Intended for healthcare professionals

Rapid response to:

Editorials

Introduction to BMJ Rapid Recommendations

BMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i5191 (Published 28 September 2016) Cite this as: BMJ 2016;354:i5191

Rapid Response:

COVID-19 and pre-existing immunity

Dear Editor

Since Peter Doshi’s excellent feature in the BMJ in September, entitled ‘Covid-19: Do many people have pre-existing immunity?’ [1], 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 [14].

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 [15]. 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. [1]

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 [18]. Moreover, memory T cell activation occurs soon after exposure, rather than having to wait before the appearance of antibodies [19].

References

[1] Doshi P, Covid-19: Do many people have pre-existing immunity? BMJ 2020;370:m3563
[2] Tso FY, Lidenge SJ, Pena PB et al. High prevalence of pre-existing serological cross-reactivity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in sub-Saharan Africa. Int J Infect Dis.102(2021)577–583
[3] Nguyen-Contant P, Embong K, Kanagaiah P et al. S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit. 10.1128/mBio.01991-20. https://doi.org/10.1128/mBio.01991-20
[4] Song G, He WT, Callaghan S et al. Cross-reactive serum and memory B cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection. https://doi.org/10.1101/2020.09.22.308965
[5] Ng KW, Faulkner N, Cornish GH. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science. 11 Dec 2020: Vol. 370, Issue 6522, pp. 1339-1343 DOI: 10.1126/science.abe1107
[6] Braun J, Loyal L, Frentsch M et al. Presence of SARS-CoV-2-reactive T cells in COVID-19 patients and healthy donors. https://doi.org/10.1101/2020.04.17.20061440
[7] Mateus J, Grifoni A, Tarke A et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science. 2020; 370, 89–94
[8] Grifoni A, Weiskopf D, Ramirez SI et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell. 2020; 181, 1489–1501
[9] Sekine T, Perez-Potti A, Rivera-Ballesteros O et al. Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19. Cell. 2020; 183, 158–168; https://doi.org/10.1016/j.cell.2020.08.017
[10] Nelde A, Bilich T, Walz JS et al. SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition. Nat Immunol, 2021; 22, 74–85
[11] Gallais F, Velay A, Wendling MJ et al. Intrafamilial Exposure to SARS-CoV-2 Induces Cellular Immune Response without Seroconversion. Emerging Infectious Diseases doi: 10.3201/eid2701.203611
[12] Mahajan S, Kode V, Bhojak K et al. Immunodominant T-cell epitopes from the SARS-CoV-2 spike antigen reveal robust pre-existing T-cell immunity in unexposed individuals. https://www.biorxiv.org/content/10.1101/2020.11.03.367375v1.full.pdf
[13] Weiskopf D, Schmitz KS, Raadsen MP et al. Phenotype and kinetics of SARS-CoV-2–specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci Immunol 26 Jun 2020: Vol. 5, Issue 48, eabd2071 DOI: 10.1126/sciimmunol.abd2071 http://immunology.sciencemag.org
[14] Le Bert N, Tan AT, Kunasegaran K et al. Different pattern of pre-existing SARS-COV-2 specific T cell immunity in SARS-recovered and uninfected individuals. https://doi.org/10.1101/2020.05.26.115832
[15] Gorse GJ, Patel GB, Vitale JN et al. Prevalence of antibodies to four human coronaviruses is lower in nasal secretions than in serum. Clin. Vaccine Immunol. 2010; 17, 1875–1880
[16] Sagar M, Reifler K, Rossi M et al. Recent endemic coronavirus infection is associated with less-severe COVID-19. J Clin Invest. 2021;131(1):e143380. https://doi.org/10.1172/JCI143380.
[17] Glinsky GV, Impact of pre-existing SARS-CoV-2 reactive T cells in uninfected individuals on COVID-19 mortality in different countries. https://doi.org/10.1101/2020.10.03.20206151
[18] Gittelman RM, Lavezzo E, Snyder TM et al. Diagnosis and Tracking of Past SARS-CoV-2 Infection in a Large Study of Vo’, Italy Through T-Cell Receptor Sequencing. https://www.medrxiv.org/content/10.1101/2020.11.09.20228023v1
[19] Snyder TM, Gittelman RM, Klinger M et al. Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels. https://www.medrxiv.org/content/10.1101/2020.07.31.20165647v3

Competing interests: No competing interests

10 January 2021
Rachel F Nicoll
Researcher
Umea University, Sweden
Umea University, Sweden