DISCUSSION
respiratory disease, anaphylaxis, pneumonia, death
RESPIRATORY DISEASE, ANAPHYLAXIS, TRANSFUSION-RELATED ACUTE LUNG INJURY, INFILTRATION, PNEUMONIA, VIRUS, ADVERSE EVENTS, DISEASE, SECONDARY, TRANSFUSION-ASSOCIATED CIRCULATORY OVERLOAD, BLOOD, VIRAL SHEDDING, INFLAMMATORY RESPONSE
The multi-center, open-label, randomized control trial demonstrated that the combination of high neutralizing antibody titer CPT and FPV treatment for outpatient management in mild-to-moderate COVID-19 with high-risk comorbidities was non-inferior to sotrovimab in preventing hospitalization within 14 and 28 days. This study may stand unique in comparing a monoclonal antibody to CCP, thereby presenting a novel contribution to the field.Although two patients in the CPT-FPV group required hospitalization and short-term oxygen supplementation due to plasma-related anaphylaxis and complete recovery within 24 hours, no hospitalizations occurred due to severe COVID-19 in either treatment group. The incidence of serious adverse events did not differ significantly from the sotrovimab group. No cases of transfusion-related acute lung injury or transfusion-associated circulatory overload were observed in the CPT group.Additionally, there were no significant differences in secondary outcomes, including emergency department visits, ICU admission rates, oxygen supplementation, invasive mechanical ventilation, and mortality. Although our study found that the CPT-FPV group had more increased infiltration evaluated by the CT severity index score on day 5, it was not clinically significant to develop severe COVID-19 that contributed to hospitalization, oxygen supplementation, or death. Although pneumonia was detected via chest CT on day 5 in 41% of individuals receiving CPT-FPV and 38% of those administered sotrovimab, a subgroup analysis of patients diagnosed with pneumonia on day 5 in both treatment groups showed no significant differences in several key indicators: clinical improvement or deterioration, oxygen saturation, WHO-CPS score, rate of pneumonia progression, Ct value, and cytokine levels (Our study demonstrated non-inferiority in early intervention, within an average of 2 days after symptom onset, using high neutralizing antibody titer CCP infusion (>1:320) in high-risk patients, including a significant proportion of patients aged 65 or older, in an outpatient setting. However, the observed effects could be influenced by the combined impact of FPV and CCP therapy.Compared to the CSSC-004 study, CPT showed an absolute risk reduction of 3.4 percent points for hospitalization; both studies involved the transfusion of CCP with a titer of more than 1:320 in an outpatient setting to reduce COVID-19-related hospitalization. Both studies administered CCP within 7 days, 2 days in our study, whereas 6 days in CSSC-004. Notably, the CSSC-004 study occurred during the surge of the B.1.1.7 and B.1.617.2 variants, with over 80% of participants being unvaccinated and of the white race. Only 7% of participants in each arm were aged over 65 years. In contrast, our study revealed that over 65% of participants were over 65 years old and about 35% of omicron BA.1, BA.1.1, and BA.2 despite 80% being vaccinated (Despite the high vaccination rate observed in our study, the PANORAMICS trial provided evidence of the effectiveness of early antiviral treatment with molnupiravir. This treatment demonstrated a reduced recovery time and alleviation of symptoms for individuals with 90% vaccination coverage, 69% high-risk comorbidities, and over 65 years of age compared to standard care. However, no significant differences were observed regarding hospitalization or death during the omicron surge (The CCP-Argentina study showed that CCP reduced the risk of severe respiratory disease by 16%, compared to a 31% risk reduction in the placebo group, which focused on patients over 65 years old, with 86% having at least one coexisting condition. These patients received a median neutralizing antibody titer of 1:3,200 CCP within 3 days. Recent studies and our data further support the beneficial effects of CCP treatment in elderly patients (In contrast, the CoV-Early trial demonstrated that CCP failed to improve the 5-point disease severity scale among individuals aged 18–65 with high-risk comorbidities during the dominance of D614G and B.1.1.7 variants. Forty percent of participants received CCP more than 5 days after onset. The trial had lower rates of full vaccination and positive immunity than our study. Furthermore, the trial’s discontinuation of 421 out of 690 participants from the almost fully vaccinated population affected its statistical power to detect large effect sizes, potentially influencing the outcomes. The trial also utilized a lower neutralizing antibody titer, with 55% of participants receiving CCP with a titer less than 386. These characteristics may have influenced the CCP outcomes (The REMAP-CAP, CONCOR-1, RECOVERY, PLACID, and RECOVER trials failed to show any clinical benefit of CCP in severe COVID-19 patients (Moreover, our study illustrated that no substantial differences were discerned in mitigating viral shedding, inflammatory markers, and cytokine alterations between the CPT and sotrovimab-treated groups. Nevertheless, the sotrovimab group manifested a more pronounced reduction in high-sensitivity C-reactive protein and interleukin-6, as well as MCP-1 levels between days 2–5 and 0–14. While no discrepancy was observed in endpoint cytokine levels on consecutive days subsequent to CPT-FPV and sotrovimab treatment, this discovery endorses the perspective that NmaB may effectively preclude the evolution of severe COVID-19 and cytokine stormsHowever, the observation of a larger decline in IL-6 among sotrovimab recipients between days 5 and 14 is nuanced by the range of measurements, complicating its evaluation. Furthermore, the anti-inflammatory activity of IL-6 warrants attention, especially considering the elevated IL-10 levels among CPT-FPV recipients, even though they span a wide measurement range. 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 (The impacts of CPT-FPV and sotrovimab on the immune response may diverge. While participants treated with CPT-FPV exhibited elevated levels of SARS-CoV-2 nucleocapsid IgG on days 2 and 5, those receiving sotrovimab demonstrated higher levels of anti-spike RBD IgG on days 2, 5, and 14 and potentially day 28, likely attributable to sotrovimab’s extended half-life. The post-administration elevation of antibody titers in participants who received sotrovimab is not unexpected, considering that the mass of antibodies delivered through monoclonal doses is typically greater than that found in CCP. Nonetheless, it is imperative to acknowledge that CCP, being a polyclonal reagent, offers diversity in the recognition of epitopes and isotype functionality. Nevertheless, recipients of CPT-FPV demonstrated higher sVNT and positive neutralizing antibodies on days 2, 5, and 14. Although these disparities were not observed on day 28, they imply that CPT-FPV may have exerted more pronounced early antiviral activity, potentially due to its inclusion of isotypes other than IgG and additional SARS-CoV-2 specificities. The SARS-CoV-2 nucleocapsid-specific antibodies derived from CCP contained a higher quantity of functional antibodies than recipients’ plasma, and these functions are associated with attenuated humoral immune evolution in patients exhibiting high-titer anti-spike IgG (Sotrovimab, NmaB therapy, had a well-known benefit from marked higher antibody content than CCP and improved the outcome from early outpatient treatment. However, the resistant variant virus was the main concern. While the efficacy difference between CCP and NmaB mainly revolves around the dose gap, this study specifically selected convalescent plasma with a titer above 320 to minimize the difference. Nonetheless, there is ongoing controversy regarding the sufficient titer of antibodies needed to combat each variant of concern (Moreover, our study did not explore using VaxPlasma (hybrid plasma) obtained from vaccinated donors, which contains antibodies with 10 times higher titers than standard high-titer CCP and has shown high effectiveness against the omicron variant. Although some CCP donors in our study may have received inactivated or ChAdOx-1 nCoV vaccinations, we could not clarify their impact (Our study suggests that a titer of CCP higher than 1:320 may be sufficient to demonstrate non-inferiority to sotrovimab. In our immunologic study, we observed that sotrovimab increased RBD spike antibodies from day 0 to 28, but there was no significant difference in antibody levels after day 14. Although there was no significant difference in sVNT changes between the two treatments at any interval after infusion, the sVNT in CCP was higher than in sotrovimab on day 5 (Our study had several limitations that need to be acknowledged. Firstly, there was a relatively low percentage of unvaccinated individuals in both CPT-FPV and sotrovimab groups (15% and 25%, respectively), which may have influenced the observed clinical outcomes and introduced a bias toward more favorable results. Secondly, the lack of information regarding the immunization status of the plasma donors including vaccinated donors may have impacted the interpretation of clinical outcomes associated with CPT. Thirdly, all patients in the CPT group received FPV following the Thai COVID-19 standard treatment guidelines, potentially confounding the outcomes due to the antiviral activity of the drug, although the efficacy of FPV in Asians remained controversial. Fourthly, the sVNT used in the study could not detect neutralizing antibodies against the delta variants and CCP from individuals infected during the surges of the alpha and delta variants. Fifth, we are unable to provide the actual level of neutralizing antibody, the isotypes of nucleocapsid, and/or spike and/or RBD antibodies titer in each bag; we can only confirm that the CCP possessed a neutralizing antibody level above 1:320, as prepared by the Thai National Blood Center. Lastly, while 30% of patients were infected with the omicron variant, most patients in both treatment arms (60%) were infected with unknown variants, which may impact the generalizability of the findings.