FDA proposes framework for updated COVID vaccines to spur discussion

Regulatory NewsRegulatory News | 06 April 2022 |  By 

The US Food and Drug Administration (FDA) has presented a framework to update the composition of COVID-19 vaccines based on new strains. During a meeting with its Vaccines and Related Biological Products Advisory Committee (VRBPAC), the agency said the framework is not final and only meant encourage discussion on how the agency can address the need to update vaccines for new antigenically distinct variants.
"The framework is tentative, it is thrown out to be placeholder to spur the discussion that is hopefully going to follow, and nothing is etched in stone,” said Jerry Weir, director of FDA’s Division of Viral Products at the Office of Vaccines Research and Review. “We would presume we'd meet again and talk to VRBPAC but we would like to get the conversation started."
FDA brought together its expert panel on 6 April to discuss what process could be used to update the composition of COVID-19 vaccines in the US and considerations for additional booster doses.
The framework proposes getting advice from the VRBPAC to make recommendations for any change in composition of authorized or approved COVID-19 vaccines in the US.

"We suggest on some routine basis the FDA and VRBPAC would review the epidemiology of circulating SARS-CoV-2 variants in the US, the effectiveness of available vaccines in use, and the available clinical data and manufacturing concerns for modified vaccines, in order to determine whether to recommend an updated vaccine for use in the US,” said Weir.
He asked the committee to think about how FDA, manufacturers and other health agencies could develop a collaborative plan to gather data needed to support the composition of updated vaccines. He also asked about developing contingency plans to respond to variants that are not sufficiently addressed with currently available vaccines.
Weir noted that if the World Health Organization (WHO) makes a recommendation on a COVID-19 vaccine composition, FDA and VRPAC would evaluate the recommendation as part of the proposed framework to determine if it is suitable for the US.
Within months of the COVID-19 outbreak, it became apparent the virus was mutating, according to Weir, and in some cases creating more virulent strains.
"As a result of this, composition of current COVID-19 vaccines may need to be updated to maintain vaccine effectiveness against clinically relevant variants," he said.
During his presentation, Weir compared COVID-19 vaccine development to how the influenza vaccine is developed. He noted the WHO evaluates dominant vaccine strains in the northern and southern hemispheres many months before vaccines are developed, manufactured and distributed.
This process can lead to a number of problems with the effectiveness of the influenza vaccine, such as more dominant strains appearing after the vaccine is produced, and manufacturers having difficulty matching the vaccine to the dominant strain in a timely manner especially when using egg-based platforms.
Weir added there are obvious challenges adapting the influenza vaccine development model to COVID-19 vaccines such as the fact that SARS-CoV-2 variants have not appeared in a predictable seasonal pattern like the influenza viruses and have not always spread globally, even though there have been substantial waves over the past two winters.
Unlike influenza, there are also more types of vaccines being developed for COVID-19, with updated compositions such as variant-specific and multivariant vaccines. Unlike influenza vaccines, modified vaccines are not being coordinated with new strain compositions.
Weir noted that some of the challenges of developing an updated COVID-19 vaccine include the time needed to manufacture them may differ significantly. Also depending on the vaccine platform, the manufacturer's experience and their facility capacity can be factors.
Another challenge compared to influenza vaccine development is that updated COVID-19 vaccines require additional considerations because of FDA’s limited experience with them. The agency requires vaccine-specific clinical safety and effectiveness data to support authorization of modified COVID-19 vaccines for any given manufacturer.
Besides challenges posed by FDA, Weir noted there are global challenges when updating vaccines due to issues such as the unpredictable nature of how the virus evolves, different regional levels of vaccination coverage, and implementing a coordinated global response.
"I think for us, a process for updating composition of COVID-19 vaccines in the US will need to be flexible as well as orderly, transparent and data-driven,” he said. “And we'd like the committee to consider a periodic review of COVID-19 epidemiology and the available clinical data for vaccines against variants of concern."
Weir also outlined some conditions necessary to make recommendations for changing COVID-19 vaccine strain composition including the need for epidemiology data to identify antigenically distinct variants that are likely to become the dominant strains. The agency also needs immunogenicity and effectiveness data to indicate the current COVID-19 vaccines provide insufficient protection against circulating variants of the virus.
The data would also need to justify recommendation for a strain composition change and manufacturers would have to provide clinical data to support the safety and effectiveness of their modified vaccines. Finally, vaccine manufacturers would have to show they can produce sufficient vaccines within a given time to make a real impact on the virus.
Weir asked the committee to think about how often COVID-19 vaccine composition should be reviewed, how smoothly can manufacturers transition the composition of their vaccines and what additional data or experience could help expedite the process for vaccine composition changes.
Trevor Bedford, a biostatistics professor at the Fred Hutchinson Cancer Research Center, spoke earlier in the day about how the SARS-CoV-2 virus mutated into different variants and compared it to variants of the influenza virus.
"What we've seen then over the course of the pandemic as these variants have emerged, the more successful ones have rapidly swept through the population and replaced existing diversity," he said.
He said that the delta variant took only a year to become the dominant variant. By comparison, the faster spreading influenza virus, H3N2, takes usually three to five years. Omicron has been even quicker, becoming the dominant variant in four months and the pattern is similar with the new omicron BA.1 variant.
Bedford added that the key to why the new variants are more virulent has to do with the spike proteins on the SARS-CoV-2 virus. He said that while the original form of the virus only had 8 to 10 mutations, the omicron variant has 25 to 30 mutations.
"SARS-CoV-2 so far has been evolving about twice as fast as influenza H3N2, about four times as fast as influenza H1N1 and about 10 times as fast as [influenza] B/Victoria,” said Bedford. “And that means if you look at omicron-like viruses, in just two-year’s time, since the start of the pandemic we've accomplished about 5 years of equivalent evolution of H3N2."
Bedford estimated by 1 March almost 10% of the US population had confirmed cases of omicron, of which a large majority contracted the disease after 15 December 2021. If assuming a case detection rate of 1 in 5 infections, he estimates estimate almost half the US population has been infected with omicron within a span of just 10 weeks. In comparison, it takes about 20 weeks to spread the seasonal influenza virus to 10 to 20 percent of the population.
"Going forward I think we can be pretty confident that there will be additional 'flu-like' drift within BA.1 and BA.2,” Bedford added when talking about how the new variant might mutate and spread.
He also notes there may be an omicron-like emergence from the delta virus that would be wildly divergent but trying to determine that probability would be difficult.
"We really don't know if these emergent viruses will be a common feature or a rare feature of endemic SARS-CoV-2 evolution," Bedford added.
Based on current 12-month data, Bedford says it’s more likely that an evolution within omicron BA.2 will happen to further increase intrinsic transmission and to escape from omicron-derived immunity. He says the scenario sees lower attack rates with a 2022-2023 epidemic driven by drift and waning of the virus, and seasonality associated with its infection rate.
However, a less likely scenario exists where another omicron-like emergence event happens, in which a chronic infection initiated in 2021 incubates a new wildly divergent virus, according to Bedford. This scenario, he said, sees high attack rates with the epidemic driven by a new variant.
"From everything we've seen, the S1 domain in SARS-CoV-2 is a very adaptable bit of protein and we should expect a lot of evolution going forward and we should have methods to keep up with this evolution in terms of vaccination platforms," said Bedford.
Christopher Murray, Director of the Institute for Health Metrics and Evaluation (IHME) echoed much of Bedford’s concerns during the meeting. He noted that more than 60% of the world will likely be infected with omicron once the current wave is complete. In the end of the wave, the world will be left with the highest levels of immunity since the beginning of the pandemic, but the immunity will wane he added.
"We do see in our hypothetical scenarios the critical factor that alters the trajectory of death is access and availability of antivirals and then endogenous response,” said Murray. “Even though we don't expect governments to impose much in the way of mandates politically going forward, to the extent we've seen in the last two years, considerable behavioral adaptation by those at risk by wearing masks and social distancing, when you add that in, you'll get some dampening of transmission if there is a new variant even without the implementation of mandates. If you do have mandates, of course you'll get more dampening."
Kanta Subbarao, Director of the WHO Collaborating Centre for Reference and Research on Influenza, also spoke at the advisory committee on her perspective on how to tackle the issue of new variants.
"The evolution of SARS-CoV-2 could substantially impact the COVID-19 pandemic as it has done and may require adaptations of the currently available countermeasures,” she said. “Adjustment of the vaccine composition may be needed to optimize the performance of COVID-19 vaccines because of the emergence of variants of concern.”
Subbarao said it’s critical to regularly review available data the variants have on countermeasures to provide timely recommendations on how to modify them and identify needs for future research and investigations.
"We do need to encourage development of COVID-19 vaccines that will have an impact on prevention of infection and transmission in addition to protecting against severe illness and death," she said. "Until such vaccines are available and as the virus evolves, the composition of the current COVID vaccines may need to be updated to ensure we achieve protection."


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