Protective immunity and titers

Clinical Problem

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

Key Findings

  • Existing evidence is promising for the presence of a sustained IgG humoral response in recovered COVID-19 patients that can effectively neutralize new challenges by the virus; however, this is largely surmised from studies of SARS-CoV1, though preliminary data suggests a similar response to SARS-CoV2. Though reinfection has been reported in news stories, there is no current scientific evidence to support or refute this.
  • A key remaining gap is assessing the quantitative level of IgG titers that correspond to immunity. Availability of testing
  • Use of titers to drive social isolation policy (for example, “immunity passports” allowing some people with positive titers to return to work) has ethical questions as well, including the risk of “incentivising” infection for those who wish/need to return to work.

Summary of Information

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][2][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:

  • UK is planning to roll out an immunity passport to patients who have contracted/recovered from COVID19, per the UK Health Secretary - this is still in the stages of assessing performance of antibody testing, and this effort will likely depend on the ability of the UK to scale a testing roll-out. As of Friday, April 3rd, 2020, the government had not found a sufficiently reliable antibody test. Cited potential challenges include: finding a reliable test, establishing a quantitative “immunity” level and duration, and scalability.[16][17][18]
  • Germany is also beginning this effort; the Helmholtz Centre for Infection Research has plans to deploy hundreds of thousands of antibody tests over the coming weeks in an effort to study the performance of antibody tests and assess the possibility of such a campaign. This initiative is spearheaded by a joint effort by the government’s public health body, the Robert Koch Institute, the German Centre for Infection Research, and the Institute for Virology at Berlin’s Charite hospital and blood donation services. Testing would serve two purposes - to free individuals from lockdown, and to aid the government in assessing locations with herd immunity.[19][20][21]
  • There are drawbacks to this approach - the largest ethical concern is that such an effort would incentivize young people to try to contract the virus to gain immunity in order to be allowed back into employment and out of the lockdown. There are also concerns of a “two-tiered” society emerging from this, driven by immune persons gaining the ability to reenter the economy while nonimmune persons continue to be subject to a lockdown.[22]

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.

Author Information:

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

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

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
  3. Li G, Chen X, Xu A. Profile of Specific Antibodies to the SARS-Associated Coronavirus. N Engl J Med. 2003;349(5):508-509. doi:10.1056/NEJM200307313490520
  4. Wu L-P, Wang N-C, Chang Y-H, et al. Duration of Antibody Responses after Severe Acute Respiratory Syndrome. Emerg Infect Dis. 2007;13(10):1562-1564. doi:10.3201/eid1310.070576
  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
  6. Casadevall A, Pirofski L-A. The convalescent sera option for containing COVID-19. J Clin Invest. 2020;130(4):1545-1548. doi:10.1172/JCI138003
  7. Maxmen A. How blood from coronavirus survivors might save lives. Nature. 2020;580(7801):16-17. doi:10.1038/d41586-020-00895-8
  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
  9. Amanat F, Nguyen T, Chromikova V, et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. medRxiv. January 2020:2020.03.17.20037713. doi:10.1101/2020.03.17.20037713
  10. Wu F, Wang A, Liu M, et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. medRxiv. April 2020:2020.03.30.20047365. doi:10.1101/2020.03.30.20047365
  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.
  12. Hinman K. NIH Is Testing People for Covid-19 Antibodies—And Looking for Volunteers. Washingtonian. April 2020. https://www.washingtonian.com/2020/04/13/nih-is-testing-people-for-covid-19-antibodies-and-looking-for-volunteers/. Accessed April 18, 2020.
  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
  16. Immunity certificates: The passport to a new life after coronavirus? Economic Times Online. https://economictimes.indiatimes.com/news/politics-and-nation/immunity-certificates-the-passport-to-a-new-life-after-coronavirus/articleshow/74963050.cms. Published April 3, 2020. Accessed April 4, 2020.
  17. Smith-Spark L. Is an “immunity certificate” the way to get out of coronavirus lockdown? CNN. https://www.cnn.com/2020/04/03/health/immunity-passport-coronavirus-lockdown-intl/index.html. Published April 3, 2020. Accessed April 3, 2020.
  18. C.D.C. Recommends Wearing Masks in Public; Trump Says, ‘I’m Choosing Not to Do It.’ The New York Times. https://www.nytimes.com/2020/04/03/world/coronavirus-news-updates.html. Published April 3, 2020. Accessed April 18, 2020.
  19. Bienkov A. The UK plans to issue coronavirus “immunity passports” so people can leave the lockdown early. Business Insider. https://www.businessinsider.com/uk-plans-coronavirus-immunity-passports-so-brits-can-leave-lockdown-2020-4. Accessed April 4, 2020.
  20. Siddique H. “Immunity passports”: can they end the UK coronavirus lockdown? The Guardian. https://www.theguardian.com/world/2020/apr/03/immunity-passports-can-they-end-uk-coronavirus-lockdown. Published April 3, 2020. Accessed April 4, 2020.
  21. COVID-19 ‘Immunity Passports’ Could Be a Good Idea – Reason.com. https://reason.com/2020/04/02/covid-19-immunity-passports/. Accessed April 4, 2020.
  22. Proctor K, Sample I, Oltermann P. “Immunity passports” could speed up return to work after Covid-19. The Guardian. https://www.theguardian.com/world/2020/mar/30/immunity-passports-could-speed-up-return-to-work-after-covid-19. Published March 30, 2020. Accessed April 4, 2020.

References

  1. He Y, Li J, Li W, et al. Cross-neutralization of human and palm civet severe acute respiratory syndrome coronaviruses by antibodies targeting the receptor-binding domain of spike protein. J Immunol. 2006;176(10):6085-92.  [PMID:16670317]
  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.  [PMID:32105090]
  3. Li G, Chen X, Xu A. Profile of specific antibodies to the SARS-associated coronavirus. N Engl J Med. 2003;349(5):508-9.  [PMID:12890855]
  4. Wu LP, Wang NC, Chang YH, et al. Duration of antibody responses after severe acute respiratory syndrome. Emerg Infect Dis. 2007;13(10):1562-4.  [PMID:18258008]
  5. Shin HS, 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. 2019;68(6):984-992.  [PMID:30060038]
  6. Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest. 2020;130(4):1545-1548.  [PMID:32167489]
  7. Maxmen A. How blood from coronavirus survivors might save lives. Nature. 2020;580(7801):16-17.  [PMID:32214238]
  8. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-273.  [PMID:32015507]
  9. Amanat F, Nguyen T, Chromikova V, et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. medRxiv. January 2020:2020.03.17.20037713. doi:10.1101/2020.03.17.20037713
  10. Wu F, Wang A, Liu M, et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. medRxiv. April 2020:2020.03.30.20047365. doi:10.1101/2020.03.30.20047365
  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.
  12. Hinman K. NIH Is Testing People for Covid-19 Antibodies—And Looking for Volunteers. Washingtonian. April 2020. https://www.washingtonian.com/2020/04/13/nih-is-testing-people-for-covid-19-antibodies-and-looking-for-volunteers/. Accessed April 18, 2020.
  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
  16. Immunity certificates: The passport to a new life after coronavirus? Economic Times Online. https://economictimes.indiatimes.com/news/politics-and-nation/immunity-certificates-the-passport-to-a-new-life-after-coronavirus/articleshow/74963050.cms. Published April 3, 2020. Accessed April 4, 2020.
  17. Smith-Spark L. Is an “immunity certificate” the way to get out of coronavirus lockdown? CNN. https://www.cnn.com/2020/04/03/health/immunity-passport-coronavirus-lockdown-intl/index.html. Published April 3, 2020. Accessed April 3, 2020.
  18. C.D.C. Recommends Wearing Masks in Public; Trump Says, ‘I’m Choosing Not to Do It.’ The New York Times. https://www.nytimes.com/2020/04/03/world/coronavirus-news-updates.html. Published April 3, 2020. Accessed April 18, 2020.
  19. Bienkov A. The UK plans to issue coronavirus “immunity passports” so people can leave the lockdown early. Business Insider. https://www.businessinsider.com/uk-plans-coronavirus-immunity-passports-so-brits-can-leave-lockdown-2020-4. Accessed April 4, 2020.
  20. Siddique H. “Immunity passports”: can they end the UK coronavirus lockdown? The Guardian. https://www.theguardian.com/world/2020/apr/03/immunity-passports-can-they-end-uk-coronavirus-lockdown. Published April 3, 2020. Accessed April 4, 2020.
  21. COVID-19 ‘Immunity Passports’ Could Be a Good Idea – Reason.com. https://reason.com/2020/04/02/covid-19-immunity-passports/. Accessed April 4, 2020.
  22. Proctor K, Sample I, Oltermann P. “Immunity passports” could speed up return to work after Covid-19. The Guardian. https://www.theguardian.com/world/2020/mar/30/immunity-passports-could-speed-up-return-to-work-after-covid-19. Published March 30, 2020. Accessed April 4, 2020.
  23. Wu F, Wang A, Liu M, et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. medRxiv. April 2020:2020.03.30.20047365. doi:10.1101/2020.03.30.20047365