Although not all that surprising in hindsight, the results of a paper recently published in Cell are nevertheless stunning: 40-60% of a group of individuals not exposed to SARS-CoV-2 were found to have T helper cells that were reactive to SARS-CoV-2.
The article summary:
“Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘megapools’, circulating SARS-CoV-2−specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.”
From the paper (see links above or below for figures):
“Pre-existing crossreactive coronavirus-specific T cells While spike− and non-spike−specific CD4+ T cell responses were detectable in all COVID-19 cases,
cells were also detected in unexposed individuals (Fig. 3A-B). These responses were statistically significant for non-spike-specific CD4+ T cell reactivity (non-spike, p = 0.039. Spike, p = 0.067. Fig. 5AB). Non-spike−specific CD4+ T cell responses were above the limit of detection in 50% of donors based on SI (Fig. S3E). All of the donors were recruited between 2015-2018, excluding any possibility of exposure to SARS-CoV-2. Four human coronaviruses are known causes of seasonal ‘common cold’ upper respiratory tract infections: HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E. We tested the SARS-CoV-2 unexposed donors for seroreactivity to HCoV-OC43 and HCoV-NL63 as a representative betacoronavirus and alphacoronavirus, respectively. All donors were IgG seropositive to HCoV-OC43 and HCoV-NL63 RBD, to varying degrees (Fig. 5C), consistent with the endemic nature of these viruses (Gorse et al., 2010; Huang et al., 2020; Severance et al., 2008). We therefore examined whether these represented true pan-coronavirus T cells capable of recognizing SARS-CoV-2 epitopes.”
The results also offer hopeful news for vaccine development:
“These data suggest that a candidate COVID-19 vaccine consisting only of SARS-CoV-2 spike would be capable of eliciting SARS-CoV-2−specific CD4+ T cell
responses of similar representation to that of natural COVID-19 disease, but the data also indicate that there are many potential CD4+ T cell targets in SARS-CoV-2 and inclusion of additional SARS-CoV-2 structural antigens such as M and N would better mimic the natural SARS-CoV-2−specific CD4+ T cell
response observed in mild to moderate COVID-19 disease.”
Regarding crossreactive immunity, the authors draw parallels to the 2009 H1N1 pandemic (where such immunity was seen in older individuals, explaining the high mortality among the young):
“CD4+ T cell responses were detected in 40-60% of unexposed individuals. This may be reflective of some degree of crossreactive, preexisting immunity to SARSCoV-2 in some, but not all, individuals. Whether this immunity is relevant in influencing clinical outcomes is unknown—and cannot be known without T cell measurements before and after SARSCoV-2 infection of individuals—but it is tempting to speculate that the crossreactive CD4+ T cells may be of value in protective immunity, based on SARS mouse models (Zhao et al., 2016). Clear identification of the crossreactive peptides, and their sequence homology relation to other coronaviruses, requires deconvolution of the positive peptide pools, which is not feasible with the cell numbers presently available, and time frame of the present study.
Regarding the value of crossreactive T cells, influenza (flu) immunology in relationship to pandemics may be instructive. In the context of the 2009 H1N1 influenza pandemic, preexisting T cell immunity existed in the adult population, which focused on the more conserved internal influenza viral proteins (Greenbaum et al., 2009). The presence of crossreactive T cells was found to correlate with less severe disease (Sridhar et al., 2013; Wilkinson et al., 2012). The frequent availability of crossreactive memory T cell responses might have been one factor contributing to the lesser severity of the H1N1 flu pandemic (Hancock et al., 2009). Cross-reactive immunity to influenza strains has been modeled to be a critical influencer of susceptibility to newly emerging, potentially pandemic, influenza strains (Gostic et al., 2016). Given the severity of the ongoing COVID-19 pandemic, it has been modeled that any degree of crossprotective coronavirus immunity in the population could have a very substantial impact on the overall course of the pandemic, and the dynamics of the epidemiology for years to come (Kissler et al., 2020).”
 Grifoni, A., Weiskopf, D., Ramirez, S.I., Mateus, J., Dan, J.M., Moderbacher,
C.R., Rawlings, S.A., Sutherland, A., Premkumar, L., Jadi, R.S., Marrama, D., de Silva, A.M., Frazier, A., Carlin, A., Greenbaum, J.A., Peters, B., Krammer, F., Smith, D.M., Crotty, S., Sette, A., Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals, Cell (2020), doi: https://doi.org/10.1016/j.cell.2020.05.015.