Disentangling the relative importance of T cell responses in COVID-19: leading actors or supporting cast?

Abstract

The rapid development of multiple vaccines providing strong protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been a major achievement. There is now compelling evidence for the role of neutralizing antibodies in protective immunity. T cells may play a role in resolution of primary SARS-CoV-2 infection, and there is a widely expressed view that T cell-mediated immunity also plays an important role in vaccine-mediated protection. Here we discuss the role of vaccine-induced T cells in two distinct stages of infection: firstly, in protection from acquisition of symptomatic SARS-CoV-2 infection following exposure; secondly, if infection does occur, the potential for T cells to reduce the risk of developing severe COVID-19. We describe several lines of evidence that argue against a direct impact of vaccine-induced memory T cells in preventing symptomatic SARS-CoV-2 infection. However, the contribution of T cell immunity in reducing the severity of infection, particularly in infection with SARS-CoV-2 variants, remains to be determined. A detailed understanding of the role of T cells in COVID-19 is critical for next-generation vaccine design and development. Here we discuss the challenges in determining a causal relationship between vaccine-induced T cell immunity and protection from COVID-19 and propose an approach to gather the necessary evidence to clarify any role for vaccine-induced T cell memory in protection from severe COVID-19.

Fig. 1. Neutralizing antibodies predict protection from acquisition of SARS-CoV-2 infection.

a | Relationship between the mean in vitro neutralizing antibody level from phase I/II trials of different vaccines and the reported phase III efficacy against symptomatic infection with the ancestral SARS-CoV-2 strain (adapted from ref.). The x axis is scaled as a proportion of the mean neutralization titre of convalescent participants analysed in the same study. b | Relationship between the predicted neutralization against SARS-CoV-2 variants and the reported efficacy of different vaccines against the variants (adapted from ref., with additional data overlaid from ref.). c | Relationship between the neutralizing antibody level and protection from severe SARS-CoV-2 infection (with the ancestral virus; adapted from ref.).

Fig. 2. Protection from acquisition of SARS-CoV-2 infection tracks the neutralizing antibody responses.

From comparison of situations where neutralizing antibody (nAb) and memory T cell responses are decoupled, protection appears to be predicted by the level of nAbs. a | The nAb levels, circulating spike-specific (AIM⁺) CD4⁺ T cell levels and AIM⁺CD8⁺ T cell levels, and protection against symptomatic infection for the Beta variant versus the ancestral SARS-CoV-2 strain. nAb titres (measured as the 50% focus-reduction neutralizing antibody titre (FRNT50)) are reduced 3.9-fold, 8.8-fold and at least 10-fold for the Delta (B.1.167.2), Beta (B.1.351) and Omicron (B.1.1.529) variants, respectively^,. By contrast, T cell responses to the variants are largely preserved, including to the Beta, Delta and Omicron variants^–,. Protection decreases as expected from the reduced nAb level^,. b | Vaccination of previously infected individuals leads to higher peak nAb levels than seen in vaccination of naive individuals. However, peak CD4⁺ T cell and CD8⁺ T cell responses are similar following vaccination of previously infected individuals and naive individuals. The effectiveness after BNT162b2 vaccination in recovered individuals (recovered from infection with the Delta variant) is significantly higher than the effectiveness after vaccination in naive individuals (93% versus 85%, P = 0.006), tracking the increased nAb responses. c | The observed waning of nAb responses (data obtained from refs^,,) has led to the suggestion that the relative contribution of T cell-mediated immunity to protection may increase over time. However, the decay rate of antigen-specific T cells in the circulation is similar to that observed for nAb titres. Although protection wanes with time, it is not possible to differentiate the contribution of humoral or T cell responses, as they decay at similar rates.

Fig. 3. Understanding protection from severe SARS-CoV-2 infection.

Vaccination provides greater protection from severe infection with SARS-CoV-2 than from acquisition of mild or asymptomatic infection. a | Studies show that breakthrough infection in vaccinees (with the Alpha variant or the Delta variant) leads to similar viral RNA levels at presentation or the peak to the levels seen in unvaccinated individuals. However, more rapid viral clearance is observed after the peak in vaccinated individuals. Data extracted from refs^,. Recall of neutralizing antibody responses (part b) (data from refs^,), CD4⁺ T cell responses (part c) (data from ref.) and CD8⁺ T cell responses (part d) (data from ref.) occurs rapidly after vaccination of previously infected individuals. AU, arbitrary units.

Fig. 4. Investigating T cell protection from severe SARS-CoV-2 infection.

Vaccination provides a high level of protection from acquisition of SARS-CoV-2 infection, and an even higher level of protection from severe disease. Thus, immunity might be thought of as having complementary actions at two stages of infection: first blocking establishment of infection and, second, even if breakthrough infection occurs, acting to reduce the severity of infection. a | The levels of neutralizing antibodies (nAbs) have been shown to be lower in vaccinated individuals with breakthrough infection. Similar studies investigating whether T cells contribute to protection from acquisition of SARS-CoV-2 infection are needed. b | Prospective studies of pre-infection T cell numbers as predictors of disease severity are challenging, due to the low frequency of severe disease. c | Studying whether the levels of CD4⁺ T cell and CD8⁺ T cell response predict disease severity in individuals with breakthrough infection may reduce the number of individuals needed to be studied. However, rapid changes in T cell numbers during the recall response may complicate analysis. d | Studying the relationship between T cell responses and viral clearance rate can be performed on smaller cohorts and has the potential to reveal a role for T cells in control of viral replication (although this is only a proxy measure for disease severity).