Louis Picker is nervous. Last month, the first volunteer was injected with an HIV vaccine he spent over 20 years designing. It’s prototype No. 2. The last shot they tested, in 2021, didn’t do much of anything, and the 66-year-old worries that if this fails, he might not get another chance to redesign it.
Truthfully, though, Picker isn’t sure his HIV vaccine stands much of a chance. He needs this study to prove the platform he built can genuinely stoke a specific type of immune response, one he believes can have important applications in cancer and tuberculosis. But as for the shot itself?
“To be honest,” said Picker, a professor at Oregon Health Sciences and co-founder of Vir Biotechnology, the company developing the shot, “I’m not completely sure that an HIV vaccine will ever be developed.”
It’s minor heresy from one of the field’s more prominent figures. An HIV vaccine has topped public health’s wish list for nearly half a century, consuming billions of dollars in research and clinical trials costs as the virus has claimed more than 40 million lives worldwide. Most of his colleagues are not yet willing to be that bleak. “Louis is a skeptic in general,” said Nina Russell, director of TB and HIV prevention at the Gates Foundation, which has long funded Picker’s work. “I’m optimistic.”
Yet they agree the field is at a crossroads. After another large study failed in January, there is today only one late-stage HIV vaccine trial ongoing, and it uses older vaccine designs some experts doubt will do much. Researchers have been forced back to lab benches and small-scale trials to test what strange, new idea might finally tame the craftiest virus humanity has ever seen.
Picker’s platform revolves around sending HIV “wanted” posters to a specific subset of immune cells by encoding them in a different wily virus called CMV. A Texas team is creating a weakened version of HIV, an idea previously discarded for fear recipients could develop AIDS. Several groups, including Moderna, the International AIDS Vaccine Initiative, and the National Institutes of Health, are pioneering an approach called germline targeting, where they give a series of jabs to nudge the immune system into making the perfect antibodies.
“If you think about everything we’ve done with HIV vaccines, we’ve been trying traditional, classic approaches: Activate T cells, activate B cells,” said Carl Dieffenbach, director of the NIH’s Division of AIDS. “And what have we gotten for it?”
Picker doesn’t doubt the new science. It’s “unbelievable,” he said. “These things are explosive in terms of their applications.” His concern is what the world will look like by the time any candidate is ready for a large clinical trial in five or six years. Even as the vaccine field has floundered, other sectors of HIV research have flourished, leading to new ways of preventing HIV infection. Paradoxically, these innovations could make it harder to develop a new shot, even if the world still needs one.
“It’s a reality we’re going to have to confront,” acknowledged Jim Kublin, executive director for the HIV Vaccine Trials Initiative at Fred Hutchinson.
The problem is long-acting PrEP. PrEP, or pre-exposure prophylaxis, for HIV has existed since 2012 in the form of daily antiviral pills that can reduce the risk of infection from sex by 99%. But in 2021, an injectable called cabotegravir was approved that can virtually eliminate the risk of contracting HIV with a shot every two months. Once-every-six-month shots are on the horizon.
As a pill, PrEP hasn’t eliminated the need for an HIV vaccine. Each year, 1.3 million people are still infected and more than 500,000 people die of the virus, many of them in Southern Africa. That’s in part because the pills have been sparsely used, due to access issues, stigma, and the difficulty some, such as people facing housing instability, face taking a drug every day.
PrEP is also usually taken only by people at high risk of getting HIV, whereas low-risk individuals still account for over half of all infections, said Larry Corey, former director of the AIDS Clinical Trial Group. A vaccine would likely be designed for everyone.
“I think we really need it, just like we did 30 years ago,” said Eugene Ruzagira, director of PrEPVacc, the sole ongoing late-stage HIV vaccine trial.
PrEP, however, makes running clinical trials harder. Even if a vaccine could be more impactful on a public health scale, researchers can’t ethically randomize volunteers to receive placebo if there is a 99% effective pill available. It’s a paradox not uncommon in medicine, in which one intervention makes it harder to invent the next.
Clinical trialists previously solved the problem by essentially using the barriers to PrEP access to their advantage. In PrEPVacc, which is run entirely in Africa, volunteers are given PrEP for the first 26 weeks, as the potential immune response to the vaccine kicks in, and then referred for more doses at local clinics. Many participants don’t take it regularly, Ruzagira said, even during the initial 26 weeks.
Picker’s concern is that long-acting PrEP will be different. There’s no guarantee these drugs will transform HIV around the world, where access to new drugs is often tenuous. Advocates are already fighting the company behind cabotegravir. But experts say it will change clinical trials, where the highest standard of care has to be offered.
Say Picker’s shot is ready for an efficacy study in 2030, after a six-month injectable is approved. Could you run a study like PrEPVacc, where each arm is offered PrEP? If every volunteer takes it and comes back in half a year for a second dose — a far lighter lift than regularly going to clinics to get pills that must be taken every day — then all volunteers would be taking a highly effective drug and it could be impossible to tease out the vaccine’s effects.
Conversely, if you tried to compare a new vaccine directly to PrEP in a so-called noninferiority trial, the study would likely fail. Although a vaccine could have tremendous public health advantages, few expect it to be initially as effective as PrEP.
“I think about this all the time,” said Dieffenbach, adding that he was optimistic. “We’re probably four or five years away from the next vaccine study. So we got lots of time to beat this idea up.”
There are potential solutions, even if the ideas are still nascent. Some researchers have proposed looking at “proxies” of HIV exposure, such as gonorrhea. For example, if participants receive a vaccine and then gonorrhea rates stay high while few people caught HIV, then researchers can assume participants were exposed to the virus but protected.
Kublin, who is editing a forthcoming publication addressing the subject, floated community randomized trials, or CRTs (as opposed to randomized controlled trials, called RCTs). These approaches randomize communities to receive different interventions, such as a free health insurance program, or stagger when an intervention is introduced in a community, to tease out the effect.
But, to Kublin’s knowledge, they have never been used to approve a vaccine or medicine before. It’s unclear how regulators might view them.
“That said, feasibility of efficacy testing is a consideration for regulatory agencies,” he added in an email, pointing to the 2016 approval of a cholera vaccine without randomized trial data. “If the community deems that a RCT is not feasible, i.e., is prohibitively expensive, requires too many people, etc., then a CRT may be an option.”
Picker speculates a pivotal study would be possible, but that it would have to be large and costly and that companies or funding organizations might only do it if the shot worked “perfectly.” Largely, they haven’t. Picker’s shot appeared about 59% effective in monkeys, though that may actually underestimate the effectiveness in humans. The germline vaccines look potent but rely on giving a long series of different shots — which could actually be harder to roll out than PrEP.
Some researchers tamp down on expectations for what at least the first shot will look like, seeing an HIV vaccine as eventually part of a preventative toolkit rather than a single solution. HIV has always been among the hardest viruses to stop because, unlike in Covid or flu, you have to prevent infection.
“We’d like to have a vaccine that is good enough, you get one injection and you get boosted in three or four or five years and, you know, you don’t need PrEP, or you don’t need other things,” said Corey, who believes a vaccine is still feasible. “But I’m not sure we’re going to achieve that with HIV.”
Researchers are making steps to make early-stage designs more practical. For germline vaccines, that includes combining different shots into one. Nina Russell compared it to a “long-acting gobstopper,” slowly releasing new flavors as it stays in the body.
For all his gloominess about the logistics of future vaccine trials, Picker remains optimistic about the field. Despite having never achieved its holy grail, the HIV vaccine field has had a massive impact on public health. The principles and technologies researchers created trying to wrangle HIV — looking at a virus in detail, pinpointing its weak spots — paved the way for vaccines for Covid and RSV.
Picker and other researchers say the same could prove true for the new technologies. No one, he noted, had previously been able to control the immune system in quite the way his platform or germline targeting allows. His vaccine for tuberculosis has shown powerful results, and his group will be submitting a paper soon showing its potential in cancer. Vir is already working on using his technology to target the precancerous lesions caused by HIV.
“I think this technology is going to really come through for the medical community overall,” he said. “So I think it’s really important to finish it.