COVID-19 and pre-existing immunity
Since Peter Doshi’s excellent feature in the BMJ in September, entitled ‘Covid-19: Do many people have pre-existing immunity?’ , further studies on unexposed subjects have now been undertaken. Although all studies so far are small, they indicate that a significant proportion of individuals globally entered the SARS-CoV-2 pandemic with some pre-existing immunity. This is true of studies of IgG antibodies, memory B cells and T cells [2-14].
All studies testing memory B cells and T cells (CD4+ and CD8+) and nearly all studies testing antibodies show cross-reactivity to SARS-CoV-2 in subjects from wide geographical locations; some T cell studies showed >90% cross-reactivity. Unsurprisingly, the cross-reactivity was at a lower level to that seen in COVID-19 patients but there was clear and robust expansion of T cells in most subjects’ peripheral blood mononuclear cells on contact with SARS-CoV-2 .
The fact that antibodies and T cells were also cross-reactive with other human coronaviruses (the seasonal cold viruses NL63; 229E; OC43; HKU1) suggests that exposure to some of the common cold viruses can induce immunity to other coronaviruses. It is worth pointing out that >90% of the population is seropositive for at least three of these human coronaviruses . Memory B and T cells were also cross-reactive with SARS-CoV-1, indicating that this type of immunity can last for at least 17 years. Importantly, T cell studies which also investigated the presence of antibodies all showed zero antibody cross-reactivity, demonstrating that the use of antibodies to indicate development of immunity is unreliable.
Patients with a previously detected human coronavirus had less severe COVID-19; despite a similar rate of infection, hospitalisation and viral burden, the milder disease seemed to be due to more subdued inflammatory responses, leading to lower ICU admission and death [16,17].
As Peter Doshi points out, the WHO and CDC acknowledged the existence of pre-existing immunity to the 2009 swine flu epidemic but then ignored the evidence 11 years later. Furthermore, cross-reactive immunity to influenza strains has been modelled to be a critical influencer of susceptibility to newly emerging, potentially pandemic, influenza strains. 
Epidemiologists have been calling SARS-CoV-2 a ‘novel virus’, implying no pre-existing immunity. Nevertheless, it is clear that some considerable pre-existing immunity is present but has not been incorporated into the modelling. Furthermore, government policy decisions are being made based on the number of positive PCR tests (indicating the presence of a viral RNA fragment rather than current infection) instead of investigating the proportion of the population that has developed antibody, B cell or T cell immunity.
Seroprevalence is currently the only general means of estimating the proportion of people who have developed immunity to SARS-CoV-2, yet it is clear that B and T cell immunity are not only alive and well but are more robust and longer-lasting than antibody immunity, which is known to decline with time. Since B cells are regulated by T cells, this makes it all the more important that a reliable, readily available clinical test for T cell immunity is developed. A recent Italian study showed that T cells were eight times more effective at identifying earlier SARS-CoV-2 infection and, unlike antibodies, they correlated with disease severity . Moreover, memory T cell activation occurs soon after exposure, rather than having to wait before the appearance of antibodies .
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Competing interests: No competing interests