Pandemics and the English Language: Concepts Critical for Conversing About COVID-19

Main Article Content

Neil S. Greenspan
Guillermo A. Pereda


We consider the multiple senses of several key terms that are used to discuss the ongoing COVID-19 pandemic and clarify meanings of the corresponding concepts. Topics addressed include: 1) the meaning of immunity to an infectious agent in varying medical and scientific contexts, 2) the scientific factors that influenced the rapid generation and clinical implementation of safe and effective vaccines for COVID-19, 3) the difference between mutational abrogation of reactivity with B- or T-cell antigen receptors (immune escape) versus active interference with host immune mechanisms mediated by gene products encoded within the genome of the infectious agent (immune evasion), 4) the different ways by which the COVID-19 pandemic has “caused” deaths, and 5) briefly, the challenge of precisely defining the term pathogen


Download data is not yet available.

Article Details

Author Biography

Neil S. Greenspan, Department of Pathology, Case Western Reserve University, Cleveland, Ohio

Dr. Neil Greenspan received his A.B., magna cum laude, in Biochemical Sciences from Harvard College in 1975. He then earned M.D. and Ph.D. (Immunology) degrees at the University of Pennsylvania. From 1981 until 1986, Dr. Greenspan was a Resident in Laboratory Medicine (Clinical Pathology) at Barnes Hospital, and from 1982-1985 he was a Postdoctoral Fellow in Molecular Immunology at Washington University, both in St. Louis. In 1986, Dr. Greenspan became a faculty member at the Case School of Medicine. He is currently Professor of Pathology at Case and the Director of the Histocompatibility and Immunogenetics Laboratory at University Hospitals Cleveland Medical Center.


1. Orwell G, Rogers B, Pforzheimer Bruce Rogers Collection (Library of Congress). Politics and the English language: an essay. New York: Typophiles; 1947.

2. Greenspan N. Opinion – Wishful Thinking and Semantic Specificity. The Scientist. 2002;16(6):12.

3. Greenspan NS. Taxicab geometry as a vehicle for the journey toward enlightenment. Humanistic Mathematics Network Journal Online. 2004;1(27):Article 5. doi: 10.5642/hmnj.200401.27.05

4. Wang Y, Perlman S. COVID-19: Inflammatory Profile. Annu Rev Med. 2022;73:65-80. doi: 10.1146/annurev-med-042220-012417. PubMed PMID: 34437814.

5. Sun J, Braciale TJ. Role of T cell immunity in recovery from influenza virus infection. Curr Opin Virol. 2013;3(4):425-429. doi: 10.1016/j.coviro.2013.05.001. PubMed PMID: 23721865; PMCID: PMC3804899.

6. van de Ven K, de Heij F, van Dijken H, Ferreira JA, de Jonge J. Systemic and respiratory T-cells induced by seasonal H1N1 influenza protect against pandemic H2N2 in ferrets. Commun Biol. 2020;3(1):564. doi: 10.1038/s42003-020-01278-5. PubMed PMID: 33037319; PMCID: PMC7547016.

7. Gigley JP, Bhadra R, Moretto MM, Khan IA. T cell exhaustion in protozoan disease. Trends Parasitol. 2012;28(9):377-384. doi: 10.1016/ PubMed PMID: 22832368; PMCID: PMC3768288.

8. Saeidi A, Zandi K, Cheok YY, Saeidi H, Wong WF, Lee CYQ, Cheong HC, Yong YK, Larsson M, Shankar EM. T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses. Front Immunol. 2018;9:2569. doi: 10.3389/fimmu.2018.02569. PubMed PMID: 30473697; PMCID: PMC6237934.

9. Excler JL, Saville M, Berkley S, Kim JH. Vaccine development for emerging infectious diseases. Nat Med. 2021;27(4):591-600. doi: 10.1038/s41591-021-01301-0. PubMed PMID: 33846611.

10. Graham BS, Mascola JR, Fauci AS. Novel Vaccine Technologies: Essential Components of an Adequate Response to Emerging Viral Diseases. JAMA. 2018;319(14):1431-1432. doi: 10.1001/jama.2018.0345. PubMed PMID: 29566112.

11. Tulleken Xv. ‘Four years’ work in one’: vaccine researchers are the unassuming heroes of Covid-19. The Guardian. December 30, 2020.

12. McKie R. The vaccine miracle: how scientists waged the battle against Covid-19. The Guardian. December 6, 2020.

13. COVID-19 Vaccines. Accessed March 3, 2022.

14. Hargrave A, Mustafa AS, Hanif A, Tunio JH, Hanif SNM. Current Status of HIV-1 Vaccines. Vaccines (Basel). 2021;9(9). doi: 10.3390/vaccines9091026. PubMed PMID: 34579263; PMCID: PMC8471857.

15. Greenspan NS. Design Challenges for HIV-1 Vaccines Based on Humoral Immunity. Front Immunol. 2014;5:335. doi: 10.3389/fimmu.2014.00335. PubMed PMID: 25076950; PMCID: PMC4099939.

16. Nussenzweig RS, Vanderberg J, Spitalny GL, Rivera CI, Orton C, Most H. Sporozoite-induced immunity in mammalian malaria. A review. Am J Trop Med Hyg. 1972;21(5):722-728. doi: 10.4269/ajtmh.1972.21.722. PubMed PMID: 4561520.

17. O’Leary K. A malaria vaccine at last. Nat Med. 2021;27(12):2057. doi: 10.1038/s41591-021-01608-y. PubMed PMID: 34907379.

18. Kuter BJ, Offit PA, Poland GA. The development of COVID-19 vaccines in the United States: Why and how so fast? Vaccine. 2021;39(18):2491-5. doi: 10.1016/j.vaccine.2021.03.077. PubMed PMID: 33824043; PMCID: PMC7997594

19. Weiss SR. Forty years with coronaviruses. J Exp Med. 2020;217(5):e20200537. doi: 10.1084/jem.20200537. PubMed PMID: 32232339; PMCID: PMC7103766.

20. Makela MJ, Puhakka T, Ruuskanen O, Leinonen M, Saikku P, Kimpimaki M, Blomqvist S, Hyypia T, Arstila P. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol. 1998;36(2):539-542. doi: 10.1128/JCM.36.2.539-542.1998. PubMed PMID: 9466772; PMCID: PMC104573.

21. Keng CT, Zhang A, Shen S, Lip KM, Fielding BC, Tan TH, Chou CF, Loh CB, Wang S, Fu J, Yang X, Lim SG, Hong W, Tan YJ. Amino acids 1055 to 1192 in the S2 region of severe acute respiratory syndrome coronavirus S protein induce neutralizing antibodies: implications for the development of vaccines and antiviral agents. J Virol. 2005;79(6):3289-3296. doi: 10.1128/JVI.79.6.3289-3296.2005. PubMed PMID: 15731223; PMCID: PMC1075733.

22. Bukreyev A, Lamirande EW, Buchholz UJ, Vogel LN, Elkins WR, St Claire M, Murphy BR, Subbarao K, Collins PL. Mucosal immunisation of African green monkeys (Cercopithecus aethiops) with an attenuated parainfluenza virus expressing the SARS coronavirus spike protein for the prevention of SARS. Lancet. 2004;363(9427):2122-2127. doi: 10.1016/S0140-6736(04)16501-X. PubMed PMID: 15220033; PMCID: PMC7112367.

23. Zhou T, Wang H, Luo D, Rowe T, Wang Z, Hogan RJ, Qiu S, Bunzel RJ, Huang G, Mishra V, Voss TG, Kimberly R, Luo M. An exposed domain in the severe acute respiratory syndrome coronavirus spike protein induces neutralizing antibodies. J Virol. 2004;78(13):7217-7226. doi: 10.1128/JVI.78.13.7217-7226.2004. PubMed PMID: 15194798; PMCID: PMC421657.

24. Pallesen J, Wang N, Corbett KS, Wrapp D, Kirchdoerfer RN, Turner HL, Cottrell CA, Becker MM, Wang L, Shi W, Kong WP, Andres EL, Kettenbach AN, Denison MR, Chappell JD, Graham BS, Ward AB, McLellan JS. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A. 2017;114(35):E7348-E57. doi: 10.1073/pnas.1707304114. PubMed PMID: 28807998; PMCID: PMC5584442.

25. Kirchdoerfer RN, Wang N, Pallesen J, Wrapp D, Turner HL, Cottrell CA, Corbett KS, Graham BS, McLellan JS, Ward AB. Stabilized coronavirus spikes are resistant to conformational changes induced by receptor recognition or proteolysis. Sci Rep. 2018;8(1):15701. doi: 10.1038/s41598-018-34171-7. PubMed PMID: 30356097; PMCID: PMC6200764.

26. Li S, Plebanski M, Smooker P, Gowans EJ. Editorial: Why Vaccines to HIV, HCV, and Malaria Have So Far Failed-Challenges to Developing Vaccines Against Immunoregulating Pathogens. Front Microbiol. 2015;6:1318. doi: 10.3389/fmicb.2015.01318. PubMed PMID: 26640461; PMCID: PMC4661278.

27. Sadanand S, Suscovich TJ, Alter G. Broadly Neutralizing Antibodies Against HIV: New Insights to Inform Vaccine Design. Annu Rev Med. 2016;67:185-200. doi: 10.1146/annurev-med-091014-090749. PubMed PMID: 26565674.

28. Hsieh CL, Werner AP, Leist SR, Stevens LJ, Falconer E, Goldsmith JA, Chou CW, Abiona OM, West A, Westendorf K, Muthuraman K, Fritch EJ, Dinnon KH, 3rd, Schafer A, Denison MR, Chappell JD, Baric RS, Graham BS, Corbett KS, McLellan JS. Stabilized coronavirus spike stem elicits a broadly protective antibody. Cell Rep. 2021;37(5):109929. doi: 10.1016/j.celrep.2021.109929. PubMed PMID: 34710354; PMCID: PMC8519809.

29. Padron-Regalado E. Vaccines for SARS-CoV-2: Lessons from Other Coronavirus Strains. Infect Dis Ther. 2020;9(2):255-274. doi: 10.1007/s40121-020-00300-x. PubMed PMID: 32328406; PMCID: PMC7177048.

30. Dong Y, Dai T, Wei Y, Zhang L, Zheng M, Zhou F. A systematic review of SARS-CoV-2 vaccine candidates. Signal Transduct Target Ther. 2020;5(1):237. doi: 10.1038/s41392-020-00352-y. PubMed PMID: 33051445; PMCID: PMC7551521.

31. Ulmer JB, Donnelly JJ, Parker SE, Rhodes GH, Felgner PL, Dwarki VJ, Gromkowski SH, Deck RR, DeWitt CM, Friedman A, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science. 1993;259(5102):1745-1749. doi: 10.1126/science.8456302. PubMed PMID: 8456302.

32. Kariko K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005;23(2):165-175. doi: 10.1016/j.immuni.2005.06.008. PubMed PMID: 16111635.

33. Mukalel AJ, Riley RS, Zhang R, Mitchell MJ. Nanoparticles for nucleic acid delivery: Applications in cancer immunotherapy. Cancer Lett. 2019;458:102-112. doi: 10.1016/j.canlet.2019.04.040. PubMed PMID: 31100411; PMCID: PMC6613653.

34. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014;15(8):541-555. doi: 10.1038/nrg3763. PubMed PMID: 25022906.

35. Langer R. What’s next for mRNA vaccines? Genetic Engineering and Biotechnology News. August 29, 2022.

36. Graham FL, Prevec L. Methods for construction of adenovirus vectors. Mol Biotechnol. 1995;3(3):207-220. doi: 10.1007/BF02789331. PubMed PMID: 7552690.

37. Robbins PD, Ghivizzani SC. Viral vectors for gene therapy. Pharmacol Ther. 1998;80(1):35-47. PubMed PMID: 9804053.

38. Saville M, Cramer JP, Downham M, Hacker A, Lurie N, Van der Veken L, Whelan M, Hatchett R. Delivering Pandemic Vaccines in 100 Days – What Will It Take? N Engl J Med. 2022;387(2):e3. doi: 10.1056/NEJMp2202669. PubMed PMID: 35249271.

39. Reid R. Episode 58: Kevin Esvelt Recipes for Future Plagues. February 28, 2022.

40. Thoms M, Buschauer R, Ameismeier M, Koepke L, Denk T, Hirschenberger M, Kratzat H, Hayn M, Mackens-Kiani T, Cheng J, Straub JH, Sturzel CM, Frohlich T, Berninghausen O, Becker T, Kirchhoff F, Sparrer KMJ, Beckmann R. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. 2020;369(6508):1249-1255. doi: 10.1126/science.abc8665. PubMed PMID: 32680882; PMCID: PMC7402621.

41. Xia H, Cao Z, Xie X, Zhang X, Chen JY, Wang H, Menachery VD, Rajsbaum R, Shi PY. Evasion of Type I Interferon by SARS-CoV-2. Cell Rep. 2020;33(1):108234. doi: 10.1016/j.celrep.2020.108234. PubMed PMID: 32979938; PMCID: PMC7501843.

42. Yuen CK, Lam JY, Wong WM, Mak LF, Wang X, Chu H, Cai JP, Jin DY, To KK, Chan JF, Yuen KY, Kok KH. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg Microbes Infect. 2020;9(1):1418-1428. doi: 10.1080/22221751.2020.1780953. PubMed PMID: 32529952; PMCID: PMC7473193.

43. Coronavirus in the U.S.: Latest Map and Case Count: New York Times. 2022.

44. Zalla LC, Mulholland GE, Filiatreau LM, Edwards JK. Racial/Ethnic and Age Differences in the Direct and Indirect Effects of the COVID-19 Pandemic on US Mortality. Am J Public Health. 2022;112(1):154-164. doi: 10.2105/AJPH.2021.306541. PubMed PMID: 34936406; PMCID: PMC8713607.

45. Woolf SH, Chapman DA, Sabo RT, Zimmerman EB. Excess Deaths From COVID-19 and Other Causes in the US, March 1, 2020, to January 2, 2021. JAMA. 2021; 325(17):1786-1789. doi: 10.1001/jama.2021.5199. PubMed PMID: 33797550; PMCID: PMC8019132.

46. Collaborators C-EM. Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020-21. Lancet. 2022;399(10334):1513-1536. doi: 10.1016/S0140-6736(21)02796-3. PubMed PMID: 35279232; PMCID: PMC8912932

47. Fonseca DM, Hand TW, Han SJ, Gerner MY, Glatman Zaretsky A, Byrd AL, Harrison OJ, Ortiz AM, Quinones M, Trinchieri G, Brenchley JM, Brodsky IE, Germain RN, Randolph GJ, Belkaid Y. Microbiota-Dependent Sequelae of Acute Infection Compromise Tissue-Specific Immunity. Cell. 2015;163(2):354-366. doi: 10.1016/j.cell.2015.08.030. PubMed PMID: 26451485; PMCID: PMC4826740.

48. Nathan C. IMMUNOLOGY. From transient infection to chronic disease. Science. 2015;350(6257):161. doi: 10.1126/science.aad4141. PubMed PMID: 26450196.

49. Casadevall A. The Pathogenic Potential of a Microbe. mSphere. 2017;2(1). doi: 10.1128/mSphere.00015-17. PubMed PMID: 28251180; PMCID: PMC5322344.

50. Greenspan N. Boundaries of categories, categories of boundaries, and evolution. The Evolution and Medicine Review. March 18, 2009.

51. Greenspan N. Epitopes, paratopes, and other topes: do immunologists know what they are talking about? Bull. Inst Pasteur. 1992:90:267-279.

52. Van Regenmortel MHV. Mapping Epitope Structure and Activity: From One-Dimensional Prediction to Four-Dimensional Description of Antigenic Specificity. Methods. 1996;9(3):465-472. doi: 10.1006/meth.1996.0054. PubMed PMID: 8812702.