Ever since HIV was identified as the virus responsible for AIDS, scientists have been eager to formulate a vaccine against it. Outsmarting HIV would probably be considered one the greatest feats in modern medicine, given the scope of the epidemic. Since the 1980s, roughly 70 million people have been infected with HIV, and in 2016 there were about 37 million people worldwide living with HIV, according to the World Health Organization. While the US, for example, has seen a decrease in HIV infections by roughly 18 percent, other countries have been hit harder. Sub-Saharan Africa, for example, continues to see the virus take a toll. About 1 in every 25 adults lives with HIV in the region, which accounts for roughly 66 percent of HIV infections worldwide. If we had a vaccine, we could prevent HIV from taking any more casualties.
But developing a vaccine hasn't been easy, because HIV doesn't play by the rules. The simplified version of how a vaccine works goes like this: Normally a vaccine introduces a greatly weakened or inactive virus or bacteria into the body, which fools the body into thinking it has been attacked. That stimulates the immune system to send out a legion of defenders: B cells that produce antibodies to bind to and neutralize pathogens, and T cells which eliminate the infected human cells and recruit other immune cells to fight off the infection. After the infection has been cleared, the body is left with a large population of veteran memory B and T cells, which essentially remember how to fight that specific pathogen and can rapidly mobilize to prevent future infection if the pathogen returns.
Sounds like a good strategy—until HIV rolls in. In perhaps one of the greatest analogies in science journalism, one researcher compared the virus's MO to the stealthy Jason Bourne. "As soon as you think you have Bourne, he changes his appearance. HIV does the same thing," says Harris Goldstein, director of the Einstein-Rockefeller-CUNY Center for AIDS Research in New York City. "HIV continuously mutates and changes its structure, making the past plan of immune attack ineffective, because the previous immune response was directed at a structural element that is absent from the mutated virus. It's now dealing with a "new" virus, one which it doesn't have any previous experience fighting."
The second problem is that HIV likes to lie low. "HIV integrates itself into the genome of the cell and can hide there indefinitely until it is activated again," says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. "With flu or polio, you get infected, the virus will replicate, and then the immune response can sweep away virus. But with HIV, as soon as the virus starts replicating, it goes into a latent reservoir that is hidden from the immune system, so the immune system can't even see it, much less remove it."
On top of all that, the body doesn't seem to know how to make a good immune response against HIV, leaving it up to researchers to figure out how to fight it, Fauci says. "If we had some people who were able to clear the virus, we would study them to see what kind of immune response they made so we could design a vaccine to induce that kind of response," he says. "But to our great dismay, the body does not make an adequate immune response, which leads to the amazing but true phenomenon that virtually no one has cleared HIV from the body. So now we, as virologists, have a problem: We have to figure out a way to induce the body to make a response that not even natural infection is good at doing. That's the main conceptual reason why we are having such trouble."
The complex and ever-changing nature of the virus has led to hundreds of clinical trials that have all failed to come up with anything effective. One almost came close—the RV 144 trial led by the US Military HIV Research Program and the Thai Ministry of Health—and was the only vaccine that showed any protection against the virus in humans. However, it only lowered infection by about 31 percent, which wasn't good enough as researchers try to hit at least 50 percent. A decade ago, Merck hit a wall with an HIV vaccine, too. The pharmaceutical company had to cancel two trials of an experimental vaccine when it increased the rate at which participants contracted HIV.
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Despite the setbacks, scientists are still pushing forward. One promising vaccine called SAV001 will be moving to phase 2 clinical trials—there are three phases total—as early as this fall. This vaccine uses what's called a genetically modified whole killed virus, a similar approach used for the polio and hepatitis A vaccines. "We use chemicals and radiation to kill the virus and its genome," explains Chil-Yong Kang, the vaccine's creator and professor of virology at the University of Western Ontario. "But HIV's structural proteins are left intact, allowing the body to make antibodies against them." Researchers have been hesitant to use the whole killed virus method with HIV—if you don't adequately kill it, you risk injecting someone with HIV. Kang's meticulous approach, however, showed that SAV001 was safe after testing it on 33 HIV-positive participants, and also produced antibodies against the virus. "SAV001 elicited a neutralizing antibody response against not only HIV-1 subtype B but also against subtypes D and A even though it is based on subtype B," he adds. That's important because it potentially means that it won't be necessary to make as many different vaccines against the different HIV subtypes.
Last month, researchers shared more encouraging news at the International AIDS Society conference in Paris. They presented results from early trials of the Ad26-env mosaic vaccine, which hopes to tackle HIV's genetic diversity. The mosaic vaccine contains three or four computer-generated sequences of HIV that represent multiple strains that are circulating. The goal is to be able to teach the body different responses so that it has immune responses ready against many strains, not just one.
"This vaccine raised immune responses in 393 humans similar to what we observed in animals, including antibody responses in 100 percent of vaccine recipients," says Dan Barouch, one of the vaccine's principal investigators and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston. "This will be only the fifth HIV vaccine concept to advance into efficacy trials in over 35 years of the global HIV epidemic."
Back at the National Institutes of Health, researchers are rolling out a new version of the RV144, HVTN 702, to be tested on 5,400 men and women in South Africa, where it's estimated that 19 percent of adults aged 15 to 49 are living with HIV.
Ultimately, what everyone wants to know is when will an HIV vaccine actually be available? Perhaps, in true scientific form, experts are hesitant to even estimate; maybe they don't want to jinx it. Kang says that in the best case scenario, if his vaccine successfully passes through all the phases of clinical trials, it could be something like ten years. Fauci says scientists aren't sure if a vaccine is even possible, but says it's imperative that they still try. "Even though you don't know it's possible, that doesn't mean it's impossible. That's what science is. You try to push the science to make it possible," Fauci says.
Though impossibility looms overhead, researchers still think it's worth it to keep going. "At the end of the day HIV has humbled everyone because what we don't think will work, works, and what we think will work, doesn't," Goldstein says. "Every so called 'failure' is an opportunity to learn how to make the next vaccine better." All scientists can do now is keep tinkering and hope that, one day, "better" will be good enough.
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