Based on reports, the COVID-19 pandemic respiratory disease emerged from Wuhan, China and is caused by the SARS-CoV-2 betacoronavirus. SARS-CoV-2 virus is believed to have zoonotic origins with genetic similarities to bat coronaviruses. The spread of SARS-CoV-2 globally has led to millions of infections and the majority of persons infected with SARS-CoV-2 have no or very mild symptoms (a mild self-limiting illness). However, an atypical pneumonia can often result in a small sub-set of higher-risk patients with infection (typically elderly persons (65 years and older) with underlying medical conditions (one or more) or morbidly obese persons or younger persons with serious co-morbid conditions, leading to moderate to severe pulmonary distress/failure (acute respiratory distress syndrome (ARDS)). The pulmonary failure can be linked to a hyperinflammatory immune response (cytokine or bradykinin storm) and can result in multiple organ failure. At-risk persons who develop ARDS require more invasive oxygenation via mechanical ventilation or even extra-corporeal membrane oxygenation (ECMO).
While the underpinning mechanisms of the spectrum of underlying disease is uncertain, evidence suggests that the hyper-inflammatory ‘dysregulated’ immune response (cytokine storm) characterized by elevated levels of cytokines (IL-1, IL-6, IL-10 etc.) can result in morbidity and mortality. Major improvements have been made since March 2020 in terms of how to manage severely ill patients in hospitals/ICUs but no treatment has yet been shown entirely effective. However, the good news is that what therapeutic options currently exists (potentially as combination treatments optimally given at varying stages of the disease sequelae) and the ramped-up healthcare capacities and personal protective equipment (PPEs) as well as the acute ‘exposure risk reduction’ focus on nursing homes for the aged populations, have resulted in steep declines in ICU use, need for aggressive mechanical ventilations, and severe illness or death. Since much is still unknown about the virus and given the limited therapeutic options and the ongoing quest for an effective vaccine to drive immunity, the focus has been on population mitigation strategies to reduce the risk of transmission to high-risk subpopulations.
Global nations have experienced lockdowns and mitigation strategies such as social distancing that sought to reduce the contacts we may have and as such, work to constrain the COVID-19 pandemic.1 Evidence also suggests that UV light, temperature, humidity and pressure may also confer reduced risk of transmission and could be important in the mitigation efforts.2 At the same time, after six to seven months of spread and infection suppression strategies, the epidemic’s course is seemingly changing and leaving us to speculate on what is contributing to what appears to be a flattening and decline in incident active cases as well as less severe cases. Is it the mitigation alone that is bending the epidemic curve or is there some form of population immunity that is playing a beneficial role? Are there emerging SARS-CoV-2 mutations contributing to less virulence and pathogenicity?
Recent research suggests that individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold (pre-print publication, not yet peer-reviewed).3 This suggests that persons in a population who are more susceptible or are more exposed, will tend to be infected much earlier, resulting in a depletion of the susceptible subpopulation of those who are at greater risk of infection. This type of selective depletion of susceptible persons can cause an increased slowing in incidence, leading researchers to argue that the susceptible numbers then become low enough to prevent epidemic growth and the herd immunity threshold (HIT) is arrived at.3 If so, this can have a significant impact on herd immunity considerations and vaccine design and development.
So why would some people get infected or severely ill and others do not? For example, why would children be less at risk of infection, or transmit less infection, as well as suffer less severe illness or death from COVID? 4-8 Evidence does seem to suggests that children are at very low risk of severe illness or death if infected (essentially near zero risk), but importantly, there is very limited spread to other children, or to adults, or even into the home. It appears that children typically get infected from home clusters, while recognizing that the risk of infection (and severity of illness) will increase with age. As an example, a recent review of 31 studies found that children are not a major source of transmission of COVID-19 and that transmission could be traced directly to the community or home settings with adults.8 Can it also be that children are unable to acquire the infection in the first place and as such, unable to spread it readily? Is this why they are not at higher risk? Or is there some form of prior immunity? Some tantalizing novel evidence seems to suggest that expression of the ACE2 receptor enzyme and TMPRSS2 serine protease enzyme (enzymes needed to bind to the virus’s surface glycoprotein S (spike) as part of invasion human host cells) in the nasal and bronchial airways is significantly lower in the upper and lower airways (nasal and bronchial) of children.9,10 Could this explain the low risk in children? This is very appealing and warrants urgent study and as we study this further, we also must consider that the pathway to infection was interrupted in April/May 2020 due to nationwide (and global) school closures and with re-openings, we will be better able to assess the impact on transmission dynamics.
Adding to this speculation, provocative and hypothetical evidence relating to our human immune system’s memory is also accumulating, and appears to shed some more light on why some become infected with SARS-CoV-2 COVID virus (or develop severe illness) and others do not. While putative and not yet definitive and while we know little about pre-existing immune memory’s role in recognizing SARS-CoV-2 virus (and protecting against it), the nascent evidence seems to indicate that prior exposure to ‘old’ coronaviruses (e.g. exposure to common-cold coronavirus), may indeed influence population immunity against the SARS-CoV-2 COVID virus. Our hypothesis is that perhaps a prior exposure or multiple rounds of exposures to one (or several) coronavirus(s) could potentially confer at least partial ‘acquired’ immunity to another (or all). This no doubt warrants further study but indeed is a very intriguing possibility.
In this regard, researchers have been taking a closer look at memory T-cells that are part of the immune system and which recognize other viruses and common-cold coronaviruses.11-19 Preliminary evidence (Table 1) suggests that these memory T-cells (potentially in some adults and children) can also cross-recognize or ‘cross-react’ with fragments of SARS-CoV-2 COVID virus in terms of specific molecular structures.15-17, 18,19 This is very encouraging and exciting for it suggests a recognition of COVID virus structures the T-cells had never encountered before. Persons never infected with SARS-CoV-2 possessing these cellular defenses can have profound implications for a vaccine search as it may uncover that T-cell immunity not only recognizes the SARS-CoV-2 spike protein, but potentially other sites on the virus. Understanding this role of pre-existing SARS-CoV-2 cross-reactive T-cells can impact the dynamics of spread in the pandemic, and also help us in vaccine research and in tailoring and more acutely gearing epidemic and pandemic control strategies.
T-cell immunity (adaptive immunity) operates a bit differently within the immune response than antibodies (adaptive immunity) which we are more familiar with, the latter latching onto and neutralizing viruses and other invading substances. In the case of SARS-CoV-2 infection, antibodies latch onto the SARS-CoV-2 spike protein and neutralizes it, working to prevent the virus from entering host cells. At the same time, researchers suggest that antibodies offer only short-term immunity against reinfection from SARS-CoV-2 virus, based on existing findings.11 If this is so, then what is the role of memory T-cells? How can it help? Is it a helpful role or is it toxic? Is it of no significance in terms of SARS-CoV-2?
T-cells function to attack invading pathogen like viruses, and plays an executive type immune system ‘enhancer’ role (synchronizing other immune systems molecules), also ramping up and driving immune B cells to manufacture antibodies as part of the overall defense (via helper T-cells). Killer T-cells on the other hand work to seek out, target, and destroy cells that are infected. Memory T-cells remain following the initial infection and are thus primed and ready for subsequent exposures, and this may be what is underpinning the emerging evidence of cross-reactivity and interest in memory T-cells’ ability to cross-recognize other ‘prior’ coronaviruses, in so doing conferring protection across a range of coronaviruses. There are indications that this occurs for influenza A with broad CD8+ and CD4 T cell cross-reactivity of distinct influenza A strains in humans,12,13 as well as for dengue and Zika viruses.14
The focus in this report has been on persons who have not been exposed to SARS-CoV-2 virus but have memory T-cells from prior common-colds which show reactivity to the SARS-CoV-2 virus. How do the memory T-cells react? What does the emerging T-cell cross-reactivity evidence show? The emerging findings are very interesting and positive15-19 (Table 1).
Table 1: Evidence of T-cell cross-reactivity between SARS-CoV-2 and prior corona viruses
| Author surname, year, reference # | Study title | Study detail and findings | Evidence of some level of cross-reactivity immunity? |
| Weiskopf, 2020, 15 | Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome | Patients (n=20) were between 49 to 72 years old (average 58.9 ± 7.2 years) (4 female, 6 male). Healthy controls were between 30 and 66 years old (average 43 ± 13.6 years, not statistically different from the patient group) and of mixed gender (4 female, 4 male, no data available for 2 donors). All patients were positive for SARS-CoV-2 via RT-PCR and ventilated during their stay at the ICU. In ten (10) COVID-19 patients who were admitted to ICU with moderate to severe ARDS (with the duration of self-reported illness varying between 5 to 14 days prior inclusion), researchers detected SARS-CoV-2 specific CD4+ T-cells in 10 of 10 patients and CD8+ T-cells in 8 of 10 patients.15 At the same time, they detected SARS-CoV-2 reactive T-cells in 2 of 10 age-matched controls who had no prior exposure to SARS-CoV-2, leaving them to conclude that there is cross-reactivity based on prior infection with common-cold coronaviruses. Researchers report that the greatest T-cell responses were against the spike surface glycoprotein of the SARS-CoV-2 complex and the T-cells mainly produced effector and Th1, Th2, and Th17 cytokines. | Yes |
| Grifoni, 2020, 16 | Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals | Patients (n=40), range of age in exposed group was 20–64 (median = 44, IQR = 9) and in the unexposed, 20–66 (median = 31, IQR = 21); 45% of exposed were males versus 35% males in the unexposed group. Researchers looked at 40 patients,16 20 which were exposed SARS-CoV-2 patients and 20 were unexposed to the SARS-CoV-2 virus. Researchers measured SARS-CoV-2-specific CD4+ and CD8+ T-cells responses in COVID-19 cases using multiple experimental approaches e.g. HLA class I and II predicted peptide ‘mega-pools’. Researchers reported that circulating SARS-CoV-2-specific CD8+ and CD4+ T-cells were uncovered in approximately 70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T-cell responses to spikes were very strong and were associated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M spike, and N proteins accounted for 11%–27% of the total CD4+ response. They reported that for the CD8+ T- cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. They also reported SARS-CoV-2-reactive CD4+ T cells in approximately 40-60% of persons that were unexposed to SARS-CoV-2, suggestive of cross-reactive T-cell recognition between circulating common-cold coronaviruses e.g. HCoV-OC43 and HCoV-229E, to varying degrees and SARS-CoV-2. Researchers reported that 6 different unexposed donors with IgG against common-cold coronaviruses had SARS-CoV-2-reactive CD4+ T cells, leading them to conclude that cross-reactivity may be common. | Yes |
| Braun, 2020, 17 | Presence of SARS-CoV-2-reactive T cells in COVID-19 patients and healthy donors | Patients (n=18 healthy donors, SARS-CoV-2 unexposed), 13 males (72%), age range 21-81 years. Researchers report on direct detection and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood, finding the presence of S-reactive CD4+ T cells in 83% of COVID-19 patients, as well as in 35% of SARS-CoV-2 seronegative healthy donors (SARS-CoV-2 naïve); researchers detected SARS-CoV-2 S-reactive CD4+ T cells in 83% of patients with COVID-19 but also in 35% of HD. S-reactive CD4+ T cells in HD reacted primarily to C-terminal S epitopes, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared to N-terminal epitopes. S-reactive T cell lines generated from SARS-CoV-2-naive HD responded similarly to C-terminal S of human endemic coronaviruses 229E and OC43 and SARS-CoV-2, demonstrating the presence of S-cross-reactive T cells, probably generated during past encounters with endemic coronaviruses. | Yes |
| Le Bert, 2020, 18 | SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls | Patients (n=96, COVID-19 recovered n=36, SARS recovered, and SARS-CoV 1 and 2 unexposed n=37), median age 42 (27-78) COVID-19 exposed, 49 (21-67) SARS recovered, and 39 (28-63) SARS-CoV 1 and 2 unexposed; males 57.2% (72% COVID-19, 26% SARS recovered, and 62% in SARS-CoV 1 and 2 unexposed. Researchers studied T cell responses against the structural (nucleo-capsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease. SARS-CoV-2-specific T- cells in uninfected healthy donors (n=37) tended to target NSP7 and NSP13 as well as the N protein. Researchers detected SARS-CoV-2-specific IFNγ responses in 19 out of 37 unexposed donors (51%). They report that while NSP peptides stimulated a dominant response in only 1 out of 59 individuals (1.7%) who had resolved COVID-19 or SARS, the peptides triggered dominant reactivity in 9 out of 19 unexposed donors (47%) with SARS-CoV-2-reactive cells; moreover, the SARS-CoV-2-reactive cells from unexposed donors had the capacity to expand after stimulation with SARS-CoV-2-specific peptides. | Yes |
| Mateus, 2020, 19 | Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans | Reactivity was determined after 17 days of in vitro stimulation of unexposed donor Peripheral blood mononuclear cells (PBMCs) (n=18) with one pool of peptides spanning the entire sequence of the spike protein (CD4-S), or a non-spike mega-pool (CD4-R) of predicted epitopes from the non-spike regions of the SARS-CoV-2 genome. Using human blood samples derived before the SARS-CoV-2 virus, researchers mapped 142 T cell epitopes across the SARS-CoV-2 genome to facilitate precise interrogation of the SARS-CoV-2-specific CD4+ T cell repertoire. Researchers demonstrate a range of pre-existing memory CD4+ T-cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses HCoV-OC43, HCoV-229E, HCoV-NL63, or HCoV-HKU1. They concluded that T-cell memory to common-cold coronaviruses could possibly underlie at least some of the extensive heterogeneity observed in COVID-19 disease. | Yes |
Discussion
Memory T-cells prompted by previous pathogens can shape predisposition to, and the clinical severity of subsequent infections. Our interest was the impact of prior exposure to common-cold coronaviruses such as HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1, and what this does to the immune response (T-cell) to SARS-CoV-2. Human coronaviruses represent approximately 20% of common-cold upper respiratory tract infections and are global and omnipresent, operating with a winter seasonality.20 Specifically, we wanted to summarize the preliminary evidence on pre-existing cross-reactive T-cell memory as it relates to SARS-CoV-2 in unexposed persons. We found that in several antigen-specific T-cell studies using varying patient cohorts and conducted in various nations e.g. USA, Germany, Singapore, Netherlands, and the UK etc.), approximately 20 to 50% of persons who had never been exposed to SARS-CoV-2 had appreciable T-cell recognition and reactivity that was trained onto peptides that corresponded to or paralleled SARS-CoV-2 sequences (principally facilitated by CD4+ T-cells). The limitations of these studies included small sample sizes, in some instances a focus on non-hospitalized patients, and limited details on common-cold history.
What can we conclude from these preliminary cross-reactivity findings? Taken together, these results are indeed exploratory and requires further validation but provides for a very intriguing hypothesis for it shows that persons who are unexposed to SARS-CoV-2 do produce memory T-cells that show some reactivity to both SARS-CoV-2 and various common-cold coronaviruses. The case is indeed building for a possible cross-reactive role in COVID-19 in terms of SARS-CoV-2 and prior common-cold coronaviruses. Larger scale, trustworthy, high-quality, prospective cohort T-cell studies are required to clarify these findings on pre-existing SARS-CoV-2 cross-reactive T cells. These ‘immune memory’ findings while still preliminary, may account for some level of COVID-19 immunity beside antibodies and potentially explain why some people have no illness or milder illness and do not go on to severe illness or death from COVID-19 relative to others. This may shed light onto the limited COVID-19 illness in young children whose tendency to contract routine colds may actually be conferring some protection. We conclude that this is speculative and preliminary at this time given the developing evidence. There is a need for additional urgent study on what exactly is the role of T-cells and prior common-cold coronavirus exposure, as part of the larger immune system response, in fighting back at COVID-19.
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Un-Mask the Data 