LONDON – The EMA has requested all COVID-19 vaccine developers to investigate if their products offer protection against new variants of SARS-CoV-2 and to submit the relevant data.

That will inform the development of guidelines EMA will publish shortly, setting out which data and studies will be needed to support modifications of existing vaccines to address current variants and new variants that occur in the future.

The EMA is working with the transnational group, the International Coalition of Medicines Regulatory Authorities, to determine possible changes to the composition of vaccines. A meeting held on Feb. 10 discussed development of an aligned global strategy.

Evidence generated to date indicates the Pfizer Inc./Biontech SE and Moderna Inc. vaccines authorized for use in the EU are able to protect against the three variants causing the most concern, B.1.1.7, first identified in the U.K., the South African variant B1.351, and the Brazil variant P.1.

However, concerns have been raised that Astrazeneca plc’s vaccine, the third product currently approved in the EU, is not effective in mild to moderate disease caused by B1.351.

Vaccines manufacturers have indicated they will be able to update their products to reflect what variants are circulating. Astrazeneca, for example, said in its annual results announcement on Feb. 11 that it is focused on adapting its vaccine, if required. The aim is “to reduce the time needed to reach production at scale to between six to nine months by utilizing existing clinical data and optimizing [the] established supply chain,” the company said.

The issue of COVID-19 vaccine modifications is being presented as akin to annual reviews of flu vaccines to match variants that are circulating. But the different nature of the virus, the rate at which it is mutating, and the novel vaccines technologies involved, means it is not possible to read directly across from influenza to SARS-CoV-2.

Based on manufacturers’ responses, the EMA will set out the options for introducing protection against a new variant into an approved vaccine, and the minimum regulatory requirement to demonstrate quality, safety and efficacy. The guidance also will specify what bridging studies will be needed to demonstrate efficacy against a new variant, as both as an initial vaccination and as a booster.

With the U.K. outside the EMA system, the U.K. Medicines and Healthcare products Agency (MHRA) is working with its own independent expert group to determine what its regulatory approach should be.

“We are in discussions with vaccine manufacturers on potential modifications that may be needed for current vaccines to be effective against new variants,” a MHRA spokesperson told BioWorld. “We can say at this stage that it is unlikely that a full new approval process will be needed.”

It is likely that some bridging studies are required and the design of those is currently being discussed with the expert group.

Evidence from a small phase I/II trial in South Africa indicating the Astrazeneca vaccine is not effective against mild to moderate disease caused by the B1.351 variant, led to rollout of the vaccine being put on hold in South Africa.

However, the study was not designed to demonstrate the vaccine reduced the risk of severe disease and hospitalization. The EMA said, “A reduction in protection from mild disease would, however, not necessarily translate into a reduction in protection from serious forms of the disease and its complications, for which we need to collect more evidence.”

That chimes with the conclusions of the World Health Organization’s SAGE group of experts, in its advice on how the Astrazeneca vaccine should be used, published on Feb. 10. SAGE reviewed all available data on the performance of the vaccine against the three key variants of concern, concluding Astrazeneca’s vaccine should be used, even if virus variants are present in a country.

Detecting variants

WHO said preliminary findings on the effect of variants on vaccines highlight the urgent need for a coordinated approach to surveillance and evaluation of variants, and of their potential impact on vaccine efficacy. As new data are made available, WHO will update its recommendations.

In truth, few countries are in a position to make that assessment, given the limited amount of viral genome sequencing that is taking place overall. Drop-out of the S gene that is detected by some PCR tests is a surrogate for direct detection of the B.1.1.7 variant, but the other two variants of concern cannot be monitored in that way.

Public Health England (PHE) is working with manufacturers to develop PCR tests that can detect other variants, but that is expected to take some time to complete.

The U.K. also is boosting viral genome sequencing, and is now completing 27,000 sequences per week. “The ambition is to keep increasing this, to monitor the variants and track and investigate clusters,” said Susan Hopkins, strategic response director at PHE. “We will see constant new mutations emerging, some with no functional weight,” she said.

The intense level of sequencing has led to the identification in the U.K. of 170 cases to date of the South African variant, of which 18 are not linked to travel.

Meanwhile, intensive testing of B.1.1.7, which now accounts for 90%-plus of U.K. cases, has shown it has acquired E484K, a mutation of particular concern that also occurs in the South African and Brazil variants. In vitro tests have shown that mutation weakens the effects of neutralizing antibodies.

There have been 21 cases of B.1.1.7 with E484K picked up so far in the U.K., but its significance for vaccine efficacy is not clear. “We don’t yet have specimen growing in the lab, so we can’t test it,” Hopkins said.