The body’s T cells provide long-lasting memory against the virus following vaccination or infection from COVID-19


Researchers at the Peter Doherty Institute for Infection and Immunity (Doherty Institute) have shown that the body’s T cells provide long-lasting memory against the virus following vaccination or infection from COVID-19.

Published today in Nature Immunology, the team utilized new technology to track the T cell responses of people who had recovered from COVID-19 for 15 months and found there was a sustained level of these cells capable of recognizing the SARS-CoV-2 spike protein.

University of Melbourne Dr. Jennifer Juno, a Senior Research Fellow at the Doherty Institute and senior author on the paper, said that despite an initial contraction of the immune response immediately following infection, the T cells stabilized at six months and remained level after 15 months of monitoring.

“Even though some parts of the immune response wane, we can now see that T cells recognizing the virus are quite stable over time. After more than a year, they were still roughly 10-fold higher than someone who had never been exposed to the spike protein through infection or vaccination,” said Dr. Juno.

While B cells are responsible for producing the antibodies that recognize SARS-CoV-2, T cells play a crucial role in supporting the development of the B cell response. Without T cell help, B cells are unable to produce high amounts of antibodies that can bind to the virus and stop infection.

When individuals were re-exposed to the COVID-19 spike protein through vaccination, the part of the virus that enables SARS-CoV-2 to attach and enter cells in humans, the T cells quickly reactivated and increased in number.

“Vaccination boosted the levels of these T cells to be up to 30 times higher than they were before,” Dr. Juno said.

The team looked at people who had recovered from mild illness, as well as people who had been vaccinated.

“In general, we saw that the vaccines generate the same amount of T cells as someone who had been infected. We also saw that the third dose does an incredible job at re-activating those T cells and bringing the levels back up again,” said Dr. Juno.

The team utilized new technology called tetramers that help identify which T cells recognize the spike protein to undertake the research, resulting in more accurate findings.

“Usually we have to stimulate the cells in the lab before we can measure the T cell response. However, using tetramers, we can look at them straight from the blood samples, meaning we are getting a more accurate picture of what is happening,” said Dr. Juno.

The team are now looking at how these T cells react when breakthrough infections happen.

“We are looking at people who have been vaccinated, but then still catch COVID-19, and trying to understand whether the T cells are still being reactivated in the same way as what we’ve seen with the vaccines and primary infections.”

The emergence of several severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) variants of concern (VOC) with multiple amino acid replacements has implications for the future control of the coronavirus disease 2019 (COVID-19) pandemic.1, 2, 3, 4 VOCs include the United Kingdom (UK) variant 501Y.V1 lineage B.1.1.7,3 the South Africa (SA) variant 501Y.V2 lineage B.1.351,4 the BR (Brazilian) variant 501Y.V3 lineage P.1,5,6 and the California (CA) variant CAL.20C lineages B.1.427–429.7,8 The B.1.1.7 variant is associated with increased transmissibility,9,10 and similar epidemiological observations have been reported for the SA and BR variants.4,5

The mutations of greatest concern are present in the viral spike (S) protein and include notable mutations in the receptor-binding domain (RBD), the N-terminal domain (NTD), and the furin cleavage site region. Several of the RBD mutations directly affect angiotensin-converting enzyme 2 (ACE2) receptor-binding affinity, which may affect infectivity, viral load, or transmissibility.11, 12, 13, 14

Multiple mutations were also noted in regions bound by neutralizing antibodies, so it is crucial to address the extent to which mutations associated with the variants may affect immunity induced by either SARS-CoV-2 infection or vaccination.

Numerous reports address the effect of variant spike (S) mutations on antibody binding and function.11,14, 15, 16, 17, 18, 19, 20, 21, 22, 23 In general, the impact of B.1.1.7 mutations on neutralizing antibody titers is moderate.15, 16, 17, 18,20,24 In contrast, mutations in B.1.351 and P.1 variants are associated with the more pronounced loss of neutralizing capacity.15,16,22,23,25

Concerning vaccination responses, the AstraZeneca ChAdOx1 vaccine has been associated with a partial loss of neutralizing antibody activity against B.1.1.715 and a large loss of neutralizing activity against B.1.351.26 ChAdOx1 maintains efficacy against B.1.1.724,27 but has a major loss in efficacy against mild COVID-19 with the B.1.351 variant.26

Current epidemiological evidence is that the BNT162b2 Pfizer/BioNTech COVID-19 vaccine retains its efficacy against B.1.1.7 in the UK24 and in reports from Israel.28,29

The Novavax COVID-19 vaccine (NVX-CoV2373) has differential protective immunity against the parental strain, B.1.1.7, and B.1.351 in clinical trials (96%, 86%, and 60%, respectively),30 whereas the Janssen Ad26.COV2.S 1-dose COVID-19 vaccine has relatively similar protection for moderate COVID-19 against both the ancestral strain and B.1.351 (72% and 64%, respectively).31,32

Several lines of evidence suggest that CD4+ and CD8+ T cell responses play important roles in the resolution of SARS-CoV-2 infection and COVID-19,33 including modulating disease severity in humans34,35 and reducing viral loads in non-human primates.36 Furthermore, individuals with agammaglobulinemia or pharmaceutical depletion of B cells generally experience an uncomplicated COVID-19 disease course.33,37,38

Robust CD4+ and CD8+ T cell memory is induced after COVID-19 ,22,39, 40, 41 and multiple COVID-19 vaccines elicit CD4+ and CD8+ T cell responses.26,42, 43, 44, 45 It is therefore key to address the potential impact of mutations associated with SARS-CoV-2 variants on T cell reactivity; however, few data are available on this topic.46

Here, we take a combined experimental and bioinformatics approach to address T cell reactivity to SARS-CoV-2 VOCs. We directly assess T cell responses from individuals recovered from COVID-19 and T cell responses from recent Moderna mRNA-1273 or Pfizer/BioNTech BNT162b2 vaccinees for their capacity to recognize peptides derived from the ancestral reference sequence and the B.1.1.7, B1.351, P.1, and CAL.20C variants. As a complementary approach, bioinformatics analyses were used to predict the impact of mutations in the VOCs with sets of previously reported CD4+ and CD8+ T cell epitopes derived from the ancestral reference sequence.

More information: Kathleen M. Wragg et al, Establishment and recall of SARS-CoV-2 spike epitope-specific CD4+ T cell memory, Nature Immunology (2022). DOI: 10.1038/s41590-022-01175-5



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