Future historians studying the 2020s may disagree about many things, but it is safe to assume all of them will agree that the COVID-19 pandemic was transformative. It has changed the way we socialize and do business, led to collective trauma and was likely a critical factor in President Joe Biden's election. When it comes to humanity's ongoing war against infectious diseases, this pandemic accelerated development of a new vaccine platform known as mRNA technology, one that scientists believe could some day be used against everything from malaria and tuberculosis to all strains of influenza. There was even an early hopeful sign with HIV vaccine research, with researchers from the National Institute of Allergy and Infectious Diseases (NIAID) announcing in December that an experimental mRNA vaccine had successfully treated an HIV-virus relative in mice and rhesus macaques.
Now Moderna — which, along with Pfizer/BioNTech, was one of the first pharmaceutical companies to develop a successful COVID-19 vaccine — has announced that it is in phase one of a clinical trial for an HIV vaccine. Just as they did when fighting COVID-19, Moderna is using mRNA technology to develop this new vaccine. The fact that it is in phase one means that they are still very early in developing the inoculation, but are confident enough in its safety and potential effectiveness that they were willing to put experimental shots in people's arms. Nor is Moderna working alone on this: The trial, known as IAVI G002, is being conducted in partnership with the International AIDS Vaccine Initiative (IAVI) and is partially funded by the Bill & Melinda Gates Foundation.
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The project to develop a vaccine against HIV has long been a holy grail of public health. The virus has become very treatable, thanks to anti-retroviral medications, but an actual vaccine has proved out of reach for decades.
Yet while IAVI CEO Mark Feinberg said in a news release that they are "tremendously excited" by the new trial, not all of the scientists who spoke with Salon shared that optimistic tone.
"This is on the much, much more difficult side by many orders of magnitude than the development of a vaccine for COVID-19," Dr. William Haseltine, a biologist renowned for his work in confronting the HIV/AIDS epidemic, told Salon. After noting that scientists have been unsuccessfully trying to create an HIV vaccine since the 1980s, Haseltine explained that the specific advantages conferred to vaccine manufacturers by the mRNA platform will not in and of themselves be enough to make this effort succeed where others have not.
"There is nothing magical about what mRNA vaccines do," Haseltine observed. "They enter a cell and the mRNA is programmed to make a protein. That protein is recognized by the immune system. And that's exactly what happens with most other vaccines. The advantage of an mRNA vaccine is it can be made quickly, but that's about its only significant advantage." When asked if he felt there was a growing cultural attitude toward mRNA vaccines that might be unrealistic, he answered in the affirmative.
"I think mRNA [vaccines are] valuable in that they can be made very quickly to adapt to new pathogens, and that's their major advantage," Haseltine pointed out. "They're not qualitatively different from other vaccine modalities. It could be very useful against viruses like COVID or influenza that change quickly. It's essentially why the Gates Foundation supported the development of the mRNA vaccines." Yet they have not always been effective, and should not be perceived as a "panacea."
Mitchell Warren, Executive Director of the AIDS Vaccine Advocacy Coalition, also struck a cautious tone when describing the new effort. Warren drew attention to the fact that while mRNA vaccines are a valuable platform, they are only as useful as the actual inoculation contained within them.
"It is clear from the success in developing multiple mRNA-based COVID-19 vaccines that mRNA is terrific platform, or vector, to deliver a vaccine into the immune system," Warren told Salon by email, adding that it was "exciting" to see the new HIV trials and noting that Moderna and colleagues had been working on an mRNA vaccine for HIV before the COVID-19 pandemic. "But a safe and effective vaccine requires both a great platform vector (like mRNA) and a great immunogen, or insert, so these new studies are critical in exploring what to actually put in the mRNA that might effectively prevent HIV infection. We'll only know this strategy works when it has been tested in an efficacy study, which is still a few years away."
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Warren also drew attention to the fact that, while the SARS-CoV-2 virus was challenging, the HIV virus has always been much more difficult.
"HIV is far, far more complicated pathogen that continues to defy vaccine developers," Warren told Salon. "As devastating as COVID-19 continues to be, from a vaccine development perspective, it is an easy pathogen; HIV is not. But COVID-19 vaccines have also taught us that terrific scientific innovation cannot end pandemics without a commitment to global, equitable access. So in HIV vaccines, we have to adapt and apply the scientific lessons of COVID-19 and do way, way better than we've done in COVID-19 in terms of translating insights into public health impact."
Dr. Monica Gandhi, an infectious disease doctor and professor of medicine at the University of California–San Francisco, explained to Salon that the fundamental difference between HIV and SARS-CoV-2 in terms of combatting them is that they HIV is a retrovirus and SARS-CoV-2 is an RNA virus.
"The challenge is that HIV is a retrovirus so its RNA is made into DNA and then that DNA integrates into our host chromosome so that HIV stays with the host long-term," Gandhi explained by email. "SARS-CoV-2 is an RNA virus and will eventually leave the host. Moreover, HIV infects CD4 T cells preferentially, leading to immunosuppression without treatment, which makes it more difficult to harness the immune system (with a vaccine, for instance) to fight it."
This does not mean, however, that Gandhi felt hope is entirely unwarranted.
"The vaccine candidates so far for HIV have not managed to elicit broadly neutralizing antibodies and T cells against the virus but preliminary work with the mRNA vaccine developed for HIV shows the development of both," Gandhi explained. "Moreover, preliminary evidence in a small group of macaques show good effectiveness in preventing SHIV with the adapted mRNA HIV vaccine. These two reasons are giving HIV researchers and clinicians hope that the mRNA vaccine for HIV may be the breakthrough the need."
Corresponding with Salon by email, Dr. Dagna Laufer — the vice president and head of clinical development at IAVI — acknowledged that there is a long road ahead in HIV vaccine research, and that this is because of the many obstacles which have always been part of that undertaking. Describing the overall challenge of HIV research and how that has shaped their approach with this vaccine, Laufer explained that "the vaccine antigens being evaluated in IAVI G002 are designed to be part of an eventual multi-step vaccination regimen designed to stimulate an immune response to neutralize, or block, HIV. On their own, the vaccine antigens being studied in this trial will not lead to this outcome. But, if this early stage trial is successful, we will see evidence that the vaccine antigens have efficiently stimulated production of rare immune cells needed to start the process of generating broadly neutralizing antibodies."
Laufer added, "Follow-on studies will be needed, if this trial is successful, to evaluate a multi-step vaccination regimen, and so we are still looking ahead to a long development timeline." That timeline, however, is likely to be much shorter than would have been the case without mRNA technology. As Laufer put it, "producing a recombinant protein for a vaccine candidate is a very long, exacting process, whereas producing an mRNA-delivered vaccine candidate is much shorter process. With conventional approaches, it can take years to advance a promising idea in the lab into a vaccine candidate that can be evaluated in humans." mRNA technology condenses that timeframe from a matter of years to one of months, "leading to a more nimble and responsive approach to vaccine design and testing, potentially shaving off years from typical vaccine development timelines."
The experimental vaccine, which was developed by researchers at IAVI and Scripps Research led by Dr. William Schief, works by using the mRNA platform to deliver HIV-specific antigens into the body. It will follow 56 HIV-negative adults, 48 of whom will have received at least one dose of the primary vaccine. Within that group, 32 will also receive a booster shot, while eight participants will only get that booster. As far as scientific studies go, this is a sign of moderate progress: It is further along than studies which are conducted in vitro or on animals, but not as rigorous as if the cohort of participants was in the hundreds or thousands.
If mRNA technology is able to produce an effective HIV vaccine, it will in some ways count as the story of this vein of medical research coming full circle. Much of the research used to develop a COVID-19 vaccine originated from research on an HIV vaccine, with Scripps Research's chair of immunology and microbiology Dr. Michael Farzan telling Salon in August that the ability to progress in developing mRNA technology was "just one of the silver linings of the COVID-19 pandemic, the manner in which that was propelled forward."
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