Cellular immunity – a contributor to COVID-19 “dark matter”?

Immunologist Karl Friston of University College London has theorized that there may be “immunological dark matter” contributing to the observed differences between COVID-19 fatality rates in different populations[1]. Evidence is building that cellular immunity is an important factor in the adaptive immune response to COVID-19. It is therefore tempting to speculate that it may be a key component of this “dark matter”, influencing an individual’s risk of developing severe disease upon exposure to the virus.  

Although detection of the antibody response has been of key importance for retrospectively determining the spread of COVID-19, there have always been doubts about the ability of antibodies to confer long-term immunity. The lessons from outbreaks of other coronaviruses are not encouraging. In SARS-recovered patients, it appears that neutralizing antibody titers and circulating memory B cells are both short-lived. Similarly, in the case of COVID-19, it seems that overall antibody levels fade quickly both in asymptomatic and symptomatic COVID-19 patients[2]. Some cause for optimism is offered by a recent study suggesting that even in individuals with low overall antibody titers may still possess potent neutralizing antibodies[3]. However, it is too early to know how long such neutralizing antibodies and the B cells producing them persist.

The potential of T-cells to provide longer-term protection has therefore attracted attention. In the case of SARS, SARS-CoV-specific memory T cells have been shown to circulate in recovered patients for up to 6 years post-infection, with the potential to offer at least partial protection from re-infection[4].

A number of recent reports have identified the presence of virus-specific T-cells in patients suffering from COVID-19 [5],[6],[7]. A team led by Alessandro Sette and Shane Crotty at the La Jolla Institute for Immunology identified circulating SARS-CoV-2-specific CD4+ cells in 100% of COVID-19 convalescing patients, while virus-specific CD8+ cells were identified 70% of patients5.  

Their study also provided a tantalizing suggestion that T cell-mediated protection may be provided by previous exposure to other coronaviruses circulating in the population. SARS-CoV-2-reactive CD4+ cells were identified in 40-60% of individuals who had not been exposed to COVID 19. It seems likely that these cells arose during an earlier infection with another virus, such as a “common cold” coronavirus. However, the protective potential of these cells remains unknown. Moreover, in contrast to these findings, researchers led by Professor Tao Dong did not identify frequent IFN-γ producing SARS-CoV-2 specific T-cell responses in healthy individuals7. Nor did they see similarity between the dominant epitopes identified and those for other coronaviruses, as might be expected in the case of significant cross-reactivity. The picture as regards to pre-existing cell-mediated immunity is therefore uncertain, but will be a fascinating area to watch. 

There are also some suggestions that cellular immune responses may contribute to another of the great unknowns of this pandemic, namely the reason why fatality rates are consistently lower in women. While there are no doubt many factors at work, one recent report suggests that CD8+ T cell responses are more robustly activated in female compared to male COVID-19 patients[8].

Finally, attention is growing around the importance of T cell responses in vaccine design. Many of the vaccines currently in development focus on the spike protein, which is the target of neutralizing antibodies. Recent reports have shown the potential for both spike and non-spike proteins to induce memory CD4+ and CD8+ T cells5, 7. In late May, Patrick Soon-Shiong’s group announced a vaccine candidate which includes the nucleocapsid protein, with a view to boosting the T helper cell response. It will be interesting to see whether these additional T cell epitopes are widely adopted in vaccine strategies, and whether they offer more complete protection.

Our understanding of immune responses to SARS-CoV-2 is evolving rapidly. Recent observations relating to cell-mediated immune responses to the virus may help to explain differences in severity of the disease between individuals, and differences in hospitalization and mortality rates at a population level (read more about the role of immune system dysregulation in Feny's blog). Insights from important work in this area may help to inform vaccine design and public health strategy for the long-term management of COVID-19.


[1] As reported in the Observer newspaper on 31 May 2020

[2] Long et al Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med (2020).

[3] Robbiani, D. F. et al. Convergent antibody responses to SARS-CoV-2 infection in convalescent individuals. Preprint at bioRxiv https://doi.org/10.1101/2020.05.13.092619 (2020)

[4] Channappanavar et al. T cell-mediated immune response to respiratory coronaviruses. Immunol. Res. 2014, 59(1):118-128

[5] Grifoni et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease. Cell 181, 1-13 (2020)

[6] Braun et al, Presence of SARS-CoV-2 reactive T cells in COVID-19 patients and healthy donors. Pre-print in bioRiv https://www.medrxiv.org/content/10.1101/2020.04.17.20061440v1

[7] Peng et al. Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients. Pre-print in bioRiv https://www.biorxiv.org/content/10.1101/2020.06.05.134551v1

[8] Takahashi et al Sex differences in immune responses to SARS-CoV-2 that underlie disease outcomes. Pre-print in bioRiv. https://www.medrxiv.org/content/10.1101/2020.06.06.20123414v1