Understanding the parameters guiding the best practice for treating B‐cell‐depleted patients with COVID‐19 convalescent plasma therapy

Abstract

The commentary by Focosi et al. 1 highlights two key aspects of the patient-blood management for coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) therapy in seronegative patients who are pre-exposed to B-cell-depleting agents. The first one relates to the qualitative composition of CCP used for patient treatment. The efficacy of CCP is strongly affected by the titres of neutralising antibodies (nAb) present at the time of donation. 2,3 Moreover, there is growing evidence that the nAb activity of plasma units collected from unvaccinated donors infected during the former COVID-19 waves is reduced against novel variants such as Omicron. 4 Hence, the efficacy of collected plasma is likely evolving alongside the exposure of potential donors to successive variant outbreaks and vaccination campaigns against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).At the beginning of the pandemic, CCP was used as a front-line treatment; however, its wide heterogeneity in nAb titres made it difficult to recruit suitable donors of high neutralising titres, as defined by the United States Food and drug Administration (FDA). In contrast, nAb induced after two doses of mRNA vaccination have generally higher and more homogenous titres, which further remain effective against Omicron following a booster dose. 5 From March to July 2021, we treated 19 immunosuppressed patients with plasma collected from COVID-naive two-dose mRNA-vaccinated donors, under a compassionate use protocol, according to the Swiss regulation rules. 6 No relevant difference was observed between patients receiving CCP (n = 17) versus vaccinated plasma (VP, n = 19), indicating that VP therapy is safe and effective in patients with B-cell lymphopenia. In the meantime, CCP donors are increasingly getting vaccinated, and three-dose VP donors are being boosted by a breakthrough infection (defined as 'hybrid plasma', Vax-CCP or CP/VP). Their plasmas contain higher nAb titres and broader antibody specificity than CCP, 4,7,8 as shown by the increase in anti-spike immunoglobulin G titres between 2021 and 2022 (Figure 1A). Thus, Vax-CCP is emerging as the most convenient available source of polyclonal antibody plasma, given the failure of many monoclonal antibody therapies, due to the Omicron immune escape variants. 9

COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis

“…Several scientific societies (eg, ECIL-9, 172 CDC/IDSA, 173 and AABB 174 ) have recently revised their guidelines to recommend the use of COVID-19 convalescent plasma in patients who are immunocompromised, 16,17 especially after concerns related to the prevalence of monoclonal antibody-resistant SARS-CoV-2 variants. The hypothesis of a significant beneficial effect of COVID-19 convalescent plasma on mortality in patients who are immunocompromised cannot be definitively demonstrated with the present data, but very strong elements support its efficacy.…”

“…[13][14][15] By contrast, COVID-19 convalescent plasma appears to have maintained clinical efficacy over time with emerging SARS-CoV-2 variants due to heterogenous, broad spectrum of neutralizing antibodies and widespread availability. 16,17 Thus, there has been a renewed interest in the clinical use of COVID-19 convalescent plasma, particularly for patients who are immunocompromised, who are not able to mount a sufficiently protective antibody response against the virus, and who have contraindications or adverse effects from small molecule antivirals. 18,19 These patients who are immunocompromised are at higher risk for morbidity and mortality associated with COVID-19.…”

“…Although neutralizing anti-spike monoclonal-antibody treatment has been widely used to manage COVID-19, evolutions of SARS-CoV-2 have been associated with monoclonal antibody-resistant SARS-CoV-2 variants, and greater virulence and transmissibility in emerging SARS-CoV-2 variants . By contrast, COVID-19 convalescent plasma appears to have maintained clinical efficacy over time with emerging SARS-CoV-2 variants due to heterogenous, broad spectrum of neutralizing antibodies and widespread availability . Thus, there has been a renewed interest in the clinical use of COVID-19 convalescent plasma, particularly for patients who are immunocompromised, who are not able to mount a sufficiently protective antibody response against the virus, and who have contraindications or adverse effects from small molecule antivirals .…”

Administration of vaccine-boosted COVID-19 convalescent plasma to SARS-CoV-2 infected hamsters decreases virus replication in lungs and hastens resolution of the infection despite transiently enhancing disease and lung pathology

“…While anti-spike monoclonal-antibodies were used to successfully treat COVID-19 early in the pandemic, more transmissible, monoclonal antibodyresistant SARS-CoV-2 variants have emerged as SARS-CoV-2 has evolved [7][8][9][10][11][12]. In contrast, CCP obtained from patients recovering from currently circulating SARS-CoV-2 variants maintains clinical efficacy against emerging SARS-CoV-2 variants [13,14]. In January 2022, the FDA revised the EUA of CCP to include patients who are hospitalized with impaired humoral immunity [15].…”