There's no question that vaccines have become a divisive topic. Thanks to vaccine hesitancy, fueled in part by politicization of the COVID-19 vaccine, now even diseases once thought to be afflictions of the past, like polio and measles, are creeping back up in pockets of the U.S.
But there is a vaccine, if ever discovered, that would be greeted with enthusiasm — at least among those most at risk, according to Dr. Anthony Fauci, who until recently led the National Institute of Allergy and Infectious Diseases (NIAID).
“If you told the general population, ‘We now have an HIV vaccine. Get it,’ I don't think there would be a lot of big uptake in the general population. But if you went to the specific people who know that they were in a risk category and were going to continue to practice risk behavior, I think the enthusiasm for taking an HIV vaccine — if we had a successful vaccine — would be far different than the anti-vax approach that we're seeing now in the general population with other vaccines,” Fauci said in a recent interview with Yahoo News.
“The mindset of the people who are at risk for HIV is a little bit different than the general population, and I think you have to factor that in,” he said.
Years before Fauci became the face of the nation's COVID-19 vaccine initiative, he was best-known for his work during the HIV/AIDS crisis — spearheading research for treatments since the early days of the discovery of the virus in 1981, when it began wreaking havoc in the gay community. Fauci once described the period before therapeutics were available as "the dark years of my life and career," and told Yahoo News he had "the experience, the privilege and the pain of for years taking care of persons with HIV who had almost a death sentence every time you had someone get infected.
“So I fully know what it means to have such a challenging and terrible situation of people getting infected with a virus that almost invariably leads to death.”
Since the beginning of the epidemic, 84 million people worldwide have been infected with HIV and about 40 million people have died. Now, thanks to the development of antiretroviral therapies, HIV, in the U.S. at least, is no longer the death sentence it once was; and preventative measures like Pre-Exposure Prophylaxis (PrEP), a once-daily pill regime, have dramatically reduced the risk of contracting HIV. In the U.S., 1.2 million people are currently living with the virus, with annual infections reduced by more than two-thirds since the height of the crisis in the mid-1980s.
Yet despite the successes of the past few decades, a vaccine — "the holy grail of unaccomplished goals" — remains elusive. Last month, experts in the so-far fruitless field of HIV vaccine research encountered yet another disappointment, when manufacturers of the only vaccine being tested in late-stage clinical trials announced they were shutting down the trial after it proved to be ineffective.
Why did this latest HIV vaccine candidate fail?
Known as Mosaico, the phase 3 clinical trial was launched in 2019 using an experimental vaccine regimen developed by Janssen Pharmaceuticals, a division of Johnson & Johnson, with funding from NIAID. The vaccine, which was tested in 3,900 volunteers across Europe, North America and South America, used a "mosaic" approach — incorporating elements of multiple HIV subtypes "with the goal of inducing immune responses against a wide variety of global HIV strains." Ultimately, the study's independent Data and Safety Monitoring Board concluded that while there were no safety issues with the vaccine, there was no difference in the number of HIV infections between those who received the vaccine and those who received a placebo.
Fauci said he was "disappointed" but "not thoroughly surprised" by the result. A year and a half earlier, Janssen announced that a sister study known as Imbokodo had proven to be safe but ineffective at preventing HIV in women in sub-Saharan Africa — which was an ominous sign to researchers that they were probably not going to see a dramatically different result in the Mosaico trial.
“[I] kind of had an inkling that there was probably not enough difference between the vaccine that was used in Mosaico than Imbokodo, so I wasn't surprised,” Dr. Carl Dieffenbach, director of NIAID’s Division of AIDS, told Yahoo News. “But it really says something about where we are in the vaccines field that this was the last remaining large clinical trial that we had going, and really is kind of a major disappointment.”
The Mosaico and Imbokodo trials were both building on the modest success of an HIV trial conducted in Thailand, the findings of which were published in 2009. That vaccine candidate was 31% effective at preventing HIV, which, while not enough to declare a victory, gave researchers enough incentive to move ahead with a similar strategy "with a little bit of a different twist," Fauci said, using mosaic antigens to broaden the immune response in the Mosaico trial.
But a key limitation of the Mosaico trial, Fauci and others said, is that it produced nonneutralizing antibodies instead of broadly neutralizing antibodies, or antibodies that originate from one virus but are capable of disabling another. Because the HIV virus is so variable, broadly neutralizing antibodies, researchers are realizing, will be crucial for an HIV vaccine to be successful.
What makes HIV/AIDS such a formidable foe?
Despite decades of effort, HIV continues to be “one of the most challenging global health problems that we have been faced with in history,” Fauci said.
“We've had 40 years of the HIV epidemic, and there really have only been about five strategies that have been tested in a clinical trial setting,” Dr. Jessica Justman, an associate professor of epidemiology at Columbia University, told Yahoo News. “So it just illustrates with numbers how much harder it has been to come up with strategies that might work.”
Part of what makes HIV so good at evading the immune system — both the antibody side and the cellular side — is that it mutates at such a high rate that the immune system doesn’t have a chance to recognize it.
“We talk about the sub-variants of SARS-CoV-2 — we had Alpha, we had Beta, we had Delta, and then we have Omicron. That amount of variation is quite small compared to the amount of variation within a single individual living with HIV,” Dieffenbach said. “HIV generates so much more variation than even coronavirus, and we've seen the havoc that coronavirus variation can have on us as a society.”
And unlike other viruses for which we’ve developed vaccines, HIV is unique in that no one has ever recovered from it.
“One of the very first things [HIV] does is it enters the group of cells in the body called CD4 cells and becomes part of that person's genome, basically, and the CD4 cells designed to 'rest.' And so it's living in you forever, at that point,” Dieffenbach said.
“Once you're exposed to HIV and you become HIV positive, you have HIV for life. Not one single person has spontaneously eliminated HIV from their body by themselves. There's people that are walking around with very low viral load and things like that, but they still have HIV in their body.”
This is part of the reason, Justman said, why traditional vaccine methods, such as giving an attenuated version of a virus — a technique successfully used against polio, for example — don't work with HIV. It also means, Fauci and others have said, that in order to be effective, an HIV vaccine would need to work even better than natural immunity.
What’s next for HIV vaccine research?
Even with preventative measures like PrEP available, experts say a vaccine is still crucial to ending the HIV/AIDS epidemic. The Food and Drug Administration has pointed out that a downside of the once-daily PrEP pill is that it requires "high levels of adherence to be effective"; in other words, people are human, and remembering to take a pill religiously every day can be difficult to commit to — especially, the FDA says, among people dealing with substance use disorders, depression, poverty and those who may be trying to conceal their medication. The FDA announced the first injectable preventative treatment in 2021, but that also requires regular bimonthly trips to a health care provider.
And despite advances in treatments that can prevent HIV and prolong the life of those infected, access still isn't equitable. Worldwide, many children, particularly in sub-Saharan Africa, are left behind when it comes to life-saving therapeutics, with just half of children receiving the treatment that they need. And though the rate of new infections has gone down since the beginning of the epidemic, in the U.S., Black and Hispanic communities are still disproportionately affected by HIV compared to other ethnic and racial groups.
“If we could have a vaccine that worked like, say, a measles vaccine, where you get vaccinated once or maybe you need a short series in order to get lifetime immunity, and we gave that to young children — imagine,” Justman said. “That would be just breathtaking.”
A lot of HIV research, Justman explained, laid the foundation for the SARS-CoV-2 vaccine. The mRNA strategy used to create the Pfizer and Moderna COVID-19 vaccines, for example, was of interest to HIV vaccine researchers long before COVID appeared; and now, researchers will be able to look at lessons learned from the COVID pandemic and apply them to the HIV virus.
“One of the great things that we learned from the COVID pandemic is how effective the mRNA nanoparticle delivery platforms that Pfizer BioNTech and Moderna used were in terms of making vaccines incredibly easily available,” Dieffenbach said. In the HIV space, he said, they "have started using the mRNA delivery technology as a platform, which will give us greater ability to look at different types of vaccines and different variables and different strategies faster than we could in the past.”
Early last year, the NIAID launched a small phase 1 trial of three mRNA HIV vaccines, which is expected to be completed by July.
An African-led trial called PrEPVacc, still underway, combines PrEP with experimental HIV vaccines and is expected to conclude in 2024. However, PrEPVacc is not on a direct path to licensure, so even if it shows safety and efficacy, it would need to be confirmed by another trial or trials.
Dieffenbach said that while he’s not usually willing to speculate, it could be seven to 10 years before another HIV vaccine candidate is ready for late-stage phase 3 clinical trials.
Still, Fauci and others say they aren’t giving up.
“I can't guarantee that we're going to have a vaccine, but I certainly think it's feasible,” Fauci said. “It's going to be a very formidable scientific challenge and scientific problem and scientific hurdle to overcome, but I don't give up on it.
“The fact that we don't have a safe and effective vaccine is obviously disappointing, but that doesn't mean you stop trying,” he added. “Because if we had stopped trying to get antiretroviral drugs back in the '80s and early-to-mid '90s, we wouldn't have had the resounding success that we have right now. So I don't get discouraged by my failures. I get more inspired to do more and to continue the fight, and to continue the efforts to get a success.”