Recent research throws light on the significance of the role T-cells play in immune response against the coronavirus

Recent clinical research work carried out on COVID-19 convalescent patients has shown that the role of memory T-cells is significant in providing protection against the newly emergent variants.

A scanning electron micrograph of a human T lymphocyte (also called as a T-cell) from the immune system of a healthy donor. Cellular immunity is mediated by T-cells, which tailor the immune response to a specific pathogen, say a virus.

Following the emergence of several variants of the COVID-19–causing virus, SARS-CoV-2—in particular the three more transmissible ones identified since December 2020 in the United Kingdom, South Africa and Brazil respectively—there has been widespread concern that they could evade the immunity conferred by recovery from earlier COVID-19 infection or vaccination. This, it is being apprehended, could potentially make reinfection more likely or vaccination less effective.

In recent clinical research work carried out on COVID-19 convalescent patients, scientists of the National Institute of Allergy and Infectious Diseases (NIAID), the Johns Hopkins University School of Medicine and the Johns Hopkins Bloomberg School of Public Health (all in Maryland, United States) have shown that the cellular immune response to SARS-CoV-2 in the form of the so-called CD8+ T-cells not only remains active in these patients but also provides protection against the new variants. The work was published on March 30 in the journal called Open Forum Infectious Diseases . The implication of this work with regard to the new variants is that if a vaccine elicits a robust T-cell response (see the table), it should work against the variants as well.

There are two kinds of immune response to an infection: Innate immunity and adaptive immunity. Innate immunity is a general immediate response to any infection. Adaptive immunity is specific to a particular infection and involves both “humoral immunity”, mediated by B-cells through the production of antigen-specific antibodies of different types, and “cellular immunity”, mediated by T-cells, which tailor the immune response to a specific pathogen, say, a virus. A subset of these pathogen-specific T-cells called “killer” or “cytotoxic” CD8+ T-cells recognise infected cells (by identifying parts of the antigenic proteins that are presented on the virus cell surface) and kill them, thus preventing virus replication. Both antibody and T-cell responses usually start six to eight days after infection (Fig. 1).

‘Immune memory’

A person gets immunised to a particular infection either through prior infection or through an efficacious vaccine. The immune response of an immunised person to a subsequent infection is through the “immune memory” of B-cells (to produce appropriate antibodies, virus-neutralising antibodies in particular) and T-cells. When these cells encounter the same virus again, they mount appropriate virus-specific responses and clear the infection before it can cause disease (Fig. 2).

The researchers analysed blood cell samples of 30 people who had contracted and recovered from COVID-19 caused by the virus strain in circulation before the emergence of the new variants. The researchers found that the CD8+ T-cell response against the virus remained largely intact. The research was aimed at investigating whether this active T-cell response could recognise the three distinct and important variants—the U.K. variant named B.1.1.7, the South African variant named B.1.351 and the Brazilian variant named B.1.1.248/P.1 (now redesignated B.1.1.28/P.1)—that have emerged in recent months and have been termed Variants of Concern.

Each of these variants has mutations throughout the genome of the SARS-CoV-2 virus, particularly in the region of the spike (S) protein that the virus uses to bind to human cells and gain entry. This research was prompted by the need to know whether the many mutations in the S-protein region, which are largely single-point amino acid substitutions, could make the virus less susceptible to previously acquired T-cell and B-cell (antibodies) immunity following infection or vaccination. “Understanding the extant immunity in previously infected individuals,” the authors write in their paper, “to any new variant is of critical importance to properly estimate what effects these variants may have in the global pandemic.”

As the authors note, although the levels and composition of antibody and T-cell responses needed to achieve immunity against COVID-19 are still not precisely known, it is assumed that both a broad humoral and cell-mediated immune response are most likely necessary to protect against the disease. “Neutralising antibody [NAb] almost certainly serves as the first line of defence against infection but the CD8+ T-cell response is also important for prevention of further disease progression,” the research paper says.

Several previous works have shown the importance of T-cell-mediated immunity in the context of SARS-CoV-2. Way back in July 2020, a team of Singapore-based researchers showed ( Nature , August 2020) that T-cells from patients who had recovered from severe acute respiratory syndrome possessed long-lasting memory (17 years after the outbreak) against the nucleoprotein of the SARS virus, and significantly, these T-cells displayed cross-reactivity to the N-protein of SARS-CoV-2 as well. That is, “infection with betacoronoviruses induces multi-specific and long-lasting T-cell immunity against the structural N-protein”, the researchers wrote.

In a paper published in March this year in Nature Communications , a Sino-Australian group of researchers has reported persistence of SARS-CoV-2-specific T-cell memory for up to five months in recovered patients and their close contacts even when the latter lacked any detectable infection. The researchers also demonstrated that the size and quality of the memory T-cell pool of COVID-19 patients were larger than those of close contacts. More significantly, asymptomatic and symptomatic COVID-19 patients were found to contain similar levels of SARS-CoV-2-specific T-cell memory. But what is new in this NIAID-led work is the finding that the role of T-cell immunity memory is significant in protecting against the newly emergent variants.

All the three variants that were considered in this work possess the N501Y mutation ( Frontline , “ Virus variants ” January 15, 2021, and “ Mutant challenge ”, April 9, 2021) in the receptor-binding domain (RBD) of the S-protein, which is the primary target for NAb binding. But the authors point out that all the three seem to have evolved independently during the pandemic as they all carry other unique mutations throughout the genome. According to them, it is for this reason that these variants have been studied extensively for their susceptibility to NAb responses in plasma taken from COVID-19 convalescent donors, from participants of preclinical or post-clinical vaccination trials and from recipients of monoclonal antibody therapies. The outcomes of these investigations are summarised below. The caveat for all these studies is that the research reports have not been published or peer-reviewed, the authors note.

Differently susceptible to neutralising antibodies

Various studies have shown that the variants are differently susceptible to NAb action, with the U.K. variant (B.1.1.7) showing only minor changes in susceptibility to convalescent and post-vaccination plasmas. Further, results from the Phase 2b/3 trials in the U.K. of the Oxford/AstraZeneca’s S-protein-based vaccine during the surge in cases due to this variant suggest that the efficacy of the vaccine did not diminish significantly.

On the other hand, the South African variant (B.1.351) displayed a significant increase in its resistance to neutralisation by convalescent plasmas of some individuals. The variant also exhibited a decline in neutralisation potential to mRNA-based vaccine-induced NAb responses, though the neutralisation potential was reportedly still high enough to offer complete protection.

However, the recombinant S-protein-based vaccine of Novavax (called NVX-CoV2373) and the adenovirus-based (single-dose) vaccine of Johnson and Johnson (called Ad26.COV2.S) exhibited a significant decrease in their efficacies in preventing symptomatic COVID-19 in their Phase 2/3 trials in South Africa when the B.1.351 variant was the predominant cause of the infection. But, according to reports, the same vaccines were equally effective in preventing severe COVID-19 as was found in their U.S. trials. This, the authors say, suggests that “while protection from the initial infection may be somewhat hindered, the vaccines’ ability to prevent further disease progression is preserved…. This… may be in part due to the cell-mediated immunity generated due to natural COVID-19 infection or vaccination.”

“Comparing vaccine efficacy between two different studies is very difficult to do given that small differences in study design and the epidemic details can have noticeable changes in the final numbers in the analysis,” said Andrew Redd of the NIAID, the lead author of the work, as he elaborated further in an email to Frontline on this apparent drop in efficacy of the above mentioned vaccines against the South African strain.

“The laboratory data,” he added, “for the vaccines suggest that they generate strong T-cell responses. However, it is possible that while the T-cell response will provide good protection once someone becomes infected by killing the infected cells, it will not protect against initial infection. For that you need neutralising antibodies, which have been shown to have decreased activity against the new South African strain primarily.”

The significance of the research work being described here lies in its demonstration that T-cell-mediated immunity is minimally affected by the mutations found in these variants. In a previous work earlier this year, the authors had carried out a detailed analysis of the CD8+ T-cell epitopes—parts of various antigens on the surface of a pathogen that the T-cells recognise and mount responses to—in the original strain of SARS-CoV-2 in a group of convalescent persons from North America with various levels of disease and NAb responses. This earlier work showed that nearly all the subjects had broad CD8+ T-cell responses to several of these epitopes in the original strain.

To investigate whether similar responses result even against the variants, the researchers mapped all the amino acid–substituting mutations, insertions and deletions (totalling 45) in the three variants on to the genome of the original SARS-CoV-2 strain. The mapping showed that of the 52 new epitopes, only one overlapped with the epitopes found earlier, and even that single overlapping mutation had a low frequency of prevalence in the earlier study. This implied that almost all the epitopes that this new study looked at for the kind of T-cell responses they elicited were unique and new.

The 30 convalescent individuals in the present study were divided into three groups of 10 each according to their overall IgG antibody titres. Males constituted 60 per cent of the total subjects. Blood samples were collected 42.5 days (median value) from their initial diagnosis of COVID-19 infection. The investigation found that there were 132 SARS-CoV-2-specific CD8+ T-cell responses corresponding to the 52 new and unique epitopes, which demonstrated reactivation of the T-cell memory against several structural and non-structural targets spanning the entire set of proteins encoded by the genomes of the new variants.

“What our data suggest,” said Redd, “is that the T-cell response appears to be able to recognise the new variants we examined. However, we still don’t know what parts, or more likely combination of parts, of the full immune response is needed to fully protect from infection or COVID-19 disease—that is, the correlate of protection. That being said, a strong protection against COVID will most certainly require a broad multi-component immune response that includes antibodies as well as T-cell immunity,” Redd added. If, as this work has shown, T-cell immunity conferred by prior infection by a virus strain circulating earlier is sufficient to protect against subsequent infection by this strain or its variants, what explains the few cases of reinfection by the Brazilian strain (B.1.1.28/P.1) observed in Manaus, Brazil (“Virus variants”, Frontline , April 9)? “Reinfection is a phenomenon that is seen in many viral diseases,” pointed out Redd. “And in the case of COVID-19, [it] appears to occur but is very rare according to most studies. In the case of Brazil, I think we need to learn more about the exact cases of reinfection before we jump to too many conclusions on that front,” he added.

Research reports have suggested that the IgG antibody response lasts for at least six to eight months. The question that naturally arises is, how long does cellular immunity (T-cell response) last? “The memory T-cell response should theoretically last your entire lifetime,” Redd explained, “but the response will wane over time if you don’t come into contact with the pathogen again (or are revaccinated). The antibody response also will remain for the lifetime of a person through the memory B-cells, but the circulating antibodies will wane after the infection unless a person is re-exposed to the virus or vaccine which will trigger the memory B-cell response to kick back into an activated state.”

The relatively small size of the sample examined and the absence of diversity in the subjects (all were from North America) are the study’s limitations, which, as the authors note, call for a bigger and more diverse population sample. But sample size also cannot be very large because, as Redd pointed out: “T-cell responses generally require relatively labour intensive assays to examine and so usually you would not do this on a large scale but instead test a representative sample like we did in our study.”

However, the take-home message of the research is clear:

The role of a multi-epitope T-cell response is significant in limiting viral evasion of host immunity by emergent variants;

The vaccines used in the current vaccination campaigns during the pandemic should be able to elicit strong multivalent T-cell responses in addition to neutralising antibodies and other humoral responses so as to optimise efficacy against the current SARS-CoV-2 strain and its variants.

The different modes or platforms being used to deliver the antigenic proteins of the virus have, as shown in the table, generated different levels of vaccine-induced humoral and cell-mediated immunity. So how does one choose the best vaccine to be used in the midst of a pandemic? From the perspective of this research work, nearly all vaccines currently in use have claimed “strong” and “robust” T-cell response following clinical trials. Is there a quantitative way of judging between them? At present, the question cannot be unequivocally answered because it is not known what the true correlate of protection is. As Redd has pointed out in his remark quoted above, “strong protection against COVID will most certainly require a broad multi-component immune response that includes antibodies as well as T-cell immunity”.

However, on the basis of the work’s findings, the authors have stressed that it will be important to continue to monitor the breadth, magnitude and durability of the anti-SARS-CoV-2 T-cell responses in recovered and vaccinated individuals as part of any assessment to determine whether booster vaccinations are needed. That, in the context of the ongoing pandemic, should be made mandatory in the Phase 4 post-vaccination survey of vaccines used in the campaigns by the country’s regulator.