons in the US, Brazil, Peru and Switzerland. A parallel study in Sub-Saharan Africa will enroll 1500 sexually active women. Every eight weeks, both groups will receive either a placebo or an infusion of antibodies. After a year and a half, researchers will measure how much antibody is in the blood of study participants receiving different doses, in addition to measuring any longer term protective effects in the event of infection.

Burton hopes his group will have their own trials up and running by some time next year, but he’s realistic about what exactly they’ll learn from them. “We know it won’t go all the way to inducing fully neutralizing antibodies, we’d be flabbergasted if it did that,” he says. The challenge is getting the antibodies to mature along a specific pathway. But HIV has enough variation to confound any simple nurturing, because they have to target multiple viral strains. “It’s like having to jump five hurdles to get to the finish—we’re hoping to answer the question; ‘does the vaccine take us over hurdle number one?’ Does it kick off a broadly neutralizing response?”

If the answer is yes, biologists will have to make still other vaccines to stack upon one another in order to give patients full immunity. HIV has proliferated into hundreds of thousands of different strains. Some researchers believe they could use a broadly neutralizing approach do develop a universal vaccine that works agains them all. Others are more prosaic, looking for full protection now, not years from now.

One Clade At A Time

The first large-scale clinical trial of an HIV vaccine in seven years began last month in South Africa. On October 21, study participants received their first of five injections they’ll need over the course of a year. The vaccine is called HVTN 702. The first three boosters are based on canarypox-based (yes, that’s like chickenpox except for canaries) vaccine called ALVAC-HIV developed by Sanofi Pasteur. The final two pokes are of a single HIV protein molecule vaccine made by GlaxoSmithKline.

It’s an extension of an earlier study called the Thai Trial, which in 2009 showed for the first (and only) time, a protective effect against HIV infection in humans. At the time, researchers were shocked to get a 30 percent reduction rate. Now with improved molecular techniques and a more targeted design, they’re hoping for even better.

Results from the South Africa trial are due in 2020. If successful, they’d be a boon not only for HIV vaccine research, but also for in-the-now human treatment. The country is the world’s HIV capital, with an estimated seven million infected people. The vaccine—customized to attack South Africa’s dominant HIV subtype—would be theoretically less effective in the US or Venezuela. But Dr. Larry Corey, HVTN’s principal investigator and former President and Director of the Fred Hutchinson Cancer Research Center, says the vaccine is showing good responses across subtypes, called clades, which bodes well for broader application. “We’re starting to think maybe we don’t have to completely re-engineer the vaccine for different geographic regions,” he says. “If we get good efficacy in Africa and there are markers for the same kinds of antibodies in clade B or clade A or clade D, then let’s go there! Let’s carry those vials all over the world!”

While a real clade-hopping HIV vaccine is still years away, this work is already showing real time impacts on vaccines against other infections. “It’s a driver for the whole modernization and evolution of vaccinology into a rigorous molecular science,” says Burton. The universal flu vaccine is a great example. Each year’s flu vaccine is based on the most recent strain available. Which works reasonably well, but is not perfect—people still get sick. This year researchers announced a new generation of universal flu vaccines ready to go to clinical trials. One covers 88 percent of global strains, and a US-specific vaccine covers 95 percent of domestic strains. With that kind of vaccine you could save all your sick days for trips to the beach.


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