In a recent study posted to the medRxiv preprint server, researchers report that convalescent plasma treatment is most effective in treating hospitalized coronavirus disease 2019 (COVID-19) patients with poor pre-existing anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody function.

Study: A role for Nucleocapsid-specific antibody function in Covid-19 Convalescent plasma therapy. Image Credit: Maxim Krivonos /

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

COVID-19 and CCP

Since the onset of the COVID-19 pandemic, the World Health Organization (WHO) COVID-19 dashboard has recorded over 769 million confirmed cases and almost seven million deaths.

Several vaccines have been developed against COVID-19; however, a significant proportion of the global population remains unvaccinated. The high mutation rate of SARS-CoV-2 has contributed to the emergence of novel strains that are both more lethal and resistant to conventional vaccines, thus emphasizing the importance of effective therapies.

Convalescent plasma therapy is a procedure that uses plasma, which is a liquid derived from blood after the removal of blood cells, of donors who have recovered from a disease to treat individuals with defective immune systems. To date, plasma-derived antibodies have been used to successfully treat influenza, Lassa virus, Ebola virus, and other pathogens.

Due to the availability of convalescent plasma before vaccine development, its ease of use, and safety, COVID-19 convalescent plasma (CCP) has been postulated as a modality to treat severe COVID-19 cases since the onset of the pandemic.

The United States Food and Drug Administration (FDA) granted emergency use authorization for CCP use in 2020. However, studies testing the efficacy of CCP have been associated with mixed results.

To this end, smaller randomized clinical trials have suggested that high-titer CCP benefits patients during the early stages of COVID-19. More extensive trials, which typically involved patients at later stages of disease, have negated these results and suggest that CCP might be harmful in patients with severe illness.

Prior immunological studies have elucidated that antibody-dependent cell cytotoxicity (ADCC) was correlated with reduced mortality risk at day 30 of infection, thus suggesting that CCP might be crucial in leveraging the host’s immune system through fragment crystallizable-effector (Fc-effector) functions. The importance of and mechanisms underlying the processes of CCP therapy remain poorly understood.

About the study

In the present study, researchers utilize system serology, a plethora of high throughput experimental techniques aimed at dissecting the antibody features and functions, to a case-cohort randomized clinical trial to evaluate the role of CCP in the evolution of patients’ immune response. Regression models were also used to estimate the Clinical Severity Score (CSC), a measure of the CCP efficacy.

The study comprised 79 patients hospitalized at the University of Pennsylvania between May 2020 and January 2021 due to severe COVID-19-induced pneumonia. Forty individuals comprised the case-cohort that received both CCP and standard care, whereas the remaining 39 patients only received standard care. All study participants were screened and tested one, three, eight, 15, 29, and 60 days following treatment initiation.

For the detection and quantification of antigens and antigen-specific humoral responses between study cohorts, a multiplexed Luminex bead array was employed. This array revealed the antigen-specific antibody isotype, subtype, and Fc-receptor (FcR) binding levels.

Ab-directed flow cytometry functional assays were used to quantify antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent complement deposition (ADCD).

Four parameter logistic regression models normalized differences in results across study groups. These regressions were built with two independent analysis paths, including the full and null models that represented cases and controls, respectively. The top 30 variables revealed by the regression models were used to calculate CSC which classifies patients according to their disease severity.

Study findings

The average age of the study cohort was 63 years, 54% of whom were female. Most patients were treated with remdesivir, a broad-spectrum antiviral medication, or corticosteroids at 81% and 83%, respectively, before study treatments. Patients were enrolled in the study at the early stages of infection and a median of six days following diagnosis.

Functional assays revealed that CCP treatment leads to an immunodominance shift from a spike (S)-targeted humoral response to a nucleocapsid (N) protein-targeted approach. These findings indicate blunted inflammation is due to a decreased S response.

Furthermore, CCP treatment facilitates the rapid clearing of N-proteins, which are responsible for lung damage in severe COVID-19. Notably, the anti-inflammatory effects of CCP are long-lasting and persist for at least two months following treatment.

Strikingly, our results show that an N-focused immunodominance in COVID-19 disease is associated with better clinical outcomes.”

CSC scores significantly improved for participants receiving CCP treatments as compared to those receiving only standard care with median scores of seven and ten, respectively. In fact, CCP treatment significantly reduced mortality and morbidity as compared to standard care alone.

Combined with the array results, these findings suggest that the primary benefits of CCP may be due to the passive shift in immunodominance through antibody functional activity, with the direct neutralizing properties of CCP antibodies a secondary outcome.

This novel immunomodulatory possibility suggests that passive antibody therapy may have distinct benefits in COVID-19 patients as compared to anti-RBD monoclonal antibodies and antivirals such nirmatrelvir/ritonavirand molnupiravir, both of which target viral invasion/replication to mediate a clinical benefit.”

These results are of critical importance in light of the emergence of Omicron and other SARS-CoV-2 variants that have rendered most conventional monoclonal antibody therapeutics ineffective. Due to their multiple-site-targeting modalities, polyclonal antibodies, including CCP, are less likely to be affected by novel strains.


In the present preprint, researchers used system serology approaches to elucidate the mechanisms underlying CCP function in treating severe COVID-19 and its efficacy at early stages of the infection. CCP primarily benefits patients by causing an immunodominance shift from an S-targeted humoral response to an N-targeted response, which contrasts with previous hypotheses assuming that CCP antibodies directly neutralize infection.

CSC results depict significantly reduced morbidity and mortality in individuals receiving CCP treatments as compared to those only receiving standard care. The anti-inflammatory effects of CCP treatments were found to persist for months after treatment cessation, thus demonstrating the long-lasting impact of the therapeutic.

Our research confirms the importance of the functional S and N antibody response in treatment of COVID-19 disease and should guide development of COVID-19 monoclonal and polyclonal antibody therapeutics that focus not only on neutralization, but also on Fc-directed functionality.”

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:

  • Preliminary scientific report.
    Herman, J. D., Wang, C., Burke, J. S., et al. (2023). A role for Nucleocapsid-specific antibody function in Covid-19 Convalescent plasma therapy. medRxiv. doi:10.1101/2022.02.19.22271230

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