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Protective immunity
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What do we know about protective immunity? Can titers be used to help health care workers back to work?

Authors: Daniella Klebaner MS3 and Payton Ottum MS3, UC San Diego School of Medicine

Completed on: March 26, 2020

Last updated on: April 14, 2020

Reviewed by: Gary Smithson

Reviewed on: April 9, 2020

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This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego.  For more information about the project, please visit http://earth2-covid.ucsd.edu

Key findings:

Related topics:

Summary breakdown by topic:

The immune response to coronaviruses: The primary effective response to coronaviruses has been shown to be humoral, with an IgG predominance on a longitudinal scale, suggesting a role for antibody serology in assessing protection from infection.1–3

Serology in prior coronaviruses:

Longitudinal data on serologic response is not yet available for the SARS-CoV2 virus responsible for the current outbreak. However, there have been numerous studies assessing quality and duration of response in SARS-CoV1, responsible for the SARS epidemic, and some data assessing serology response to MERS-CoV. There is ample evidence for sustained, durable IgG antibody responses to SARS-CoV1, which appear to be present in 100% of sick patients at 21-90 days (depending on the study) from onset of symptoms, and persist in 90% of patients for 2 years from primary infection.2,4 Peak IgG response was found in these patients at week 12 from symptom onset. IgM responses peaked during acute illness and declined within weeks of infection.3 One key difference between SARS-CoV1 and the SARS-CoV2 is the near absence of asymptomatic or “mild” illness in SARS-CoV1. An analysis of MERS-CoV patients demonstrated that an antibody response (IgM, IgG, and neutralizing antibodies) was only present in patients with severe or moderate illness, and not in patients with mild or asymptomatic presentations.5

Serology in SARS-CoV2:

Though there is limited patient-specific data for the current circulating coronavirus, in vitro studies have demonstrated that, consistent with prior coronaviruses, serum from patients with anti-SARS-CoV-2 IgG neutralize SARS-CoV-2, providing support for the use of IgG testing to assess immunity (https://www.nature.com/articles/s41586-020-2012-7). Initial reports of the use of convalescent sera have been promising, though this has not been reported in a formal study,6,7 (See article on convalescent antibodies). One study of seven patients in China demonstrated the presence of SARS-CoV-2 specific IgG antibodies in five patients 20 days after disease onset, which was not present in healthy controls.8 Similar to SARS-CoV, in one patient tested on 7, 8, 9 and 18 days after the onset of disease IgM responses peaked on day 9, then started to decline as noted on day 18. This lines up with prior data suggesting a primary IgG-based humoral response in SARS coronaviruses. The technological capability to employ such testing already exists, with new tests purported to detect initial antibody responses within 3 days of symptom onset.9 A study of 175 hospitalized patients that did not require ICU level of care developed SARS-CoV-2 neutralizing antibodies by day 10-15 after disease onset. Antibodies persisted in 47 patients who were tested two weeks after discharge (up to 24 days post-disease onset). Quantitative antibody titers varied greatly among them, and interestingly patients over 60 tended to have the highest titers. Antibody levels were undetectable in 10 (5.7%) of patients.10 Furthermore assays are currently being developed and validated around the world including at the CDC. The CDC and NIH will launch studies to widely test the population for the presence of antibodies in order to expand on our understanding of the true number of infected individuals.11,12 

Can patients with a primary infection of SARS-CoV2 become reinfected?

News reports of possible reinfection have led to fears in the community that a primary infection with SARS-COV2 does not translate to immunity. This has not been reported in the scientific literature, but two news stories described cases of patients, one 70 years old, and one 40 years old, who became ill twice, with the second illness occurring 30 days after the first; in the second case, the clinical symptoms correlated with a new positive test.13,14 While there is no evidence of such presentations in official case reports; however, there has been at least one confirmed case of the current virus whose oropharyngeal swab test of SARS-CoV2 RNA turned positive in convalescence, suggesting that RNA in the respiratory tract may be persistent or recurrent positive during the course of disease and recovery.12 Furthermore, there are reports of 91 recovered patients in South Korea who tested positive for SARS-CoV-2 days after having tested negative post-infection. It is unclear whether there is a persistence of low levels of virus that may be detected with no real clinical significance or if this represents viral “reactivation”. Though ethically, we cannot do studies where the virus is re-introduced to humans, there has already been a study of reinfection in rhesus macaque monkeys, which demonstrated that using virologic, radiologic, and pathologic assessments, monkeys with re-exposure to SARS-COV2 showed no recurrence of the virus, identical to previously infected monkeys who were not re-exposed.15

Immunity Passports:

Knowledge gaps:

What quantitative level of IgG titer is sufficient to impart humoral immunity to an individual? This is an especially important question as some of the above data suggest that patients with more severe illness mount a more robust antibody response. This leads one to question whether the likely large number of “asymptomatic” or “mild” presentations in otherwise healthy healthcare workers are sufficient to produce a neutralizing antibody response that would enable them to deploy to the frontlines with adequate humoral protection.

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References:

1.         He Y, Li J, Li W, Lustigman S, Farzan M, Jiang S. Cross-neutralization of human and palm civet severe acute respiratory syndrome coronaviruses by antibodies targeting the receptor-binding domain of spike protein. J Immunol Baltim Md 1950. 2006;176(10):6085-6092. doi:10.4049/jimmunol.176.10.6085

2.         Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020;38(1):1-9. doi:10.12932/AP-200220-0772

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5.         Shin H-S, Kim Y, Kim G, et al. Immune Responses to Middle East Respiratory Syndrome Coronavirus During the Acute and Convalescent Phases of Human Infection. Clin Infect Dis Off Publ Infect Dis Soc Am. 2019;68(6):984-992. doi:10.1093/cid/ciy595

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8.         Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-273. doi:10.1038/s41586-020-2012-7

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11.         CDC developing serologic tests to full scope of U.S. coronavirus outbreak. STAT. March 2020. https://www.statnews.com/2020/03/11/cdc-developing-serologic-tests-that-could-reveal-full-scope-of-u-s-coronavirus-outbreak/. Accessed April 18, 2020.

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13.         Osumi M. Questions raised over COVID-19 reinfection after Japanese woman develops illness again. The Japan Times Online. https://www.japantimes.co.jp/news/2020/02/28/national/coronavirus-reinfection/. Published February 28, 2020. Accessed April 4, 2020.

14.         Japanese man tests positive for coronavirus again | NHK WORLD-JAPAN News. https://www3.nhk.or.jp/nhkworld/en/news/20200315_13/amp.html. Accessed April 4, 2020.

15.         Bao L, Deng W, Gao H, et al. Reinfection could not occur in SARS-CoV-2 infected rhesus macaques. bioRxiv. January 2020:2020.03.13.990226. doi:10.1101/2020.03.13.990226

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