Today we're tackling a question with a lot of public health implications as we consider how to move forward in this pandemic (and potentially being to loosen restrictions). A huge part of that equation is the question of immunity: are people who have previously been infected immune to COVID; or could they become re-infected and continue to transmit the virus? And could antibody tests help us determine who has already been infected (perhaps asymptomatically)?

 

Antibody tests for COVID-19

• Several different types of tests available1
  • GICA: gold immunochromatographic assay
  • CLIA: chemiluminescent immunoassay
  • ELISA: enzyme-linked immunosorbent assay
  • Point-of care lateral flow tests
• ELISA tests are the most common (most studies below use ELISA assays)
  • Plate-based technique for detecting and quantifying peptides, proteins, antibodies, etc
  • May have slightly different targets
• Several assays available each with slightly varying test characteristics
  • Generally sensitivity is good (>90% for most tests)2
  • False positives are rare but have been reported3
• Some assays show cross-reactivity with other coronaviruses4

 

Initial antibody response and seroconversion

• Most studies support a high rate of seroconversion after acute illness
  • One study found 50% of pts had detectable antibodies by day 7 post-Sx onset5
  • Most pts who seroconvert do so by day 10-156
  • Seroconversion rates varied but are generally high: 83% to 100% by day 21-353,5,7-11
• However -
  • One study classified patients as "strong responders" vs "weak responders" vs "non-responders"12
    • Strong responders: >2x the cutoff value; weak responders: 1-2x the cutoff value; non-responders: below assay cutoff value
      • The clinical implications of this stratification system have NOT been determined
    • A significant portion of patients were non- or weak-responders by the end of the follow-up period (1 month)
      • 7% (IgM) and 16.7% (IgG) were non-responders
      • 2% (IgM) and 61.1% (IgG) were weak responders
    • Another group found that 30% of patients had very low titers at day 10-15 post-symptom onset – again, the clinical implications of these low levels are unclear13
  • Patients with more severe disease seem to mount a stronger antibody response (IgG in particular)12,14
    • Weak antibody responders had a higher rate of viral clearance in one study12

 

Lasting immunity?  

• IgM levels decline over time, as expected
  • 33% of pts had no detectable IgM by week 7 in one study15
• Some evidence that IgG levels also fall with time
  • One group did weekly serial testing of IgG levels and found that levels decreased with time16
  • Adams et al reported that IgG levels decreased by 8 weeks (but remained above detection threshold)17
  • In contrast, another group found stable IgG levels up to 7 weeks after symptom onset15
• No one has looked beyond 2 months post-Sx onset yet à we don't know how long immunity might last!

UPDATE – May 18/20

• An interesting new basic science study has come out looking at the role of T-cells in COVID-1918
  • Reminder: T-cells are key players in cell-mediated immunity (vs B-cells in humoral immunity discussed above)
• This group found that SARS-CoV2-reactive CD4+ T cell were detected in 40-60% of healthy historical controls who had never been exposed to COVID
• They theorize that this may reflect a degree of cross-reactivity between SARS-CoV-2 and other coronaviruses
  • BUT the clinical implications of this re: immunity are not known
• This is a potentially hopeful study – if there is some degree of cross-reactivity, we may be closer to herd immunity than previously suspected

 

 

Sources

1. Gao HX, Li YN, Xu ZG et al. Detection of serum immunoglobulin M and immunoglobulin G antibodies in 2019-nCoV-infected cases from different stages. Chinese Medical Journal, Mar 2020. doi:10.1097/CM9.0000000000000820

 

1. Lassauniere R, Frische A, Harboe ZB et al. Evaluation of nine commercial SARS-CoV-2 immunoassays. MedRxiv pre-print, Apr 2020. doi: 10.1101/2020.04.09.20056325

 

1. Xiang F, Wang X, He X et al. Antibody detection and dynamic characteristics in patients with COVID-19. Clin Infect Dis, Apr 2020. doi: 10.1093/cid/ciaa461/5822173

 

1. Okba N, Muller M, Li W et al. Severe Acute Respiratory Syndrome Coronavirus 2−Specific Antibody Responses in Coronavirus Disease 2019 Patients. Emerg Infect Dis, Apr 2020. doi:10.3201/eid2607.200841

 

1. Wölfel, R., Corman, V.M., Guggemos, W. et al. Virological assessment of hospitalized patients with COVID-19. Nature, Apr 2020. doi:10.1038/s41586-020-2196-x

 

1. 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 pre-print, Apr 2020. doi:10.1101/2020.03.30.20047365

 

1. Zhang B, Zhou X, Zhu C et al. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.12.20035048

 

1. Zhao J, Yuan Q, Wang H et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis, Mar 2020. doi:10.1093/cid/ciaa344

 

1. Lou B, Li T, Zheng S et al. Serology characteristics of SARS-CoV-2 infection since the exposure and post symptoms onset. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.23.20041707

 

1. Long Q, Deng H, Chen J et al. Antibody responses to SARS-CoV-2 in COVID-19 patients: the perspective application of serological tests in clinical practice. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.18.20038018v1

 

1. To K, Tsang O, Leung W et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infec Dis, Mar 2020. doi:10.1016/S1473-3099(20)30196-1

 

1. Tan W, Lu Y, Zhang J et al. Viral kinetics and antibody responses in patients with COVID-19. MedRxiv pre-print, Mar 2020. doi:10.1101/2020.03.24.20042382v1

 

1. 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 pre-print, Apr 2020. doi:10.1101/2020.03.30.20047365

 

1. Huang A, Garcia-Carreras B, Hitchings M et al. A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.04.14.20065771

 

1. Xiao A, Gao C, Zhang S. Profile of specific antibodies to SARS-CoV-2: The first report. J Infect, Mar 2020. doi:10.1016/j.jinf.2020.03.012

 

1. Du Z, Zhu F, Guo F et al. Detection of antibodies against SARS‐CoV‐2 in patients with COVID‐19. J Med Virol, Apr 2020. doi: 10.1002/jmv.25820

 

1. Adams E, Ainsworth M, Anand R et al. Evaluation of antibody testing for SARS-CoV-2 using ELISA and lateral flow immunoassays. MedRxiv pre-print, Apr 2020. doi:10.1101/2020.04.15.20066407

 

1. Grifoni A, Weiskopf D, Ramirez SI et al. Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals, Cell, May 2020, doi:10.1016/j.cell.2020.05.015