Does the world still need an HIV vaccine? Experts say yes
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Fifteen years ago, an HIV vaccine trial conducted in Thailand and sponsored by the U.S. Army found something no other HIV vaccine trial ever had: a regimen that seemed to work.
A combination of two experimental vaccines reduced the rate of new HIV infections in the phase 3 trial by more than 31% compared with placebo, according to results announced in 2009.
More than a decade later, however, a trial of a similar vaccine regimen adapted to match HIV viruses in southern Africa was stopped by the NIH because it was not preventing infections. In the years since, every other late-stage HIV vaccine trial has met the same fate — ending without success.
Developing an effective HIV vaccine has been complicated for numerous reasons, including the makeup of the virus itself, which is prone to mutation and difficult to target.
Things could get even harder, experts told Healio.
‘So much that needs to be worked through’
Barely a decade since oral PrEP hit the market, long-acting injectables have changed the landscape of HIV prevention, allowing people to go months between doses of medication that can protect them from the virus instead of taking a pill every day. If Gilead Sciences’ lenacapavir is approved for PrEP, people will be able to go as long as 6 months without doses of medication.
The advent of long-acting PrEP has energized the field of HIV prevention research, but also muddied the future of HIV vaccine research, experts indicated. Since the PrEPVacc trial was stopped last year, there are no late-stage HIV vaccine trials underway, and researchers are unsure what future trials will even look like now that there are long-acting prevention options available.
For instance, how will a trial evaluate the efficacy of an investigational HIV vaccine if participants are also offered injections of lenacapavir, which they almost certainly will be for ethical reasons? That would make a control group “almost impossible,” said Healio | Infectious Disease News Chief Medical Editor Paul A. Volberding, MD.
“We as a field are discussing how we can conduct future trials ethically in the era of long-acting PrEP,” Sandhya Vasan, MD, an HIV researcher for The Henry M. Jackson Foundation for the Advancement of Military Medicine and U.S. Military HIV Research Program, told Healio during the recent HIV Research for Prevention (HIVR4P) conference in Lima, Peru.
The solution is probably carefully designed trials with large cohorts that take a long time to complete, Volberding said.
“There’s just so much that needs to be worked through,” Carl W. Dieffenbach, PhD, director of the National Institute of Allergy and Infectious Diseases’ Division of AIDS, told Healio at HIVR4P. “There are some really outstanding ethicists who will help us with the design, and ultimately, it is going to be through community consultations that help us finalize the design.”
Bar is raised
Future trials will also have to reckon with the high level of protection offered by long-acting injectables, including lenacapavir, which prevented 96% of new HIV infections in one phase 3 trial and 100% in another. Gilead said it would begin regulatory filings for the antiretroviral by the end of the year.
Another long-acting injectable, ViiV Healthcare’s cabotegravir, is already approved by the FDA for PrEP and has also been shown to reduce infections by close to 100%, while cutting down on the anxiety and stigma people feel from taking a daily pill.
The effectiveness of long-acting injectables has raised the bar for any future vaccine candidate, experts indicated.
For instance, if a vaccine is not found to be 100% effective, people may consider twice-yearly PrEP a better option, Volberding hypothesized after data from the PURPOSE 1 trial of lenacapavir were published in The New England Journal of Medicine.
“In a sense, these treatments could be considered a twice-yearly chemical vaccination,” Volberding said for this story. “The lenacapavir results make a compelling case for its broad and immediate implementation worldwide to end the epidemic.”
Mitchell Warren, executive director of the nonprofit AVAC, which focuses on HIV prevention, compared the current situation with the aftermath of the Thai vaccine trial.
“At the time, people said if we got to 50% [efficacy for a vaccine], that was the new bar,” Mitchell said at HIVR4P. “I personally think that was true then. It is no longer true.”
We asked experts during HIVR4P if, given the success of long-acting injectables, there is still a need for an HIV vaccine. They all said yes, and for a variety of reasons. Volberding noted that an effective vaccine is still considered the holy grail of HIV prevention research.
“You need prevention interventions for every single stage and every single context,” NIAID director Jeanne Marrazzo, MD, MPH, said at HIVR4P, “and that gets very complicated.”
‘Choice is really important’
Choice was a major topic at HIVR4P and one of the reasons there is still a need for an HIV vaccine, experts said.
Multiple presentations at the conference focused on the necessity of providing people with as many HIV prevention choices as possible.
“What we hear from our community is that choice is really important,” William Hahn, MD, a clinical assistant professor and HIV vaccine researcher at the University of Washington and Fred Hutchinson Cancer Institute in Seattle, told reporters at HIVR4P.
The more strategies there are, the easier it will be to address focused epidemics of HIV — like those occurring in more vulnerable groups — and the overall epidemic at the same time, Dieffenbach said.
“People also are bad at admitting or acknowledging their risk, so we have to have something that is universal that would be destigmatized, like a vaccine,” he said.
Even if there eventually is a vaccine breakthrough, there would still be a need for other HIV prevention options to provide people with choices, experts said. For it to replace the other options, a vaccine would have to be a panacea — “affordable, available to all and with a delivery operation on the level of Coca-Cola,” Vasan said.
“The ultimate strategy to truly end the HIV epidemic may well require multiple strategies,” Volberding said.
Cost could tip the scales toward a vaccine
Another reason to continue the search for an HIV vaccine is cost. Long-acting injectable medications are highly effective but also come with a big price tag.
The wholesale list price of long-acting cabotegravir is more than $23,500 per year, according to ViiV. Gilead has not said what lenacapavir will cost as PrEP, but as treatment for highly resistant HIV — for which it has been approved by the FDA since 2022 — it costs more than $42,000 per year in the United States.
Both companies have fulfilled promises to make their medications available in cheaper generic forms. ViiV signed a voluntary licensing agreement with the Medicines Patent Pool in 2022 to allow generic manufacturers to sell long-acting cabotegravir in 90 countries, and Gilead facilitated expanded access to lenacapavir by signing royalty-free agreements with six pharmaceutical companies to allow them to make generic versions of lenacapavir for 120 low-resource countries with high incidences of HIV. According to Gilead, the plan will prioritize 18 countries that account for approximately 70% of new HIV infections.
The International AIDS Society applauded Gilead’s decision but said it “still leave(s) out millions around the world.”
Because there is no available HIV vaccine, the cost of one cannot be directly compared with the cost of the long-acting medications. But a 2017 systematic review and meta-analysis of studies that modeled the potential cost effectiveness of HIV vaccines estimated the cost of an HIV vaccine would be between $1.54 to $75 in low-income countries to $500 to $1,000 in the U.S.
Durability is a factor
There are two outcomes to think about when it comes to HIV prevention methods, Warren said: durability and efficacy.
Durability is an attribute that could favor vaccines over PrEP, including long-acting injectables, and would be another reason to continue pursuing HIV vaccine research. The injectables might be more effective, but a vaccine could provide longer protection.
“The conversation has to be as much on the durability of the protection as on the level of protection,” Warren said.
But how effective would a vaccine have to be — and for how long — to make it a better option than a long-acting injectable?
“I would argue that if you can get into the 80% or 90% range and it lasts 3 or more years, that’s probably better from a public health perspective than lenacapavir, which is close to 100% effective, but you need it every 6 months,” Warren said.
“But if a vaccine is 70% effective and only lasts a year ... ” he said, trailing off — an indication that a long-acting injectable that is close to 100% effective might be preferable in that situation.
Vaccine research informs cure research
Although an HIV vaccine remains elusive, the research behind attempts to develop one has informed other areas of science, including the development of COVID-19 messenger RNA vaccines.
That is one more reason to continue pursuing HIV vaccine research — the funding of which “promises yet more insight into the biology of this and potentially other chronic viral pathogens,” Volberding said.
Additionally, HIV vaccine research can lead to advancements that could help scientists find a cure.
“Vaccine research continues to inform us on the intricate relationship between immune recognition and HIV transmission and control of replication,” Volberding said. “This research is also important in considering strategies that might ultimately allow HIV curative interventions.”
According to Dieffenbach, a lot of new agents are evaluated for both prevention and cure.
“A vaccine doesn’t have to be a single-purpose prevention technology,” Dieffenbach said. “Assuming it would be able to induce strong broadly neutralizing antibodies and a cellular response, it could be a cornerstone of HIV cure. A large number of the more promising HIV immunogens are being simultaneously evaluated in people living with HIV to see if those germlines have already been activated. That’s a very important area of research, and irrespective of the answer, a very important question.”
‘That would be pretty exciting’
To even be debating if an HIV vaccine is still necessary is a nice problem to have, Marrazzo said.
“Could you imagine how amazing it would be if we’re actually having this conversation 3 years from now? Let’s say our prayers,” she said. “Because if we’re having a conversation about if we should implement a vaccine that has 70% efficacy vs. lenacapavir, that would be pretty exciting.”
References:
- Adamson B, et al. Pharmacoecon Open. 2017;doi:10.1007/s41669-016-0009-9.
- Gilead signs royalty-free voluntary licensing agreements with six generic manufacturers to increase access to lenacapavir for HIV prevention in high-incidence, resource-limited countries. https://www.gilead.com/news/news-details/2024/gilead-signs-royalty-free-voluntary-licensing-agreements-with-six-generic-manufacturers-to-increase-access-to-lenacapavir-for-hiv-prevention-in-high-incidence-resource-limited-countries. Published Oct. 2, 2024. Accessed Nov. 25, 2024.
- New HIV drug can only offer hope of ending AIDS if all have access, UNAIDS says. https://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2024/july/20240710_lenacapavir. Published July 10, 2024. Accessed Nov. 25, 2024.
- ViiV Healthcare. What is the list price of Apretude? https://viivuspricing.com/apretude.html. Accessed Nov. 25, 2024.
For more information:
Carl W. Dieffenbach, PhD, can be reached at niaidnews@niaid.nih.gov.
William Hahn, MD, can be reached at whahn@fredhutch.org.
Jeanne Marrazzo, MD, MPH, can be reached at niaidnews@niaid.nih.gov.
Sandhya Vasan, MD, can be reached at communications@hivresearch.org.
Paul A. Volberding, MD, can be reached at paul.volberding@ucsf.edu.
Mitchell Warren can be reached at media@avac.org.
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