Heterotypic immunity from prior SARS-CoV-2 infection but not COVID-19 vaccination associates with lower endemic coronavirus incidence

Editor’s summary

In addition to SARS-CoV-2 and other highly pathogenic coronaviruses, humans can be infected with a number of so-called endemic coronaviruses (eCoVs). These eCoVs, such as HCoV-OC43, are one of the causes of the common cold. Although there is similarity between SARS-CoV-2 and many eCoVs, the degree of cross-protection between the two has not been fully elucidated. Here, Bean et al. asked whether prior infection with or vaccination against SARS-CoV-2 protected against symptomatic eCoV infection. Unlike vaccination, prior infection was associated with fewer cases of symptomatic eCoV infection in a retrospective cohort. To identify the potential mediators of this protection, peripheral blood was obtained from a second cohort. The authors found that CD8⁺ T cell responses specifically targeting two nonstructural eCoV proteins, nsp12 and nsp13, were enriched only in those with prior infection. These data suggest that CD8⁺ T cell responses against conserved proteins may confer protection against a broad array of coronaviruses. —Courtney Malo

Abstract

Immune responses from prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 vaccination mitigate disease severity, but they do not fully prevent subsequent infections, especially from genetically divergent strains. We examined the incidence of and immune differences against human endemic coronaviruses (eCoVs) as a proxy for response against future genetically heterologous coronaviruses (CoVs). We assessed differences in symptomatic eCoV and non-CoV respiratory disease incidence among those with known prior SARS-CoV-2 infection or previous COVID-19 vaccination but no documented SARS-CoV-2 infection or neither exposure. Retrospective cohort analyses suggest that prior SARS-CoV-2 infection, but not previous COVID-19 vaccination alone, associates with a lower incidence of subsequent symptomatic eCoV infection. There was no difference in non-CoV incidence, implying that the observed difference was eCoV specific. In a second cohort where both cellular and humoral immunity were measured, those with prior SARS-CoV-2 spike protein exposure had lower eCoV-directed neutralizing antibodies, suggesting that neutralization is not responsible for the observed decreased eCoV disease. The three groups had similar cellular responses against the eCoV spike protein and nucleocapsid antigens. However, CD8⁺ T cell responses to the nonstructural eCoV proteins nsp12 and nsp13 were higher in individuals with previous SARS-CoV-2 infection as compared with the other groups. This association between prior SARS-CoV-2 infection and decreased incidence of eCoV disease may therefore be due to a boost in CD8⁺ T cell responses against eCoV nsp12 and nsp13, suggesting that incorporation of nonstructural viral antigens in a future pan-CoV vaccine may improve vaccine efficacy.

Register and access this article for free

As a service to the community, this article is available for free.

Access the full article

View all access options to continue reading this article.

Supplementary Materials

This PDF file includes:

Figs. S1 to S3

Tables S1 to S6

Download
810.60 KB

Other Supplementary Material for this manuscript includes the following:

MDAR Reproducibility Checklist

Download
436.61 KB

REFERENCES AND NOTES

P. V’kovski, A. Kratzel, S. Steiner, H. Stalder, V. Thiel, Coronavirus biology and replication: Implications for SARS-CoV-2. Nat. Rev. Microbiol. 19, 155–170 (2021).

E. R. Gaunt, A. Hardie, E. C. J. Claas, P. Simmonds, K. E. Templeton, Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method. J. Clin. Microbiol. 48, 2940–2947 (2010).

T. S. Fung, D. X. Liu, Similarities and dissimilarities of COVID-19 and other coronavirus diseases. Annu. Rev. Microbiol. 75, 19–47 (2021).

B. Hu, H. Guo, P. Zhou, Z.-L. Shi, Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. 19, 141–154 (2021).

N. Andrews, E. Tessier, J. Stowe, C. Gower, F. Kirsebom, R. Simmons, E. Gallagher, S. Thelwall, N. Groves, G. Dabrera, R. Myers, C. N. J. Campbell, G. Amirthalingam, M. Edmunds, M. Zambon, K. Brown, S. Hopkins, M. Chand, S. N. Ladhani, M. Ramsay, J. Lopez Bernal, Duration of protection against mild and severe disease by Covid-19 vaccines. N. Engl. J. Med. 386, 340–350 (2022).

D. J. Bean, J. Monroe, J. Turcinovic, Y. Moreau, J. H. Connor, M. Sagar, Severe acute respiratory syndrome coronavirus 2 reinfection associates with unstable housing and occurs in the presence of antibodies. Clin. Infect. Dis. 75, e208–e215 (2022).

N. Andrews, J. Stowe, F. Kirsebom, S. Toffa, T. Rickeard, E. Gallagher, C. Gower, M. Kall, N. Groves, A.-M. O’Connell, D. Simons, P. B. Blomquist, A. Zaidi, S. Nash, N. I. B. A. Aziz, S. Thelwall, G. Dabrera, R. Myers, G. Amirthalingam, S. Gharbia, J. C. Barrett, R. Elson, S. N. Ladhani, N. Ferguson, M. Zambon, C. N. J. Campbell, K. Brown, S. Hopkins, M. Chand, M. Ramsay, J. Lopez Bernal, Covid-19 vaccine effectiveness against the Omicron (B.1.1.529) variant. N. Engl. J. Med. 386, 1532–1546 (2022).

A. Rössler, L. Riepler, D. Bante, D. von Laer, J. Kimpel, SARS-CoV-2 omicron variant neutralization in serum from vaccinated and convalescent persons. N. Engl. J. Med. 386, 698–700 (2022).

J. Miller, N. P. Hachmann, A. Y. Collier, N. Lasrado, C. R. Mazurek, R. C. Patio, O. Powers, N. Surve, J. Theiler, B. Korber, D. H. Barouch, Substantial neutralization escape by SARS-CoV-2 omicron variants BQ.1.1 and XBB.1. N. Engl. J. Med. 388, 662–664 (2023).

A. T. Tan, M. Linster, C. W. Tan, N. Le Bert, W. N. Chia, K. Kunasegaran, Y. Zhuang, C. Y. L. Tham, A. Chia, G. J. D. Smith, B. Young, S. Kalimuddin, J. G. H. Low, D. Lye, L.-F. Wang, A. Bertoletti, Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients. Cell Rep. 34, 108728 (2021).

A. Grifoni, D. Weiskopf, S. I. Ramirez, J. Mateus, J. M. Dan, C. R. Moderbacher, S. A. Rawlings, A. Sutherland, L. Premkumar, R. S. Jadi, D. Marrama, A. M. de Silva, A. Frazier, A. F. Carlin, J. A. Greenbaum, B. Peters, F. Krammer, D. M. Smith, S. Crotty, A. Sette, Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell 181, 1489–1501.e15 (2020).

A. Tarke, J. Sidney, C. K. Kidd, J. M. Dan, S. I. Ramirez, E. D. Yu, J. Mateus, R. da Silva Antunes, E. Moore, P. Rubiro, N. Methot, E. Phillips, S. Mallal, A. Frazier, S. A. Rawlings, J. A. Greenbaum, B. Peters, D. M. Smith, S. Crotty, D. Weiskopf, A. Grifoni, A. Sette, Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases. Cell Rep. Med. 2, 100204 (2021).

I. Jungreis, R. Sealfon, M. Kellis, SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes. Nat. Commun. 12, 2642 (2021).

C. Feng, J. Shi, Q. Fan, Y. Wang, H. Huang, F. Chen, G. Tang, Y. Li, P. Li, J. Li, J. Cui, L. Guo, S. Chen, M. Jiang, L. Feng, L. Chen, C. Lei, C. Ke, X. Deng, F. Hu, X. Tang, F. Li, Protective humoral and cellular immune responses to SARS-CoV-2 persist up to 1 year after recovery. Nat. Commun. 12, 4984 (2021).

T. Bilich, A. Nelde, J. S. Heitmann, Y. Maringer, M. Roerden, J. Bauer, J. Rieth, M. Wacker, A. Peter, S. Hörber, D. Rachfalski, M. Märklin, S. Stevanović, H.-G. Rammensee, H. R. Salih, J. S. Walz, T cell and antibody kinetics delineate SARS-CoV-2 peptides mediating long-term immune responses in COVID-19 convalescent individuals. Sci. Transl. Med. 13, eabf7517 (2021).

K. W. Ng, N. Faulkner, G. H. Cornish, A. Rosa, R. Harvey, S. Hussain, R. Ulferts, C. Earl, A. G. Wrobel, D. J. Benton, C. Roustan, W. Bolland, R. Thompson, A. Agua-Doce, P. Hobson, J. Heaney, H. Rickman, S. Paraskevopoulou, C. F. Houlihan, K. Thomson, E. Sanchez, G. Y. Shin, M. J. Spyer, D. Joshi, N. O’Reilly, P. A. Walker, S. Kjaer, A. Riddell, C. Moore, B. R. Jebson, M. Wilkinson, L. R. Marshall, E. C. Rosser, A. Radziszewska, H. Peckham, C. Ciurtin, L. R. Wedderburn, R. Beale, C. Swanton, S. Gandhi, B. Stockinger, J. McCauley, S. J. Gamblin, L. E. McCoy, P. Cherepanov, E. Nastouli, G. Kassiotis, Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science 370, 1339–1343 (2020).

N. Le Bert, A. T. Tan, K. Kunasegaran, C. Y. L. Tham, M. Hafezi, A. Chia, M. H. Y. Chng, M. Lin, N. Tan, M. Linster, W. N. Chia, M. I.-C. Chen, L.-F. Wang, E. E. Ooi, S. Kalimuddin, P. A. Tambyah, J. G.-H. Low, Y.-J. Tan, A. Bertoletti, SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls. Nature 584, 457–462 (2020).

M. Sagar, K. Reifler, M. Rossi, N. S. Miller, P. Sinha, L. F. White, J. P. Mizgerd, Recent endemic coronavirus infection is associated with less-severe COVID-19. J. Clin. Invest. 131, e143380 (2021).

R. Kundu, J. S. Narean, L. Wang, J. Fenn, T. Pillay, N. D. Fernandez, E. Conibear, A. Koycheva, M. Davies, M. Tolosa-Wright, S. Hakki, R. Varro, E. McDermott, S. Hammett, J. Cutajar, R. S. Thwaites, E. Parker, C. Rosadas, M. McClure, R. Tedder, G. P. Taylor, J. Dunning, A. Lalvani, Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts. Nat. Commun. 13, 80 (2022).

C. J. Reynolds, C. Pade, J. M. Gibbons, D. K. Butler, A. D. Otter, K. Menacho, M. Fontana, A. Smit, J. E. Sackville-West, T. Cutino-Moguel, M. K. Maini, B. Chain, M. Noursadeghi, UK COVIDsortium Immune Correlates Network, T. Brooks, A. Semper, C. Manisty, T. A. Treibel, J. C. Moon, UK COVIDsortium Investigators, A. M. Valdes, Á. McKnight, D. M. Altmann, R. Boyton, Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose. Science 372, 1418–1423 (2021).

Z. Zhang, J. Mateus, C. H. Coelho, J. M. Dan, C. R. Moderbacher, R. I. Gálvez, F. H. Cortes, A. Grifoni, A. Tarke, J. Chang, E. A. Escarrega, C. Kim, B. Goodwin, N. I. Bloom, A. Frazier, D. Weiskopf, A. Sette, S. Crotty, Humoral and cellular immune memory to four COVID-19 vaccines. Cell 185, 2434–2451.e17 (2022).

P. Sinha, K. Reifler, M. Rossi, M. Sagar, Coronavirus disease 2019 mitigation strategies were associated with decreases in other respiratory virus infections. Open Forum Infect. Dis. 8, ofab105 (2021).

H. Kalish, C. Klumpp-Thomas, S. Hunsberger, H. A. Baus, M. P. Fay, N. Siripong, J. Wang, J. Hicks, J. Mehalko, J. Travers, M. Drew, K. Pauly, J. Spathies, T. Ngo, K. M. Adusei, M. Karkanitsa, J. A. Croker, Y. Li, B. I. Graubard, L. Czajkowski, O. Belliveau, C. Chairez, K. R. Snead, P. Frank, A. Shunmugavel, A. Han, L. T. Giurgea, L. A. Rosas, R. Bean, R. Athota, A. Cervantes-Medina, M. Gouzoulis, B. Heffelfinger, S. Valenti, R. Caldararo, M. M. Kolberg, A. Kelly, R. Simon, S. Shafiq, V. Wall, S. Reed, E. W. Ford, R. Lokwani, J.-P. Denson, S. Messing, S. G. Michael, W. Gillette, R. P. Kimberly, S. E. Reis, M. D. Hall, D. Esposito, M. J. Memoli, K. Sadtler, Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States. Sci. Transl. Med. 13, eabh3826 (2021).

M. Norman, T. Gilboa, A. F. Ogata, A. M. Maley, L. Cohen, E. L. Busch, R. Lazarovits, C.-P. Mao, Y. Cai, J. Zhang, J. E. Feldman, B. M. Hauser, T. M. Caradonna, B. Chen, A. G. Schmidt, G. Alter, R. C. Charles, E. T. Ryan, D. R. Walt, Ultrasensitive high-resolution profiling of early seroconversion in patients with COVID-19. Nat. Biomed. Eng. 4, 1180–1187 (2020).

V. Indenbaum, R. Koren, S. Katz-Likvornik, M. Yitzchaki, O. Halpern, G. Regev-Yochay, C. Cohen, A. Biber, T. Feferman, N. C. Saban, R. Dhan, T. Levin, Y. Gozlan, M. Weil, O. Mor, M. Mandelboim, D. Sofer, E. Mendelson, Y. Lustig, Testing IgG antibodies against the RBD of SARS-CoV-2 is sufficient and necessary for COVID-19 diagnosis. PLOS ONE 15, e0241164 (2020).

P. D. Burbelo, F. X. Riedo, C. Morishima, S. Rawlings, D. Smith, S. Das, J. R. Strich, D. S. Chertow, R. T. Davey Jr., J. I. Cohen, Sensitivity in detection of antibodies to nucleocapsid and spike proteins of severe acute respiratory syndrome coronavirus 2 in patients with coronavirus disease 2019. J. Infect. Dis. 222, 206–213 (2020).

J. M. Dan, C. S. Lindestam Arlehamn, D. Weiskopf, R. da Silva Antunes, C. Havenar-Daughton, S. M. Reiss, M. Brigger, M. Bothwell, A. Sette, S. Crotty, A cytokine-independent approach to identify antigen-specific human germinal center T follicular helper cells and rare antigen-specific CD4⁺ T cells in blood. J. Immunol. 197, 983–993 (2016).

S. Reiss, A. E. Baxter, K. M. Cirelli, J. M. Dan, A. Morou, A. Daigneault, N. Brassard, G. Silvestri, J.-P. Routy, C. Havenar-Daughton, S. Crotty, D. E. Kaufmann, Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells. PLOS ONE 12, e0186998 (2017).

E. D. Yu, E. Wang, E. Garrigan, B. Goodwin, A. Sutherland, A. Tarke, J. Chang, R. I. Gálvez, J. Mateus, S. I. Ramirez, S. A. Rawlings, D. M. Smith, G. Filaci, A. Frazier, D. Weiskopf, J. M. Dan, S. Crotty, A. Grifoni, A. Sette, R. da Silva Antunes, Development of a T cell-based immunodiagnostic system to effectively distinguish SARS-CoV-2 infection and COVID-19 vaccination status. Cell Host Microbe 30, 388–399.e3 (2022).

D. S. Khoury, D. Cromer, A. Reynaldi, T. E. Schlub, A. K. Wheatley, J. A. Juno, K. Subbarao, S. J. Kent, J. A. Triccas, M. P. Davenport, Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat. Med. 27, 1205–1211 (2021).

Y. Galipeau, V. Siragam, G. Laroche, E. Marion, M. Greig, M. McGuinty, R. A. Booth, Y. Durocher, M. Cuperlovic-Culf, S. A. L. Bennett, A. M. Crawley, P. M. Giguère, C. Cooper, M.-A. Langlois, Relative ratios of human seasonal coronavirus antibodies predict the efficiency of cross-neutralization of SARS-CoV-2 spike binding to ACE2. EBioMedicine 74, 103700 (2021).

K. Shrwani, R. Sharma, M. Krishnan, T. Jones, M. Mayora-Neto, D. Cantoni, N. J. Temperton, S. L. Dobson, K. Subramaniam, P. S. McNamara, N. A. Cunliffe, L. Turtle, Q. Zhang, Detection of serum cross-reactive antibodies and memory response to SARS-CoV-2 in prepandemic and post-COVID-19 convalescent samples. J. Infect. Dis. 224, 1305–1315 (2021).

W. N. Voss, Y. J. Hou, N. V. Johnson, G. Delidakis, J. E. Kim, K. Javanmardi, A. P. Horton, F. Bartzoka, C. J. Paresi, Y. Tanno, C.-W. Chou, S. A. Abbasi, W. Pickens, K. George, D. R. Boutz, D. M. Towers, J. R. McDaniel, D. Billick, J. Goike, L. Rowe, D. Batra, J. Pohl, J. Lee, S. Gangappa, S. Sambhara, M. Gadush, N. Wang, M. D. Person, B. L. Iverson, J. D. Gollihar, J. M. Dye, A. S. Herbert, I. J. Finkelstein, R. S. Baric, J. S. McLellan, G. Georgiou, J. J. Lavinder, G. C. Ippolito, Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes. Science 372, 1108–1112 (2021).

D. Sterlin, A. Mathian, M. Miyara, A. Mohr, F. Anna, L. Claër, P. Quentric, J. Fadlallah, H. Devilliers, P. Ghillani, C. Gunn, R. Hockett, S. Mudumba, A. Guihot, C.-E. Luyt, J. Mayaux, A. Beurton, S. Fourati, T. Bruel, O. Schwartz, J.-M. Lacorte, H. Yssel, C. Parizot, K. Dorgham, P. Charneau, Z. Amoura, G. Gorochov, IgA dominates the early neutralizing antibody response to SARS-CoV-2. Sci. Transl. Med. 13, eabd2223 (2021).

K. W. Cohen, S. L. Linderman, Z. Moodie, J. Czartoski, L. Lai, G. Mantus, C. Norwood, L. E. Nyhoff, V. V. Edara, K. Floyd, S. C. De Rosa, H. Ahmed, R. Whaley, S. N. Patel, B. Prigmore, M. P. Lemos, C. W. Davis, S. Furth, J. B. O’Keefe, M. P. Gharpure, S. Gunisetty, K. Stephens, R. Antia, V. I. Zarnitsyna, D. S. Stephens, S. Edupuganti, N. Rouphael, E. J. Anderson, A. K. Mehta, J. Wrammert, M. S. Suthar, R. Ahmed, M. J. McElrath, Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells. Cell Rep. Med. 2, 100354 (2021).

L. Swadling, M. O. Diniz, N. M. Schmidt, O. E. Amin, A. Chandran, E. Shaw, C. Pade, J. M. Gibbons, N. Le Bert, A. T. Tan, A. Jeffery-Smith, C. C. S. Tan, C. Y. L. Tham, S. Kucykowicz, G. Aidoo-Micah, J. Rosenheim, J. Davies, M. Johnson, M. P. Jensen, G. Joy, L. E. McCoy, A. M. Valdes, B. M. Chain, D. Goldblatt, D. M. Altmann, R. J. Boyton, C. Manisty, T. A. Treibel, J. C. Moon, L. van Dorp, F. Balloux, Á. McKnight, M. Noursadeghi, A. Bertoletti, M. K. Maini, Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2. Nature 601, 110–117 (2022).

A. P. Ferretti, T. Kula, Y. Wang, D. M. V. Nguyen, A. Weinheimer, G. S. Dunlap, Q. Xu, N. Nabilsi, C. R. Perullo, A. W. Cristofaro, H. J. Whitton, A. Virbasius, K. J. Olivier, L. R. Buckner, A. T. Alistar, E. D. Whitman, S. A. Bertino, S. Chattopadhyay, G. MacBeath, Unbiased screens show CD8+ T cells of COVID-19 patients recognize shared epitopes in SARS-CoV-2 that largely reside outside the spike protein. Immunity 53, 1095–1107.e3 (2020).

S. K. Saini, D. S. Hersby, T. Tamhane, H. R. Povlsen, S. P. Amaya Hernandez, M. Nielsen, A. O. Gang, S. R. Hadrup, SARS-CoV-2 genome-wide T cell epitope mapping reveals immunodominance and substantial CD8⁺ T cell activation in COVID-19 patients. Sci. Immunol. 6, eabf7550 (2021).

H. Kared, A. D. Redd, E. M. Bloch, T. S. Bonny, H. Sumatoh, F. Kairi, D. Carbajo, B. Abel, E. W. Newell, M. P. Bettinotti, S. E. Benner, E. U. Patel, K. Littlefield, O. Laeyendecker, S. Shoham, D. Sullivan, A. Casadevall, A. Pekosz, A. Nardin, M. Fehlings, A. A. Tobian, T. C. Quinn, SARS-CoV-2-specific CD8⁺ T cell responses in convalescent COVID-19 individuals. J. Clin. Invest. 131, e145476 (2021).

J. Mateus, A. Grifoni, A. Tarke, J. Sidney, S. I. Ramirez, J. M. Dan, Z. C. Burger, S. A. Rawlings, D. M. Smith, E. Phillips, S. Mallal, M. Lammers, P. Rubiro, L. Quiambao, A. Sutherland, E. D. Yu, R. da Silva Antunes, J. Greenbaum, A. Frazier, A. J. Markmann, L. Premkumar, A. de Silva, B. Peters, S. Crotty, A. Sette, D. Weiskopf, Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 370, 89–94 (2020).

I. Schulien, J. Kemming, V. Oberhardt, K. Wild, L. M. Seidel, S. Killmer, F. D. Sagar, M. S. Lago, A. Decker, H. Luxenburger, B. Binder, D. Bettinger, O. Sogukpinar, S. Rieg, M. Panning, D. Huzly, M. Schwemmle, G. Kochs, C. F. Waller, A. Nieters, D. Duerschmied, F. Emmerich, H. E. Mei, A. R. Schulz, S. Llewellyn-Lacey, D. A. Price, T. Boettler, B. Bengsch, R. Thimme, M. Hofmann, C. Neumann-Haefelin, Characterization of pre-existing and induced SARS-CoV-2-specific CD8⁺ T cells. Nat. Med. 27, 78–85 (2021).

A. Nelde, T. Bilich, J. S. Heitmann, Y. Maringer, H. R. Salih, M. Roerden, M. Lübke, J. Bauer, J. Rieth, M. Wacker, A. Peter, S. Hörber, B. Traenkle, P. D. Kaiser, U. Rothbauer, M. Becker, D. Junker, G. Krause, M. Strengert, N. Schneiderhan-Marra, M. F. Templin, T. O. Joos, D. J. Kowalewski, V. Stos-Zweifel, M. Fehr, A. Rabsteyn, V. Mirakaj, J. Karbach, E. Jäger, M. Graf, L.-C. Gruber, D. Rachfalski, B. Preuß, I. Hagelstein, M. Märklin, T. Bakchoul, C. Gouttefangeas, O. Kohlbacher, R. Klein, S. Stevanović, H.-G. Rammensee, J. S. Walz, SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition. Nat. Immunol. 22, 74–85 (2021).

H.-H. Bui, J. Sidney, K. Dinh, S. Southwood, M. J. Newman, A. Sette, Predicting population coverage of T-cell epitope-based diagnostics and vaccines. BMC Bioinformatics 7, 153 (2006).

M. Dugas, T. Grote-Westrick, U. Merle, M. Fontenay, A. E. Kremer, F. Hanses, R. Vollenberg, E. Lorentzen, S. Tiwari-Heckler, J. Duchemin, S. Ellouze, M. Vetter, J. Fürst, P. Schuster, T. Brix, C. M. Denkinger, C. Müller-Tidow, H. Schmidt, P.-R. Tepasse, J. Kühn, Lack of antibodies against seasonal coronavirus OC43 nucleocapsid protein identifies patients at risk of critical COVID-19. J. Clin. Virol. 139, 104847 (2021).

I. A. Abela, C. Pasin, M. Schwarzmüller, S. Epp, M. E. Sickmann, M. M. Schanz, P. Rusert, J. Weber, S. Schmutz, A. Audigé, L. Maliqi, A. Hunziker, M. C. Hesselman, C. R. Niklaus, J. Gottschalk, E. Schindler, A. Wepf, U. Karrer, A. Wolfensberger, S. K. Rampini, P. M. Meyer Sauteur, C. Berger, M. Huber, J. Böni, D. L. Braun, M. Marconato, M. G. Manz, B. M. Frey, H. F. Günthard, R. D. Kouyos, A. Trkola, Multifactorial seroprofiling dissects the contribution of pre-existing human coronaviruses responses to SARS-CoV-2 immunity. Nat. Commun. 12, 6703 (2021).

G. Song, W. He, S. Callaghan, F. Anzanello, D. Huang, J. Ricketts, J. L. Torres, N. Beutler, L. Peng, S. Vargas, J. Cassell, M. Parren, L. Yang, C. Ignacio, D. M. Smith, J. E. Voss, D. Nemazee, A. B. Ward, T. Rogers, D. R. Burton, R. Andrabi, Cross-reactive serum and memory B-cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection. Nat. Commun. 12, 2938 (2021).

T. Dangi, N. Palacio, S. Sanchez, M. Park, J. Class, L. Visvabharathy, T. Ciucci, I. J. Koralnik, J. M. Richner, P. Penaloza-MacMaster, Cross-protective immunity following coronavirus vaccination and coronavirus infection. J. Clin. Invest. 131, e151969 (2021).

T. Westphal, M. Mader, H. Karsten, L. Cords, M. Knapp, S. Schulte, L. Hermanussen, S. Peine, V. Ditt, A. Grifoni, M. M. Addo, S. Huber, A. Sette, M. Lütgehetmann, S. Pischke, W. W. Kwok, J. Sidney, J. S. Z. Wiesch, Evidence for broad cross-reactivity of the SARS-CoV-2 NSP12-directed CD4⁺ T-cell response with pre-primed responses directed against common cold coronaviruses. Front. Immunol. 14, 1182504 (2023).

G. Dagotto, J. D. Ventura, D. R. Martinez, T. Anioke, B. S. Chung, M. Siamatu, J. Barrett, J. Miller, A. Schäfer, J. Yu, L. H. Tostanoski, K. Wagh, R. S. Baric, B. Korber, D. H. Barouch, Immunogenicity and protective efficacy of a rhesus adenoviral vaccine targeting conserved COVID-19 replication transcription complex. NPJ Vaccines 7, 125 (2022).

D. A. T. Cummings, L. J. Radonovich, G. J. Gorse, C. A. Gaydos, M. T. Bessesen, A. C. Brown, C. L. Gibert, M. D. T. Hitchings, J. Lessler, A.-C. Nyquist, S. M. Rattigan, M. C. Rodriguez-Barradas, C. S. Price, N. G. Reich, M. S. Simberkoff, T. M. Perl, Risk factors for healthcare personnel infection with endemic coronaviruses (HKU1, OC43, NL63, 229E): Results from the Respiratory Protection Effectiveness Clinical Trial (ResPECT). Clin. Infect. Dis. 73, e4428–e4432 (2021).

K. E. N. Clarke, J. M. Jones, Y. Deng, E. Nycz, A. Lee, R. Iachan, A. V. Gundlapalli, A. J. Hall, A. MacNeil, Seroprevalence of infection-induced SARS-CoV-2 antibodies - United States, September 2021-February 2022. MMWR Morb. Mortal. Wkly Rep. 71, 606–608 (2022).

M. Loesche, E. W. Karlson, O. Talabi, G. Zhou, N. Boutin, R. Atchley, G. Loevinsohn, J. B. P. Chang, M. A. Hasdianda, A. Okenla, E. Sampson, H. Schram, K. Magsipoc, K. Goodman, L. Donahue, M. MacGowan, L. A. Novack, P. Jarolim, L. R. Baden, E. J. Nilles, Longitudinal SARS-CoV-2 nucleocapsid antibody kinetics, seroreversion, and implications for seroepidemiologic studies. Emerg. Infect. Dis. 28, 1859–1862 (2022).

S. Feng, D. J. Phillips, T. White, H. Sayal, P. K. Aley, S. Bibi, C. Dold, M. Fuskova, S. C. Gilbert, I. Hirsch, H. E. Humphries, B. Jepson, E. J. Kelly, E. Plested, K. Shoemaker, K. M. Thomas, J. Vekemans, T. L. Villafana, T. Lambe, A. J. Pollard, M. Voysey, Oxford COVID Vaccine Trial Group, Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection. Nat. Med. 27, 2032–2040 (2021).

A. T. Huang, B. Garcia-Carreras, M. D. T. Hitchings, B. Yang, L. C. Katzelnick, S. M. Rattigan, B. A. Borgert, C. A. Moreno, B. D. Solomon, L. Trimmer-Smith, V. Etienne, I. Rodriguez-Barraquer, J. Lessler, H. Salje, D. S. Burke, A. Wesolowski, D. A. T. Cummings, A systematic review of antibody mediated immunity to coronaviruses: Kinetics, correlates of protection, and association with severity. Nat. Commun. 11, 4704 (2020).

E. M. Anderson, E. C. Goodwin, A. Verma, C. P. Arevalo, M. J. Bolton, M. E. Weirick, S. Gouma, C. M. McAllister, S. R. Christensen, J. Weaver, P. Hicks, T. B. Manzoni, O. Oniyide, H. Ramage, D. Mathew, A. E. Baxter, D. A. Oldridge, A. R. Greenplate, J. E. Wu, C. Alanio, K. D’Andrea, O. Kuthuru, J. Dougherty, A. Pattekar, J. Kim, N. Han, S. A. Apostolidis, A. C. Huang, L. A. Vella, L. Kuri-Cervantes, M. B. Pampena, Upenn COVID Processing Unit, M. R. Betts, E. J. Wherry, N. J. Meyer, S. Cherry, P. Bates, D. J. Rader, S. E. Hensley, Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection. Cell 184, 1858–1864.e10 (2021).

A. R. Crowley, H. Natarajan, A. P. Hederman, C. A. Bobak, J. A. Weiner, W. Wieland-Alter, J. Lee, E. M. Bloch, A. A. R. Tobian, A. D. Redd, J. N. Blankson, D. Wolf, T. Goetghebuer, A. Marchant, R. I. Connor, P. F. Wright, M. E. Ackerman, Boosting of cross-reactive antibodies to endemic coronaviruses by SARS-CoV-2 infection but not vaccination with stabilized spike. eLife 11, e75228 (2022).

J. Tang, C. Zeng, T. M. Cox, C. Li, Y. M. Son, I. S. Cheon, Y. Wu, S. Behl, J. J. Taylor, R. Chakaraborty, A. J. Johnson, D. N. Shiavo, J. P. Utz, J. S. Reisenauer, D. E. Midthun, J. J. Mullon, E. S. Edell, M. G. Alameh, L. Borish, W. G. Teague, M. H. Kaplan, D. Weissman, R. Kern, H. Hu, R. Vassallo, S.-L. Liu, J. Sun, Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination. Sci. Immunol. 7, eadd4853 (2022).

A. Hurme, P. Jalkanen, J. Heroum, O. Liedes, S. Vara, M. Melin, J. Teräsjärvi, Q. He, S. Pöysti, A. Hänninen, J. Oksi, T. Vuorinen, A. Kantele, P. A. Tähtinen, L. Ivaska, L. Kakkola, J. Lempainen, I. Julkunen, Long-lasting T cell responses in BNT162b2 COVID-19 mRNA vaccinees and COVID-19 convalescent patients. Front. Immunol. 13, 869990 (2022).

W. Tai, S. Feng, B. Chai, S. Lu, G. Zhao, D. Chen, W. Yu, L. Ren, H. Shi, J. Lu, Z. Cai, M. Pang, X. Tan, P. Wang, J. Lin, Q. Sun, X. Peng, G. Cheng, An mRNA-based T-cell-inducing antigen strengthens COVID-19 vaccine against SARS-CoV-2 variants. Nat. Commun. 14, 2962 (2023).

P. A. Nesterenko, J. McLaughlin, B. L. Tsai, G. Burton Sojo, D. Cheng, D. Zhao, Z. Mao, N. J. Bangayan, M. B. Obusan, Y. Su, R. H. Ng, W. Chour, J. Xie, Y.-R. Li, D. Lee, M. Noguchi, C. Carmona, J. W. Phillips, J. T. Kim, L. Yang, J. R. Heath, P. C. Boutros, O. N. Witte, HLA-A^∗02:01 restricted T cell receptors against the highly conserved SARS-CoV-2 polymerase cross-react with human coronaviruses. Cell Rep. 37, 110167 (2021).

E. J. Chow, T. M. Uyeki, H. Y. Chu, The effects of the COVID-19 pandemic on community respiratory virus activity. Nat. Rev. Microbiol. 21, 195–210 (2023).

R. L. Hajnik, J. A. Plante, Y. Liang, M.-G. Alameh, J. Tang, S. R. Bonam, C. Zhong, A. Adam, D. Scharton, G. H. Rafael, Y. Liu, N. C. Hazell, J. Sun, L. Soong, P.-Y. Shi, T. Wang, D. H. Walker, J. Sun, D. Weissman, S. C. Weaver, K. S. Plante, H. Hu, Dual spike and nucleocapsid mRNA vaccination confer protection against SARS-CoV-2 Omicron and Delta variants in preclinical models. Sci. Transl. Med. 14, eabq1945 (2022).

J. M. Dan, J. Mateus, Y. Kato, K. M. Hastie, E. D. Yu, C. E. Faliti, A. Grifoni, S. I. Ramirez, S. Haupt, A. Frazier, C. Nakao, V. Rayaprolu, S. A. Rawlings, B. Peters, F. Krammer, V. Simon, E. O. Saphire, D. M. Smith, D. Weiskopf, A. Sette, S. Crotty, Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 371, eabf4063 (2021).

R. P. Dos Santos Alves, J. Timis, R. Miller, K. Valentine, P. B. A. Pinto, A. Gonzalez, J. A. Regla-Nava, E. Maule, M. N. Nguyen, N. Shafee, S. Landeras-Bueno, E. Olmedillas, B. Laffey, K. Dobaczewska, Z. Mikulski, S. McArdle, S. R. Leist, K. Kim, R. S. Baric, E. Ollmann Saphire, A. Elong Ngono, S. Shresta, Human coronavirus OC43-elicited CD4⁺ T cells protect against SARS-CoV-2 in HLA transgenic mice. Nat. Commun. 15, 787 (2024).

W. F. Garcia-Beltran, E. C. Lam, M. G. Astudillo, D. Yang, T. E. Miller, J. Feldman, B. M. Hauser, T. M. Caradonna, K. L. Clayton, A. D. Nitido, M. R. Murali, G. Alter, R. C. Charles, A. Dighe, J. A. Branda, J. K. Lennerz, D. Lingwood, A. G. Schmidt, A. J. Iafrate, A. B. Balazs, COVID-19-neutralizing antibodies predict disease severity and survival. Cell 184, 476–488.e11 (2021).

C.-W. Tan, W.-N. Chia, B. E. Young, F. Zhu, B.-L. Lim, W.-R. Sia, T.-L. Thein, M. I.-C. Chen, Y.-S. Leo, D. C. Lye, L.-F. Wang, Pan-sarbecovirus neutralizing antibodies in BNT162b2-immunized SARS-CoV-1 survivors. N. Engl. J. Med. 385, 1401–1406 (2021).

M. W. Tenforde, W. H. Self, K. Adams, M. Gaglani, A. A. Ginde, T. McNeal, S. Ghamande, D. J. Douin, H. K. Talbot, J. D. Casey, N. M. Mohr, A. Zepeski, N. I. Shapiro, K. W. Gibbs, D. C. Files, D. N. Hager, A. Shehu, M. E. Prekker, H. L. Erickson, M. C. Exline, M. N. Gong, A. Mohamed, D. J. Henning, J. S. Steingrub, I. D. Peltan, S. M. Brown, E. T. Martin, A. S. Monto, A. Khan, C. L. Hough, L. W. Busse, C. C. ten Lohuis, A. Duggal, J. G. Wilson, A. J. Gordon, N. Qadir, S. Y. Chang, C. Mallow, C. Rivas, H. M. Babcock, J. H. Kwon, N. Halasa, J. D. Chappell, A. S. Lauring, C. G. Grijalva, T. W. Rice, I. D. Jones, W. B. Stubblefield, A. Baughman, K. N. Womack, J. P. Rhoads, C. J. Lindsell, K. W. Hart, Y. Zhu, S. M. Olson, M. Kobayashi, J. R. Verani, M. M. Patel, Influenza and Other Viruses in the Acutely Ill (IVY) Network, Association between mRNA vaccination and COVID-19 hospitalization and disease severity. JAMA 326, 2043–2054 (2021).

D. Groff, A. Sun, A. E. Ssentongo, D. M. Ba, N. Parsons, G. R. Poudel, A. Lekoubou, J. S. Oh, J. E. Ericson, P. Ssentongo, V. M. Chinchilli, Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: A systematic review. JAMA Netw. Open 4, e2128568 (2021).

S. Su, W. Li, S. Jiang, Developing pan-β-coronavirus vaccines against emerging SARS-CoV-2 variants of concern. Trends Immunol. 43, 170–172 (2022).

M. A. Whitt, Generation of VSV pseudotypes using recombinant ΔG-VSV for studies on virus entry, identification of entry inhibitors, and immune responses to vaccines. J. Virol. Methods 169, 365–374 (2010).

J. Nie, Q. Li, J. Wu, C. Zhao, H. Hao, H. Liu, L. Zhang, L. Nie, H. Qin, M. Wang, Q. Lu, X. Li, Q. Sun, J. Liu, C. Fan, W. Huang, M. Xu, Y. Wang, Quantification of SARS-CoV-2 neutralizing antibody by a pseudotyped virus-based assay. Nat. Protoc. 15, 3699–3715 (2020).

X. Yu, P. B. Gilbert, C. E. Hioe, S. Zolla-Pazner, S. G. Self, Statistical approaches to analyzing HIV-1 neutralizing antibody assay data. Stat. Biopharm. Res. 4, 1–13 (2012).

R. R. Yuen, D. Steiner, R. M. F. Pihl, E. Chavez, A. Olson, E. L. Smith, L. A. Baird, F. Korkmaz, P. Urick, M. Sagar, J. L. Berrigan, S. Gummuluru, R. B. Corley, K. Quillen, A. C. Belkina, G. Mostoslavsky, I. R. Rifkin, Y. Kataria, A. J. Cappione, W. Gao, N. H. Lin, N. Bhadelia, J. E. Snyder-Cappione, Novel ELISA protocol links pre-existing SARS-CoV-2 reactive antibodies with endemic coronavirus immunity and age and reveals improved serologic identification of acute COVID-19 via multi-parameter detection. Front. Immunol. 12, 614676 (2021).