Bamlanivimab improves hospitalization and mortality rates in patients with COVID-19: A systematic review and meta-analysis.

Dear editor,

The coronavirus disease 2019 (COVID-19) pandemic has spread globally and poses a serious threat to the world. As of August 9, 2021, there were over 200 million COVID-19 cases and 4 million deaths. The clinical manifestations of COVID-19 range from mild to severe, the incidence of illness and mortality is high in some vulnerable subgroup of patients. Until now, treatment option for patients to prevent progression to severe COVID-19 is limited. Although, vaccination is considered as an effective method to stop the spread of the COVID-19 pandemic, the newly emerged SARS-CoV-2 variants have led to breakthrough infections after completion of vaccination regimen.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attaches to host cells by binding its spike protein to angiotensin-converting enzyme 2 (ACE2) receptors on target cells. Bamlanivimab (also knowns as LY-CoV555 or LY3819253), a recombinant human IgG1 monoclonal antibody, binds to the receptor binding domain of the spike protein of SARS-CoV-2 and blocks viral entry into host cells. Bamlanivimab(BAM) was granted emergency use authorization by the Food and Drug Administration (FDA) in November 2020. Currently, there were a few studies that evaluated the effect of BAM on clinical outcomes in patients with mild-to-moderate COVID-19. Thus, we aim to perform a systematic review and meta-analysis of the available evidence to investigate the efficacy of BAM in COVID‐19.

An electronic search of the PubMed, Embase, and Cochrane Library databases was conducted from December 1 2019, to August 9 2021, with no language restrictions. The following key words and/or medical subject heading terms searched were used: (“COVID-19″ or “novel coronavirus” or “2019-nCoV” or “coronavirus disease 2019″ or “SARS-CoV-2″) AND (“Bamlanivimab” or “LY3819253” or “LY-CoV555”). A manual search of possible articles that were relevant to the topic were carried out. “PROSPERO (International Prospective Register of Systematic Reviews) database” registration was done with study number as CRD42021274064.

The inclusion criteria in our meta-analysis were as follows: (1) Patients with confirmed COVID-19; (2) reported information of comparison of clinical outcomes between BAM treatment (administered alone) and various control groups (no treatment, usual care according to the hospital guidelines, NIH guidelines). Studies were excluded if they were (1) case reports, conference abstracts, non-clinical studies, editorials and reviews; and (2) duplicated publications. All data from studies were extracted by independent investigators (GA and YW) onto prespecified. Any discrepancies were resolved through discussion in group conference. We also extracted baseline information of name of the first author, study design, country, the participants, number of participants, demographics data (mean/median age, male gender), dose of Bamlanivimab used, outcomes (mortality, hospitalizations, deterioration and progression to the complications). The quality of randomized controlled studies (RCTs) was evaluated using the Jadad scale. The quality of observational studies was assessed using a nine-item Newcastle-Ottawa Quality scale. High-quality studies were defined as a study with a Jadad score of ≥ 2 (maximum, 5), or a modified Newcastle-Ottawa score (NOS) of ≥ 6 (maximum, 9).

The analysis was done using Review Manager and Stata software version 15.1. Reported odd ratios (ORs) and 95% CIs were extracted from each study. We selected OR as an effect estimate. The heterogeneity of outcomes was calculated using Cochran's Q test and the I2 statistic. The I2 value of 25%, 50%, and 75% represented low, moderate, and high degrees of heterogeneity, respectively. If I2 ≤ 50%, the meta-analysis was performed using the fixed effect model (Mantel-Haenszel). If I2 > 50%, the random-effect model (DerSimonian and Laird) was preferred. Sensitivity or subgroup analyses were performed to identify potential sources of heterogeneity. Sensitivity analysis was performed to evaluate the stability of the results by sequentially omitting one study at a time. P < 0.05 was considered to be statistically significant.

The search strategy yielded 263 potentially eligible literatures. Among them, 47 literatures were excluded due to duplicated searches. 168 studies were subsequently screened and regarded as absolute irrelevant studies by examining titles and abstracts. 48 studies were identified for full-text review and 40 studies were excluded because they had no comparison groups between Bamlanivimab treatment and control or outcomes were not available. A total of 8 studies – comprising of 13,573 adult patients with COVID-19, including 4191 in the BAM (administered alone) and 9382 in the control group arm, were included in this meta-analysis.

The study characteristics of the included RCT, cohort studies and case-controls are shown in Table 1 . All studies were from America. Four studies were retrospective cohort, two studies were case-control and only one study was RCT. Most studies included mild to moderate COVID-19 nonhospitalized patient and used a dosage of 700 to 7000 mg infusion of Bamlanivimab. All of the eligible studies were published in 2021 with different sample patient sizes that ranged from 46 to 6117 patients with COVID-19. The details of quality assessment are presented in the Supplemental Tables 1 and 2. All studies included in our meta-analysis were considered as high quality (RCT with a Jadad score of ≥ 2 and observational studies with a modified NOS score of ≥ 6).

Table 1

Characteristics of included studies.

Study	Country	Study design	Study population	Definition of severity used	Dose of bamlanivimab	Sample size	Bamlanivimab group		Control group
							Age	Male (%)	Age	Male (%)
Alam4	America	Case-control	Mild-to-moderate COVID-19 in nursing homes and long-term care facilitie	Requiring mechanical ventilation	700 mg	246	81.42 ± 0.68	82 (51.2)	84.42 ± 0.89	35 (40.7)
Bariola5	America	Retrospective cohort	Mild to moderate COVID-19 nonhospitalized patient	NR	700 mg	1392	67.3 ± 13	108 (46.6)	67.1 ± 13.4	510 (44)
Corwin6	America	Retrospective cohort	Outpatients with mild to moderate COVID-19	NR	700 mg	6117	62.6 ± 15.6	352 (45.1)	56.7 ± 2.0	2309 (43.3)
Destache7	America	Retrospective cohort	Mild to moderate COVID-19 nonhospitalized patient	NR	NR	234	72 (65–80)	55 (47.0)	72 (65–80)	55 (47.0)
Ganesh8	America	Retrospective cohort	Mild to moderate COVID-19 do not hospitalize	ICU admissions	Single-dose bamlanivimab infusion	4670	63 (52,71)	1183 (50.7)	63(52,72)	1181 (50.6)
Gottlieb9	America	RCT	Mild-to-moderate COVID-19 nonhospitalized patient	NR	700 mg, 2800 mg, 7000 mg	465	39 (31–58)	38 (37.6)	46 (35–57)	71 (45.5)
Karr10	America	Retrospective cohort	Mild-to-moderate COVID-19 nonhospitalized patient	NR	700 mg	46	69	26 (65)	69	3 (50)
Kumar11	America	Case-control	Inpatient and outpatient	ICU admissions	700 mg	403	66 (57–74)	115 (52.8)	62 (50–72)	95 (51.4)

RCT: randomized controlled study; ICU: intensive care unit; NR: not reported.

The meta-analysis showed the overall mortality was lower in the BAM group compared to control group (OR = 0.27, 95%CI: 0.15, 0.49, P < 0.0001, I2 = 0%) (Fig. 1A ). Moreover, BAM treatment were associated with lower risk of hospitalization (OR = 0.60, 95%CI: 0.49 to 0.73, P < 0.00001; I2 = 31%) (Fig. 1B) and developing severe COVID-19 disease (OR = 0.43, 95%CI: 0.23 to 0.81, P = 0.008; I2 = 0%) (Fig. 1C). Pooled analysis of adjusted results revealed that BAM group had a lower risk of mortality (OR = 0.49, 95%CI: 0.27 to 0.89, P = 0.019; I2 = 0%) (Fig. 1D) and hospitalization compared with control group (OR = 0.55, 95%CI: 0.44 to 0.67, P < 0.001; I2 = 0%) (Fig. 1E). In addition, sensitivity analyses by excluding each study at a time did not significantly alter the overall results.

Figure. 1A

Association between Bamlanivimab treatment and mortality

Figure. 1B Association between Bamlanivimab treatment and hospitalization

Figure. 1C Association between Bamlanivimab treatment and developing severe COVID-19

Figure. 1D Pooled analysis of adjusted results of association between Bamlanivimab treatment and mortality

Figure. 1E Pooled analysis of adjusted results of association between Bamlanivimab treatment and hospitalization

COVID-19 remains a public health emergency. Although people have taken many measures to control the virus, the treatment of COVID-19 remains a challenge. Until now, vaccines are still the primary option for COVID-19 prevention. Unlike vaccine-derived immunity that develops over time, the use of neutralizing monoclonal antibodies is an immediate and passive immunotherapy. In the current meta-analysis, our results demonstrated that patients received BAM treatment had a better outcome in hospitalization and mortality. With limited therapeutic options for COVID-19, BAM provide an effective treatment option.

Prevention of hospitalization is an important part of COVID-19 management. High patient volumes in the hospital from COVID-19 strain medical resources and supplies. The shortage of personal protective equipment and air isolation wards will bring greater risks to health care workers. As for mild-to-moderate COVID-19, treatments administered in outpatient is a more reasonable approach to preserver hospital supplies and reduce overcrowding. Our study affirmed the efficacy of BAM in the treatment of mild-to-moderate COVID-19, which was consistent with previous clinical trials (BLAZE-1 and −2). , Before monoclonal antibodies treatment, there was no strategies to reduce the rates of hospitalization or death in outpatients with COVID-19.

SARS-CoV-2 infection is mediated by the interaction between the viral spike and the ACE2 receptors. BAM can specifically block this event. With the evolution of SARS-CoV-2 spike protein, the effect of monoclonal antibody therapy may be affected. Due to the evolution of SARS-CoV-2 variants, the emergency use authorization (EUA) for Bamlanivimab monotherapy was rescinded by the FDA on April 16, 2021. Another dual monoclonal antibody treatment, Bamlanivimab plus Etesevimab remains in place. Despite this, the results of this study indicated that treatment with neutralizing antibody was an effective way to mitigate the current COVID-19 pandemic.

Several limitations of our study should be noted. Most of the studies included were retrospective in design and had relatively small sample size, which were subject to potential confounders that may weaken the overall results. Moreover, all studies were conducted in America, which may not provide sufficient statistical power to explore accurate correlations. Furthermore, lack of data of individual patient, it is uncertain which patients will benefit most when treated with BAM. Therefore, large clinical RCTs are needed to overcome these limitations Despite these limitations, there were advantages of our meta-analysis. First, to our best knowledge, this is the first meta-analysis assess the clinical impact of Bamlanivimab monoclonal antibody monotherapy on mortality and disease severity in patients with COVID-19. In addition, the heterogeneity across the studies was low, which enhances the reliability of our results.

In conclusion, our meta-analysis provide evidence that BAM is effective in the treatment in COVID-19 patients. There is an urgent need for well-designed randomized trials to determine the effectiveness and safety of BAM in severe COVID-19.