5. Immunity and COVID-19

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

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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