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COVID-19 vaccines modified to work against circulating virus variants should have clinical immunogenicity studies supporting their effectiveness, and ensure they work not only against the variant strain, but the initial strain, the FDA said in on Monday.

Manufacturers will also need to conduct booster studies, where the modified vaccine is given to those already vaccinated with the initial vaccine, to measure immune response in those individuals as well.

While the agency also updated guidance about, such as monoclonal antibodies, and related to virus mutations, discussion of vaccines dominated a call with reporters Monday afternoon.

Peter Marks, MD, PhD, director of the FDA Center for Biologics Evaluation and Research, said the FDA would ultimately like to see if "immune response is comparable against the new variant [and] also make sure it's safe to boost those who have already been vaccinated."

These studies would include several hundred people and would likely take a few months to complete, Marks said. He likened the process of potentially switching out a different strain in a vaccine to combat against COVID-19 variants to the process used to develop vaccines for pandemic influenza strains.

"We need to have studies conducted to facilitate potential strain changes, so if we need to swap something in, we can do it in a relatively quick manner because variants can move through the population quickly," he said. "Ideally, the studies we describe in the guidance describe how we would like manufacturers to work to see if the vaccine ... can cover for an existing strain ... and not have to make a bivalent or multivalent vaccine."

Marks noted that once studies were in hand, when to trigger swapping out strains for new variants would involve consultation with global colleagues and input from FDA vaccine advisory committees, as well as weighing the risks and benefits before ramping up a production change.

"This is a global problem and variants in one location seem to be making [their way] to other locations fairly quickly," he added.

The guidance recommended immunogenicity studies compare neutralizing antibody seroresponse rates and geometric mean titers (GMTs) for the modified vaccine against the variant, as well as the modified vaccine against the initial virus used for the initial vaccine.

They noted the study should be adequately powered to assess non-inferiority of seroresponse rates and GMTs for the modified vaccine against the variant compared to initial seroresponse rates and GMTs for the prototype vaccine against the original virus. The non-inferiority margins should be -10% and 1.5-fold for GMTs, they noted, though alternate non-inferiority margins can be used on a case-by-case basis.

In a booster study, the same non-inferiority criteria should be used, though the FDA noted the study could also evaluate a booster dose of the prototype vaccine, and additional analysis to compare immune responses between a booster of the prototype vaccine and a dose of the modified vaccine booster against COVID-19 variants.

Marks said while clinical data is required for COVID-19 vaccines for now, particularly as no immune correlate of protection has been identified, he said that perhaps once a few more studies have been done, and "everything seems consistent," FDA may move towards an influenza-like model where only lab studies would be required.

Draft Guidance on Therapeutics, Testing

In addition to guidance on vaccines against variants, the agency also released updated guidance about monoclonal antibodies. They suggested evaluating monoclonal antibodies based on "clinically meaningful aspects of the disease," such as COVID-19-related hospitalizations or deaths from any cause through at least 28 days among outpatients with mild-to-moderate disease.

The agency also noted manufacturers should attempt to enroll patients from populations disproportionately affected by the pandemic, such as racial and ethnic minorities.

FDA's new draft guidance for also contained similar cautions about appropriate representation in clinical trials among racial and ethnic minorities, adults ages 75 and older, as well as trials in nursing homes or other long-term care facilities.

They also recommended enrolling pregnant and lactating women in phase III trials, where appropriate, and added, "children should not be categorically excluded from clinical trials of investigational COVID-19 products in which there is a prospect for direct benefit."

The new guidance contains a section about monitoring for variants, especially those that could impact drug activity.

In terms of diagnostic testing, FDA's new guidance document urges test manufacturers to take variants into their design consideration and to monitor viral mutations that may impact the performance of molecular diagnostic tests.

"Tests with multiple targets and appropriate result interpretation criteria have been used to identify signals that a patient sample may include a variant and should be followed up with additional testing and/or sequencing of the viral genome," FDA staff wrote in the guidance document.

The agency already issued a warning that variants may cause false negatives with certain diagnostic tests, though officials at the briefing emphasized that so far, the impact on testing does not appear to be significant.

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