The questions are urgent, and the funding is in place. But a highly anticipated, $130 million clinical trial, meant to test the efficacy of the novel messenger RNA (mRNA) vaccines for COVID-19 against a key variant of the pandemic coronavirus as well as in people living with HIV and pregnant women, is stalled. It is ready to launch in eight countries in sub-Saharan Africa, yet neither maker of the vaccines, Pfizer and Moderna, wants to participate—or even provide their vaccines.
A group of prominent HIV advocates and activists in South Africa has written a letter complaining about the delay to U.S. government officials, including Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), which agreed to pay for the study. They stress that COVID-19 strikes people living with HIV especially hard, and that dangerous variants of SARS-CoV-2 evolve in them because many have weakened immune systems. “We believe this will be a landmark study for this region and … the world,” they wrote. “We respectfully ask that you do all in your power to enable this study to take place.”
The efficacy trial could yield answers in as little as 12 weeks given the rapid spread of SARS-CoV-2 in the region. “This is the most important yet-to-be-done study” in the entire portfolio of adult COVID-19 vaccine trials funded by the U.S. government to date, says Lawrence Corey of the Fred Hutchinson Cancer Research Center who helped organize the trial.
The trial aims to follow up on hints that mRNA vaccines can protect against a coronavirus variant first seen in South Africa, originally called B.1.351 and now dubbed Beta under the World Health Organization’s new naming system. The variant, widely prevalent in Africa, escapes critical antibody responses in lab studies, and non-mRNA vaccines have shown lower efficacy against it (see table, below). Two of those vaccines, from Novavax and Johnson & Johnson, also appeared to offer only modest, if any, protection in people with HIV. “We have a real problem with HIV-infected individuals,” says Glenda Gray, who heads the South African Medical Research Council, the study’s sponsor. And whether current COVID-19 vaccines protect pregnant women remains uncertain, as initial efficacy trials excluded them.
The new trial would be organized by the COVID-19 Prevention Network (CoVPN), which Corey co-leads, that previously staged efficacy trials of the Moderna vaccine and four other vaccine candidates that were part of the U.S. government’s multibillion-dollar Operation Warp Speed program. Positive results would strengthen the case that mRNA vaccines, now scarce in the developing world, should be more widely available. But a Pfizer spokesperson says it considers the study unnecessary because evidence shows its vaccine works well against the Beta variant, and the company has an international study underway in pregnant women.
When the trial designers turned to Moderna, the company initially said it would provide its mRNA vaccine, although it wanted the trial to compare the current version with a newer version under development. Then a few weeks ago, just as the trial was preparing to launch, Moderna began to back out. The company and its would-be collaborators say a complex mix of liability concerns, reluctance to have Moderna scientists help with required oversight known as pharmacovigilance, and concerns about the design of the study led to the change of heart.
Some of the trial organizers, however, suspect business considerations factor in, too: Both companies may be wary that new data would complicate getting full approval for their vaccines from regulatory agencies; the vaccines have received only an emergency use authorization in the United States and other countries.
The proposed trial would involve 14,000 people in South Africa, Botswana, Zimbabwe, Eswatini, Malawi, Zambia, Uganda, and Kenya, where adult HIV prevalence ranges from 4.5% to 27%. Half the participants in the study, dubbed CoVPN 3008, would receive the current Moderna vaccine, which contains mRNA that codes for the surface protein, spike, of SARS-CoV-2. The other participants initially would receive placebo shots. But as soon as clear evidence emerged that the current vaccine protects against COVID-19, the placebo group would be offered a new “bivalent” vaccine Moderna has developed. It contains mRNA for the original spike protein as well as mRNA for the slightly mutated version in the Beta variant.
Ethicists have long debated whether vaccine trial participants should still be given placebos once a proven product exists, but a South African researcher who helped design the study notes it has received approvals from multiple bodies after intensive ethical reviews. At the moment, says Linda-Gail Bekker, director of the Desmond Tutu HIV Centre and a CoVPN 3008 investigator, “There is no vaccine for most people” in the region, and trial participants will likely receive doses earlier than they would otherwise. If participants do become eligible for any authorized COVID-19 vaccine during the trial, they will be encouraged to drop out.
Gray is surprised that Moderna is balking. NIAID worked closely with the company to design its vaccine, and Warp Speed gave the firm $1.5 billion for related R&D and efficacy trials. (Pfizer did not receive government support to develop or test its vaccine.) “This is a request from the U.S. government to a drug company to help answer a critical question,” Gray says. “It just seems weird.”
Moderna, however, says it wants to move on to assessing its new formulation. “We believe science and public health will be better served by investigating the safety and efficacy of a multivalent vaccine which includes the sequence against B.1.351,” a spokesperson said. “We are in active discussions with potential investigators in Africa to conduct such a study.” But Gray and other leaders of the planned study say the company also expressed concern to them about liability for vaccine side effects and staffing the required pharmacovigilance effort.
The case for the new trial remains strong, they add. Tantalizing results from a South African trial of the Pfizer vaccine suggested mRNA vaccines might work well against the Beta variant: Only nine people, all in the placebo group, developed symptomatic COVID-19 among the 800 participants. But the small numbers mean the finding is far from conclusive. A bigger study is critical for both science and policy, Corey says. “Having data showing the efficacy of mRNA in this region provides the hard facts that excluding these countries from access [to this type of vaccine] is medically inappropriate.”
Trial organizers hope a deal can still be reached with Moderna. They note that in theory, the U.S. government could assume liability and provide the trial with the vaccine. A U.S. government official familiar with the negotiations says the hitch is the Public Readiness and Emergency Preparedness Act, which indemnifies COVID-19 vaccine manufacturers but only in the United States. Amending the act to provide international indemnity would require action at the highest government levels. Alternatively, the South African government could indemnify the company, and Gray says such negotiations are underway.
If the mRNA vaccine trial goes forward and proves that the current Moderna vaccine works against the Beta variant, Gray predicts Moderna and Pfizer will still move forward with reformulated vaccines targeting different variants as well as the original virus. And that could lead to a windfall for the African continent, as rich countries embrace the new formulations. “There would be a whole lot of [original] mRNA vaccine lying around that nobody wants,” she envisions. “There’d be all these stashes of it all over the place, and we could acquire it cheaper.”