COVID-19 antibody tests not recommended for measuring immunity after vaccination

COVID-19 antibodies [1-3]: COVID-19 antibodies are of two types, nucleocapsid antibodies (wane within 2 - 8 months of infection) and spike antibodies (develop within 1 -3 weeks of infection). Most COVID-19 vaccines generate only spike antibodies. The neutralizing antibodies are part of the receptor-binding domains (RBD) of the spike protein developing post-vaccination and protecting against severe infection. Although neutralizing antibodies are very effective in protecting against the virus, the minimal quantity of these antibodies required is unknown, suggesting the need to develop standardized assays to measure neutralization titers. While a positive antibody result could suggest a prior infection, a negative result would only suggest the absence of a recent infection but has no say in case of a prior or current infection. Thus, antibody test results need to be evaluated carefully.

Immunity apart from antibodies [4-8]: Protection against SARS-CoV-2 is conferred by humoral and cellular immunity. Studies have shown that long-lasting B and T memory cells can persist in recovered individuals even after the neutralizing antibodies have waned. Moreover, T-cell responses can persist even in humoral immunodeficiency and the absence of a detectable viral infection. Similarly, a study found evidence of serological and immunological memory following COVID-19 vaccination, suggesting both short-term and long-term vaccine efficacy. 

Antibody test post-COVID-19 vaccination [2,3,9-11] Recently, the Centers for Disease Control and Prevention (CDC) have advised against using antibody tests to assess immunity to COVID-19 post-vaccination to assess the need for vaccination in an unvaccinated person. 

Reasons why antibody tests are not recommended post-vaccination:

1. Antibody tests fail to determine the cellular immunity triggered by some vaccines. 
2. Common antibody titers predicting a certain level of efficacy or neutralization against infection are still unknown.
3. It takes at least two to four weeks to develop a robust antibody response post-vaccination; thus, antibody testing timing is crucial. 
4. Vaccines induce antibodies to specific viral protein targets. If the test does not detect antibodies against those specific targets, the test will give negative results in the absence of prior infection. For example, nucleocapsid antibodies are generated only after a natural infection. If a test is conducted for these antibodies post-vaccination without any history of prior infection, the test results will undoubtedly be negative. 
5. Antibody tests may also fail to detect low levels of antibodies that are below the seronegativity cut-off values.

Conclusion: COVID-19 antibody tests may not be a reliable source for determining protective immunity post-vaccination or determining the superiority of one vaccine over another. The best measure of protection against infection would be a combined value of cellular and humoral immunity. However, antibody tests could benefit immune-compromised individuals and those on immune-suppressive medications; needless to say, the timing, antigen, and sensitivity of the test should be evaluated thoroughly before testing. 

References: 

1. Van Elslande J, Oyaert M, Ailliet S, et al. Longitudinal follow-up of IgG anti-nucleocapsid antibodies in SARS-CoV-2 infected patients up to eight months after infection. J Clin Virol. 2021;136:104765. doi:10.1016/j.jcv.2021.104765
2. CDC - Interim Guidelines for COVID-19 Antibody Testing. https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html?utm_source=mahoning%20matters&utm_campaign=mahoning%20matters&utm_medium=referral
3. Khoury, D.S., Cromer, D., Reynaldi, A. et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med (2021). https://doi.org/10.1038/s41591-021-01377-8
4. Persistence of functional memory B cells recognizing SARS-CoV-2 variants despite loss of specific IgG. Stephan Winklmeier, Katharina Eisenhut, Damla Taskin, Heike Rübsamen, Celine Schneider, Peter Eichhorn, Oliver T. Keppler, Matthias Klein, Simone Mader, Tania Kümpfel, Edgar Meinl medRxiv 2021.05.15.21257210; doi: https://doi.org/10.1101/2021.05.15.21257210
5. Ahluwalia P, Vaibhav K, Ahluwalia M, Mondal AK, Sahajpal N, Rojiani AM and Kolhe R (2021) Infection and Immune Memory: Variables in Robust Protection by Vaccines Against SARS-CoV-2. Front. Immunol. 12:660019. doi: 10.3389/fimmu.2021.660019
6. Gupta S, Su H, Narsai T, Agrawal S. SARS-CoV-2-Associated T-Cell Responses in the Presence of Humoral Immunodeficiency. Int Arch Allergy Immunol. 2021;182(3):195-209. doi:10.1159/000514193
7. Wang, Z., Yang, X., Zhong, J. et al. Exposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection. Nat Commun 12, 1724 (2021). https://doi.org/10.1038/s41467-021-22036-z
8. Goel RR, Apostolidis SA, Painter MM, et al. Longitudinal Analysis Reveals Distinct Antibody and Memory B Cell Responses in SARS-CoV2 Naïve and Recovered Individuals Following mRNA Vaccination. Preprint. medRxiv. 2021;2021.03.03.21252872. Published 2021 Mar 6. doi:10.1101/2021.03.03.21252872
9. Sewell H F, Agius R M, Kendrick D, Stewart M. Covid-19 vaccines: delivering protective immunity BMJ 2020; 371 :m4838 doi:10.1136/bmj.m4838
10. Wondering if the Vaccine Worked? Get the Right Test, at the Right Time. https://www.nytimes.com/2021/06/20/health/covid-vaccine-antibody-test.html?searchResultPosition=1 
11. Antibody (Serology) Testing for COVID-19: Information for Patients and Consumers. https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/antibody-serology-testing-covid-19-information-patients-and-consumers  

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