Efficacy and safety of three passive immunotherapies for Corona Virus Disease 2019：a system review and network meta-analysis

doi:10.21203/rs.3.rs-2118946/v1

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Efficacy and safety of three passive immunotherapies for Corona Virus Disease 2019：a system review and network meta-analysis

https://doi.org/10.21203/rs.3.rs-2118946/v1

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Background

Passive immunotherapies to augment the humoral immunity against virus have been associated with prevention of severe illnesses and reduction of mortality of patients with coronavirus disease 2019 (COVID-19). However, less is known about the comparative effectiveness of different types of passive immunotherapies. The aim of this study is to compare efficacy and safety of passive immunotherapy in patients with COVID-19.

Methods

This is a two-part network meta-analysis which evaluate the efficacy of passive immunotherapy in outpatients and hospitalized patients separately. Electronic databases, including PubMed, EMBASE, and Cochrane CENTRAL were systematically searched for articles published before 26th April 2022. Randomized clinical trials that compared COVID-19 specific antiviral antibodies, convalescence plasma and hyperimmune anti-COVID-19 Intravenous Immunoglobulin with placebo, or control plasma, or standard of care in patients with COVID-19 were included. Two authors screened the studies independently. We extracted data and assessed the risk of bias of studies using the revised Cochrane risk of bias tool (RoB 2 tool) at study level. The primary outcome for outpatients is hospitalization within 30 days from randomization and are mortality, need of invasive mechanical ventilation, and severe advent events for hospitalized patients.

Results

In this systematic review and network meta-analysis, data were pooled from 41 eligible randomized control trials involving 42298 participants. In the first part of network meta-analysis which is consist of 9 eligible trials with 10093 participants, compared with control, specific antiviral antibodies (odds ratio [OR]: 0.22, 95% CI: 0.16, 0.28) rather than CP (OR: 0.75, 95%CI: 0.56, 1.01) reduced the risk of hospitalization; treatment with antibody reduced a greater risk of hospitalization (OR: 0.29, 95%CI: 0.19, 0.43) when compared with CP. For the analysis of secondary outcome in outpatients, antibody (OR: 0.10, 95%CI: 0.01, 0.37) rather than CP (OR: 0.81, 95%CI: 0.23, 2.78) reduced the risk of mortality. In the second party of meta-analysis, none of the passive immunotherapy was associated with the reduction of mortality, need of invasive mechanical ventilation and severe adverse events. Furthermore, none of passive immunotherapy was associated with improvement in 6 secondary outcomes. However, in subgroup analysis, the administration of antibody was associated with improvement of mortality, need of invasive mechanical ventilation, rate of discharge, duration of hospital stay, time to death and with less adverse events.

Conclusions

In this network meta-analysis of clinical trials of patients with COVID-19, we found that treatment with antiviral antibodies reduced the risk of hospitalization in outpatients. Among hospitalized adult patients, all three passive immunotherapies compared with control did not result in a statistically significant improvement of the primary outcomes, but use of neutralizing antibodies may lead to improvement of primary outcomes and key secondary outcomes in seronegative patients. Further development of broader-spectrum antibodies targeting to highly conserved domain of spike protein which avoids immune escape of new variants are needed.

Passive immunotherapies

COVID-19

COVID-19-specific antiviral antibodies

Convalescence plasma

Hyperimmune anti-COVID-19 Intravenous Immunoglobulin

After two-plus years of circulating around the world, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) which is the causative virus for coronavirus disease 2019 (COVID-19) is still far from being optimally contained and remains a major threat for global health-care system. Although different kinds of COVID-19 vaccines with proved effectiveness have been authorized and massively injected in most of countries, vaccines shortage in underdeveloped countries due to the unbalanced distribution, the vaccine hesitancy, waned immunity after vaccination and keeping emerging of variants of concern have leaded to multiple waves of outbreak, a large number of patients needing hospitalization and death in the world. Globally, as of 15 July 2022, there have been over 550 million confirmed cases of COVID-19 and over 6 million deaths reported to WHO[1]. Due to the high morbidity and mortality in severe and critical case, development of the effective antiviral therapy to prevent the risk of hospitalization in patients with mild symptoms or reduce the mortality in hospitalized patients remains an important priority.

The antiviral drugs such as Remdesivir[2], Paxlovid[3] and Molnupiravir[4], which have been shown to decrease the time to recovery in hospitalized patients with Covid-19 or reduce the risk of hospitalization or death in nonhospitalized patients, have received FDA emergency use authorization and been recommended by WHO for patients with indication[5]. Limitations to their use include the availability, cost, very narrow time window of use and the potential for a relapse of symptoms with viral rebound in some patients after treatment[6]. Thus, additional effective therapies are urgently needed.

The long history of use of passive immunotherapies in infectious disease can tracked back 19th century when the serum therapy was used in diphtheria and tetanus[7]. Most prominent types of passive immunotherapies which provided antibodies to defend against infection by SARS-COV-2 fall under three major categories: convalescent plasma from recovered patients, SARS-CoV-2 intravenous immune globulin, and antibodies against to SARS-CoV-2. In the past, convalescent plasma which contain antiviral neutralizing antibodies has been evaluated in clinical trials and used wildly to treat a variety of infectious diseases, including severe acute respiratory syndrome[8], influenza[9], Ebola[10], and Middle East respiratory syndrome[11], as well as COVID-19 at the very beginning of the outbreak[12], with some degrees of success. However, the titers of antiviral neutralizing antibody may vary among donors which explained in some degree the inconsistent effectiveness of convalescent plasma on treatment of COVID-19[13]. In contrast, SARS-CoV-2 intravenous immune globulin is manufactured from pooled plasma derived from multiple donors who have recovered from COVID-19 and comprised of purified immunoglobulin G standardized to high neutralizing titers to SARS-CoV-2[14]. Meanwhile, with the development of technologies on single cell sequencing and antibody engineering, neutralizing monoclonal antibodies with high affinity to SARS-CoV-2 were identified and produced rapidly, which show to accelerate reduction in viral loads and reduce the illness of disease in animal models [15–20]. Moreover, since the onset of COVID-19 pandemic, passive immunotherapies to augment the humoral immune response to infection has been intensively studied in unprecedented scale for clinical evaluation in patients with COVID-19, but which one yields the best efficacy in treating patients of COVID-19 remain unknown.

Given that it is not pragmatic to perform direct (head-to-head) RCT comparisons among different kinds of passive immunotherapies, we here performed a two-part network meta-analysis of RCTs of passive immunotherapy in patients with COVID-19. The aim of first part of meta-analysis is to estimate efficacy of passive immunotherapy in published RCTs recruiting out-patients in terms of preventing risk of hospitalization. The second part of the study aimed to evaluate the safety and efficacy of passive immunotherapies on improving the outcomes of hospitalized patients with COVID-19, with mortality, need of invasive mechanical ventilation and severe adverse events as the predefined primary endpoints.

This meta-analysis was performed in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension statement for reporting network meta-analyses (PRISMA- NMA)[21]. The study was prospectively registered on PROSPERO database (Registration number: CRD42022311821).

Data Sources and Study Search

Electronic databases, including PubMed, EMBASE, and Cochrane CENTRAL, were searched from their inception until 26th April 2022. Reference lists of relevant articles were also reviewed. The search strategies combined terms for patients’ conditions and relevant interventions. Details were showed in supplementary materials (Supplementary materials: Appendix 1).

Eligibility criteria

We included randomized trials in people with suspected, probable, or confirmed COVID-19 that compared COVID-19-specific antiviral antibodies, convalescence plasma (CP) and hyperimmune anti-COVID-19 Intravenous Immunoglobulin (IVIG) against one another or against no intervention, control plasma, placebo, or standard of care (SOC). No restrictions were applied based on type of care or setting. We excluded non-randomized trials, randomized trials evaluating vaccines, pharmacologic drugs, and other interventions. Relevant trials without interested outcomes were also excluded.

Data extraction and quality assessment

This is a two-part meta-analysis and patients receiving relevant interventions were stratified into the two groups based on type of care facilities where they were treated: outpatients and hospitalized patients. We defined “Antibody” as all the COVID-19-specific antiviral antibodies including bamlanivimab, casirivimab-imdevimab, bamlanivimab-etesevimab, sotrovimab, XAV-19 polyclonal antibody, CT-P59 monoclonal antibody, INM005 polyclonal antibody and BRII-196 +BRII-198, and “Control” as all the co-interventions in individual trial including no intervention, control plasma, placebo, or SOC. The predefined outcomes included are as follows: The primary outcome for outpatients is hospitalization (time frame: up to 30 days from randomization) and for hospitalized patients are all-cause mortality (time frame: up to 30 days from randomization), need of invasive mechanical ventilation (excluding patients not receiving invasive mechanical ventilation at randomization, time frame: up to 30 days from randomization) and serious adverse events (time frame: up to 30 days from randomization). The secondary outcomes contained 1) all-cause mortality rate (time frame: up to 30 days from randomization ) in outpatients and 2) discharge (time frame: up to 30 days from randomization ), 3) length of hospital stay (time frame: up to 30 days from randomization ), 4) time to death (time frame: up to 28 days from randomization ), 5) time to virus clearance (defined as time to conversion to negative nasopharyngeal swab specimen based on RT-qPCR, time frame: up to 14 days), 6) virus clearance at 14 days (defined as conversion to negative nasopharyngeal swab specimen at 14 days based on RT-qPCR), 7) adverse events (time frame: up to 30 days from randomization )

Two authors (YZ and YRP) screened the studies on RCTs independently, extracted data, and assessed the risk of bias of studies using the revised Cochrane risk of bias tool (RoB 2 tool) at study level^[22], Discrepancies were resolved by consensus with a third author (YBC).

Data synthesis and analysis

A random effects network meta-analysis was performed using a Bayesian framework. We also calculated mean differences for continuous outcomes, odds ratios (ORs) for dichotomous outcomes and hazard ratio (HR) for time to event outcomes. Then we converted medians and interquartile ranges to means and standard deviations as previously described^[23] and If HRs were not reported, we extracted available data from the Kaplan-Meier curve (K-M curve) via an open-source Engauge Digitizer software version 12.1. The Engauge Digitizer digitizes image files containing graphs by placing points along axes and curves and recovers the data points from those graphs. Then, we reconstructed the necessary data through several established practical methods for meta-analysis^[24]^,^[25]. Network meta-analysis was performed using the “gemtc” package (version 0.8–2) implemented in R version 4.1.0. This package is based on an approach that follows the graph-theoretical methodology. Surface under the cumulative ranking (SUCRA) probabilities is the ratio of the area under the cumulative ranking curve to the entire area in the plot. SUCRA reports the overall probability, based on the ranking of all interventions that a given intervention is among the best treatments^[26]. We also used the “network” suite of STATA version 13.0^[27] to perform the network map to illustrate the distribution of the evidence between all intervention comparisons. The size of the nodes in the map was proportional to the number of patients who received this intervention in the network, and the width of the edges was proportional to the number of trials that compared the two interventions. Certainty of the evidence was assessed using CINeMA (Confidence in Network Meta-Analysis) web application, which allows for confidence in the results to be graded as high, moderate, low, and very low. This approach was based on a methodology developed by the Grading of Recommendations Assessment, Development and Evaluation Working Group for pairwise meta-analysis ^[28].

Subgroup analysis

For subgroup analysis, we extracted and analyzed data for all the outcomes based on their serostatus: seropositive and seronegative patients if the trials reported the relevant data. To explore in hospitalized patients with primary outcomes whether the time of infusion is relative to the efficacy of treatments, we also divided data to two groups for subsequence analyze based on whether the infusion within 5 days since symptom onset. Unfortunately, only data in which treatments infused latter than 5 days since symptom onset with all-cause mortality rate is sufficient to perform analyses.

The description of included RCTs

Figure 1 shows the selection process for included studies. As of 26th April 2022, A total 57981 citations were identified through literature search in three databases including PubMed, Embase and CENTRAL, among of which 491 full-text articles were assessed for eligibility. Finally, 41 RCTs involving 42298 patients with COVID-19 were included in this meta-analysis, including 9 enrolling outpatients and 32 enrolling hospitalized patients (Supplementary materials: Appendix 2). Among these included RCTs, 12 of 41 studies evaluated efficacy of anti-virus antibody, 27 for CP, 2 for IVIG. The assessment of risk of bias for each included study was presented in supplementary materials (Supplementary materials: Appendix 3) Generally, most of included trials were proved at lower risk in overall bias.

Efficacy of passive immunotherapies in outpatients

In the first part of the study, we evaluated the efficacy of antibodies and CP (there is no trials evaluating IVIG) in outpatients with hospitalization within 30 days after randomization as primary outcome and mortality within 30 days after randomization as secondary outcome. Of 9 eligible trials with 10093 participants reporting hospitalization within 30 days, 6 trials were for Antibody and 3 for CP. Compared with the Control group, patients who randomized to Antibody (odds ratio (OR): 0.22, 95%CI: 0.16, 0.28) but not CP (OR: 0.75, 95%CI: 0.56, 1.01) had a lower risk of hospitalization (Fig. 2). Furthermore, when compared with CP, treatment with Antibody reduced a greater risk of hospitalization (OR: 0.29, 95%CI: 0.19, 0.43) (Fig. 2). Results from ranking analysis also showed Antibody treatment ranked the first in reducing the risk of hospitalization, followed by CP and the Control (Fig. 3). Regarding the secondary outcome analysis, of 7 eligible trials with 8870 participants reported data about mortality (4 trials were for Antibody, and 3 for CP). Antibody (OR: 0.10, 95%CI: 0.01, 0.37) rather than CP (OR: 0.81, 95%CI: 0.23, 2.78) reduced a greater risk of mortality (Supplementary materials: Appendix 4. Fig. 4.1.1) and Antibody ranked the best (Supplementary materials: Appendix 4. Fig. 4.1.2).

Effects of three immunotherapies in hospitalized patients

In the second part of the studies, we evaluated the association of three immunotherapies with three primary outcomes including mortality, need of invasive machinal ventilation and serious adverse events in hospitalized COVID-19 patients.

Mortality—Across the 28 eligible trials with 30512 participants reporting valid data on mortality (5 trials were for Antibody, 2 for IVIG and 21 for CP), results from Network Meta-Analysis revealed there is no difference between any interventions (Antibody, OR: 0.92, 95% CI: 0.83, 1.01, IVIG, OR 0.62, 95% CI: 0.34, 1.12, CP, OR: 0.98, 95%CI: 0.91, 1.05) and Control in reducing the morality, as well as among all the interventions (Fig. 4A). In the subgroup analysis, similar results were found in seropositive participants (Fig. 4A), and none of interventions ranked better than Control (Fig. 5A). However, in seronegative participants, treatment with Antibody (OR: 0.74, 95%CI: 0.63, 0.87) was significantly associated with lower mortality and ranked the best (Fig. 5A).

Need of invasive mechanical ventilation— Of 14 eligible trials with 20851 participants reporting need of invasive mechanical ventilation (2 trials were for Antibody and 12 for CP), although no intervention was found to lead to a significant reduction in mechanical ventilation use in all participants (Fig. 4B), Antibody and CP appeared to be associated with greater benefit in reducing need of ventilation support than Control according to SUCRA (Fig. 5B). In subgroup analysis, in contrast with seropositive participants, Antibody treatment ranked the best (Fig. 5B) and reduced the risk of invasive mechanical ventilation (OR: 0.65, 95%CI: 0.49, 0.87) (Fig. 4B) in seronegative participants.

Serious adverse events— Of 12 eligible trials with 4314 participants reporting serious adverse events, (3 trials were for Antibody, 1 for IVIG and 8 for CP). participants who were subject to any interventions did not suffer from more serious adverse events than participants randomized to Control group in all the population (Fig. 4C).

Efficacy of passive immunotherapies on secondary outcome in hospitalized COVID-19 patients

Discharge— Of 15 eligible trials with 25031 participants reporting discharge data (4 trials were for Antibody, 2 for IVIG and 9 for CP), although SUCRA ranking showed the superiority of IVIG, followed by Antibody and CP (Supplementary materials: Appendix 4. Fig. 4.2.1 A), none of which proved to increase chance of discharge with 30 days. However, in seropositive participants, Antibody seemed to be the worst in improving discharge rate (data from 1 trial for Antibody and 2 trials for CP with a total of 12087 patients) and the best in seronegative participants (a total number of 6555 patients from the same trials). On the contrary, Antibody (OR: 1.33, 95% CI: 1.14, 1.55) significantly improved rate of discharge in seronegative participants (Supplementary materials: Appendix 4. Fig. 4.2.1 A).

Length of hospital stay— Of 12 eligible trials with 11805 participants reporting length of hospital stay (3 trials were for Antibody and 9 for CP), no intervention including Antibody (mean difference: −0.21 days (95% CI: −2.66,2.27)) and CP (mean difference: 0.12 days (95% CI: −1.32,1.67)) reduced length of hospital stay (Supplementary materials: Appendix 4. Fig. 4.2.1 B). SUCRA showed Antibody was most likely associated with the reduction of the duration of hospitalization (Supplementary materials: Appendix 4. Fig. 4.2.2 B).

Time to death— Of 20 eligible trials with 28191 participants reporting time-to- death outcomes (4 trials were for Antibody, 1 for IVIG and 15 for CP in all participants), no intervention was found to affect time to death in all participants as well as in seropositive participants (Supplementary materials: Appendix 4. Fig. 4.2.1 C). Nevertheless, in seronegative participants, Antibody (hazard ratio (HR): 0.78, 95% CI: 0.68, 0.9) improved time to survival compared with Control (Supplementary materials: Appendix 4. Fig. 4.2.1 C). Results from SUCRA showed the opposite trend in seropositive and seronegative participants, in which Antibody ranked the worst and best, respectively (Supplementary materials: Appendix 4. Fig. 4.2.2 C).

Time to virus clearance— Of 4 eligible trials with 911 participants reporting time to virus clearance (1 trial were for Antibody and 3 for CP), neither Antibody (hazard ratio (HR): 1.19, 95% CI: 0.77, 1.82) or CP (hazard ratio (HR): 1.14, 95% CI: 0.93, 1.41) was found to affect time to virus clearance (Supplementary materials: Appendix 4. Fig. 4.2.1 D). However, these two interventions appeared greater than Control for speeding up virus clearance (Supplementary materials: Appendix 4. Fig. 4.2.2 D).

Virus clearance at 14 days— Of 2 eligible trials with 319 participants reporting virus clearance at 14 days (1 trial were for Antibody and 1 for CP in all participants), none of the interventions appeared to increase viral clearance at 14 days: Antibody (OR: 1.31, 95%CI: 0.64, 2.69); CP (OR: 0.84, 95%CI: 0.38, 1.82) (Supplementary materials: Appendix 4. Fig. 4.2.1 E).

Adverse events— Of 13 eligible trials with 4850 participants reporting adverse events (3 trials were for Antibody, 2 for IVIG and 8 for CP), treatment with Antibody did not increase the incidence of adverse events, while patients treated with IVIG (OR: 1.56, 95%CI: 1.06, 2.32) or CP (OR: 1.33, 95%CI: 1.11, 1.59) suffer more adverse events (Supplementary materials: Appendix 4. Fig. 4.2.1 F).

The funnel plot and Egger’s test did not detect any significant publication bias in any outcomes (Supplementary materials: Appendix 5). Details about certainty assessment of all the results were showed in supplementary materials (Supplementary materials: Appendix 6)

Passive immunotherapies to augment the patient’s humoral immunity to combat with the virus are crucial for the management of COVID-19 and have been thoroughly studied during the era of COVID-19 pandemic. However, to our best knowledge, there was lacking in evaluating the comparative effect and safety of passive immunotherapies for COVID-19 infection. This meta-analysis is based on 41 RCTs which included 42298 patients randomly assigned to 3 types of immunotherapies, no intervention, control plasma, SOC or placebo. We found that antibodies treatment prevented the risk of hospitalization and reduced the mortality in outpatients. For hospitalized patients, none of three immunotherapies improve the primary outcomes including mortality, need of mechanical ventilation and secondary outcomes including discharge, length of hospital stay, time-to-death event, and two virologic outcomes. Nevertheless, antibody treatment may outperform than other CP, IVIG and Control in seronegative participants in several key outcomes which imply the need for further identification of population who might be benefit from this therapy modality.

The results of CP in our studies are in consistent with conclusions of previous publications. Although administration of CP with high titer of neutralizing antibodies may associate with improve survival in retrospective study, it fail to show benefits in survival or clinical status of patients in several large RCTs[29-34] and meta-analysis[35-38]. Thus, WHO and majority of treatment guidelines of COVID-19 recommend against the use of convalescent plasma for COVID-19[39], specifically for those who required hospitalization. Nevertheless, our results showed that CP was associated with a lower risk of hospitalization in outpatients though no statistically significance was achieved, which indicates that treatment with convalescent plasma may still play a role if it is administered in those who are highly risky for disease progressing to severe form in early stage of the disease course.

IVIG is extracted from the plasma of convalescent patients so that the titer of antibody may be higher than that of plasma. It is also possible that in IVIG, the neutralizing capability of antibodies is low as the half-life may be short, and it may not be effective against a mutant variant. However, IVIG may theologically have a protective effect on patient with congenital immunoglobulin deficiency who infected with COVID-19. To the current stage, there are few studies on IVIG and lack of studies on specificity for SARS-CoV-2[14, 40].

Clinical trials of neutralizing antibodies have shown that it can reduce the hospitalization rate of non-critically ill patients. However, the ACTIV-3 study showed that neutralizing antibodies did not improve the outcome of hospitalized patients in the score of respiratory function at 5 days or clinical recovery at 90 days[41]. Our research also shows that antibodies did not lead to improvement of primary outcomes and secondary outcomes in overall hospitalized patients but may be beneficial for seronegative patients. Judging from the disease progression of COVID-19 patients, the emerge of neutralizing antibodies in vivo usually occurs about a week after infection, while the virus replicates rapidly in the patients with strong transmission, and patients may develop to a severe status in about 10-14 days with persist worsening lung function. Therefore, the early admiration of neutralizing antibodies may inhibit the proliferation of the virus and prevent lung damage. Our study suggests that the use of neutralizing antibodies early after infection in high-risk groups provides effective protection and may reduce the risk of hospitalization, severe cases and mortality. One of the limitations of monoclonal antibodies is that they are susceptible to the evolution of viral resistance if substitutions in the targeted epitope reduce or abrogate antibody binding. Yet, despite the success of antibodies, the last dominant of omicron variant of SARS-CoV-2 evade almost all available monoclonal antibody–based drugs. Therefore, when considering the evolving information and evidence, the FDA revoked the emergency use authorization for monoclonal antibody bamlanivimab due to resistance in circulating virus variants[42] and limited the use of two monoclonal antibodies treatments - combination use of bamlanivimab and etesevimab and REGEN-COV (casirivimab and imdevimab) – only to the patients who is likely to have been infected with a variant susceptible to these treatments[43].

We also found that studies have shown that patients with positive SARS-CoV-2 antibodies may not benefit from the treatment of antibody. Theoretically, infusion of antibody may cause antibody-dependent enhancement effect. Reassuringly, there is no clear evidence for the ADE of antibodies treatment at present but need to be further clarified by clinical and basic research. The emerge of autoantibodies may indicate that patients are in the late course of disease when the inflammatory damage is dominated. In this stage, only the immune-modulation therapies such as corticosteroids and IL-6 receptors antagonist may improve the outcome of patients. Taken together, we recommend that the antibodies treatment should be administered in COVID-19 patients before the appearance of autologous antibodies.

Our study has several limitations. First, only two trials evaluating IVIG in hospitalized patient, it is far away to make a definite conclusion of IVIG for patients with COVID-19, especially for outpatients. Second, this is not an individual patient data meta-analysis, so we are not able to further stratify the patient into interested subgroups i.e., those are at older age, unvaccinated, received treatment in early stage of disease, to identify the sub-populations who may most likely benefit from the treatment. Thirdly, heterogeneity exits among three intervention groups as well as in the control group. Fourth, since almost of trials included have been finished before the of omicron variants, we could not generalize our finding to the patients who infected with omicron variants. Nevertheless, our study shows the signal that antibodies which is capable to inhibit the omicron, or its sub-lineage may still a promised option for COVID-19 patients. Finally, some trials use the ordinal scale of severity of patient as primary outcome; however, due to the technical issue, we did not analyze this outcome in this study.

In this network meta-analysis, we found that treatment with antiviral antibodies reduced the risk of hospitalization in outpatients with COVID-19. Among hospitalized adult patients with COVID-19, all three passive immunotherapies compared with control did not result in a statistically significant improvement of the primary outcomes i.e., mortality and the key secondary outcomes, but use of antibodies may lead to improvement of primary outcomes and key secondary outcomes in seronegative patients. Reassuringly, frequency of serious adverse events did not differ between each treatment group with control group and the safety of antibody might be inferior to other treatment interventions for the therapy of hospitalized COVID-19 patients in terms of adverse events. The observed benefits of antibodies highlight the ongoing need for further development of broader-spectrum antibodies targeting to highly conserved domain of spike protein which avoids immune escape of new variants.

CP, Convalescence plasma; IVIG, Hyperimmune anti-COVID-19 Intravenous Immunoglobulin, SOC: Standard of care

Competing interests

There are no competing interests.

Author contributions

YX and XL conceived the study idea. YX, YH and XL coordinated the systematic review. YC and ZL designed the search strategy. YC and ZL screened abstracts and full texts. Y Zeng and YP acquired the data and judged risk of bias in the studies. YC, Y Zeng and YP verified the data and performed the analyses. YC created the GRADE evidence profiles. YX, JZ, Y Zhang, YM Li, XY, YC Li, YH and XL interpreted the data. All authors co-wrote and revised the manuscript for intellectual content. All authors provided their final approval for manuscript submission

Acknowledgments

None

Ethics approval and consent to participate

The study did not require ethical approval given that the data were extracted from published articles, with no direct patient contact or use of patient health information.

Consent for publication

Not applicable.

Availability of data and materials

Available upon request.

Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81870069, 81970071 and 82070084), Project of Guangdong Science and Technology Department (Nos. 2020B1111340013 and 2020B1111340017), the National Key Plan for Scientific Research and Development of China (2021YFC0864500), Emergency Key Program of Guangzhou Laboratory (No. EKPG21-29) and The Science and Technology Program of Guangzhou, China (Nos. 202201020444 and 202102010366).The funding sources were not involved in study design; collection, analysis, and interpretation of data; or writing of the manuscript.

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Coronavirus (COVID-19) Update: FDA Revokes Emergency Use Authorization for Monoclonal Antibody Bamlanivimab [https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-monoclonal-antibody-bamlanivimab]
Coronavirus (COVID-19) Update: FDA Limits Use of Certain Monoclonal Antibodies to Treat COVID-19 Due to the Omicron Variant [https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-limits-use-certain-monoclonal-antibodies-treat-covid-19-due-omicron]

No competing interests reported.

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Efficacy and safety of three passive immunotherapies for Corona Virus Disease 2019：a system review and network meta-analysis

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