ScienceThe COVID-19 reporting is supported by the Heising-Simons Foundation.

The questions are urgent and the funding is in place. But a highly anticipated $ 130 million clinical trial to test the effectiveness of new messenger RNA (mRNA) vaccines for COVID-19 against a key variant of the pandemic coronavirus as well as in people living with HIV and women pregnant, is at a standstill. It’s set to launch in eight countries in sub-Saharan Africa, but none of the vaccine makers, Pfizer and Moderna, want to participate, or even provide their vaccines.

A group of prominent HIV advocates and activists in South Africa wrote 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), who agreed to pay for the study. They point out that COVID-19 hits people living with HIV particularly hard and that dangerous variants of SARS-CoV-2 evolve in them as many have weakened immune systems. “We believe this will be a landmark study for this region and… the world,” they wrote. “We respectfully ask you to do everything in your power to enable this study to be carried out. “

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 study left to do” of the entire US government-funded adult COVID-19 vaccine trial portfolio to date, said Lawrence Corey of Fred Hutchinson Cancer Research Center which helped organize the trial.

The trial aims to follow up on clues that mRNA vaccines may protect against a variant of the coronavirus first seen in South Africa, originally called B.1.351 and now dubbed Beta under the new naming system of the World Health Organization. The variant, widely distributed in Africa, escapes critical antibody responses in laboratory studies, and vaccines without mRNA have been shown to be less effective against it (see table below). Two of these vaccines, from Novavax and Johnson & Johnson, also appeared to offer little or no protection to people living with HIV. “We have a real problem with people infected with HIV,” said Glenda Gray, who heads the South African Medical Research Council, which sponsored the study. And whether current COVID-19 vaccines protect pregnant women remains unclear, as early efficacy trials ruled them out.

The new trial would be hosted by the COVID-19 Prevention Network (CoVPN), which Corey co-leads, which previously hosted efficacy trials of the Moderna vaccine and four other candidate vaccines that were part of Operation Warp Speed. Multi-billion dollar US government. program. Positive results would strengthen the argument that mRNA vaccines, now scarce in developing countries, should be more widely available. But a spokesperson for Pfizer said he viewed the study as unnecessary because evidence shows that its vaccine works well against the beta variant, and the company has an ongoing international study in pregnant women.

When the designers of the trial turned to Moderna, the company initially announced it would supply its mRNA vaccine, although it wanted the trial to compare the current version with a newer version in development. Then, a few weeks ago, as the trial was getting ready to start, Moderna started to back down. The company and its potential collaborators say a complex mix of liability issues, reluctance to aid Moderna scientists in the required oversight known as pharmacovigilance, and concerns about the study design led to a change of mind.

Some of the trial organizers, however, suspect that business considerations are also being taken into account: both companies may fear new data will make it difficult for regulatory agencies to fully approve their vaccines; the vaccines have only received 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 of the study participants, dubbed CoVPN 3008, would receive the current Moderna vaccine, which contains mRNA that encodes the surface protein, the peak, of SARS-CoV-2. The other participants would initially receive placebo injections. But as soon as clear evidence emerges that the current vaccine protects against COVID-19, the placebo group would be offered a new “bivalent” vaccine developed by Moderna. 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 participants in vaccine trials should still receive placebos once a proven product exists, but a South African researcher who helped design the study notes that it has received approvals from several organizations after intensive ethical reviews. At the moment, says Linda-Gail Bekker, director of the Desmond Tutu HIV Center and CoVPN 3008 investigator, “there is no vaccine for most people” in the area, and trial participants will likely receive doses sooner than they would otherwise. If participants become eligible for an authorized COVID-19 vaccine during the trial, they will be encouraged to drop out.

Gray is surprised that Moderna balks. NIAID worked closely with the company to design its vaccine, and Warp Speed ​​gave the company $ 1.5 billion for R&D and related efficacy trials. (Pfizer has not received government support to develop or test its vaccine.) “This is a request from the US government for a pharmaceutical company to help answer a critical question,” Gray said. “It just seems weird.”

Moderna, however, says he wants to move on to evaluating his new formulation. “We believe science and public health will be better served by investigating the safety and efficacy of a multivalent vaccine that includes the sequence against B.1.351,” a spokesperson said. “We are in active discussions with potential researchers in Africa to conduct such a study. But Gray and other executives at the planned study said the company had also raised concerns with them about liability for vaccine side effects and staffing the required pharmacovigilance effort.

The case for the new trial remains strong, they add. The tantalizing results of a South African trial of the Pfizer vaccine suggest that mRNA vaccines may 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 conclusion is far from conclusive. A larger study is essential for both science and policy, says Corey. “Having data showing the effectiveness of mRNA in this region clearly shows that excluding these countries from access [to this type of vaccine] is medically inappropriate.

The organizers of the trial hope that an agreement can still be reached with Moderna. They note that in theory, the US government could take responsibility and provide the trial with the vaccine. A US government official familiar with the negotiations said the problem was the Public Readiness and Emergency Preparedness Act, which compensates manufacturers of COVID-19 vaccines but only in the United States. Changing the law to provide international compensation would require action at the highest level of government. Alternatively, the South African government could compensate the company, and Gray says such negotiations are ongoing.

If the mRNA vaccine trial continues and proves that the current Moderna vaccine works against the beta variant, Gray predicts that Moderna and Pfizer will continue to move forward with reformulated vaccines targeting different variants as well as the virus. origin. And that could lead to a boon for the African continent, as rich countries embrace the new formulations. “There would be a lot of [original] An mRNA vaccine that is lying around and that nobody wants, ”she considers. “There would be all these hiding places everywhere, and we could get it for less.”