T cell responses to SARS-CoV-2 infection provides insights into vaccine development

Karthik Shankar, Neuroscientist

Our immune system is the first line of defense against invading pathogens. It detects the pathogen and tries to destroy it immediately. It also develops antibodies that are specific against a particular pathogen, so that the body is ready to fight that pathogen in case of future infections. The immune system uses various specialized cells, one of them is T cell, to detect and destroy pathogens. Some T cells detect the virus by specifically binding to novel viral proteins. These T cells will be manufactured in bulk by the immune system to be deployed to latch-on and kill the virus. To create an effective vaccine for COVID-19, we need to understand the existence of such T cells and which proteins on the virus they specifically respond to. This is precisely what the following studies tried to understand.

Patients recovered from Covid-19 exhibited T cell responses to the spike protein, membrane protein, nucleocapsid protein, and several other proteins of SARS-CoV-2 (Figure). This is of course expected because it just shows that the patient's immune system is working to fight the virus. The spike protein on the surface of the virus is generally the primary focus of most vaccine developers because it leads the entry path for the virus into the human /host cells. But, the scientists observed that only 83% (not 100%) of the COVID-19 patients developed T cell responses to the spike protein. So, we cannot develop a vaccine targeting just the spike protein, it has to be a cocktail targeting several viral proteins.
 

(Figure modified from //commons.wikimedia.org/wiki/User:SPQR10)
 

The other aspect studied in these papers is the cross-reactive T cells, which are T cells developed by the immune system for a previous infection but are fighting a new infection caused by a different pathogen. In the case of Covid-19, the SARS-Cov-2 virus, SARS-CoV-1 virus (of the SARS epidemic of 2003), and some ‘common cold’ causing viruses are all coronaviruses and this may lead to cross-reactivity. One of the interesting results is that about 40-60% of healthy, uninfected subjects had cross-reactive T cells from prior “common cold” viruses that now respond to SARS-CoV-2. They observe T cell responses to a part of spike protein that is similar to protein fragments in the “common cold” virus, essentially making them cross-reactive T cells from the common cold. The existence of such cross-reactive T cells from the common cold virus is possibly the reason behind so many of us being asymptomatic to COVID-19.

There are several puzzling findings as well. For example, T cells specific to the Nucleocapsid protein of SARS-CoV-1 (of SARS epidemic 2003) are robustly cross-reactive to the Nucleocapsid protein of SARS-CoV-2. But cross-reactive T cells specific to the spike proteins in both the SARS viruses were surprisingly not detected. Also, about 50% of healthy uninfected subjects exhibit T cells specific to other viral proteins, but Covid-19 and SARS patients who fully recovered from the infections, did not have these T cells.

There is clearly a lot of population-level variability in the distribution of T cell responses to various viral proteins. These results should help the vaccine developers choose the suitable cocktail of various proteins so as to trigger the required T cell response across the population spectrum.

[Last update 25 June 2020]