Abbreviations
- CCP
COVID‐19 convalescent plasma
- EUA
Emergency Use Authorization
- FDA
Food and Drug Administration
- NCP
new CCP program
- OCP
original CCP program
Since early 2020, COVID‐19 Convalescent Plasma (CCP), a source of passive antibody therapy, has been under investigation as a means to prevent or mitigate disease progression. Initially available only through the Mayo Clinic's Expanded Access Program, the United States Food and Drug Administration (FDA) issued an initial Emergency Use Authorization (EUA) in August 2020 for CCP transfusion to hospitalized patients with moderate and severe disease. However, in February 2021 the FDA limited the use of CCP to high‐titer units for hospitalized patients with early disease or compromised humoral immunity. On December 28, 2021, the FDA further modified the authorization of CCP for use only in immunocompromised patients but in both the inpatient and outpatient settings. Not surprisingly, recommendations have changed as more data has become available or re‐analyzed. Unfortunately the studies reviewed by the FDA to formulate their EUA recommendations as well as those studies evaluated in recent publications suggesting expanded clinical indications for CCP were conducted using CCP almost exclusively collected from non‐vaccinated individuals. With CCP currently being collected predominantly from previously immunized individuals after recovery from “breakthrough” infections, we were concerned that the current CCP inventory might be qualitatively and quantitatively different from the CCP collected and transfused in the pre‐vaccination era.
Our hospital‐based blood collection service collected CCP from April 15, 2020 to March 15, 2021 (our Original CCP program, OCP) and has preserved frozen sera from many donors obtained on the day of CCP collection. In response to the FDA's December 2021 modified EUA, and anticipating a renewed interest in CCP use we reinstituted CCP collections on April 15, 2022 (our New CCP program, NCP), and again stored serum samples from the day of donation. None of our initial OCP donors had received vaccination prior to donation. Of the 36 recent NCP donors, 35 had been vaccinated prior to their “breakthrough” infection. Limiting our analysis to samples obtained from donations occurring 28–79 days following symptom resolution (prior to an expected decline of virus neutralization activity) resulted in an NCP Cohort of 19 subjects whose results are analyzed in Table 1. Sera were assayed on the Abbott Alinity platform for IgG anti‐spike antibody receptor binding domain (anti‐RBD; “AdviseDx SARS‐COV‐2 IgGII”), IgM anti‐spike antibody (“AdviseDx SARS‐CoV‐2 IgM”), and IgG anti‐nucleocapsid antibody ( “AdviseDx SARS‐COV‐2 IgG”). Of the 19 NCP donations evaluated, vaccines previously administered were 10 from Pfizer, 4 from Moderna, 1 from J&J, and 4 were of an uncertain manufacturer. From a total of over 600 OCP donation episodes prior to March 2021, 40 stored serum samples were selected in a 2:1 ratio to our NCP specimens with approximate matching for both blood type and for the length of time post symptom resolution prior to donation (NCP median of 58 days and OCP median of 52 days). Sex and age parameters proved to be not significantly different on post hoc analysis.
TABLE 1.
Comparison of COVID‐19‐related antibodies between the new and original cohorts
| IgM anti‐spike index >0.99 (positive donations) | IgG anti‐spike >1280 AU/ml (FDA high‐titer cut‐off) | Mean IgG anti‐nucleocapsid index (>1.40 = positive) | Donors with both IgM and IgG positive assays | |
|---|---|---|---|---|
| New program (N = 19) | 3 (15.8%) | 19 (100%) | 3.09 (SD 1.71) | 2 (10.5%) |
| Original program (N = 40) | 25 (62.5%) | 14 (35.0%) | 4.99 (SD 2.55) | 26 (65.0%) |
| p value of difference | <.001 (Chi Square) | <.001 (Chi Square) | .006 (2‐tailed t‐test) | <.001 (Chi Square) |
The lower IgG anti‐nucleocapsid antibody, lower IgM anti‐spike antibody, and higher IgG anti‐ RBD antibody present in post‐breakthrough COVID‐19 CCP are likely due to extensive affinity maturation and a decreased presence of IgM memory‐cells post‐vaccination 1 and to a component of “original antigenic sin” in which the immune system is focused on producing those anti‐spike antibodies previously developed in response to prior vaccination, while relatively ignoring additional newly presented viral immunogens. While high‐titer neutralizing anti‐spike antibody appears to successfully constrain disease progression in patients having an adequate immune system (one rationale for ongoing vaccination programs) there are data suggesting that IgM anti‐spike and IgG anti‐nucleocapsid may also contribute to effective disease resolution. Recent publications suggest that (1) IgM anti‐spike may be at least as effective as IgG anti‐spike in virus neutralization, 2 that (2) both the IgM and IgG anti‐spike responses are associated with increased clinical immunity, 3 that (3) anti‐nucleocapsid antibody confers protection from symptomatic reinfection, 4 and that nucleocapsid and its proteolytic fragments released with viral shedding or upon cell death can be neutralized by IgG anti‐N. 5
Our data suggest that because of significant antibody differences, and perhaps because of other different biologic differences not yet elucidated, results of clinical studies using CCP donated by non‐vaccinated individuals at the beginning of the COVID epidemic cannot be directly extrapolated to the use of CCP being currently collected. Additionally, a lack of adequate IgM anti‐RBD and/or IgG anti‐nucleocapsid, rather than lower neutralizing IgG anti‐spike antibody, may be partially responsible for the poor outcomes occasionally encountered during breakthrough infections. In conclusion, further study of post‐vaccination, post‐breakthrough infection CCP appears to be necessary to best guide future CCP use, especially in immunocompromised COVID‐19 patients.
FUNDING INFORMATION
This work was supported by Department of Pathology and Laboratory Medicine, Cedars‐Sinai Health System, Los Angeles, CA 90048, USA.
CONFLICT OF INTEREST
The authors have disclosed no conflicts of interest.
Funding information Department of Pathology and Laboratory Medicine, Cedars‐Sinai Health System
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