Do mRNA-based COVID-19 vaccines induce memory T cell response similar to natural infection?

A team of scientists from the United States has recently compared the epitope-specific T cell response after natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination in both naïve and previously infected individuals.

The study reveals that mRNA-based coronavirus disease 2019 (COVID-19) vaccines are highly potent in inducing spike-specific T cell response in naïve individuals and triggering memory T cell response in COVID-19 recovered individuals. The study is currently available on the medRxiv* preprint server.


Among various COVID-19 vaccines developed during the pandemic, mRNA-based vaccines, including Pfizer/BioNTech-developed BNT162b2, have shown about 90% efficacy in preventing SARS-CoV-2 infection and symptomatic COVID-19. Although it is now well-documented that BNT162b2 elicits robust and durable antibody and T cell responses, its efficacy in triggering pre-existing memory T cell response in COVID-19 recovered individuals remain largely unknown.

Molecular detection of antibodies is a comparatively easy process as antibodies directly bind to antigens. In contrast, T cells recognize and bind to antigens that are displayed on the surface of antigen-presenting cells via the Major Histocompatibility Complex (MHC). Because of the high variability of peptide-MHC molecules across and within individuals, measurement of epitope-specific T cell response is highly challenging.

In the current study, the scientists have conducted MHC-multimer staining together with single cell-based RNA and T cell receptor (TCR) sequencing to measure epitope-specific T cell responses in naïve, and COVID-19 recovered individuals who have been vaccinated with BNT162b2. They have conducted MHC-multimer staining specific for epitopes derived from the spike and non-spike proteins.

Important observations

For the characterization of T cell responses to multiple immunodominant epitopes, peripheral blood mononuclear cells were collected from 19 adult individuals who received two doses of the BNT162b2 vaccine. Of all participants, nine were without prior SARS-CoV-2 infection, and ten were COVID-19 recovered individuals.  

Regarding humoral immunity, both COVID-19 recovered and naïve participants exhibited comparable levels of IgG-specific anti-spike and anti-receptor binding domain (RBD) antibodies after vaccination.

Epitope-specific CD8+ T cell responses

Six epitopes from the spike protein and 12 epitopes from non-spike proteins were selected to measure T cell responses. The comparison of T cell response after infection or vaccination revealed no significant difference in magnitudes of response, memory phenotypes, T cell receptor repertoire diversity, and αβ T cell receptor sequence motifs in memory T cells generated by natural SARS-CoV-2 infection and vaccination. These findings indicate that the BNT162b2 is capable of boosting pre-existing vaccine-induced as well as infection-induced immunity after the prime-boost immunization.

Importantly, the study identified T cell responses to a spike-derived epitope that is cross-reactive to common cold coronaviruses. Moreover, the analysis of longitudinal samples from COVID-19 recovered participants before and after vaccination identified a subset of T cells, including differentiated effector cells or actively proliferating T cells, which was transient and could not be observed in the same donor at later timepoints. However, the expanded clones from which these transient T cells were derived persisted in other T cell subsets with long-lived memory phenotypes. This indicates that robust T cell memory can be generated by both natural infection and vaccination.

Further analysis of samples collected from COVID-19 recovered, vaccinated participants revealed clonal expansion and a phenotypic shift of pre-existing memory T cells towards a more differentiated effector phenotype. Moreover, the analysis of T cell receptor repertoires indicated that both infection and vaccination induce almost identical repertoires. This highlights the potency of the vaccine in triggering a recall response in convalescent participants.

Study significance

The study reveals that both natural SARS-CoV-2 infection and immunization with mRNA vaccines lead to the induction of equivalent levels of spike-specific memory T cell responses. Moreover, in previously infected individuals, mRNA vaccines can further expand these responses.

Overall, the study highlights the importance of prime-boost immunization with mRNA-based COVID-19 vaccines in inducing, shaping, and persistently maintaining T cell memory in naïve and COVID-19 recovered individuals.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Sanchari Sinha Dutta

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.


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  1. Bruce Keefe Bruce Keefe United States says:

    Actually Studies have shown that prolonged exposure to the immune system response may be responsible for blood clots as your study of 19 individuals shows is possible

  2. Allen Dilliplane Allen Dilliplane United States says:

    "triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state."
    Look at Figure 2, chart G. It shows that the diverse immune response you get from prior infection immunity gets altered to be more geared towards the spike. Why would this be a good thing?

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