Forty years ago, researchers described the mysterious cases of five homosexuals who had fallen ill with pneumonia caused by the bacterium Pneumocystis carinii. Two of the five men had already died.
That type of pneumonia usually affects only severely immunocompromised individuals, the researchers wrote in the weekly Morbidity and Mortality Report of June 5, 1981. Scientists would soon discover that a disease known as AIDS was devastating men's immune systems.
Three years later, scientists blamed AIDS on a virus called HIV or the human immunodeficiency virus. Margaret Heckler, then American. The Secretary of Health and Human Services said at an April 1984 press conference that a vaccine to protect against the virus would be ready to be tested within two years, keeping the promise that protection was on the way.
We are still waiting.
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Meanwhile, the HIV pandemic, which probably began in the Congo in the 1920s, caused a devastating loss. More than 75 million people became infected worldwide by the end of 2019. Approximately 32.7 million people died.
That toll would undoubtedly be much higher if it were not for the advances in antiviral treatments that can prevent infected people from dying from HIV and transmitting the virus to others (SN: 3/4/20; SN: 15/11/19) . To date, only three people have overcome an HIV infection (SN: 26/08/20). For most, it lasts a lifetime.
That long-term infection is just one of the reasons there is no HIV vaccine yet. It is also a complicated virus to identify, with many variants and a strange ability to bypass the immune system.
And money is also an issue. The lack of an effective HIV vaccine contrasts fully with COVID-19 vaccines which took less than a year to develop (SN: 11/9/20). For the development of the COVID-19 vaccine, “the money shed, which was the right thing to do,” says Susan Zolla-Pazner, an immunologist at the Icahn School of Medicine on Mount Sinai in New York City. Funding for HIV vaccine research is done in five-year installments, making it difficult to allocate money efficiently to get the vaccine out. Still, that funding flow has allowed for advances in HIV research, which has allowed in part the rapid success of several COVID-19 vaccines.
The technology behind Johnson & Johnson’s COVID-19 jab, for example, was first developed as a strategy to combat HIV because it triggers a strong immune response (SN: 27/02/21). The shot uses a common cold virus that has been altered so that it no longer causes disease. That carrier delivers instructions to the cells so that the viral proteins needed to train the immune system to recognize the invader. Johnson & Johnson’s COVID-19 vaccine uses a virus called adenovirus 26; the first candidates for the HIV vaccine used adenovirus 5.
Unfortunately, a clinical trial to test for the HIV vaccine showed that participants who had already been naturally infected with adenovirus 5 were more likely to become infected with HIV. Investigators stopped the trial. They speculated that these participants were more susceptible to HIV because they already had immunity to adenovirus 5 and that they dampened the vaccine’s HIV protective responses.
Gallo Images / The Times / Jackie Clausen
The absence of a good HIV vaccine is not for lack of evidence, says Mark Feinberg, a viral immunologist who is president and CEO of the International AIDS Initiative in New York. "The work dedicated to developing the HIV vaccine has been by far the most sophisticated and creative."
Complexities of HIV
Much of the difficulty in getting a vaccine comes from the complex biology of the virus.
A major challenge is the immense genetic diversity among HIV viruses that infect people around the world. Like coronavirus, which has more transmissible variants or are able to bypass parts of the immune system (SN: 27/01/21), HIV also has variants. But “it’s a completely different world for HIV,” says Morgane Rolland, a virologist with the Military HIV Research Program at the Walter Reed Army Research Institute in Silver Spring, Md.
That’s because the virus makes new copies of its genetic plan at a dizzying pace, generating tens of thousands of new copies every day in a single person, Rolland says. Each of these new copies carries on average at least one unique mutation. Over the years, a single person can carry countless variants in their body, although only a few variants can be passed on to other people.
The main problem that these variants pose for vaccines is that some mutations are in parts of the virus that the immune system tends to attack. These changes can essentially help the virus to be incognito. Good vaccines should elicit an immune response capable of handling that great diversity to provide broad protection against infection.
What’s more, the virus deploys various tactics to hide from the immune system. One of the tactics the virus uses is to cover parts of its surface in a dense layer of sugar molecules. Many of these surfaces would be the main targets of immune proteins called antibodies that bind to viral particles.
NIAID / Flickr (CC BY 2.0)
The body recognizes these sugars as “own,” says Barton Haynes, an immunologist at the Duke University School of Medicine’s Human Vaccines Institute. Basically, what the virus tells our immune system is, “Of course, you can make a protective immune response, go for it.” But if the antibodies attack, they look like coatings and are removed. That means the body can’t fight. the virus so effectively.
However, perhaps the biggest hurdle is the lifelong nature of the infection. Many viruses disappear from the body after the immune system fights. But HIV has the ability to insert its genetic plan into the host’s DNA, establishing a hidden deposit in immune cells called T cells, which normally fight infections (SN: 24/10/13). That deposit makes the virus invisible to the immune system. Once the virus inhabits its new hiding place, the immune system cannot eradicate it or even drug treatments.
That means “you have to have protective immunity there on the day, the time of transmission,” Haynes says. "If (the immune system) doesn't get rid of the virus within 24 hours, the virus has won."
Most vaccines do not generate this type of sterilizing immunity that prevents infection from occurring in most people who receive the vaccine. On the contrary, shooting is more likely to prevent people from becoming seriously ill. Many COVID-19 vaccines, for example, are highly effective in preventing people from developing symptoms, especially severe ones. But some vaccinated people can still become infected with the coronavirus (SN: 05/05/21).
That’s not an option with HIV as it never leaves the body, Zolla-Pazner says. "It's a very different bar to the one we have to jump for an HIV vaccine."
HIV vaccine candidate testing
To date, there have only been a handful of clinical trials to test the effectiveness of potential HIV vaccines in people. Of the six trials the scientists saw at their conclusion, only one vaccine candidate was effective in preventing infection.
That single successful trial, known as RV144, used a “prime-boost” strategy in which participants received a total of six shots. The four “primary” strokes contained a canary virus that is unable to replicate in cells and contains genetic instructions for selected HIV proteins. Participant cells manufacture these viral proteins and develop an immune response against them.
Then participants also received two “boosts,” an injection of a fragment of HIV protein that is essential for the virus to enter cells. The hope was that participants would develop a strong and broad immune response, giving those people broad protection against a variety of HIV subtypes.
Ultimately, this vaccine strategy reduced the risk of infection by 31.2 percent in vaccinated participants compared to the unvaccinated group. Although the shot showed only modest effectiveness, those results changed the field by identifying the type of immune response people needed to prevent infection, Zolla-Pazner says.
“Until then, there was this furious debate about whether T cells or antibodies were more important in terms of protection,” says Zolla-Pazner. The results of RV144, first published in December 2009 in the New England Journal of Medicine, suggested that specific antibodies were the crucial factor in reducing the risk of infection. "That doesn't mean T cells aren't important. But I think it's established the primacy of antibodies," he points out. If researchers could push people to make protective antibodies against HIV, then perhaps it would be within reach of a vaccine.
More recently, however, the strategy against canary and protein has produced some less promising results. In February 2020, when COVID-19 was spreading around the world, researchers stopped a follow-up trial in South Africa that used the same vaccine platform with the goal of improving RV144 discovery (SN: 2/3/20). The results of the trial did not reduce the risk of HIV infection in vaccinated people, the researchers reported on March 25 in the New England Journal of Medicine.
This is where more money for HIV vaccine research could help, Zolla-Pazner says. "If they had the money up front and used it as needed … (scientists) would be doing science more efficiently and therefore would get the answers faster." That investment is especially crucial for early animal testing. Instead of spending decades testing approaches on a handful of animals at once to see if something works, a cash flow could support more robust experiments. And that could accelerate promising approaches in the arms of clinical trial volunteers.
Making the right immune response
There are now promising signs that vaccine developers working on a variety of platforms may be on track to make an effective shot that provides sterilizing immunity. Still, “I don’t think we should take any approach from the table right now,” Zolla-Pazner says.
One approach is to take advantage of the idea that some infected people naturally make antibodies capable of attacking a wide variety of HIV variants and preventing these viruses from infecting cells (SN: 20/07/17). These antibodies take a long time to develop. Sometimes they don’t develop until years after an HIV infection was fixed, Haynes says. HIV vaccine manufacturers want to speed up the process.
There are several ways to do this. One of them, which is now being tested in a clinical trial led by Johnson & Johnson, is to elicit a broad immune response using an HIV protein composed of a mosaic of different strains of HIV circulating around the world. Another way is to teach the immune system how to make widely neutralizing antibodies.
To do this, researchers identify widely neutralizing antibodies in HIV-infected people. They can then analyze the steps the body has taken to create those immune proteins. The goal is to develop a vaccine that tells vaccinated people to make similar antibodies when they are exposed to specific viral fragments, says Kevin Saunders, a vaccinologist at the Duke Human Vaccine Institute.
In a December 2019 scientific study, Saunders, Haynes, and colleagues demonstrated that in vaccinated cattle and monkeys could stimulate the first steps of HIV antibodies that could eventually be neutralized. A separate effort by Feinberg and colleagues recently showed that 97 percent of human participants in an early-stage clinical trial caused those same rare immune cells to be exposed to a piece of HIV designed to specifically generate cells.
Other groups focus on T cells to fight infection. Louis Picker and Klaus Früh, for example, have developed a vaccine that causes specialized T cells to kill other HIV-infected T cells, rather than relying on antibodies to prevent infection altogether, the team reported in March in Science Immunology.
The team has already shown that half of the monkeys who were given the vaccine were protected. The animals became infected with SIV, the primate equivalent of HIV, but the virus could not replicate very well and over time the infection disappeared, says Picker, an immunologist at Oregon Health & Science University in Portland.
The next step is to transfer the vaccine to people. “Everything we see in the clinical trial is paving a new path,” says Früh, a viral immunologist also at Oregon Health & Science University. "It's the first time it's been done, so we're very excited about it."
After nearly four decades of trying, there is little light at the end of the tunnel. “I really think we’re going to have a vaccine,” Zolla-Pazner says. "But I don't know how long it's going to take."
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