The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has infected over 37 million people worldwide, causing over 1 million deaths to date. Various strategies have been investigated, and many adopted to control the spread of infection and provide successful treatment options for the infected. Some of the preventive and therapeutic options in use are passive immunotherapy with convalescent plasma, hyperimmune gamma globulin, or monoclonal antibodies.
Convalescent plasma has SARS-CoV-2-specific antibodies that may protect from re-infection and disease among susceptible populations. This rationale may be employed to use plasma containing SARS-CoV-2 neutralizing antibodies (nAb) as a treatment for COVID-19.
Jim Boonyaratanakornkit et al., in a recent paper published as a preprint on the preprint medRxiv*, study the clinical factors, the laboratory assays to streamline plasma donor selection, and the durability of nAb responses in adults. Adults recovered from SARS-CoV-2 virus infection were screened for serum IgG to SARS-CoV-2 spike protein S1 domain, nucleoprotein (NP), and for nAb. The researchers evaluated the antibody levels in the plasma donors and examined its trajectory over a period in a subset of donors. They observed nAb titers correlated with clinical factors; old age, male sex, presence of fever during acute illness episode, and hospitalization were significantly associated with higher nAb titers.
They also assessed comparative information on two rapid commercially available assays for nAb titers. These immunoassays - the Euroimmun assay and the Abbott assay - could reliably test high nAb tires when used early during the recovery period, after COVID-19. Both assays are EUA (Emergency Use Authorization)-approved as qualitative and not quantitative, yielding results that plateau at different thresholds.
Among the 250 participants in this study, 34.4% had titers of 1:80, making this cohort eligible for donation to a pooled immunoglobulin product protocol.
However, it was observed that 7 individuals were seronegative and lacked T cell responses. These individuals were tested further for their immune status. As opposed to the convalescent SARS-CoV-2 seropositive individuals who had robust T-cell responses, SARS-CoV-2 seronegative individuals’ immune responses were similar to the pre-2019 healthy donors.
Post recovery from COVID-19, the antibody titers (nAb titers, anti-S1 IgG, and anti-NP IgG) over time were found to be low. The antibody kinetics showed that the neutralization titer decreased with time except for 4 participants. In this study, the nAb half-life was calculated at 62.2 days. This guides one to use the functional nAb sooner - right after the recovery.
In this study, the authors associated the clinical factors such as old age, higher disease severity, male sex, the shorter interval from recovery, with higher levels of nAb. This could help us understand future plasma donor requirements and streamline recruitment. This higher antigen load with higher B cell responses observed in this study is supported by observations of severe infection with higher T cell responses, in particular, circulating CD4+ T follicular helper cells.
This study reports that 3% of the cohort did not exhibit adaptive immune responses in multiple antibody and T cell assays despite SARS-CoV-2 infection. The researchers discuss the various possibilities of a positive SARS-CoV-2 RNA detection and a seronegative observation, one of the most likely being sero-revert in the early convalescent phase. The decrease in SARS-CoV-2 nAb titers over a period shows that: 1) poor germinal center reactions are occurring, and 2) re-infection is debatable and a concern. The authors reaffirm that additional research will be needed to address the waning immunity and the protection it may fail to provide in case of re-infection. Some studies show that a baseline SARS-CoV-2 specific circulating antibodies protect the individuals from infection in an occupational outbreak.
It is important to note that the NIH (National Institutes of Health) hyperimmune globulin protocol NCT04344977 focuses on high nAb titers. Previous data also show that infection is neutralized with anti-S antibodies - with quicker clinical improvement and reduced mortality rates.
Passive immunotherapy approaches were investigated for treatment or prophylaxis of SARS-CoV-2 infection in COVID-19 patients. While pointing out the limitations in this study, the authors emphasize the importance of this study in selecting potential convalescent plasma donors - with the predictive value of clinical factors and commercially available immunoassay results for high nAb titers. This study helps increase access to and efficiency of donor sample testing. They believe that the issues addressed in this study are critical for understanding herd immunity and implementing immunization programs.
- Clinical, laboratory, and temporal predictors of neutralizing antibodies to SARS-CoV-2 after COVID-19, Jim Boonyaratanakornkit, Chihiro Morishima, Stacy Selke, Danniel Zamora, Sarah McGuffin, Adrienne E Shapiro, Victoria L Campbell, Christopher L McClurkan, Lichen Jing, Robin Gross, Janie Liang, Elena Postnikova, Steven Mazur, Anu Chaudhary, Marie K Das, Susan L Fink, Andrew Bryan, Alex L Greninger, Keith R Jerome, Michael R Holbrook, Terry B Gernsheimer, Mark H Wener, Anna Wald, David M Koelle, medRxiv 2020.10.06.20207472; doi: https://doi.org/10.1101/2020.10.06.20207472