ABSTRACT
Although severe coronavirus disease 19 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. Additionally, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 (vax-plasma). Thus, we report the clinical outcome of 208 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19 specific therapeutics (standard of care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 1% (1 of 123 patients) in the vax-plasma group and 6% (5 of 85 patients) in the standard of care group, which corresponded to a relative risk reduction of 83%. Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (196 of 208 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19 specific therapies reduced the risk of disease progression leading to hospitalization.
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
Abstract IMPORTANCE. Many hospitalized patients with COVID-19 have been treated with convalescent plasma. However, it is uncertain whether this therapy lowers mortality and if so, if the mortality benefit is larger among specific subgroups, such as recipients of plasma with high antibody content and patients treated early in the disease course. OBJECTIVE. To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19. DATA SOURCES. On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature. STUDY SELECTION. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3,841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of five reviewers. DATA EXTRACTION AND SYNTHESIS. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using inverse-variance random-effects model. MAIN OUTCOMES AND MEASURES. Prespecified end point was all-cause mortality during hospitalization. RESULTS. Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses demonstrated that transfusion of COVID-19 convalescent plasma was associated with a significant decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio (OR), 0.87 [95% CI, 0.76-1.00]) and matched cohort studies (OR, 0.77 [95% CI, 0.64-0.94]). Meta-analysis of subgroups revealed two important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared to convalescent plasma containing low antibody levels (OR, 0.85 [95% CI, 0.73 to 0.99]). Second, earlier treatment with COVID-19 convalescent plasma was associated with a significant decrease in mortality compared with the later treatment cohort (OR, 0.63 [95% CI, 0.48 to 0.82]). CONCLUSIONS AND RELEVANCE. COVID-19 convalescent plasma use was associated with a 13% reduced risk in mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.
Subject(s)
COVID-19ABSTRACT
The Omicron variant of SARS-CoV-2, first detected in November 2021, is rapidly becoming the dominant lineage worldwide. We assessed the affinities of two monoclonal antibodies (mAbs), casirivimab and imdevimab, to wild type, Delta and Omicron spike; to provide context, we compared the properties of these therapeutic mAbs to the affinities and concentrations of wild-type RBD specific antibodies in 74 convalescent sera. The affinities of both mAbs to wild type and Delta RBDs were in the same range as the polyclonal responses of the convalescents. Antibodies in a pooled, convalescent plasma from early 2020 retained nanomolar affinities to wild type, Delta and Omicron RBDs; however, the concentration of Omicron-specific antibodies decreased considerably. By contrast, the affinity of casirivimab to Omicron RBD decreased by factors >1000 and 600 compared with wild type and Delta RBDs, respectively. Imdevimab did not bind to Omicron at [≤]10 M. These results corroborate the finding that casirivimab and imdevimab do not prevent infection of cells by the Omicron variant.
ABSTRACT
OBJECTIVETo determine the seroprevalence of SARS-CoV-2 antibodies in employees of the Cantonal Police Bern, Switzerland; to investigate individual and work-related factors associated with seropositivity; and to assess the neutralizing capacity of the antibodies of seropositive study participants. DESIGNCross-sectional analysis of a cohort study. SETTINGWearing face masks was made mandatory for employees of the police during working hours at the rise of the second wave of the pandemic in mid-October 2020. Protests and police fieldwork provided a high exposure environment for SARS-CoV-2 infections. The investigation was performed prior to initiation of a vaccine programme. Study participants were invited for serological testing of SARS-CoV-2 and to complete questionnaires on sociodemographic, work and health-related questions. PARTICIPANTS978 police personnel working in four different geographic districts, representing 35% of the entire staff, participated from February to March 2021. MAIN OUTCOME MEASURESSeroprevalence of anti-SARS-CoV-2 antibodies in February to March 2021, geographic and work-related risk factors for seropositivity, and serum neutralization titres towards the wild-type SARS-CoV-2 spike protein (expressing D614G) and the alpha and beta variants. RESULTSSeroprevalence was 12.9% (126 of 978 employees). It varied by geographic region within the canton; ranged from 9% to 13% in three regions, including the city; and was 22% in Bernese Seeland/Jura. Working in the latter region was associated with higher odds for seropositivity (odds ratio 2.38, 95% confidence interval 1.28 to 4.44, P=0.006). Job roles with mainly office activity were associated with a lower risk of seropositivity (0.33, 0.14 to 0.77, P=0.010). Most seropositive employees (67.5%) reported having had coronavirus disease 2019 (COVID-19) 3 months or longer prior to serological testing, and the proportion of agreement between positive nasopharyngeal test results and seroconversion was 95% to 97%. Among reported symptoms, new loss of smell or taste was the best discriminator for seropositivity (odds ratio 52.4, 30.9 to 89.0, P<0.001). Compliance with mask wearing during working hours was 100%, and 45% of all seropositive versus 5% of all seronegative participants (P<0.001) reported having had contact with a proven COVID-19 case living in the same household. The level of serum antibody titres correlated well with neutralization capacity. Antibodies derived from natural SARS-CoV-2 infection effectively neutralized the SARS-CoV-2 spike protein (expressing D614G), but were less effective against the alpha and beta variants. A regression model demonstrated that anti-spike antibodies had higher odds for neutralization than did anti-nucleocapsid protein antibodies. CONCLUSIONSSeroprevalence in the pre-vaccinated police cohort was similar to that reported in the general population living in the same region. The high compliance with mask wearing and the low proportion of seroconversion after contact with a presumed or proven COVID-19 case during working hours imply that personal protective equipment is effective and that household contacts are the leading transmission venues. The level of serum antibody titres, in particular that of anti-spike antibodies, correlated well with neutralization capacity. Low antibody titres were not effective against the alpha and beta variants. SUMMARY BOXESO_ST_ABSWHAT IS ALREADY KNOWN ON THIS TOPICC_ST_ABSO_LIThe seroprevalence of anti-SARS-CoV-2 antibodies in the general population shows variations, depending on the geographic location of investigated study participants. C_LIO_LISocial distancing by avoiding crowds and maintaining a distance of 6 feet from others when in public are recommended. These recommendations are not realistic for security personnel and employees of a police department. C_LIO_LIPreventive strategies for individuals in a health care setting are warranted and effective to reduce potential exposures. The effect of preventive strategies on individuals working for the police force has not been investigated. C_LI WHAT THIS STUDY ADDSO_LIThe study suggests that the overall seroprevalence of anti-SARS-CoV-2 antibodies among police officers is not higher than that in the general population, despite presumed higher exposure (e.g., public protests). C_LIO_LICompliance with use of personal protective equipment among police officers was very high. The study results suggested that household contacts, rather than exposure during working hours, is the main source for viral transmission. C_LIO_LIAnti-SARS-CoV-2 antibodies derived from natural infection demonstrated good neutralization capacity towards strains that epidemiologically likely caused the infection, but moderate to poor neutralization capacity towards the alpha and beta variant. C_LI
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
Treatment and prevention of coronavirus disease 2019 (COVID-19) have attempted to harness the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including the development of successful COVID-19 vaccines and therapeutics (e.g., Remdesivir, convalescent plasma [CP]). Evidence that SARS-CoV-2 exists as quasispecies evolving locally suggests that immunological differences may exist that could impact the effectiveness of antibody-based treatments and vaccines. Regional variants of SARS-CoV-2 were reported in the USA beginning in November 2020 but were likely present earlier. There is available evidence that the effectiveness of CP obtained from donors infected with earlier strains in the pandemic may be reduced when tested for neutralization against newer SARS-Cov-2 variants. Using data from the Expanded Access Program to convalescent plasma, we used a gradient-boosting machine to identify predictors of 30-day morality and a series of regression models to estimate the relative risk of death at 30 days post-transfusion for those receiving near sourced plasma (defined as plasma transported [≤] 150 miles) vs. distantly sourced plasma (> 150 miles). Our results show a lower risk of death at 30 days post-transfusion for near sourced plasma. Additional analyses stratified by disease severity, time to treatment, and donor region further supported these findings. The results of this study suggest that near sourced plasma is superior to distantly sourced plasma, which has implications for interpreting the results of clinical studies and designing effective treatment of COVID-19 patients as additional local variant are likely to emerge.
Subject(s)
COVID-19 , Coronavirus Infections , DeathABSTRACT
Although neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of most COVID-19 vaccines and being developed as therapeutics, escape mutations could compromise such countermeasures. To define the immune-mediated mutational landscape in S protein, we used a VSV-eGFP-SARS-CoV-2-S chimeric virus and 19 neutralizing monoclonal antibodies (mAbs) against the receptor binding domain (RBD) to generate 48 escape mutants. These variants were mapped onto the RBD structure and evaluated for cross-resistance by convalescent human plasma. Although each mAb had unique resistance profiles, many shared residues within an epitope, as several variants were resistant to multiple mAbs. Remarkably, we identified mutants that escaped neutralization by convalescent human sera, suggesting that some humans induce a narrow repertoire of neutralizing antibodies. By comparing the antibody-mediated mutational landscape in S protein with sequence variation in circulating SARS-CoV-2 strains, we identified single amino acid substitutions that could attenuate neutralizing immune responses in some humans.
Subject(s)
COVID-19ABSTRACT
The current pandemic of the coronavirus disease-2019 (COVID-19) has badly affected our life during the year 2020. SARS-CoV-2 is the primary causative agent of the newly emerged pandemic. Natural flavonoids, Terpenoid and Thymoquinone are tested against different viral and host-cell protein targets. These natural compounds have a good history in treating Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). Molecular docking combined with cytotoxicity and plaque reduction assay is used to test the natural compounds against different viral (Spike, RdRp, and Mpro) and host-cell (TMPRSS II, keap 1, and ACE2) targets. The results demonstrate the binding possibility of the natural compounds (Thymol, Carvacrol, Hesperidine, and Thymoquinone) to the viral main protease (Mpro). Some of these natural compounds were approved to start clinical trail from Egypt Center for Research and Regenerative Medicine ECRRM IRB (Certificate No.IRB00012517)
Subject(s)
HIV Infections , Drug-Related Side Effects and Adverse Reactions , COVID-19 , Hepatitis CABSTRACT
Importance: Passive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain. Objective: To explore potential signals of efficacy of COVID-19 convalescent plasma. Design: Open-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma. Setting: Multicenter, including 2,807 acute care facilities in the US and territories. Participants: Adult participants enrolled and transfused under the purview of the US Convalescent Plasma EAP program between April 4 and July 4, 2020 who were hospitalized with (or at risk of) severe or life threatening acute COVID-19 respiratory syndrome. Intervention: Transfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. Convalescent plasma was donated by recently-recovered COVID-19 survivors, and the antibody levels in the units collected were unknown at the time of transfusion. Main Outcomes and Measures: Seven and thirty-day mortality. Results: The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the intensive care unit (ICU) and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% [95% CI 8.3%-9.2%] in patients transfused within 3 days of COVID-19 diagnosis but 11.9% [11.4%-12.2%] in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); for recipients of medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6% (10.3%, 13.1%); and for recipients of low IgG plasma (<4.62 S/Co) mortality was 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units. Conclusions and Relevance: The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma. Trial Registration: ClinicalTrials.gov Identifier: NCT04338360
Subject(s)
Critical Illness , Communicable Diseases , COVID-19 , Respiratory InsufficiencyABSTRACT
Antibody-based interventions against SARS-CoV-2 could limit morbidity, mortality, and possibly disrupt epidemic transmission. An anticipated correlate of such countermeasures is the level of neutralizing antibodies against the SARS-CoV-2 spike protein, yet there is no consensus as to which assay should be used for such measurements. Using an infectious molecular clone of vesicular stomatitis virus (VSV) that expresses eGFP as a marker of infection, we replaced the glycoprotein gene (G) with the spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and developed a high-throughput imaging-based neutralization assay at biosafety level 2. We also developed a focus reduction neutralization test with a clinical isolate of SARS-CoV-2 at biosafety level 3. We compared the neutralizing activities of monoclonal and polyclonal antibody preparations, as well as ACE2-Fc soluble decoy protein in both assays and find an exceptionally high degree of concordance. The two assays will help define correlates of protection for antibody-based countermeasures including therapeutic antibodies, immune {gamma}-globulin or plasma preparations, and vaccines against SARS-CoV-2. Replication-competent VSV-eGFP-SARS-CoV-2 provides a rapid assay for testing inhibitors of SARS-CoV-2 mediated entry that can be performed in 7.5 hours under reduced biosafety containment.