Discussion
Assessing the composition, scope, and durability of protective immunity
generated after SARS-CoV-2 infection or vaccination are critical for
control of the pandemic and future vaccination strategies. It is likely
that analyzing immune responses to SARS-CoV-2 has garnered more
attention and information than any other human infection in history.
Traditional assessments have included antibody responses which are often
transient or rapidly declining in patients with moderate infections.
However, we now know that T-cell immunity against SARS-CoV-2 is more
diverse and cross-reactive with peptides expressed on other
Coronaviruses9,11-12. These observations suggest that
robust T-cell responses are an important and essential element of
long-term immunity to SARS-CoV-2. However, assessments of T-cell
immunity to SARS-CoV-2 are not readily available. In this regard, we
present data from a flow cytometry-based assay detecting dual
cytokine-producing, SARS-CoV-2-antigen-specific memory T-cells which
demonstrates specificity and accuracy for detection of CD4+/CD8+ T-cell
responses to SARS-CoV-2 peptides and differentiates infected and
vaccinated individuals from those not exposed to SARS-CoV-2.
Finally, analysis of T-cell responses to an important VOC (B.1.1.7)
showed that exposure to SARS-CoV-2 infection or BNT162b2 vaccine
elicited nearly equivalent T-cell responses. Recent observations suggest
that IgG responses to SARS-CoV-2 infection did not reduce viremia in
patients infected with the B.1.1.7 variant8 however,
SARS-CoV-2 T-cell responses were not explored in that study. Long term
analysis of immune responses will be important since memory responses
differ greatly from acute responses, especially at the antibody
level7,14-15. Here, dormancy of memory T-cells,
B-cells, and plasma cells that can rapidly be activated upon re-exposure
to SARS-CoV-2 exposure are likely to have an important role in
preventing SARS-CoV-2 infection and possibly infection from current and
emerging VOC13.
Acknowledgements :
We wish to thank the members of the Transplant Immunology Laboratory and
Division of Infectious Diseases at Cedars-Sinai Medical Center for their
hard work and dedication to this project. We also want to express our
gratitude to the patients with COVID-19 and vaccine participants for
donating their time and blood for this study.
Figure Legends :
Figure 1. Detection of SARS-CoV-2-specific T-cells in whole blood. Fresh
whole blood from participants was stimulated by SARS-CoV-2 Spike
peptides. Activated CD4+ T-cells were
identified as CD45+CD3+CD4+IL-2+/TNF-α+ cells while activated CD8+
T-cell were CD45+CD3+CD8+TNF-α+/IFN-γ+ cells. Also shown is Blood + PHA
which is positive control and Blood only which is negative control.
Figure 2. T cell immune response in SARS-CoV-2 infected patients and
vaccinated individuals. A.CD4+ and CD8+ T-cell immune responses to
SARS-CoV-2 peptides from 134 patients with confirmed SARS-CoV-2
infection. T-cells were stimulated separately using 5 major CoV-2
peptides: Spike, VME, NCAP, AP3A, NS7A. Activated CD4+ and CD8+ T cells
were enumerated in Figure 1. Each dot represents one individual reading.
B. CD4+ and CD8+ T-cell immune responses to SARS-CoV-2 Spike peptides in
healthy, infected and vaccinated individuals. C. The correlation of
Nucleocapsid-specific IgG levels with CD4+ T-cell immune responses to
one or more of 5 major SARS-CoV-2 peptides in 25 patients. D. The
correlation between Spike-specific CD4+ T-cell immune responses and
Spike-specific IgG levels in 13 patients with elevated CD4+
Spike-specific T-cell immune responses (IL-2+/TNF-α+ cell% in CD4+
> 0.3%).
Figure 3. Immunogenicity of variant B.1.1.7 spike peptides. A&B. CD4+
& CD8+ T-cell immune responses to Spike-specific peptides are shown in
infected/recovered and vaccinated patients. T cells were stimulated by
the original SARS-CoV-2 Spike (Wuhan) or variant B.1.1.7 Spike peptides.
Activated CD4+ (A) and CD8+ T- cell (B) in 19 infected patients and 18
vaccinated individuals are shown. C&D.The paired data for immune
responses to SARS-CoV-2 Spike peptides and UK (B.1.1.7)Spike peptides
for each individual.
References :
- https://www.worldometers.info/coronavirus/ July 3, 2021
- Thompson MG, Burgess JL, Naleway AL, et al. Prevention and Attenuation
of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines. N Engl J Med.
2021 Jun 30. Doi: 10.1056/NEJMoa2107058. Epub ahead of print.
- Krause PR, Fleming TR, Longini IM,et al. SARS-CoV-2 Variants and
Vaccines. N Engl J Med. 2021 Jun 23. Doi: 10.1056/NEJMsr2105280. Epub
ahead of print.
- Dan JM, Mateus J, Kato Y, et al Immunological memory to SARS-CoV-2
assessed for up to 8 months after infection. Science. 2021 Feb
5;371(6529):eabf4063. Doi: 10.1126/science.abf4063. Epub 2021 Jan 6.
PMID: 33408181; PMCID: PMC7919858.
- Jordan SC. Innate and adaptive immune responses to SARS-CoV-2 in
humans: relevance to acquired immunity and vaccine responses. Clin Exp
Immunol. 2021 Jun;204(3):310-320. Doi: 10.1111/cei.13582. Epub 2021
Mar 4. PMID: 33534923
- Anand SP, Prévost J, Nayrac M, et al Longitudinal analysis of humoral
immunity against SARS-CoV-2 Spike in convalescent individuals up to 8
months post-symptom onset. Cell Rep Med. 2021 Jun 15;2(6):100290. Doi:
10.1016/j.xcrm.2021.100290. Epub 2021 May 5. PMID: 33969322; PMCID:
PMC8097665.
- Radbruch A, Chang HD. A long-term perspective on immunity to COVID.
Nature. 2021 Jun 14. Doi: 10.1038/d41586-021-01557-z. Epub ahead of
print
- Ratcliff J, Nguyen D, Fish M, et al. Virological and serological
characterization of critically ill patients with COVID-19 in the UK:
Interactions of viral load, antibody status and B.1.1.7 variant
infection. J Infect Dis. 2021 May 24:jiab283. doi:
10.1093/infdis/jiab283. Epub ahead of print. PMID: 34031695; PMCID:
- Braun J, Loyal L, Frentsch M et al. SARS-CoV-2-reactive T-cells in
healthy donors and patients with COVID-19. Nature 2020; 587:270–274.
- Mateus J, Grifoni A, Tarke A et al. Selective and cross-reactive
SARS-CoV-2 T-Cell epitopes in unexposed humans. Science 2020;
370:89–94.
- Peng Y, Mentzer A, Liu G et al. Broad and strong memory CD4+ and CD8+
T cells induced by SARS-CoV-2 in UK convalescent individuals following
COVID-19. Nat Immunol 2020; 21:1336–1345.
- Swadling L, Maini M. T-cells in COVID-19 – united in diversity. Nat
Immunol 2020; 21:1307–1308.
- Tarke A, Sidney J, Methot N, Negligible impact of SARS-CoV-2 variants
on CD4 + and CD8 + T-cell reactivity in COVID-19 exposed donors and
vaccinees. bioRxiv [Preprint]. 2021 Mar 1:2021.02.27.433180. doi:
10.1101/2021.02.27.433180. PMID: 33688655;
- Turner JS, Kim W, Kalaidina E, Goss CW, Rauseo AM, Schmitz AJ, Hansen
L, Haile A, Klebert MK, Pusic I, O’Halloran JA, Presti RM, Ellebedy
AH. SARS-CoV-2 infection induces long-lived bone marrow plasma cells
in humans. Nature. 2021 May 24. doi: 10.1038/s41586-021-03647-4. Epub
ahead of print.
- Wang, Z., Muecksch, F., Schaefer-Babajew, D. et al. Naturally enhanced
neutralizing breadth against SARS-CoV-2 one year after infection.
Nature (2021). https://doi.org/10.1038/s41586-021-03696-9