COVID-19 vaccine developers should begin testing their vaccines against emerging variants now and assessing booster regimens, the FDA said in an update to its October guidance on emergency use authorizations (EUAs) for the vaccines.

“This is a matter of getting prepared,” Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, said Feb. 22 in a media briefing on a suite of new and revised guidances the agency released to help vaccine, diagnostic and drug developers respond to emerging COVID-19 variants.

“We know the country is eager to return to a new normal and the emergence of the virus variants raises new concerns about the performance of these products,” acting FDA Commissioner Janet Woodcock said. “By issuing these guidances, we want the American public to know that we are using every tool in our toolbox to fight this pandemic, including pivoting as the virus adapts.”

While the two vaccines with U.S. emergency use authorization (EUA) have so far remained effective against the currently circulating strains of the coronavirus, the FDA said it may be necessary to tailor the current generation of COVID-19 vaccines to protect against variants that may be moderately or fully resistant to the antibody response the vaccines elicit.

Thus, vaccine makers need to test their vaccines, or modified versions, against each new strain. They also should test whether a vaccine modified for a variant provokes a good immune response with no safety concerns in people who already have received the prototype vaccine, Marks said.

To test efficacy and safety against variants, the updated vaccine guidance recommends clinical immunogenicity studies comparing a recipient’s immune response to virus variants induced by the modified vaccine with the immune response to the prototype vaccine, using a -10% noninferiority margin in seroresponse rates.

The update also urges developers of authorized vaccines to conduct booster studies in individuals who previously received the prototype vaccine according to the authorized dose and dosing regimen. Again, a -10% noninferiority margin is recommended, but the guidance indicates that alternate noninferiority margins may be considered, with adequate justification for both the immunogenicity and booster studies, on a case-by-case basis.

Marks said such trials likely would enroll a few hundred participants and would last a few months. The studies can be conducted in a single age group, with the results extrapolated to other age groups for which the prototype vaccine has been authorized and to people in those age groups who have previously been infected with the coronavirus, according to the guidance.

While the studies will be necessary for the first vaccines, Marks said they likely won’t be required in the future as the knowledge gaps are closed. However, there are other issues the FDA will have to work through as it determines when and how often modified vaccines should be introduced. Marks acknowledged that introducing modified vaccines too often could strain a production system that is still ramping up to meet global demand.

Meanwhile, sponsors of all COVID-19 products should be continuously monitoring genomic databases and be aware of SARS-CoV-2 variants circulating outside the U.S., Woodcock said. “We need to anticipate this before the threshold is upon us,” she added, noting that the FDA is developing scenario planning, based on its years of experience with mutating influenza viruses, to keep pace with changes in the coronavirus.

Diagnostics, therapies challenges

The variants currently circulating have proved a bit more challenging for developers of tests and some therapies. The FDA already has issued a safety alert to caution that viral genetic mutations can potentially change the performance of a diagnostic test, and it has identified three tests that are known to be impacted by those mutations. Although that impact doesn’t appear to be significant at this time, Woodcock said it illustrates that variants could affect testing.

One of the new guidances advises diagnostic sponsors on evaluating the potential impact of viral genetic mutations on their COVID-19 tests. The guidance encourages test developers to consider the potential for future mutations when designing their test, as molecular tests designed to detect multiple SARS-CoV-2 genetic targets will be less susceptible to genetic variations than tests designed to detect a single genetic target.

Test sponsors also should routinely evaluate the potential impact of new and emerging viral genetic mutations on the performance of their molecular, antigen and serology SARS-CoV-2 tests, according to the new guidance.

The other two guidances released Feb. 22 deal with therapies. Recognizing that some of the monoclonal antibodies (MAbs) that have been authorized as COVID-19 treatments are less active against variants that have emerged, the FDA issued a new guidance addressing the development of MAbs targeting SARS-CoV-2 and variants. The guidance describes a streamlined approach to generate the nonclinical, clinical, and chemistry, manufacturing and controls data that could potentially support an EUA for MAbs to treat COVID-19 caused by mutations.

In the guidance, the FDA said it “strongly recommends” that individual MAbs be developed with the expectation that they will be combined with one or more other MAbs that bind to different epitopes to minimize the risk of the therapy losing activity against variants. Addressing this unmet medical need will require collaborations between sponsors of individual MAb products, the agency said.

The final guidance is a revision of the agency’s May 2020 guidance on phase II and III trials for drugs and biologics to treat or prevent COVID-19. The update reflects “the evolving landscape of COVID-19 drug development, including the emergence of SARS-CoV-2 variants and the availability of authorized COVID-19 vaccines,” the FDA said.

For instance, the revised guidance advises sponsors to address the possibility of drug and COVID-19 vaccine interactions for drugs that may interfere with vaccine effectiveness. It also cautions that using an antiviral to treat COVID-19 “may contribute to the emergence of viruses with reduced susceptibility to the drug or to other approved or investigational drugs.” The FDA said sponsors should use nonclinical and clinical studies to characterize drug-resistance pathways and the potential for cross-resistance to other drugs.