TOPLINE Some of the Covid-19 vaccines currently in development could increase the risk of acquiring HIV, warned a group of researchers in the The Lancet medical journal Monday, potentially leading to an increase in infections as vaccines are rolled out to vulnerable populations around the world.

Coronavirus COVID-19 medical test vaccine research and development

Some Covid-19 vaccines could increase risk of HIV infection, warn researchers who have seen INCREASES IN SIMILAR VACCINES.

The researchers warn of a “cautionary tale” from efforts to create an HIV vaccine over a decade ago, where a promising vaccine candidate actually increased the risk of some men catching the virus.

The vaccine made use of a modified virus — called adenovirus 5 (Ad5) — as a vector to transport some of HIV’s genetic material into the body.

Exactly how the vaccine increased the risks of HIV transmission is unknown, but a conference convened by the National Institutes of Health recommended against further use of Ad5 as a vector in HIV vaccines (Dr. Anthony Fauci was lead author of the paper outlining this position.)

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Ad5 is used as a vector in some Covid-19 vaccines — Science identifies four such candidates that are currently undergoing clinical trials in various countries around the world, including the U.S., with two in large scale phase 3 trials ongoing in Russia and Pakistan.

The researchers stressed the need to understand the role Ad5 might play in increasing the risks of HIV in vulnerable populations before developing and deploying vaccines using the vector, adding that informed consent documents should reflect the “considerable literature” on the risk of HIV acquisition with Ad5 vectors.

KEY BACKGROUND

Lots of vaccines make use of modified viruses to transport material into the human body. Many make use of a modified adenovirus to do this, a virus which is usually harmless except the ability to cause the common cold. Some of the leading candidates for a Covid-19 vaccine, including those from Johnson & Johnson and AstraZeneca, use adenoviruses as vectors. There is no evidence that those vectors increase the risk of HIV infection.

CRUCIAL QUOTE

The authors said they went public because Ad5 vaccines for Covid-19 might soon be tested in populations with high HIV prevalence. Lawrence Corey, one of the authors who now co-leads the Covid-19 prevention network in the U.S. that is testing vaccines on behalf of the NIH, told Science that if he were in a sub-Saharan African country, where there’s a high prevalence of HIV, “I don’t see why I would pick an Ad5 vector (vaccine) when there are many other alternative choices.”

Could certain COVID-19 vaccines leave people more vulnerable to the AIDS virus?

Certain COVID-19 vaccine candidates could increase susceptibility to HIV, warns a group of researchers who in 2007 learned that an experimental HIV vaccine had raised in some people the risk for infection with the AIDS virus. These concerns have percolated in the background of the race for a vaccine to stem the coronavirus pandemic, but now the researchers have gone public with a “cautionary tale,” in part because trials of those candidates may soon begin in locales that have pronounced HIV epidemics, such as South Africa.

Some approved and experimental vaccines have as a backbone a variety of adenoviruses, which can cause the common cold but are often harmless. The ill-fated HIV vaccine trial used an engineered strain known as adenovirus 5 (Ad5) to shuttle into the body the gene for the surface protein of the AIDS virus. In four candidate COVID-19 vaccines now in clinical trials in several countries, including the United States, Ad5 similarly serves as the “vector” to carry in the surface protein gene of SARS-CoV-2, the viral cause of the pandemic; two of these have advanced to large-scale, phase III efficacy studies in Russia and Pakistan.

In today’s issue of The Lancet, four veteran researchers raise a warning flag about those COVID-19 vaccine candidates by recounting their experience running a placebo-controlled AIDS vaccine trial dubbed STEP. An interim analysis of STEP found that uncircumcised men who had been naturally infected with Ad5 before receiving the vaccine became especially vulnerable to the AIDS virus. The vaccine, made by Merck, had been the leading hope for what was then a 20-year search for a shot that could thwart HIV. But after the STEP results appeared, the field went into a tailspin. “It took a decade to recover,” says one of the co-authors of the Lancet correspondence, Lawrence Corey of the Fred Hutchinson Cancer Research Center.

Corey, who now co-leads the COVID-19 prevention network in the United States that is testing vaccines at the behest of the National Institutes of Health, says he and his co-authors went public because Ad5-based COVID-19 vaccines may soon be tested in populations with high HIV prevalence and thus a greater risk of accidental infection during a clinical trial. “If I were in a sub-Saharan African country and making a decision as to what I would want for my country for a general population use of a SARS-CoV-2 vaccine, I don’t see why I would pick an Ad5 vector [vaccine] when there are many other alternative choices,” Corey says.

The backfire in STEP—which evaluated the efficacy of the Merck vaccine in people at high risk of HIV infection in the Americas and Australia—also appeared in a second study, dubbed Phambili, of the same vaccine. It was taking place simultaneously in South Africa and was stopped early because of the STEP data.

Precisely how Merck’s Ad5 vaccine increased the risk of HIV transmission in STEP and Phambili remains murky. The Lancet editorial spells out several possibilities, including dampening of HIV immunity, enhancing replication of the AIDS virus, or setting up more target cells for it.

In addition to the Ad5 COVID-19 vaccine candidates, several other leading vaccines, including ones made by Johnson & Johnson and AstraZeneca/the University of Oxford, use different adenoviruses as vectors. There’s no evidence that any of those adenoviruses increases the risks of an HIV infection.

I don’t see why I would pick an Ad5 vector [vaccine] when there are many other alternative choices.

Lawrence Corey, Fred Hutchinson Cancer Research Center

Of the Ad5-based COVID-19 vaccine candidates, from China-based CanSino Biologics, has developed the furthest. In a Lancet report in May, researchers from the company recognized the “controversial” possibility of their vector increasing the risk of HIV infection and said they would watch for it in the candidate’s trials. CanSino’s COVID-19 vaccine is being tested in efficacy trials in Russia and Pakistan that together hope to enroll more than 40,000 people, and the company is discussing starting studies in Saudi Arabia, Brazil, Chile, and Mexico.

China has already approved a CanSino vaccine against Ebola that uses the Ad5 vector. Yu Xuefeng, CanSino’s CEO, tells Science the risk of increased HIV susceptibility may be limited to Ad5 vaccines that produce an AIDS virus protein. “There’s no clear answer yet,” Yu says. “We certainly haven’t seen anything with the Ebola vaccine.” The company’s Ebola vaccine was tested in a population in Sierra Leone that, he notes, had a relatively high HIV prevalence, making it more likely to have detected the problem if it existed.

Russia’s Gamaleya Research Institute has a COVID-19 vaccine candidate that uses a combination of Ad5 and Ad26 vectors; it’s now in an efficacy trial in that country.

Last week, ImmunityBio received approval from the U.S. Food and Drug Administration to begin human trials of its COVID-19 vaccine, which uses Ad5 as a vector. The first trial will take place in Newport Beach, California, but Patrick Soon-Shiong, the company’s CEO, says he also hopes to test it in South Africa, where he grew up and went to medical school.

He calls the STEP study results “very, very fuzzy” and stresses that ImmunityBio’s Ad5 has four deleted genes that reduce the immune responses it triggers. “It’s 90% muted,” he says.

ImmunityBio is discussing the risks with scientists and regulators in South Africa of a trial there to test its modified Ad5 COVID-19 vaccine. The informed consent process for that proposed study would tell participants about potential risks given the previous STEP and Phambili results.

Soon-Shiong emphasizes that his company’s experimental COVID-19 vaccine, unlike every other candidate that uses an adenovirus vector, presents two different SARS-CoV-2 genes and might therefore offer more protection from infection or disease. Why only test this in wealthy enclaves of Southern California, he asks? “Why not South Africa? Why not for the underserved people of the world?”

Pediatrician Glenda Gray, who heads the South African Medical Research Council and was the protocol chair of Phambili, has taken part in several discussions with the ImmunoBio team. “When [Soon-Shiong] contacted South Africa, we were obviously quite concerned,” Gray says. “All of us who were in Phambili and quite traumatized by what happened asked whether there was an appetite to do something in South Africa.”

But after several months of deliberations, the South Africans concluded that regulators should consider a small trial of the vaccine there in people at low risk of HIV infection, Gray says. “We decided not to throw the baby out with the bath water just yet,” she adds. “If it does go ahead in South Africa, there has to be huge consultation with communities, and we have to make doubly sure that the participants understand what happened in the past.”

Gray says South Africa appreciates ImmunoBio’s offer to allow the country to manufacture the product. “We’re in the middle of a COVID-19 epidemic in South Africa, and we don’t know if we’ll ever get access to the current suite of vaccines” produced elsewhere, she says.

The decision to move forward, she insists, has to be left to South African scientists, regulators, and ethics committees. “It’s incredibly patronizing for people to determine what science is good or bad for other countries,” she says. “Everyone knows about Phambili and STEP, and the scientists understand that there’s an important need to be cautious.”

Gray, who has co-authored papers about HIV vaccines with Corey and the other three authors of the Lancet correspondence, says there are no easy answers. “What if this vaccine is the most effective vaccine?” she asks. “If this works out to be an important vaccine, we’ll have some experience with it.”

Posted in: HealthCoronavirus

doi:10.1126/science.abf3359

We are writing to express concern about the use of a recombinant adenovirus type-5 (Ad5) vector for a COVID-19 phase 1 vaccine study,1 and subsequent advanced trials. Over a decade ago, we completed the Step and Phambili phase 2b studies that evaluated an Ad5 vectored HIV-1 vaccine administered in three immunisations for efficacy against HIV-1 acquisition.2, 3 Both international studies found an increased risk of HIV-1 acquisition among vaccinated men.2, 4 The Step trial found that men who were Ad5 seropositive and uncircumcised on entry into the trial were at elevated risk of HIV-1 acquisition during the first 18 months of follow-up.5 The hazard ratios were particularly high among men who were uncircumcised and Ad5 seropositive, and who reported unprotected insertive anal sex with a partner who was HIV-1 seropositive or had unknown serostatus at baseline, suggesting the potential for increased risk of penile acquisition of HIV-1. Importantly for considering the potential use of Ad5 vectors for COVID-19 infection, a similar increased risk of HIV infection was also observed in heterosexual men who enrolled in the Phambili study.4 This effect appeared to persist over time. Both studies involved an Ad5 construct that did not have the HIV-1 envelope. In another HIV study, done only in men who were Ad5 seronegative and circumcised, a DNA prime followed by an Ad5 vector were used, in which both constructs contained the HIV-1 envelope.6 No increased risk of HIV infection was noted. A consensus conference about Ad5 vectors held in 2013 and sponsored by the National Institutes of Health indicated the most probable explanation for these differences related to the potential counterbalancing effects of envelope immune responses in mitigating the effects of the Ad5 vector on HIV-1 acquisition.7 The conclusion of this consensus conference warned that non-HIV vaccine trials that used similar vectors in areas of high HIV prevalence could lead to an increased risk of HIV-1 acquisition in the vaccinated population. The increased risk of HIV-1 acquisition appeared to be limited to men; a similar increase in risk was not seen in women in the Phambili trial.4

Several follow-up studies suggested the potential mechanism for this increased susceptibility to HIV infection among men. The vaccine was highly immunogenic in the induction of HIV-specific CD4 and CD8 T cells; however, there was no difference in the frequency of T-cell responses after vaccination in men who did and did not later become infected with HIV in the Step Study.8 These findings suggest that immune responses induced by the HIV-specific vaccine were not the mechanism of increased acquisition.

Participants with high frequencies of preimmunisation Ad5-specific T cells were associated with a decreased magnitude of HIV-specific CD4 responses and recipients of the vaccine had a decreased breadth of HIV-specific CD8 responses,9 suggesting that pre-existing Ad5 immunity might dampen desired vaccine-induced responses. Additional exploratory studies suggest that Ad5 immune complexes activate the dendritic cell–T cell axis, which might enhance HIV-1 replication in CD4 T cells.10 Additionally, Ad5-specific CD4 T cells could have an increased susceptibility to HIV infection.11 In a non-human primate challenge study, infecting rhesus macaques with Ad5 and then immunising them with a replication-incompetent Simian immunodeficiency virus (SIV) vaccine based on Ad5 increased the risk of SIV acquisition from low-dose SIV penile challenge.12 Furthermore, subclinical inflammation and alterations to epithelial barriers at the inner foreskin, including increased densities of CCR5-positive CD4 T cells could contribute to high rates of sexually transmitted infections, including HIV, in uncircumcised men.13 On the basis of these findings, we are concerned that use of an Ad5 vector for immunisation against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could similarly increase the risk of HIV-1 acquisition among men who receive the vaccine. Both the HIV and COVID-19 pandemics disproportionately affect vulnerable populations globally. Roll-out of an effective SARS-CoV-2 vaccine globally could be given to populations at risk of HIV infection, which could potentially increase their risk of HIV-1 acquisition. This important safety consideration should be thoroughly evaluated before further development of Ad5 vaccines for SARS-CoV-2, and informed consent documents of these potential risks should reflect the considerable literature on HIV-1 acquisition with Ad5 vectors.