Nucleocapsid-specific antibody function is associated with therapeutic benefits from COVID-19 convalescent plasma therapy

Herman, Jonathan D.; Wang, Chuangqi; Burke, John S.; Zur, Yonatan; Compere, Hacheming; Kang, Jaewon; Macvicar, Ryan; Taylor, Sabian; Shin, Sally; Frank, Ian; Siegel, Don L.; Tebas, Pablo; Choi, Grace; Shaw, Pamela A.; Yoon, Hyunah; Pirofski, Liise-anne; Jülg, Boris; Bar, Katharine J.; Lauffenburger, Douglas A.; Alter, Galit

doi:10.1016/j.xcrm.2022.100811

Cited by 17 publications

(16 citation statements)

References 70 publications

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“…The titer of CCP administered across these 4 trials was marginally lower in the positive efficacy trials compared with the negative trials, though the same neutralization assay was not used to test samples from the different trials ( 17 ); this is evidence that the dose of antibody was not the sole determinate of outcome in the CCP trials. Recent data suggest that N-specific Fc-mediated antibody maybe an important effector pathway for CCP ( 28 ), and in mouse models, CCP with low neutralization activity can still provide some protection from SARS-CoV-2 through Fc-mediated functions such as antibody dependent cellular cytotoxicity ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

COVID-19 convalescent plasma boosts early antibody titer and does not influence the adaptive immune response

McDyer¹,

Azimpouran²,

Durkalski‐Mauldin³

et al. 2023

JCI Insight

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Multiple randomized, controlled clinical trials have yielded discordant results regarding the efficacy of convalescent plasma in outpatients, with some showing an approximate two-fold reduction in risk and others showing no effect. We quantified binding and neutralizing antibody levels in 492 of the 511 participants from the C3PO trial of a single unit of COVID-19 convalescent plasma (CCP) vs. saline infusion. In a subset of 70 participants, peripheral blood mononuclear cells were obtained to define the evolution of B and T cell responses through day 30. Binding and neutralizing antibody responses were approximately two-fold higher one hour post-infusion in recipients of CCP compared to saline plus multivitamin, but levels achieved by the native immune system by day 15 were almost ten-fold higher than seen immediately after CCP administration.Infusion of CCP did not block generation of the host antibody response or skew B or T cell phenotype or maturation. Activated CD4+ and CD8+ T cells were associated with more severe disease outcome. These data show that CCP leads to a measurable boost in anti-SARS-CoV-2 antibodies, but that the boost is modest and may not be sufficient to alter disease course.*The C3PO primary efficacy outcome of disease progression was defined as an emergency department (ED) or urgent care (UC) visit, hospital admission or death without a hospital admission within 15-days from randomization. ¶ The overall population is defined as randomized C3PO patients who had a baseline assay result and at least 1 post-baseline assay result.

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Section: Discussionmentioning

confidence: 99%

COVID-19 convalescent plasma boosts early antibody titer and does not influence the adaptive immune response

McDyer¹,

Azimpouran²,

Durkalski‐Mauldin³

et al. 2023

JCI Insight

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“…Interestingly, the CONCOR-1 (Convalescent Plasma for COVID-19 Respiratory Illness) trial found that donor plasma with high levels of neutralization activity and Fc-dependent effector functionality (such as ADCC) achieved a significant reduction in severe outcomes and death 169 . Donor plasma with enhanced nucleocapsid-specific antibody responses and spike-specific antibodies inducing ADCP by neutrophils may also provide benefit 170 , 171 . Passive-transfer studies in animal models of COVID-19 have also shown that functions beyond neutralization have an important role in the in vivo protection afforded by monoclonal antibodies 30 , 91 .…”

Section: Vaccines and Antibody Therapeuticsmentioning

confidence: 99%

Beyond neutralization: Fc-dependent antibody effector functions in SARS-CoV-2 infection

et al. 2022

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Neutralizing antibodies are known to have a crucial role in protecting against SARS-CoV-2 infection and have been suggested to be a useful correlate of protection for vaccine clinical trials and for population-level surveys. In addition to neutralizing virus directly, antibodies can also engage immune effectors through their Fc domains, including Fc receptor-expressing immune cells and complement. The outcome of these interactions depends on a range of factors, including antibody isotype–Fc receptor combinations, Fc receptor-bearing cell types and antibody post-translational modifications. A growing body of evidence has shown roles for these Fc-dependent antibody effector functions in determining the outcome of SARS-CoV-2 infection. However, measuring these functions is more complicated than assays that measure antibody binding and virus neutralization. Here, we examine recent data illuminating the roles of Fc-dependent antibody effector functions in the context of SARS-CoV-2 infection, and we discuss the implications of these data for the development of next-generation SARS-CoV-2 vaccines and therapeutics.

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“…Noteworthily, the anti-inflammatory cytokine, TGF-β, can be induced by MCP-1, which was observed to be higher in CPT-FPV recipients. These findings give rise to the hypothesis that CPT-FPV may modulate the inflammatory response toward an anti-inflammatory profile, potentially mediated by nucleocapsid antibodies ( 47 , 48 ). These cytokine findings might elucidate previous results regarding cytokine levels, albeit with the caveat that plasma cytokine concentrations may not accurately mirror those within tissues.…”

Section: Discussionmentioning

confidence: 89%

Efficacy of combined COVID-19 convalescent plasma with oral RNA-dependent RNA polymerase inhibitor treatment versus neutralizing monoclonal antibody therapy in COVID-19 outpatients: a multi-center, non-inferiority, open-label randomized controlled trial (PlasMab)

Siripongboonsitti,

Nontawong,

Tawinprai

et al. 2023

Microbiol Spectr

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The effectiveness of neutralizing monoclonal antibodies against emerging variants with spike protein mutations has been limited. Early high-titer convalescent plasma therapy (CPT) tends to be effective and a potential treatment option for COVID-19 outpatient treatment. An open-label, 1:1, randomized controlled trial compared the efficacy of high neutralizing titer CPT with favipiravir (CPT-FPV) versus sotrovimab. The study aimed to evaluate the non-inferiority of CPT-FPV treatment compared to sotrovimab in preventing hospitalization within 14 and 28 days. Among the 136 randomized participants, 68 received CPT-FPV, while 68 received sotrovimab. The study demonstrated that CPT-FPV was non-inferior to sotrovimab in preventing hospitalization within 14 and 28 days. No significant differences between the two treatment arms were observed in emergency room visits, oxygen supplementation, or mortality. Although there were no significant disparities in radiological, virological, or inflammatory marker outcomes, sotrovimab exhibited a more pronounced reduction in IL-6 levels during days 2–5 and lower MCP-1 levels on day 14. High neutralizing titer convalescent plasma and favipiravir demonstrated non-inferior to sotrovimab in preventing hospitalization, emergency room visit, oxygen supplementation, and mortality in mild-to-moderate COVID-19. The evidence may be a choice for treatment for new variants despite the need for further study. (The trial protocol was registered in the Thai clinical trials registry no. 20220319002.) IMPORTANCE This pivotal study reveals that high neutralizing titer COVID-19 convalescent plasma therapy (CPT) combined with favipiravir (FPV) is non-inferior to sotrovimab in preventing hospitalization and severe outcomes in outpatients with mild-to-moderate COVID-19 and high-risk comorbidities. It underscores the potential of CPT-FPV as a viable alternative to neutralizing monoclonal antibodies like sotrovimab, especially amid emerging variants with spike protein mutations. The study’s unique approach, comparing a monoclonal antibody with CPT, demonstrates the efficacy of early intervention using high neutralizing antibody titer CPT, even in populations with a significant proportion of elderly patients. These findings are crucial, considering the alternative treatment challenges, especially in resource-limited countries, posed by the rapidly mutating SARS-CoV-2 virus and the need for adaptable therapeutic strategies.

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Nucleocapsid-specific antibody function is associated with therapeutic benefits from COVID-19 convalescent plasma therapy

Cited by 17 publications

References 70 publications

COVID-19 convalescent plasma boosts early antibody titer and does not influence the adaptive immune response

COVID-19 convalescent plasma boosts early antibody titer and does not influence the adaptive immune response

Beyond neutralization: Fc-dependent antibody effector functions in SARS-CoV-2 infection

Efficacy of combined COVID-19 convalescent plasma with oral RNA-dependent RNA polymerase inhibitor treatment versus neutralizing monoclonal antibody therapy in COVID-19 outpatients: a multi-center, non-inferiority, open-label randomized controlled trial (PlasMab)

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