Natural Immunity, Vaccines, and Children: Getting Beyond this COVID-19 Pandemic
By Scott S. Field, MD, FCP
This commentary’s references have been vetted by the American College of Pediatricians Scientific Policy Committee, but the views expressed are those of the author and do not necessarily represent the views of ACPeds.
November 29, 2021
Over a year and a half into the COVID-19 pandemic, we are still learning about the infection, its response to vaccination, and its sequela. It was apparent from the start of the pandemic that the SARS-CoV-2 virus can cause severe COVID-19 disease, mostly in older adults, but that children can rarely develop severe disease as well. The United States is currently following the experience of India and Great Britain in coming down from a deadly wave of infection caused by the much more transmissible and possibly more deadly Delta variant.1 Notably, all COVID-19 waves experienced to date have subsided, even in populations with little vaccine protection. Despite this and despite limited mitigation efforts during the recent Delta variant surge, cases, hospitalizations, and deaths have fallen substantially in recent weeks, at least in states with lower vaccination coverage that experienced the surge earlier.
Vaccinations against SARS-CoV-2, first administered to the public in December 2020 under an Emergency Use Authorization, have been described as “critical tools for controlling the COVID-19 pandemic.”2 Since the advent of widespread (at least in some countries) availability of these vaccines, some have called the current situation a “pandemic of the unvaccinated.”3 Yet it has become clear in the recent months that fully vaccinated individuals, can contract 4-7 and transmit COVID-19 5,7 and may have comparable viral loads to unvaccinated COVID-19 patients.5,7 In the highly vaccinated country of Israel, a surge of infections including a significant number of severe to deadly cases has occurred this past summer. Vaccination was remarkably helpful in limiting severe disease, but not any more than the protection of natural immunity following COVID-19 infection.6,7 Booster doses of Pfizer’s mRNA vaccine (which was predominately used in Israel), given ≥ 5 months after the original doses, were found to help prevent serious disease from the Delta variant in older individuals.8 New variants have the potential of evading vaccine protection despite using booster doses, because the current vaccines only immunize against the spike protein.9 In contrast, natural immunity (with or without vaccine immunity) protects against the other components of SARS-CoV-2, like nuclear proteins. Remarkably, according to epidemiological data as of August 2021, new cases in U.S. and in many other countries have not inversely correlated with vaccination rates.10
So, where do children fit into this picture? Children have demonstrated a natural resistance to moderate and severe COVID-19 disease and this may come from cross-immunity to pre-pandemic endemic coronaviruses 11,12 and from antibodies to certain vaccines like measles, mumps, and rubella (MMR).13,14 Since children have a high frequency of exposure to endemic coronaviruses,15 and are routinely vaccinated with MMR twice in early childhood, they are likely to have more of this cross-immunity. In fact, children were found to have more cross-reacting antibodies to SARS-CoV-2 spike protein than adults in the absence of SARS-CoV-2 exposure.16 An unknown, but important factor, in the development of herd immunity is how many adults and children have already had minimally symptomatic or asymptomatic disease. A substantial number of vaccinated individuals probably also have had symptomatic and/or asymptomatic disease. Based on blood donor data, rates of seropositivity (having antibodies to SARS-CoV-2) reached close to 50% in Kenya with little vaccine exposure, even prior to the emergence of the Delta variant.17 By May 2021, U.S. seropositivity rate from infection was estimated at 20% and from infection plus immunization at 83%.18 Seropositivity, however, may not be as important as T-cell immunity in preventing serious disease, and this T-cell cross-protection may persist from past endemic coronavirus infections.19 Also, many children unknowingly experience mild or asymptomatic COVID-19 infection.
COVID-19 vaccines are designed to elicit an immune reaction to the spike protein by introducing that protein into the body. The spike protein is responsible for much of the pathology seen with COVID-19.20 Antibodies to the spike protein as well as those to the nuclear protein of SARS-CoV-2 have demonstrated affinity for a number of normal human tissue proteins, including neurofilament protein and mitochondrial (M2) antigen.21 It is possible that autoimmunity caused by such antibodies play a role in the COVID-19 symptoms of “brain fog”and chronic fatigue. Vaccine-associated myocarditis may be caused directly by the spike protein and/or by the immunologic reaction to the vaccine-produced spike protein.22 These potential autoimmune problems might also be enhanced by breakthrough COVID-19 after vaccination, as well as by vaccination after disease. Concern that specifically eliciting anti-spike antibodies might predispose some to unexpected long-term pathology and symptoms is therefore reasonable. The potential for chronic symptoms in children as well as in adults after COVID-19, with or without COVID-19 vaccination, is a needed area of research.
If vaccines do not prevent infection, are subject to waning immunity, and may offer less protection against new variants, then their utility will mainly be to limit severe disease for limited time periods in vulnerable populations. Although some children do get very sick and can rarely die from COVID-19 or its related Multisystem Inflammatory Syndrome in Children (MIS-C), children are generally not at risk for severe or prolonged disease.23 Vaccine limitations, the significant decline in cases following the latest Delta surge even without vaccinating children under 12 years of age, and without mitigation efforts used with previous waves in the US, argue against the utility of vaccinating younger children. There is a real possibility that herd immunity will prevent another severe COVID-19 wave, even without significant mitigation efforts. There is evidence that having had COVID-19 provides protection at least as good as full vaccination.24,25 If a vaccine is given after infection, there is good evidence that two doses are not needed to substantially boost the neutralizing antibody titers.26 A recent CDC report purporting that vaccination is more protective than past COVID-19 surprisingly reported a higher incidence (3.6 times) of hospitalization with COVID-19 in those who had been fully vaccinated than with those unvaccinated who had been previously infected with COVID-19.27 Mandating these vaccines, especially for children and for those who have had COVID-19 infection, is unwarranted in my opinion.
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6. Goldberg Y, Mandel M, Woodbridge T, et al. Protection of previous SARS-CoV-2 infection is similar to that of BNT 162b2 vaccine protection: a three-month nationwide experience from Israel. MedRxiv preprint doi:https://doi.org/10.1101/2021.02.20.21255670
7. Griffin S. Covid-19: fully vaccinated people can carry as much delta virus as unvaccinated people, data indicate. BMJ. 2021;374:n2074. http://dxdoi.org/10.1136/bmj.n2074
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10. Subramanian SV, Kumar A. Increases in COVID-19 are unrelated to levels of vaccination across 68 countries and 2947 counties in the United States. Eur J Epidemiol. Online Sep 30, 2021. https://doi.org/10.1007/s10654-021-00808-7
11. Doshi P. Covid-19: do many people have pre-existing immunity? BMJ. Online Sep 17,2020;370:m3563. http://dx.doi.org/10.1136/bmj.m3563
12. Dugas M, Grote-Westrick T, Vollenberg R, et al. Less severe course of COVID-19 is associated with elevated levels of antibodies against seasonal human coronaviruses OC43 and HKU1 (HCoV OC43, HCoV HKU1). Int J Infect Dis. 2021. https://doi.org/10.1016/j.ijid.2021.02.085
13. Young A, Neumann B, Mendez RF, et al. Homologous protein domains in SARS-CoV-2 and measles, mumps and rubella viruses: preliminary evidence that MMR vaccine might provide protection against COVID-19. medRxiv preprint. Doi: https://doi.org/10.1101/2020.04.10.20053207
14. Gold JE, Baumgartl WH, Okyay RA, et al. Analysis of measles-mumps-rubella (MMR) titers of recovered COVID-19 patients. mBio. 2020;11:e02628-20.
15. Dijkman R, Jebbink MF, Gaunt E, et al. The dominance of human coronavirus OC43 and NL 63 infections in infants. J ClinVirol. 2012;53:135-139.
16. Ng KW, Faulkner N, Cornish GH, et al. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science. Online Nov 6, 2020;370(6522):1339-1343. Doi: 10.1126/science.abe1107
17. Uyoga S, Adetifa IMO, Otiende M, et al. Prevalence of SARS-CoV-2 antibodies from a national serosurveilance of Kenyan blood donors, January-March 2021. JAMA. Online Sep 2, 2021. Doi: 10.1001/jama.2021.15265
18. Jones JM, Stone M, Sulaeman H, et al. Estimated US infection- and vaccine-induced SARS-CoV-2 seroprevalence based on blood donations, July 2020-May 2021. JAMA. Online Sep 2, 2021. Doi: 10.1001/jama.2021.15161
19. Mateus J, Grifoni A, Tarke A, et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science. Online Oct 2, 2020;370(6512):89-94.https://science.org/doi/10.1126/science.abd3871
20. Suzuki YJ, Gychka SG. SARS-CoV-2 spike protein elicits cell signaling in human host cells: implications for possible consequences of COVID-19 vaccines. Vaccines. 2021;9,36. https://doi.org/10.3390/vaccines9010036
21. Vojdani A, Vogdani E, Kharrazian D. Reaction of human monoclonal antibodies to SARS-CoV-2 proteins with tissue antigens: implications for autoimmune diseases. Front Immunol. 2021;11:617089. Doi:10.3389/fimmu.2020.617089
22. Shay D, Shimabukuro TT, Destefano F. Myocarditis occurring after immunization with mRNA-based COVID-19 vaccines. JAMA Cardiology. Online Jun 29,2021:e1-e2.
23. Radtke T, Ulyte A, Puhan MA, Krienler S. Long-term symptoms after SARS-CoV-2 infection in children and adolescents. JAMA. Online Jul 15, 2021. Doi: 10.1001/jama.2021.11880
24. Shrestha NK, Burke PC, Nowacki AS, Terpeluk P, Gordon SM. Necessity of COVID-19 vaccination in previously infected individuals. medRxiv preprint doi: https://doi.org/10.1101/2021.06.01.21258176
25. Gazit S, Shlezinger R, Perez G, et al. Comparing SARS-CoV-2 natural immunity to vaccine-induced immunity: reinfections versus breakthough infections. medRxiv preprint. Online Aug 25, 2021. Doi: https://doi.org/10.1101/2021.08.24.21262415
26. Ebinger JE, Fert-Bober J, Printsev I, et al. Antibody response to the BNT 162b2 mRNA vaccine in individuals previously infected with SARS-CoV-2. Nat Med. Online Apr 1, 2021. https://doi.org/10.1038/s41591-021-01325-6
27. Bozio CH, Grannis SJ, Naleway AL, et al. Laboratory-confirmed COVID-19 among adults hospitalized with COVID-19-like illness with infection-induced or mRNA vaccine-induced SARS-CoV-2 immunity – nine states, January – September 2021. MMWR. Online Oct 29, 2021;70: https://www.cdc.gov/mmwr/volumes/70/wr/mm7044el.htm?s_cid=mm7044el_w.