T cells And Covid-19: Immunity, Cross-reactivity And Vaccines.

Everyone is suddenly talking about T cells. Why? And, more importantly, should you care? 

Simple answer: Yes. 

Long answer: We are starting to understand the immune response against the SARS-CoV-2. A lot of the ongoing research is focused on the adaptive immune system, which is mediated by T and B cells and can provide long-term immunity. Understanding T cell responses can tell us whether there will be long-term immunity against SARS-CoV-2 and inform vaccine development. In addition, looking into the different kinds of T cell responses mounted against the virus may help understand why the course of disease is different in people.

But before we get into the details of the new data: An intro to T cells. 

T cells are, together with B cells, the main pillar of the adaptive (or learned) immune system. All T cells carry so-called TCRs (T cell receptors). TCRs are highly specific and recognise short protein fragments, which are part of viruses and other pathogens. Each T cell recognises only one protein fragment (hence one specific part of one specific pathogen). The cells patrolle the body until cells infected by the virus or so called antigen-presenting cells “show” them their protein fragment. Upon activation, and depending on type, T cells then either kill the infected cell (CD8+ cytotoxic T cells) or produce messenger molecules to further activate the immune system and induce antibody production by B cells (CD4+ helper T cells). 

While CD8+ T cells can kill virus-infected cells, antibodies prevent the spread of the virus within the body. Neutralising antibodies can bind the virus, hindering it from binding and infecting more cells. Both responses are key in getting an infection under control quickly.

Once the infection is over, or the immune response following a vaccine, most T cells will die. However, a small proportion of cells persist and become so-called memory cells. These are highly specialised and allow a quicker, more effective response in case of re-infection with the same pathogen. Antibody titers will stay in the blood for varying amounts of time post infection as well – this is the basis of antibody-tests to uncover infections after the acute phase.

T cells responses against SARS-CoV-2

Several groups have now looked at immune responses in (recovered) Covid-19 patients and reported robust (memory) T cell responses. One study found that of recovered patients, 70 and 100% had SARS-CoV-2- specific CD8+ and CD4+ T cells in their body, respectively. A second study reported CD4+ T cell responses in 83% of patients. In addition, SARS-CoV-2 specific antibodies were detectable and correlated with the mounted CD4+ T cell response. A correlation between the number of virus-specific T cells and antibody titers was also found by a different group. 

Lacking and/or rapidly decreasing antibody levels, especially in asymptomatic patients, paired with the knowledge that other types of coronaviruses do not mount long lasting neutralising antibodies, led to the worry that one bout of Covid-19 may not protect you from future encounters with SARS-CoV-2 – particularly if your first disease course was mild. But (and this is a big BUT) diminishing antibody levels do not exclude the existence of memory cells (both T and antibody producing B cells). These cells stay in your body and get reactivated (and help mount a new round of antibody production) once you encounter SARS-CoV-2 again. Indeed, a study from Karolinska in Sweden, found that asymptomatic or mild cases also mount T cell responses, even if no SARS-CoV-2 specific antibodies are present. So right now, it appears that people recovering from SARS-CoV-2 (no matter how severe their disease was) carry memory T cells, which should reactivate upon reinfection and protect the person from getting ill again.

Covid-specific T cell responses in not- infected people

Studying memory T cell responses in recovered Covid-19 patients, researchers used health donor blood samples as control for their experiments. Several made an unexpected discovery. Researchers reported that 35–50% of control samples also contain T cells that recognise proteins from SARS-CoV-2. These control samples were unexposed to the new SARS-CoV-2 virus, in one study the blood was collected before the pandemic broke out. In both studies, unexposed donors tested positive for other members of the coronaviruses family (HCoVs) and T cells in these donors recognised specifically the parts of SARS-CoV-2’s outer layer that similar to that of HCoVs. Compared to SARS-CoV-2, HCoVs cause mild symptoms and account for up to 20% of common colds during the winter months. 

These findings led to the speculation that a common cold could protect against Covid-19. Given genomic and protein overlap within the coronavirus family, it is plausible that “pan-corona T cells”, which recognise a protein sequence several coronaviruses share, exist. Indeed, a new study found pre-existing memory CD4+ T cells that have comparable affinity to SARS-CoV-2 and the common cold coronaviruses. While it seems likely that these cells could help fight the new virus and explain the many mild or even asymptomatic cases – it remains to be proven if these cells are really capable of eliminating SARS-CoV-2 faster – hence making for milder symptoms or could even protect from an infection altogether. 

The fact that young children appear to have milder symptoms or be asymptomatic may support this line of thinking, as they are also the cohort most exposed to common colds. However, this is not proven. Nor can it be easily proven, as it would need matching blood samples from before and after a Covid-19 infection to see if the existence of pan- corona-memory T cells has a positive influence on disease outcome. And given the possible asymptomatic progression of the disease it is largely impossible to be 100% sure who had the virus and who had not.

T cells and vaccines

Most vaccines currently under development target so-called Spike proteins on the surface of the virus. Priming the immune system against these molecules lets it recognise the virus as a whole and by antibody-binding stops it from entering into cells – thereby hindering infection. While CD4+ T cell responses to spike proteins were shown to be robust and correlated with antibody levels, thereby validating spike proteins as vaccine targets, there is also evidence, suggesting other parts of the virus as vaccine potential targets.

Exposure to different parts of the virus, allows the immune cells more ways of attack. Keep in mind that adaptive immune cells like T cells carry highly specific receptors recognising only one short protein sequence. Only a handful will recognise spike proteins, but a handful more could mount responses against internal viral proteins. It is likely that different viral proteins can evoke different responses and engage different parts of the immune system inducing a layered immune response. 

Indeed, in a pre-print – which has yet to be peer reviewed-, authors looked at T cell responses in recovered Covid-19 patients, comparing mild and severe cases. They identified 39 protein sequences (!) against which the immune system of one of the recovering patients had mounted a response, including 6 clusters found in many different patients. Of these three were spike-proteins, two membrane proteins and one nucleoprotein. Patients recovering from mild cases showed a strong CD8+ cytotoxic T cells response against the membrane and nucleoproteins, implicating the role of these types of T cell responses in the immunity against Covid-19 and suggesting them as vaccine targets. 

Current RNA-vaccine, taking aim at one spike protein can not induce such a layered immunity. However, several vaccine candidates (ChAdOx1 nCoV-19, CanSino Biologics , BNT162b1 mRNA vaccine, mRNA-1273)  have during safety trials already shown that they induce good immune responses – mainly measured by neutralising antibodies depending on CD4+ T helper cell responses. Detailed Phase 2/3 studies are currently ongoing. Paired vaccine strategies aiming at spike proteins as well as internal proteins may be an approach to induce both CD4+ and CD8+ T cells and a balanced immune response. 

A lot left unknown – but so far the news are good.

So while a lot is still unknown about SARS-CoV-2 and the immune responses mounted against the virus, it appears most patients mount strong CD4+ T cell responses which correlate with antibody production in the acute phase (and the ability to kick-start production again upon a re-infection). Understanding the immune systems reaction to the virus will continue to inform vaccine development.