Marks says evaluating T cell immunity for future COVID vaccines ‘makes sense’

Regulatory NewsRegulatory News | 23 December 2022 |  By 

CBER Director Peter Marks

The US Food and Drug Administration’s (FDA) top vaccines regulator, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER) told vaccine experts that it “makes sense” to consider T cell responses in evaluating the next generation of COVID-19 vaccines in light of waning immunity with existing vaccines and the emergence of new variants.
These responses could be evaluated from phase 2 trials for potential vaccine candidates and not necessarily larger phase 3 trials, where it is more difficult to assess T cell response.
He agreed with experts at a 16 December meeting sponsored by Northwestern University’s COVID-19 Communication and Evaluation Network (CoVAXCEN) that these evaluations could be used in conjunction with existing antibody assessments to better understand the immune response to the virus. CoVAXCEN is a forum for experts in immunology, infectious disease, epidemiology and regulatory science to discuss issues related to the safety and efficacy of COVID-19 vaccines.
Despite the progress made in detecting and preventing COVID-19, the emergence of new variants and waning immunity is compromising the long-term efficacy of existing vaccines, said experts at the meeting. It is also becoming evident that antibody assessments alone are not enough to measure the long-term effectiveness of vaccine immune responses.
“There is a continued increase in infection rates,” said panel moderator Sharon Benzeno, chief commercial officer of immune medicine at Adaptive Biotechnologies. While antibodies have been the main tool for assessing vaccine efficacy because they were “better understood and easy to measure” looking at this response alone may not be enough anymore.
“As we are looking ahead to year four of the pandmeic, there is a lot of population level data and it is clear that we need to understand the full story of the immune system including antibodies and T cells. We have to reckon with the reality that the virus is not going away.”
Benzeno said that one key question that remains unanswered is whether T cell assessments should be included with antibody data in large vaccine studies and in COVID-19 research overall, and if so, in what form this should take.
Marks agreed that waning immunity and the new variants are “continuing to challenge the agency.”
“We are in the midst of another wave of COVID-19. This past week there were 40,000 hospitalizations per day, and we do seem to be on the way up again for COVID-19 along with other respiratory viruses that are circulating. The problem is that the new variants are more resistant to neutralization by our current vaccines, and this is an issue.”
In the early days of pandemic, said Marks, FDA’s overarching concern was protecting the public health, which “quickly turned into what you could get your hands on as opposed to what was best.”
For the next generation vaccines, Marks said, “I’m not sure that these antibody responses will get us there. I’m not sure they will help us predict what is most effective over a longer haul.”
Unanswered questions about immune response
Experts at the meeting said that additional data emanating from T cell studies may help to address “unanswered questions” about the immune response to current vaccines.
These questions include the robustness of the immune response, the duration of the immune response and how to best protect elderly and immunocompromised populations.
When asked about the viability of evaluating T cell responses, Marks responded that “obviously having the antibody protection is a  great thing, but as we start thinking about the new variants and population in need of new vaccines, it is pretty clear from observational data that there is a story to be sold by the T cell response that has not been told, so I think it does make sense.” He compared antibody assessment with the “carpenter and the nail, what you have is what you are going to use.”
Marks also addressed a possible testing approach for evaluating T cell immune responses in COVID vaccine trials, when asked how the consortium could advance this idea.
“It’s true that you cannot really assess T cells in large scale phase 3 trials. But if you think about what vaccine development would look like for new vaccines, the essential part is that for the most part it won’t be large phase 3 trials, the most essential part of it will be phase 2 trials that will actually help you understand if you have a candidate likely succeed in phase 3.”
From a regulatory perspective, Marks said he thinks “we would want to see something that is fit for purpose. The idea is that you would study something that will bring value to this above and beyond what we know.”
Marks said the consortium could also suggest that the agency update its guidance on COVID-19 vaccine development to include looking at T cell response in addition to the current testing approach of antibody assessment.
It would be necessary to “translate the data we have into a compelling story that is of equal value to the compelling story we currently have.”


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