April 21, 2022

VIA Electronic Mail to: robert.califf@fda.hhs.gov, peter.marks@fda.hhs.gov

Robert Califf, MD
U.S. Food and Drug Administration
10903 New Hampshire Ave.
Silver Spring, MD 20993

Peter Marks, MD, PhD

Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
10903 New Hampshire Ave.
Silver Spring, MD 20993

Dear Dr. Califf and Dr. Marks:

We urge the FDA to include in its guidance to vaccine developers a

recommendation for T-cell assessment in COVID-19 vaccine clinical trials to more
comprehensively measure immune response. Measuring T-cell responses in
addition to antibodies is critical to help better evaluate vaccine efficacy and
inform decisions regarding ongoing protection against current and future
variants.

Despite remarkable advances in detecting, treating, and preventing SARS-CoV-2

infection, the emergence of the Omicron variant was a striking reminder of how much
there still is to learn about the immune response to this virus. To date, we lack a clear-
cut correlate of protection for the SARS-CoV-2 vaccines and the assessment of the
adaptive immune response to SARS-CoV-2 infection and vaccination has largely
focused on antibodies (Abs), with much less emphasis on the T-cell response despite a
likely role in protection from severe disease.

The limited study of T cells in SARS-CoV-2 research is impeding our ability to inform
policies related to emerging variants and long-term immune protection after Ab titers
have appropriately declined following infection and/or vaccination. The focus on Abs
stems in part from the ease of their quantitative measurement, making them more
convenient to include in research and clinical trials. Recent advances now enable
comparable T-cell assessment with precision and at scale, and it is opportune to
incorporate assessment of this other half of the adaptive immune system in vaccine
trials and other research now.

As discussed below, if thorough data had been collected on the broader adaptive
immune response – including Abs and T cells – since the beginning of the COVID-19
pandemic, we would better understand the risks posed by the emerging variants and
could more readily provide swift messaging to counter misinformation and associated
vaccine hesitancy. This gap was also highlighted in the initially announced results of the
BNT162b2 vaccine trial in a pediatric population ranging from ages 2 to under 5 years
that were deemed insufficient to support emergency use authorization, yet only antibody
results were considered in the analysis. Better understanding of correlates of protection,
including the contribution of cellular immunity in the form of a T-cell response, may have
informed decisions regarding potential authorization of the vaccines in this population.

Examining the T-cell response has applications for clinical diagnosis and management,
evaluation of protective immunity, and vaccine assessment. Studying the broader
adaptive immune response to COVID-19 may also help determine why some patients
become critically ill while others are asymptomatic1, which may help advance solutions
to diagnose, treat and prevent the disease. As mounting research continues to
demonstrate the importance of T cells in COVID-19, we urge including the study of
cellular immunity broadly across research, and especially in discovery and development
of new or modified vaccines.

Improving Information for Vulnerable Populations

There are ~7 million immunocompromised people living in the U.S. who struggle with
how to protect themselves2. We are lacking data on the full adaptive immune response
in these populations. Information about the T-cell response may help tailor vaccine
schedules, use of prophylactic interventions, or other measures to address the
increased risk of these populations.

With COVID-19 disproportionately impacting certain populations, we must utilize every

tool at our disposal, including T-cell assessment, to fully understand immunity and
address inequities worsened by the pandemic. Conducting this research and better
understanding the role of T cells in protective immunity will provide more robust
information about correlates of protection that will benefit our understanding for the
entire population, but especially those who are most vulnerable.

Strengthening the Public Health Response & Public Confidence

It is important to note that there are two dimensions to protection: (1) the prevention of
an individual being infected with SARS-CoV-2, and (2) if a person is infected, reducing
the likelihood of severe illness and death. Studying the Ab response helps inform the
first dimension, but the Delta and Omicron variants have highlighted the risk of an
exclusive focus on Ab-based protection because of the potential of these variants to
partially evade antibody responses.

However, with the emergence of the Omicron variant, a distinct discourse emerged:
expert voices began pointing to the importance of T cells almost immediately, providing
balance to concerns about the predicted loss of Ab-mediated protection. Multiple
studies3-7 have shown the preservation of vaccine-induced T-cell response against
Omicron, likely contributing to continued vaccine efficacy in protecting against severe
illness and death. This work must continue and be amplified by those informing policy
and explaining the latest science to the lay public.

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For example, one study8 generated sensationalized national media headlines
suggesting the ineffectiveness of the Johnson & Johnson vaccine against Delta. These
findings were directly refuted by the company’s study9 that demonstrated “strong,
persistent” protection, a conclusion supported by independent studies10,11. The first
study only reported the Ab response, not the full nature of the immune response
including T cells. This type of misinformation can impair the public health effort to
identify optimal vaccines, affect vaccine confidence, and exacerbate vaccine hesitancy,
and could be avoided with research on the broader adaptive immune response,
including T cells.

Given the important and complementary roles of Abs and T cells, we cannot truly
understand immunity by assessing only the humoral aspect of the adaptive immune
response. For example, robust protection against hospitalization with SARS-CoV-2
Omicron in South Africa has been reported for the 2-dose Pfizer and JnJ vaccines,
largely in the absence of Omicron neutralizing Abs12,13. Additionally, T-cell responses
appear more durable than serum NAb titers for all the vaccines which impacts boosting
considerations14.

While important for protection, Abs alone may not be sufficient to protect against
disease. In support of this, a pre-clinical study demonstrated lack of protection in some
vaccinated nonhuman primates with moderate Omicron NAb titers but undetectable
Omicron specific CD8 T cells15. Furthermore, depletion of CD8 T cells in convalescent
macaques partially abrogated protection against SARS-CoV-2 rechallenge, suggesting
a role for cellular immunity in the settings of waning antibody titers16. Yet, neutralizing
Ab activity continues to serve as the primary immune response measure evaluated by
the FDA for modified COVID-19 vaccines and in “immune-bridging” studies of in
pediatric cohorts.

As the pandemic continues to evolve, our response must as well. Emphasis on T-cell
immunity will be particularly important moving forward for durable protection against
severe disease with variants that largely escape NAb response. We need a concerted
effort to collect data on the broad immune response beyond Abs, especially for our most
vulnerable, to best inform public health strategies and federal policy decisions. We need
clinical trial protocols that include investigations of the full range of adaptive immune
responses in order to ensure that countermeasures keep pace with an evolving virus
and lay the foundation for responses to future epidemics and pandemics. We need
research funded and conducted by government agencies involving the human adaptive
immune response to help deliver actionable correlates of protection to decision makers
and reduce misinformation surrounding COVID-19. We pledge to work with you to
provide robust science and evidence to support these efforts.

We are sincerely grateful for your tremendous efforts and commitment to leading
America – and the world – through this crisis.

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Sincerely,

E. John Wherry, PhD

Richard and Barbara Schiffrin President’s Distinguished Professor
Director, Institute for Immunology
Chair, Department of Systems Pharmacology and Translational Therapeutics,
University of Pennsylvania Perelman School of Medicine
wherry@pennmedicine.upenn.edu

Santosha Vardhana, MD, PhD

Assistant Member, Human Oncology and Pathogenesis Program
Assistant Attending, Department of Medicine, Lymphoma Service
Memorial Sloan Kettering Cancer Center
vardhans@mskcc.org

William Morice, MD, PhD

President, Mayo Clinic Labs
Chair, Lab Medicine and Pathology, Mayo Clinic
morice.william@mayo.edu

Lance Baldo, MD
Chief Medical Officer
Freenome
lance.baldo@freenome.com

Authors of Enclosed Science Immunology Viewpoint:

Vardhana S, Baldo L, Morice William G, Wherry EJ. Understanding T-cell responses to
COVID-19 is essential for informing public health strategies. Science Immunology.
2022. doi:10.1126/sciimmunol.abo1303

Signatures in Alphabetical Order

Andrew Allen, MD, PhD Dan Barouch, MD, PhD

Chief Executive Officer William Bosworth Castle Professor of
Gritstone Bio., Inc. Medicine, Harvard Medical School, Beth
aallen@gritstone.com Israel Deaconess Medical Center
dbarouch@bidmc.harvard.edu
Jeff Allen, PhD
President and CEO Arie Belldegrun, M.D.
Friends of Cancer Research Executive Chairman and Co-Founder
jallen@focr.org Allogene Therapeutics, Inc.
arie@allogene.com
Mara Aspinall
Managing Director Diana Berrent
Health Catalysts Group Founder
Mara.aspinall@healthcatalysts.com Survivor Corps

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 Diana@SurvivorCorps.com
Luciana Borio Shane Crotty
Venture Partner Professor, Center for Infectious Disease
ARCH Venture Partners and Vaccine Research, La Jolla Institute
LBorio@archventure.com for Immunology (LJI), Adj. Professor,
UCSD School of Medicine, Dept. of
Jonathan Braun, MD, PhD Medicine, Division of Infectious Diseases
Professor and Director, IBD Enterprise and Global Public Health
Operations shane@lji.org
Cedars Sinai Medical Center
Jonathan.Braun2@cshs.org Anne S. De Groot, MD
Chief Executive Officer, Chief Scientific
Rick A. Bright, PhD Officer, and Co-Founder
CEO, Pandemic Prevention Institute EpiVax, Inc.
Sr. Vice President of Pandemic annied@epivax.com
Prevention and Response, The
Rockefeller Foundation Don J. Diamond, PhD
RBright@Rockfound.org Consultant
Geovax Labs Inc
Darrick Carter, PhD ddodd@geovax.com
Chief Scientific Office, Affiliate Professor
of Medicine and Global Health, University Lorella Di Donato, PhD
of Washington SVP & Chief Operating Officer
HDT Bio CellCarta
Darrick.carter@hdt.bio lorella.didonato@cellcarta.com

David Chang, MD, PhD Richard J. DiPaolo, PhD

Co-Founder and Chief Executive Officer Professor and Interim Chair
Allogene Therapeutics, Inc. Department of Molecular Microbiology &
David@allogene.com Immunology
Saint Louis University School of Medicine
Todd Chermak R.Ph, PhD richard.dipaolo@health.slu.edu
Chief Regulatory & Government Affairs
Officer Bill Enright
CellCarta Chief Executive Officer
Todd.chermak@cellcarta.com Vaccitech plc
bill.enright@vaccitech.co.uk
Lindsay G. Cowell, MS, PhD
Associated Professor, Department of Keith T. Flaherty, MD
Population and Data Sciences, Director of COVID-19 Clinical Research,
Department of Immunology Massachusetts General Hospital (2020-
University of Texas Southwestern 21)
Medical Center at Dallas Director of Clinical Research, MGH
Lindsay.Cowell@UTSouthwestern.edu Cancer Center
kflaherty@mgh.harvard.edu

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Agenete Fredriksen, PhD Karin Joos, PhD
Chief Innovation & Strategy Officer and Co- Executive Vice President and Head of
founder Research & Development
Nykode Therapeutics Gritstone Bio, Inc.
abfredriksen@nykode.com kjooss@gritstone.com

Allison Greenplate, PhD Alexander Koglin, PhD

Associate Director, Immune Health Chief Executive Officer and Chief
University of Pennsylvania Perelman School Scientific Officer
of Medicine Nature's Toolbox (NTx Inc.)
Allie.greenplate@pennmmedicine.upenn.edu alex.koglin@ntxbio.com

Alba Grifoni, PhD Rejko Krüger, MD

Instructor/Rsearch Faculty, Sette Lab, Director, Transversal Translational
Center for Infectious Disease and Vaccine Medicine, Luxembourg Institute of
Research Health
agrifoni@lji.org Professor for Neuroscience,
Luxembourg Centre for Systems
Matthew J. Hawryluk, PhD Biomedicine, University of
Chief Business Officer Luxembourg, and Senior Consultant,
Gritstone Bio, Inc. Centre Hospitalier de Luxembourg,
mhawryluk@gritstone.com Luxembourg
rejko.krueger@lih.lu
James R. Heath
President Bruce L. Lambert, PhD
Institute for Systems Biology Professor, Director, Center for
Jim.heath@isbscience.org Communication and Health,
Department of Communication Studies
Ramin Herati, MD Northwestern University
Assistant Professor, NYU Grossman School bruce.lambert@northwestern.edu
of Medicine
ramin.herati@nyulangone.org Scott P Layne, MD FACP FIDSA
Professor, Providence Saint John's
Adrian V. S. Hill KBE, FRCP, FRS Cancer Institute, Santa Monica, CA
Lakshmi Mittal Professor of Vaccinology and Professor Emeritus, Fielding UCLA
Director of the Jenner Institute School of Public Health, Los Angeles,
Oxford University CA
Adrian.Hill@ndm.ox.ac.uk scottplayne@gmail.com

Jeffrey Huber
Founding CEO, GRAIL
Managing Partner, Triatomic Capital
jhuber@gmail.com

6
Bruce Levine, PhD Stephen M. McLean
Barbara and Edward Netter Professor in Senior Partner & Chairman,
Cancer Gene Therapy Healthcare
Founding Director, Clinical Cell and Vaccine Arsenal Capital Partners
Production Facility smclean@arsenalcapital.com
Center for Cellular Immunotherapies Director
of Technology Innovation Ira Mellman, PhD
Department of Pathology and Laboratory VP, Cancer Immunology
Medicine Genentech
Perelman School of Medicine mellman.ira@gene.com
Abramson Cancer Center, University of
Pennsylvania Miriam Merad, MD, PhD
levinebl@pennmedicine.upenn.edu Director Precision Immunology
Institute, Mount Sinai School of
Ofer Levy, MD, PhD Medicine
Director, Precision Vaccines Program New York, NY
Boston Children’s Hospital & Harvard Miriam.merad@mssm.edu
Medical School
Ofer.levy@childrens.harvard.edu Robert Nelsen
Co-founder and Managing Director
Michela Locci, PhD ARCH Venture Partner
Assistant Professor of Microbiology rn@archventure.com
Perelman School of Medicine
University of Pennsylvania Gwen Nichols, MD
Michela.locci@pennmedicine.upenn.edu Chief Medical Officer
Leukemia & Lymphoma Society
Joel Marcus gwen.nichols@lls.org
Executive Chairman & Founder
Alexandria Real Estate Equities, Inc. Luigi D. Notarangelo, MD
Alexandria Venture Investments Chief, Laboratory of Clinical
jmarcus@are.com Immunology and Microbiology
National Institute of Allergy and
John Mattison, MD Infectious Diseases
Operating Partner, Chief Medical Information National Institutes of Health
Officer, Formerly Chief Medical Information Luigi.notarangelo2@nih.gov
Officer, Kaiser Permanente, SCAL
Arsenal Capital Partners Prof. Dr. med. Markus Ollert, MD
jmattison@arsenalcapital.com Director, Department of Infection and
Immunity, Luxembourg Institute of
Thomas McDade, PhD Health
Carlos Montezuma Professor, Faculty Luxembourg Institute of Health (LIH)
Fellow, Institute for Policy Research Markus.Ollert@lih.lu
Northwestern University
t-mcdade@northwestern.edu

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Eustache Paramithiotis, PhD Rafick-Pierre Sekaly, PhD
Vice President, R&D Professor & Vice-Chair of
CellCarta Biosciences, Inc. Translational Medicine, Director of
eustache.paramithiotis@cellcarta.com Pathology Advanced Translational
Research Unit, Emory Vaccine Center,
Michael Pellini, MD Department of Pathology, and
Managing Partner Laboratory Medicine
Section 32, LLC Emory University, School of Medicine
mikep@section32.com rafick.sekaly@emory.edu

Marion Pepper Alessandro Sette, Dr.Biol.Sci.

Associate Professor and interim Chair, Professor and Member
Department of Immunology La Jolla Institute for Immunology,
University of Washington School of Medicine Division of Vaccine Discovery
mpepper@uw.edu Center for Infectious Disease and
Vaccine Research
Sonia N. Rao, PharmD, BCIDP, BCPS Center for Autoimmunity and
Associate Director, Head of Global MSLs, Inflammation
Medical Affairs University of California, School of
QIAGEN Inc. Medicine
sonia.rao@qiagen.com alex@lji.org

Gili Regev-Yochay, MD, MSc, MPH Ellen Sigal, PhD

Infection Prevention & Control Unit, Director Founder and Chairperson
Sheba Medical Center, Tel Hashomer, Friends of Cancer Research
Ramat Gan, Israel esigal@focr.com
gili.regev@sheba.health.gov.il
Megan Smithey, PhD
Chad Robins Director, Clinical Immunology
CEO and co-founder Vir Biotechnology
Adaptive Biotechnologies msmithey@vir.bio
crobins@adaptivebiotech.com
Paul G. Thomas, PhD
Harlan Robins, PhD Member, Department of Immunology,
Chief Scientific Officer and Co-founder St. Jude Children’s Research Hospital
Adaptive Biotechnologies Memphis, TN
hrobins@adaptivebiotech.com paul.thomas@stjude.org

Jamie Kathleen Scott, MD, PhD Eric Topol, MD

Professor Emerita, and former Canada Professor and Executive Vice-
Research Chair in the Molecular Basis of President, Scripps Research; Founder
Immunity and Director, Scripps Research
Simon Fraser University Translational Institute
jkscott@sfu.ca Scripps Research
etopol@scripps.edu

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Bruce D Walker, MD Edus H. Warren, MD, PhD
Director, Ragon Institute of MGH, MIT Program Head, Global Oncology
and Harvard, Co-Leader, Massachusetts Professor, Clinical research Division
Corsortium and Pathogen Readiness, Professor, Vaccine and Infectious
Investigator, Howard Hughes Medical Disease Division
Institute, Phillip T. And Susan M. Ragon Fred Hutchinson Cancer Research
Professor, Harvard Professor of the Center
Practice, MIT Associate, Center for the Ehwarren@u.washington.edu
AIDS Programme of Research in South
Africa Daniela Weiskopf, PhD
Bwalker@mgh.harvard.edu Research Assistant Professor, Center for
Infectious Disease and Vaccine Research
Prof. Dr. Juliane Walz La Jolla Institute for Immunology (LJI)
Chair Department for Peptide-based dweiskopf@lji.org
Immunotherapy
Medical Faculty, University of Tübingen Lynne Zydowsky
Medical Director CCU Translational Chief of Science
Immunology Alexandria Real Estate Equities, Inc.
Department Internal Medicine lynne@zydowskyconsultants.com
University Hospital Tübingen
University of Tübingen
Juliane.Walz@med.uni-tuebingen.de

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