HIV vaccine research ‘at a crossroads’ after recent failures
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It has been more than 40 years since HIV emerged, causing a pandemic that has left more than 40 million people dead and more than 38 million currently living with the infection worldwide.
There are no HIV vaccines currently available, and after the recent failures of three experimental vaccines in development, there are now zero candidates in late-stage trials.
Source: Joy Folkvord
“There’s an obvious agreement that we need a vaccine. However, this has proved to be probably the toughest vaccine scientists have worked to create,” Paul A. Volberding, MD, Infectious Disease News Chief Medical Editor and professor emeritus of medicine at the University of California, San Francisco, said in an interview. “I think we’re still a long way from having an effective vaccine, and it is going to get harder and harder to test a candidate vaccine because other measures that we’re using to control the epidemic are working so well.”
Larry Corey, MD, co-principal investigator of the HIV Vaccine Trials Network (HVTN) and former president of the Fred Hutchinson Cancer Center in Seattle, explained the “enormous need” to develop an HIV vaccine, noting that only half of new HIV infections in the United States — at most — occur among high-risk people who perceive themselves to be high risk. The rest, he said, are people who perceive themselves to be — and are, by all criteria — low risk and do not take the proper preventive measures. From there, all it takes is a “chance encounter” to become infected, Corey said.
“The way you handle that for any other infectious disease is to vaccinate, and a lot of times we vaccinate people when they’re totally low risk during adolescence or childhood,” Corey said in an interview. “It’s unlikely that we’re going to be able to get 100 million people on PrEP, like we could vaccinate 100 million people or even vaccinate a billion people. And that, in essence, is the reason why we need an HIV vaccine.”
We spoke with Volberding, Corey and other experts about the HIV vaccine pipeline, how new technology is being embraced and what can be done in the meantime as the world waits for an effective HIV vaccine.
‘Pretty disappointed’
The most recent large-scale HIV vaccine trial, Mosaico, began in 2019 and assessed an investigational HIV vaccine regimen given to 3,900 cisgender men and transgender people who have sex with cisgender men, transgender people or both at more than 50 sites in Europe, North America and South America. The regimen was found to be safe but did not provide protection from HIV acquisition compared with placebo, ultimately leading Janssen to stop the phase 3 trial in January of this year.
“Unfortunately, I was not surprised by these results,” Volberding said. “I think it’s been so hard to make a vaccine that does better in terms of protecting against this virus than anything in nature, so it’s been a tough battle from the start.”
In 2021, Janssen also stopped the phase 2b Imbokodo trial assessing a similar HIV vaccine regimen among young women in sub-Saharan Africa. Much like Mosaico, a data and safety monitoring board determined that the experimental vaccine regimen was safe but ineffective.
“Most people in the field are pretty disappointed after the failure of these two large HIV vaccine trials over the past 2 years,” Elizabeth Connick, MD, Infectious Disease News Editorial Board Member, professor of medicine and chief of infectious diseases at the University of Arizona College of Medicine - Tucson, said in an interview. “Nevertheless, new strategies are being investigated.”
The discontinuation of the Mosaico and Imbokodo trials followed an announcement by the NIH in 2020 that it was stopping a phase 2b/3 trial of an investigational HIV vaccine that was based on the only regimen ever to demonstrate protection, which was during a trial in Thailand more than a decade before.
According to Corey, there are six or seven trials ongoing, none of which are efficacy trials.
“The field is shifting to an area where we’re developing vaccines that elicit high titers of neutralizing antibodies against a broader array of viruses,” he said. “The six or seven trials are all about to start that process.”
During the HIV Research for Prevention conference in 2021, Corey announced the first evidence that infusions of antibodies can prevent HIV infection: a trial that found infusions of a broadly neutralizing antibody called VRC01 prevented infection from HIV strains that were sensitive to it.
“HVTN is devoted to developing a neutralizing antibody vaccine, as well as ... developing a sort of combination monoclonal antibody to give by injection or infusion to prevent HIV acquisition,” Corey said. “It’s not as cheap or population-based as getting just the jab in your arm like we all got with COVID-19, but [HVTN] is dedicated [to] both of those, and we have a lot going on and a significant number of clinical trials in both areas.”
The ‘beauty of mRNA’ technology
Another area being heavily explored for HIV prevention is messenger RNA technology, which Volberding said could allow researchers to design a vaccine much more efficiently than other technologies, “almost certainly” shortening the time to develop an mRNA candidate. The technology is currently being assessed in several vaccine candidates.
“With the success of safe and highly effective COVID-19 vaccines, we have an exciting opportunity to learn whether mRNA technology can achieve similar results against HIV infection,” Anthony S. Fauci, MD, former director of the National Institute of Allergy and Infectious Diseases, said in a press release last year announcing the launch of a phase 1 clinical trial evaluating three experimental HIV vaccines based on an mRNA platform.
The trial, HVTN 302, will examine whether any of the three experimental HIV mRNA vaccines are safe and can induce an immune response. According to the NIAID, the trial will enroll up to 108 adults aged 18 to 55 years at 11 sites in the U.S.
The International AIDS Vaccine Initiative (IAVI) and Moderna — one of the companies to develop a COVID-19 mRNA vaccine — have also launched a trial of an mRNA HIV vaccine, to be conducted at the Center for Family Health Research in Kigali, Rwanda, and The Aurum Institute in Tembisa, South Africa.
“With our mRNA technology and IAVI’s discovery and development expertise, we are looking forward to advancing a novel approach to overcome some of the long-standing hurdles to developing a protective HIV vaccine,” Moderna CEO Stéphane Bancel said in a press release.
Corey said development of mRNA vaccines is “high risk” for manufacturers because an HIV vaccine will be significantly more challenging to produce compared with a COVID-19 vaccine.
“It’s not like COVID-19, where you say, ‘I’m pretty certain this one structure is going to work.’ No, we’re in the situation where we’re not at all certain this thing will work,” Corey said. “We know that we actually have to design something else to make the unusual mutations that are required to actually make and get to an antibody that is broadly neutralizing.”
“Therefore,” Corey added, “we need a plan B, plan C and plan D. And that’s the beauty of mRNA. It allows you to make different constructs and make more in a shorter period of time and cheaper.”
Although mRNA technology could accelerate iterative testing of HIV vaccines, it “will not solve the primary challenge facing HIV vaccines that involve immunogen design,” Dan H. Barouch, MD, PhD, William Bosworth Castle Professor of Medicine at Harvard Medical School and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, told Healio | Infectious Disease News.
Experts agreed that pinpointing exactly when an HIV vaccine might be available is not possible — at least, not yet.
“Given the long history of failed vaccines, I’m reluctant to speculate,” Connick said. “I think it is important, however, not to give up. Theoretically, a vaccine should be possible. The benefit of a protective vaccine would be immense.”
“HIV vaccine research is at a crossroads,” Barouch said. “There are currently no HIV vaccines that are in clinical efficacy trials, and there will likely not be any HIV vaccines ready for clinical efficacy trials for at least several years. As such, it is not possible to predict when we will have a safe and effective HIV vaccine, but basic research continues to advance our understanding of immunity to HIV.”
The ‘tools in hand already’
In the absence of a vaccine, Volberding said, “we’re really fortunate to have such amazing tools in hand already. And they’re getting better.”
He cited PrEP, which has been approved for more than a decade and can reduce the risk for HIV infection from sex by 99% when taken as prescribed, according to the CDC. He also mentioned the public health message of “Undetectable = Untransmittable (U = U)” — the concept that people with HIV who adhere to ART and maintain an undetectable viral load cannot sexually transmit the virus to others. It is seen as a powerful means of removing barriers to treatment as prevention.
“If they’re applied in a population, they can change the curve of this epidemic, and they can keep people from getting infected,” Volberding said.
Many studies have validated PrEP as an effective HIV prevention tool with few, if any, adverse effects.
“PrEP needs to be advertised to the general public, and certainly to be a requirement for any medical program that treats people with sexually transmitted infections,” Connick said. “U = U needs to be systematically taught in all HIV care venues.”
Volberding said more attention needs to be focused on implementing prevention strategies and answering several questions: How do we define the best candidates? How do we get these approaches to them? Can we make it easy for people to participate?
“We have to realize that this is a lifelong commitment, so we really need to stick with these people,” he said.
Convenience and access to preventive services may become even harder for some high-risk populations following the Braidwood Management v. Becerra decision, which ruled against requiring health insurers to cover PrEP under the Affordable Care Act. In one study assessing the potential impact of Braidwood, researchers estimated that upward of 2,000 men who have sex with men — a population that is critically at-risk for HIV acquisition — could be newly infected with HIV in the year after the ruling alone.
Another issue, Corey said, boils down to human behavior. For example, the COVID-19 pandemic demonstrated that many people did not see themselves at high risk and were not willing to take simple but necessary precautions.
“We need to be smart about it and to use psychology or social media savvy to convince people that they are high risk and that they should use prophylactics,” he said.
“People who get HIV don’t want to get HIV, but the people who are transmitting it often don’t know,” he added, “Reality is sexual behavior is a part of human life.”
- References:
- CDC. HIV. https://www.cdc.gov/hiv/basics/prep/prep-effectiveness.html. Accessed March 11, 2023.
- Experimental HIV vaccine regimen safe but ineffective, NIH study finds. https://www.niaid.nih.gov/news-events/experimental-hiv-vaccine-regimen-safe-ineffective-nih-study-finds. Published Jan. 18, 2023. Accessed March 6, 2023.
- HIV vaccine candidate does not sufficiently protect women against HIV infection. https://www.niaid.nih.gov/news-events/hiv-vaccine-candidate-does-not-sufficiently-protect-women-against-hiv-infection. Published Aug. 31, 2021. Accessed March 6, 2023.
- IAVI and Moderna launch first-in-Africa clinical trial of mRNA HIV vaccine development program. https://www.iavi.org/news-resources/press-releases/2022/iavi-and-moderna-launch-first-in-africa-clinical-trial-of-mrna-hiv-vaccine-development-program. Published May 18, 2022. Accessed March 10, 2023.
- NIH launches clinical trial of three mRNA HIV vaccines. https://www.nih.gov/news-events/news-releases/nih-launches-clinical-trial-three-mrna-hiv-vaccines. Published March 14, 2022. Accessed March 10, 2023.
- Paltiel AD, et al. Open Forum Infect Dis. 2023;doi:10.1093/ofid/ofad139.
- WHO. HIV. https://www.who.int/data/gho/data/themes/hiv-aids. Accessed on March 21, 2023.
- For more information:
- Dan H. Barouch, MD, PhD, can be reached at dbarouch@bidmc.harvard.edu.
- Elizabeth Connick, MD, can be reached at connick3e@arizona.edu.
- Larry Corey, MD, can be reached at lcorey@fredhutch.org.
- Paul A. Volberding, MD, can be reached at paul.volberding@ucsf.edu.
Click here to read the At Issue, "At what point can we consider PrEP an HIV vaccine?"
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