Efficacy and Safety of Anti-SARS-CoV-2 Monoclonal Antibodies: An Updated Review

Abstract

Monoclonal antibodies (mAbs) had received emergency use authorization for mild-to-moderate coronavirus disease 2019 (COVID-19) or for prophylaxis against COVID-19, including casirivimab plus imdevimab (C+I), bamlanivimab plus etesevimab (B+E), tixagevimab plus cilgavimab (T+CG), and sotrovimab (S) and bebtelovimab (BEB). This systematic review was done to assess the efficacy and safety of the same. PubMed, Embase, Scopus, medRxiv, bioRxiv, and FDA fact sheets were searched for the studies published between January 2021 and May 2022, and appropriate search terms related to the mentioned mAbs were used for data collection. Review included original research including randomized clinical trials and observational studies published or preprints. Studies included in the review had compared with placebo or standard of care or no treatment or mAbs with each other and also of various doses. Data extraction was done and reviewed the same for both efficacy and safety. Total of 20 studies were included in this review. The rate of hospitalization within 30 days showed ∼2% in comparison to ∼7% with placebo. Significant reduction in viral load was more observed with combination mAbs. Combination therapy showed faster virological cure against the Gamma variant. With C + I as postexposure prophylaxis (PEP), 29.0% of asymptomatic participants developed symptomatic COVID-19. Pre-exposure prophylaxis with T+CG reduced the incidence of infection by 77%. Infusion-related reaction was the most common adverse event (AE). The neutralizing mAbs reduced hospitalization in mild-to-moderate patients with infusion-related reactions as common AE. The response was better in the seronegative patients. Most of these studies were conducted in unvaccinated individuals and against Alpha, Gamma, and Delta variants.

Introduction and Background

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been an ongoing pandemic, having its impact on global health care system causing significant mortality with its emerging variants. Once a person gets infected with this virus, based on the immune system's capacity to fight against the same, some patients will experience dysregulated host immune response, overexpression of inflammatory markers leading to wide range of clinical manifestations ranging from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome (ARDS), which may further lead to respiratory compromise and death.^1,2

Antiviral drugs such as remdesivir, approved drug by the U.S. FDA, though initially believed to be effective in treating mild-to-moderate COVID-19, was later found to be of not much use.^3,4

Mild COVID-19 patients are usually managed at home (nonhospitalized) with symptomatic treatment. Patients with risk factors such as older age (≥65 years), obesity, pregnancy, chronic kidney disease, diabetes, immune compromised/on immunosuppressive treatment, cardiovascular disease or hypertension, chronic lung diseases, and neurodevelopmental disorders are more prone to develop severe disease. Remdesivir is the first antiviral drug approved by the U.S. FDA for hospitalized COVID-19 patients that is available as injectable preparation.

Later molnupiravir and nirmatrelvir plus ritonavir oral antiviral agents received emergency use authorization (EUA) by the U.S. FDA for mild-to-moderate COVID-19 patients who are at high risk for severe disease.^5,6 These drugs have to be used within 5 days of symptom onset.

The U.S. FDA has also given EUA for monoclonal antibodies (mAbs) such as casirivimab plus imdevimab (C+I) combination, bamlanivimab plus etesevimab (B+E) combination, sotrovimab (S), and bebtelovimab (BEB) for the treatment of mild-to-moderate COVID-19 in adult and pediatric patients >12 years of age who are at high risk for progression to severe COVID-19, including hospitalization or death. The C + I combination and B + E combination also received EUA for post-exposure prophylaxis (PEP).^7–10

Tixagevimab–cilgavimab (AZD7442; T+CG) has received EUA for pre-exposure prophylaxis (PrEP) in adults and pediatric patients ≥12 years who are not currently infected with SARS-CoV-2 and immunocompromised individuals who may not mount an adequate response to COVID-19 vaccination, and for individuals for whom COVID-19 vaccination is not recommended due to a history of a severe adverse reaction.¹¹

For the prevention of COVID-19 infection, vaccination may help. The difference between vaccines and mAbs is the efficacy. Vaccines will give protection for longer period whereas mAbs protection will be of shorter duration. Nevertheless, the mAbs will be useful as immediate option for prevention of COVID-19 infection in high-risk individuals.

All these neutralizing mAbs have a similar mechanism of action where they prevent binding of virus to the angiotensin converting enzyme 2 (ACE2), thereby preventing the entry into human cells and thus neutralizing the virus (Fig. 1).^9–14 Most of the mAbs receiving EUA are the combination of two mAbs. This combination of mAbs has been given approval to reduce escape mutation and to show more effectiveness. The pharmacokinetic parameters, the activity of mAbs against various SARS-CoV-2 variants, dose, and other details are given in Table 1.

FIG. 1.

Mechanism of action of anti-SARS-CoV-2 mAbs. All these neutralizing mAbs have a similar mechanism of action, where they act as neutralizing antibodies by binding to the RBD of the viral spike protein and inhibit the attachment of the virus to human ACE2, but with different binding affinities. They bind to either overlapping or nonoverlapping epitopes on RBD, prevent virus binding to the ACE2, thereby preventing the entry into human cells and thus neutralizing the virus. Sotrovimab, tixagevimab–cilgavimab bind in a region of the RBD that does not overlap with the ACE2 binding site and others will bind to overlapping site. The bind site for bebletovimab was not reported in the literature.^9–14 ACE2, angiotensin converting enzyme 2; mAb, monoclonal antibody; RBD, receptor binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Table 1.

Pharmacokinetics and Pharmacodynamics of Anti-SARS-CoV-2 Monoclonal Antibodies for COVID-19

	Casirivimab plus imdevimab	Bamlanivimab plus etesevimab	Sotrovimab	Bebtelovimab	Tixagevimab–cilgavimab
Alternative terms	Antibody cocktail drug/REGEN-COV, REGN10933 (casirivimab), REGN10987 (imdevimab)	Bamlanivimab (LY-CoV555) Etesevimab (LY-CoV016)	GSK-4182136; VIR-7831; WBP 2275; Xevudy	LY-CoV1404, 1404	EVUSHELD
Antibody type	IgG1 mAbs with unmodified Fc regions	Bamlanivimab: IgG1-kappa mAb with unmodified Fc region Etesevimab: IgG1-lambda mAb with a modified Fc region	IgG1-kappa mAb with a modified Fc region	IgG1-lamba mAb with unmodified Fc region	Recombinant human IgG1κ mAbs with amino acid substitutions
Target site	Nonoverlapping epitopes on the RBD	Overlapping epitopes in RBD	Non-overlapping epitopes on RBD	NA	Blocks RBD in turn inhibits binding to human ACE2
Dissociation constant (Kd)	45.8 and 46.7 pM	0.071 and 6.45 nM	0.21 nM	0.046–0.075 nM	Of Kd = 2.76 pM
Route of administration	IV/S.C.	IV infusion	IV infusion	IV infusion	IM, as two separate consecutive injections
Dose	600 + 600 mg	700 + 1400 mg	500 mg	175 mg	300 + 300 mg
Terminal half-life	NA	BAM: 20.9 days ETE: 32.6 days	≈49 Days	11.5 Days	T: 87.9 days Cil: 82.9 days
Effect of covariates^a	Unknown	Nil	Unknown	Nil	Nil
Effect of renal impairment on PK	Nil	Nil	Nil^b	Nil	Nil
Effect of mild hepatic impairment	Unknown	Nil^c	Unknown	Nil^c	Nil
Geriatric use (˃65 years)	Effect on PK unknown	No effect on PK	Effect on PK unknown	No effect on PK	Nil
Use in pediatric population (<12 years and <40 kg	Not authorized	Recommended with dose adjustment as per body weight	Not authorized	Not authorized	Not authorized
Approval status	EUA—U.S. FDA DCGI—restricted emergency use	EUA—U.S. FDA DCGI—restricted emergency use	EUA—US FDA	EUA—US FDA	EUA—US FDA
Activity against variants	Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) variants	Alpha (B.1.1.7), reduced susceptibility to Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) variants	Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Epsilon (B.1.427/B.1.429), Iota (B.1.526), Kappa (B.1.617.1), Delta (B.1.617.2), Lambda (C.37). Delta Plus (AY.1/AY.2), Mu (B.1.621), and Omicron (B.1.1.529) variants	Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Epsilon (B.1.427/B.1.429), Iota (B.1.526), Kappa (B.1.617.1), Delta (B.1.617.2), Lambda (C.37). Delta Plus (AY.1/AY.2), Mu (B.1.621), and Omicron (B.1.1.529) variants	Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Epsilon (B.1.427/B.1.429), Iota (B.1.526), Kappa (B.1.617.1), Delta (B.1.617.2), Lambda (C.37). Delta Plus (AY.1/AY.2), Mu (B.1.621), and Omicron (B.1.1.529) variants

Age, gender, race, body weight, disease severity.

No data available.

No data available in moderate-to-severe hepatic impairment.

ACE2, angiotensin converting enzyme 2; COVID-19, coronavirus disease 2019; EUA, emergency use authorization; IV, intravenous; mAb, monoclonal antibody; NA, not available; PK, pharmacokinetics; RBD, receptor binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

There is one systematic review conducted by Kreuzberger et al. to assess the effectiveness and safety of SARS-CoV-2-neutralizing mAbs for treating patients with COVID-19 by including the clinical trials on the mAbs published between January 2020 and June 2021. The data from the four studies in nonhospitalized participants who have received either bamlanivimab or bamlanivimab/etesevimab or sotrovimab or regdanvimab showed low certainty of evidence and very low-to-moderate evidence for hospitalized patients who had received either bamlanivimab or casirivimab/imdevimab.¹⁵

Later many other anti-SARS-CoV-2 mAbs were approved; many studies published with these mAbs against changed COVID-19 variants. After July 2021, the Omicron variant has become the dominant SARS-CoV-2 variant in most parts of the world. In in vitro neutralization assays, Omicron variant and its subvariants have shown reduced susceptibility to many anti-SARS-CoV-2 mAbs especially bamlanivimab plus etesevimab and casirivimab plus imdevimab. Sotrovimab is active against the Omicron BA.1 and BA.1.1 subvariants, but reduced susceptibility with other subvariants.

Bebtelovimab that received approval recently had shown retaining of the neutralizing activity against circulating Omicron subvariants.^16–18 Tixagevimab–cilgavimab also known as AZD7442, a long-acting antibody combination, given as two consecutive intramuscular injections, one each of tixagevimab and cilgavimab also received EUA for prophylaxis of COVID-19.

Considering the approval of many anti-SARS-CoV-2 antibodies and change in variants, there is a need to do systematic review on efficacy and safety of these mAbs used for either treatment or for PrEP of COVID-19.

Objectives

Primary objective

To assess the efficacy and safety of SARS-CoV-2-neutralizing mAbs in the treatment mild-to-moderate COVID-19 patients

Secondary objective

To assess the efficacy and safety of SARS-CoV-2-neutralizing mAbs in prevention of COVID-19 infection

Materials and Methods

Study designs

Clinical studies conducted that evaluated the effect of mAbs either in combination or as monotherapy were considered for the review. Both prospective and retrospective studies using these mAbs for treatment of mild COVID-19 nonhospitalized patients or as PrEP have been included in the analysis. The search words used are bamlanivimab (B) alone or bamlanivimab plus etesevimab (B+E), casirivimab plus imdevimab (C+I), sotrovimab, bebtelovimab, and tixagevimab–cilgavimab (T+CG).

Original research articles and articles with full text published and preprints only were considered. Review articles, editorials, conference proceedings, author responses, commentaries, preclinical studies, and book chapters were excluded. Studies with duplicates or exact matching or data that cannot be reliably extracted were also excluded.

We included studies that compared with placebo or standard of care or no treatment or other mAbs with each other and also studies that compare several doses of one type of mAb with another treatment, placebo, or no treatment.

Search strategy

Search engines such as PubMed, Embase, Scopus, medRxiv (preprint), bioRxiv (preprint), and FDA fact sheets were searched for studies published between January 2021 and May 2022. Search strategy using MeSH terms is mentioned in Table 2.

Table 2.

Search Strategy Using MeSH Terms

(1)	COVID-19	COVID-19 OR (COVID-19 virus disease) OR (COVID-19 virus disease) OR (COVID-19 virus) OR (virus disease, COVID-19) OR (COVID-19 virus infection) OR (infection, COVID-19 virus) OR (2019-nCoV infection) OR (2019 nCoV infection) OR (2019-nCoV infections) OR (infection, 2019-nCoV) OR (coronavirus disease-19) OR (coronavirus disease 2019) OR (2019 novel coronavirus disease) OR (2019 novel coronavirus infection) OR (2019-nCoV disease) OR (2019 nCoV disease) OR (2019-nCoV diseases) OR (disease, 2019-nCoV OR COVID19) OR (coronavirus disease 2019) OR (disease 2019, coronavirus) OR (SARS coronavirus 2 infection) OR (SARS-CoV-2 infection) OR (infection, SARS-CoV-2) OR (SARS CoV 2 infection) OR (SARS-CoV-2 infections) OR (COVID-19 pandemic) OR (COVID-19 pandemic) OR (COVID-19 pandemics) OR (pandemic, COVID-19)
(2)	Casirivimab	Casirivimab OR (REGN-10933)
(3)	Imdevimab	ImdevimabOR (REGN-10987)
(4)	Casirivimab plus imdevimab	Casirivimab–imdevimab OR (casirivimab plus imdevimab) OR (casirivimab, imdevimab drug combination) OR (casirivimab and imdevimab) OR (REGEN-COV) OR (ronapreve) OR (ronpreve) OR (REGN-COV-2) OR (REGN-COV2) OR (REGN-COV) OR (REGN10987) OR (REGN10933 mixture)
(5)	Bamlanivimab	Bamlanivimab OR (LY-3819253) OR (LY-COV555) OR (LY3819253)
(6)	Etesevimab	Etesevimab OR (LY-CoV016) OR (JS016)
(7)	Bamlanivimab plus etesevimab	Bamlanivimab–etesevimab OR (bamlanivimab and etesevimab) OR (bamlanivimab plus etesevimab) OR (bamlanivimab, etesevimab drug combination) OR (LY-COV555 and LY-CoV016) OR (LY-3819253 and LY-CoV016)
(8)	Sotrovimab	Sotrovimab OR (xevudy) OR (VIR-7831) OR (VIR7831) OR (GSK-4182136) OR (GSK4182136)
(9)	Bebtelovimab	Bebtelovimab OR (LY-CoV1404) OR (LY-CoV-1404) OR (LY-3853113) OR (LY3853113)
(10)	Tixagevimab plus cilgavimab	Tixagevimab–cilgavimab OR (tixagevimab and cilgavimab mixture) OR (cilgavimab, tixagevimab drug combination) OR (cilgavimab and tixagevimab antibody combination) OR (cilgavimab and tixagevimab mixture) OR (tixagevimab and cilgavimab antibody combination) OR (tixagevimab and cilgavimab drug combination) OR (evusheld) OR (AZD7442) OR (AZD-7442) OR (AZD1061 and AZD8895) OR (AZD 7442)
(11)	Tixagevimab	Tixagevimab OR (AZD8895) OR (AZD 8895) OR (AZD-8895)
(12)	Cilgavimab	Cilgavimab OR (AZD1061) OR (AZD-1061) OR (AZD 1061)

Data extraction and management

Two authors (G.R., K.R.M.) independently extracted data using a standard data extraction sheet. The extracted data included general characteristics of the articles, study population, intervention details, samples size, male and female ratios, median age, and study type and outcome parameters as per the study objectives. Discrepancies were resolved by discussion or by third author.

Statistical analysis

As this is a qualitative synthesis of evidence, no statistical test was applied for comparison.

Study registration

The study was not registered in PROSPERO.

Risk of bias

Risk of bias assessment was not done.

Outcomes reviewed

Primary outcome

Rate of hospitalization or emergency department (ED) visit or death within 30 days.

Secondary outcomes

Change in viral load

Median time for symptom resolution

Proportion of patients requiring intensive care unit (ICU) admission

Duration of hospitalization

Mortality on day 28

Proportion of patients experiencing adverse events (AEs) and serious adverse events (SAEs).

Results

In total of 10,651 articles were screened. After duplication, 7613 articles were considered for further analysis. Figure 2 shows summarizing of the search strategy. The literature search identified 30 full-text articles, of which 20 studies were eligible for inclusion in this review after a full-text read.

FIG. 2.

Study flow chart. The flow chart shows the details of our search and selection of articles during the review process.

A total of 28,447 patients were included, of which 13,974 patients received mAbs and 14,473 received standard care or placebo and two studies compared the efficacy and safety of mAbs against the other mAb combination. Prophylactically 3460 patients received mAbs. The details of the number of studies for each mAb are shown in Figure 3. Most of the studies included in this review were conducted in mild nonhospitalized COVID-19 patients and one study was conducted in hospitalized patients and two studies prophylactically. Most of the studies compared mAbs with placebo, and in three studies they were compared with other anti-SARS CoV-2 mAbs. The results were discussed as primary and secondary outcomes.

FIG. 3.

Details of collected articles. The diagram shows the number of articles included in this review based on the type of mAb and study.

Primary outcomes

Rate of hospitalization or death within 30 days

Most of the mAbs were evaluated in nonhospitalized mild COVID-19 patients who are at high risk for progressing to severe disease. Hence rate of hospitalizations or death or ED visit within 30 days was the outcome parameter measured in most of these studies. There were 10 studies conducted with either bamlanivimab alone or combination of B+E. Out of these, three were randomized controlled trials (RCTs), three studies were retrospective, three were prospective observational studies, and one was a quasi-experimental study.

The absolute risk ratio (ARR) of COVID-19-related hospitalization or death from any cause by day 29 with combination of B + E (dose 2800 + 2800 mg) was −4.9% (95% confidence interval [CI], −8.9% to −0.8%; p = 0.049)¹⁹ and −4.8%; (95% CI, −7.4 to −2.3; p < 0.001).²⁰ Monotherapy of bamlanivimab at 2800 mg showed ARR of −3.9% (95% CI, −8.4% to 0.6%; p = 0.21) in a prospective study.¹⁹

Significant reduction in the rate of hospitalization or death or ED visit was reported in other prospective studies and was found to be 2.5% versus 3.9%,²³ 6.9% versus15.5%,²⁶ 12.1% versus 20.3% with B compared with control, respectively.²⁷ In retrospective studies, 1.9% versus 12% (p < 0.01),²² 7.3% versus 20.0%,²⁴ and 6.3% versus 39.3%²⁵ with bamlanivimab treatment compared with control group, respectively.

In a quasi-experimental study where B was compared with C+I, results showed that 14-day hospitalization or all-cause mortality was 12.1% (B) compared with 8.7% in (C+I)-treated group with odds ratio (OR), 0.52 (95% CI, 0.17 to 1.63, p = 0.26).²⁸

In an RCT study, C + I showed that the relative risk reduction (RRR) was 71.3% (p < 0.001) and 70.4% (p = 0.002) with 2400 and 1200 mg, respectively.³⁰ The C + I was compared with B + E in a prospective observational study where the hospitalization/death within 30 days was 4.3% versus 5.7% and 17.4% versus 55% (p = 0.013) against Alpha (B.1.1.7) and Gamma (P.1) variants, respectively.³² In retrospective studies it was 1.6% and 2.6% with C + I compared with control (4.8% and 16.6%).^33,34

Efficacy of this combination mAbs in vaccinated and unvaccinated persons infected with Delta variant was studied by Bierle et al. and results showed that there was a significant decrease in the rate of hospitalization 2.6% (C+I) compared with the control group 16.6%.³⁴

Only one RCT was conducted with sotrovimab at 500 mg intravenous (IV) infusion in 1057 mild-to-moderate COVID-19 patients, who are at risk for progressing to severe disease. The interim analysis of this COVID-19 Monoclonal Antibody Efficacy Trial–Intent to Care Early (COMET-ICE) trial had shown significant reduction in hospitalization, ED visit OR death, with single infusion of sotrovimab, and it was 2% (sotrovimab) versus 7% (placebo) with absolute difference of −4.91% (95% CI, −7.50% to −2.32%; p < 0.001).³⁵

The BLAZE-4 trial tested single IV infusion of BEB (175 mg) and combination of BEB + B (700 mg) + E (1400 mg) in low- and high-risk patients with mild-to-moderate COVID-19, within 3 days of first real time-polymerase chain reaction positive test. A total of 706 patients were recruited in the study. Authors reported that COVID-19 hospitalization was equal in BEB (1.6%) and placebo (1.6%) and 2.4% with BEB+B+E in the low-risk group.³⁶

Secondary outcomes

Change in viral load

Significant reduction in SARS-CoV-2 log viral load −0.57 (95% CI, −1.00 to −0.14; p = 0.01) and −1.20 (95% CI, −1.46 to −0.94; p < 0.001) at days 11 and 7 was reported with combination of B + E (2800 + 2800 mg), respectively.^19,20

The C + I combination had shown significant decrease in number of weeks of high viral load (>4 log₁₀ copies/mL) in nasopharyngeal swab samples per 1000 participants (489.8 [C+I] vs. 811.9 [placebo]).²⁹

The same combination in another RCT showed reduction in viral load by day 7, from baseline −0.71 log₁₀ copies/mL (95% CI, −0.90 to −0.53) with 1200 mg and −0.86 log₁₀ copies/mL (95% CI, −1.00 to −0.72) with 2400 mg.³⁰

In one study, B + E was compared with C + I for time to virological cure against Alpha and Gamma variants and it was 14 versus 15 and 17 versus 14 days, respectively. Results were significant against Gamma variant.³²

Median time for symptom resolution

The change in symptom resolution from baseline to day 11 with treatment of B + E was 9.0% (95% CI, −3.1% to 21.1%; p = 0.16).¹⁹ It was reported that (C+I) caused reduction symptomatic duration per 1000 participants (895.7 weeks vs. 1637.4 weeks [placebo]; p = 0.03)²⁹ and time for COVID-19 symptoms to resolve was significant (14 [C+I] vs. 18 days [P] p < 0.001).³⁰

The BLAZE 4 trial showed time to symptom resolution was less in BEB (6%)-treated group compared with the group treated with combination BEB+B+E (7%) and placebo (8%) in the low-risk group.³⁶

Proportion of patients requiring ICU admission, duration of hospitalization, mortality on day 28, and other details are given in Table 3.

Table 3.

Efficacy Data of the Anti-SARS-CoV-2 Monoclonal Antibodies in COVID-19

Author^Ref.		Study type	Age in years, median (±SD)/median (IQR)	Male/female	Study population	Intervention	Comparator	Outcome parameters	Results
(1)	Gottlieb et al.¹⁹	RCT phase 2/3, multicentric trial	44.7 ± 15.7	54.6%/45.4%	Mild-to-moderate COVID-19 patients who are not hospitalized ambulatory patients (N = 613) who tested positive for SARS-CoV-2 infection and had one or more mild-to-moderate symptoms	Bamlanivimab alone 700 mg (n = 101), 2800 mg (n = 107), 7000 mg (n = 101) AND combination of 2800 mg of bamlanivimab +2800 mg of etesevimab (n = 112)	Placebo (n = 156)	Primary Change in SARS-CoV-2 log viral load at day 11 (±4 days) compared with placebo	0.09 (95% CI, −0.35 to 0.52; p = 0.69), 700 mg −0.27 (95% CI, −0.71 to 0.16; p = 0.21), 2800 mg 0.31 (95% CI, −0.13 to 0.76; p = 0.16), 7000 mg −0.57 (95% CI, −1.00 to −0.14; p = 0.01), combination
								Secondary Proportion of patients with hospitalization/death on day 29	4.8% (95% CI, −8.9% to −0.6%; p = 0.09), 700 mg−3.9% (95% CI, −8.4% to 0.6%; p = 0.21), 2800 mg−3.8% (95% CI, −8.3% to −0.8%; p = 0.21), 7000 mg−4.9% (95% CI, −8.9% to −0.8%; p = 0.049), combination
								Change in symptom resolution from baseline to day 11	13.7% (95% CI, 1.2% to 26.1%; p = 0.04), 700 mg3.3% (95% CI, −8.7% to 15.4%; p = 0.61), 2800 mg6.7% (95% CI, −5.6% to 19.1%; p = 0.30), 7000 mg9.0% (95% CI, −3.1% to 21.1%; p = 0.16), combination
								Viral clearance	No significant change between the groups
								Change in mean total symptom score from baseline to day 11	−0.78 (95% CI, −1.37 to −0.20; p = 0.009), 700 mg−0.60 (95% CI, −1.18 to −0.03; p = 0.04), combinationNo significant change in the remaining groups
(2)	Dougan et al.²⁰	Phase 3 RCT	53.8 ± 16.8	48.0%/52.0%	A cohort of ambulatory patients with mild-to-moderate COVID-19 who were at high risk for progression to severe disease	Bamlanivimab 2800 mg plus etesevimab 2800 mg (n = 518)	Placebo (n = 517)	Primary COVID-19–related hospitalization or death from any cause by day 29	2.1% (B+E) 7.0% (placebo)ARR, −4.8%; 95% CI, −7.4 to −2.3; RRR, 70%; p < 0.001
								Deaths	Nil (B+E) vs. 10 (placebo)
								Secondary Change in viral load from baseline to day 7 compared with placebo	−1.20 log₁₀ copies/mL (95% CI, −1.46 to −0.94; p < 0.001)
(3)	ACTIV-3/TICO Study Group²¹	RCT phase 2/3	61 (49, 71)		COVID-19 patients	Bamlanivimab 7000 mg (n = 163)	Placebo (n = 151)	Primary Median time to sustained recovery	19 Days (RRR = 0.99; 95% CI: 0.79 to 1.22; p = 0.89)
	ACTIV-3/TICO Study Group²¹	RCT phase 2/3	61 (49, 71)		COVID-19 patients	Bamlanivimab 7000 mg (n = 163)	Placebo (n = 151)	Secondary: Mortality, organ failure, serious infections, SAEs, or grade 3/4 AEs	Incidence at day n: B vs. placeboDay 5: 28% (B) vs. 19% (placebo); OR = 1.83 (95% CI: 1.01 to 3.29); p = 0.05Day 28: 32% (B) vs. 28% (Placebo): p = 0.35Day 90: 28% (B) vs. 27% (placebo); p = 0.85Deaths at day 90: 8.0% vs. 7% (placebo)Hazard ratio = 1.09 (95% CI: 0.49 to 2.43)
(4)	Rainwater-Lovett et al.²²	Retrospective observational study	62.3 ± 17.0	38.8%/61.2%	COVID-19 patients	Bamlanivimab (n = 270)	Untreated (n = 328)	Effect of mAb treatment on the risk of hospitalization or ED visit within 30 days diagnosis	1.9% (bamlanivimab) 12% (untreated patients; p < 0.001)Presented to the ED or required hospitalization within 30 days of a positive SARS-CoV-2 test
(5)	Ganesh et al.²³	Prospective observational studyRetrospective cohort study	63 (Median)	49.3%/50.7%	Outpatients with mild-to-moderate COVID-19	Bamlanivimab (n = 2335)	Untreated (n = 2335)	Primary outcome: Rate of hospitalization at days 14, 21, and 28	Day 14 (1.5% vs. 3.5%; OR, 0.38)Day 21 (1.9% vs. 3.9%; OR, 0.46)Day 28 (2.5% vs. 3.9%; OR, 0.61)
								Secondary ICU admission rates at days 14, 21, and 28	Day 14 (0.14% vs. 1%; OR, 0.12)Day 21 (0.25% vs. 1%; OR, 0.24)Day 28 (0.56% vs. 1.1%; OR, 0.52)
								All-cause mortality at days 14, 21, and 28	Day 14 (0% vs. 0.33%)Day 21 (0.05% vs. 0.4%; OR, 0.08)Day 28 (0.11% vs. 0.44%; OR, 0.01)
(6)	Kumar et al.²⁴	Retrospective case–control study	≥1864 (53–73)	52.1%/47.9%	High-risk patients with mild-to-moderate COVID-19	BamlanivimAb Therapy (n = 218)	No bamlanivimab (n = 185)	Primary Hospitalization within 30 days after confirmation by RT-PCR	7.3% (bamlanivimab) vs. 20.0% controls)RR 0.37, 95% CI: 0.21 to 0.64, p < 0.001
								ICU admission	0.9% (B) 2.7% (controls; p = 0.572)^a (p = 0.892)
								Mechanical ventilation requirement	0.5% (B) vs. 2.1% (controls; p = 0.427)
								Mortality	0.5% (B) vs. 2.1% (controls; p = 0.124)
								Duration of hospitalization, median days (IQR)	4 (2.75–8) (B) vs. 5 (4–8) (controls)
(7)	Iqbal et al.²⁵	Retrospective observational study	68 (SD = 13.5)	47%/53%	Mild COVID-19 positive cases	Bamlanivimab (n = 144)	No bamlanivimab (n = 140)	30-day hospitalization and mortality rates	6.3% (B) vs. 39.3% (No B); OR, 0.103 (95% CI, 0.048 to 0.219)Mortality: could not establishNone of the groups showed an association of bamlanivimab infusion with a reduced mortality rate
(8)	Bariola et al.²⁶	Prospective observational study (matched cohort)	67	44%/56%	Mild-to-moderate SARS-CoV-2	Bamlanivimab (propensity-matched cohort n = 232)	No bamlanivimab (propensity matched cohort n = 1160)	Primary: 28-day hospitalization or all-cause mortality	6.9% (bamlanivimab)15.5% (no bamlanivimab)OR, 0.40 (95% CI, 0.24 to 0.69); p < 0.001
(8)	Bariola et al.²⁶	Prospective observational study (matched cohort)	67	44%/56%	Mild-to-moderate SARS-CoV-2	Bamlanivimab (propensity-matched cohort n = 232)	No bamlanivimab (propensity matched cohort n = 1160)	Secondary Hospitalization or ED visit without hospitalization
(9)	Destache et al.²⁷	Prospective observational study (matched cohort)Patient propensity matching was performed for BAM administration to get two discrete groups of patients: those who received BAM (N = 117) and those who did not (N = 117)	72 (65–80)	47%/53%	Mild-to-moderate SARS-CoV-2	Bamlanivimab (n = 117)	No bamlanivimab (n = 117)	Subsequent ED Admission	18% (B) vs. 29.1% (no B); p = 0.045
								Subsequent hospitalization 60 days after the positive SARS-CoV-2 viral test	12.0% (B) 23.1% (no B); p = 0.025
								Mortality	0.0% (B) 9.4% (no B); p < 0.001
(10)	Webb et al.²⁸	Quasi-experimental pre-/postimplementation study	61 (±15)	61.2%/38.8%	High-risk ambulatory adults with COVID-19	Bamlanivimab (n = 157)	Casirivimab/imdevimab (n = 115)	Primary Composite of ED visits or hospitalizations within 14 days of positive test	12.1% (B) vs. 8.7% (C+I)OR, 0.52 (95% CI 0.17 to 1.63, p = 0.26) primary outcome occurred in 75 (12.6%) mAb recipients, 1018 (18.4%) contemporaneous controls, and 1525 (20.6%) historical controlsEmergency hospital visit: 22 (4.6) (B) vs. 1 (0.9) (C/I)Hospital admission: 22 (4.6) (B) vs. 1 (0.9) (C+I)Mortality (0.2) (B) vs. 0 (0) (C+I)
(11)	O'Brien et al.²⁹	RCT phase 3	41.0	48.4%/51.6%	Asymptomatic COVID-19 adults and adolescents	Casirivimab/imdevimab (600 + 600 mg) (n = 158)	Placebo (n = 156)	Primary Proportion of participants developing symptomatic COVID-19 on day 28	29.0% (C+I) vs. 42.3% (placebo), OR, 0.54 (95% CI, 0.30 to 0.97); p = 0.04; ARR, −13.3% (95% CI, −26.3% to −0.3%)
								Secondary Duration of symptomatic infection	Symptomatic duration per 1000 participants = 895.7 weeks (C+I) 1637.4 weeks (placebo); p = 0.03
								No. of weeks of high viral load (>4 log₁₀ copies/mL)	489.8 weeks/1000 participants (C+I) 811.9 weeks/1000 participants (placebo); p = 0.001
(12)	Weinreich et al.³⁰	RCT phase 3	50 (38–59) REGEN-COV2400 mg48.5 (37.0–57.5) REGEN-COV1200 mg	47.2%/52.8% (2400 mg)49.5%/50.5% (1200 mg)	Patients who are not hospitalized, with at least one risk factor for severe COVID-19	REGEN-COV 2400 mg (n = 1355)REGEN-COV 1200 mg (n = 736)	Saline placebo (n = 1341	Primary: Percent of participants with COVID-19–related hospitalization or death from any cause by day 29	1.3% (REGEN-COV 2400 mg) vs. 4.6% (placebo); RRR, 71.3%; p < 0.0011.0% (REGEN-COV 1200 mg) vs. 3.2% (placebo); RRR, 70.4%; p = 0.002
								Secondary Reduction in viral load by day 7, from baseline	−0.71 log₁₀ copies/mL (95% CI, −0.90 to −0.53; REGEN-COV 120 mg−0.86 log₁₀ copies/mL (95% CI, −1.00 to −0.72; REGEN-COV 2400 mg)
								Time for COVID-19 symptoms to resolve	10 Days (REGEN-COV 2400 mg) vs. 14 days for placebo; p < 0.00114 days (REGEN-COV 1200 mg) vs. 18 days for placebo; p < 0.001
(13)	RECOVERY Collaborative Group³¹	Randomized, open-label, randomized controlled	61.9	Seronegative patients −61%/39%All patients-63%/37%	Hospitalized COVID-19 patients	Usual care plus casirivimab 4 g and imdevimab 4 g (n = 4839)	Usual standard of care (n = 4946)	Primary28-day all-cause mortality	Seronegative24% (C+I) vs. 30% (usual care)RR: 0.79, 95% CI: 0.69 to 0.91Seropositive16% (C+I) vs.15% (usual care)RR: 1.09, 95% CI: 0.94 to 1.25(Ⲭ₁² = 9.8; p = 0.002)
								Secondary Time to discharge from hospital	Seronegative64% (C+I) vs. 58% (usual care)RR: 1.19, 95% CI: 1.09 to 1.31Seropositive75% (C+I) vs. 77% (usual care)RR: 0.94, 95% CI: 0.88 to 1.00(Ⲭ₁² = 17.2; p < 0.001)
								Invasive mechanical ventilation	Seronegative31% (C+I) vs. 37% (usual care)RR: 0.83, 95% CI: 0.75 to 0.92Seropositive19% (C+I) vs. 17% (usual care)RR: 1.10, 95% CI: 0.98 to 1.24(Ⲭ₁² = 12.5; p < 0.001)
(14)	Falcone et al.³²	Prospective observational study	65 (56.25–75.75)	47.8%/52.2%	Mild-to- moderate COVID-19 (wild type; Alpha and Gamma variants)	Casirivimab/imdevimab (n = 92)	Bamlanivimab/e tesevimab (73)	Primary Composite of hospitalization/death within 30 days after mAbs infusion	B + E vs. C + IAlpha (B.1.1.7) variant: 5.7% vs. 4.3%Gamma (P.1) variant: 55% vs. 17.4%p = 0.013
								Secondary ICU admission	B + E vs. C + IAlpha (B.1.1.7) variant: 0% vs. 0%Gamma (P.1) variant:15% vs. 0%p = 0.092
								Time to virological cure, median (IQRs)	B + E vs. C + IAlpha (B.1.1.7) variant: 14 (10.5 to 22.5) vs. 15 (9 to 21)Gamma (P.1) variant: 17 (12.5 to 30) vs. 14 (0 to 16)p = 0.04
(15)	Razonable et al.³³	Retrospective observational study	63 (52–71)	48.9%/51.1%	Mild-to-moderate COVID-19	Casirivimab–imdevimab (n = 696)	Control (n = 696)	Primary Hospitalization rate at days 14, 21, 28 (C + I vs. control)	Day 14: 1.3% (0.7%, 2.5%) vs. 3.3% (2.2%, 5.0%)Day 21: 1.3% (0.7%, 2.5%) vs. 4.2% (3.0%, 6.0%)Day 28: 1.6% (0.9%, 2.9%) vs. 4.8% (3.5%, 6.7%)ARR2.0% (0.5%, 3.7%)2.9% (1.2%, 4.7%)3.2% (1.4%, 5.1%)
								Secondary ICU admission at days 14, 21, 28 (C + I vs. control)	Day 14: 0.73% (0.3%, 1.7%) vs. 0.87% (0.4%, 1.9%),Day 21: 0.73% (0.3%, 1.7%) vs. 0.87% (0.4%, 1.9%)Day 28: 0.73% (0.3%, 1.7%) vs. 1.0% (0.5%, 2.1%)ARR0.15% (−0.8%, 1.1%)0.15% (−0.8%, 1.1%)0.30% (−0.7%, 1.3%)
								Death at days 14, 21, 28 (C + I vs. control)	Day 14: 0.15% (0.0%, 1.0%) vs. 0.44% (0.1%, 1.4%)Day 21: 0.15% (0.0%, 1.0%) vs. 0.44% (0.1%, 1.4%)Day 28: 0.15% (0.0%, 1.0%) vs. 0.59% (0.2%, 1.6%)ARR0.29% (−0.3%, 0.9%)0.29% (−0.3%, 0.9%)0.33% (−0.2%, 1.1%)
(16)	Bierle et al.³⁴	Retrospective observational study	46.5 years	47%/53%	High-risk patients for progression to severe COVID-19	Casirivimab/imdevimab (N = 112)	Control (n = 291)	28-day hospitalization rate	2.6% (Casirivimab/imdevimab)16.6% (control)OR: 0.138, 95% CI: 0.0426 to 0.4477, p = 0.001
(17)	Gupta et al.³⁵	Phase 3, multicenter, randomized, double-blind, placebo-controlled trial	53 years	43% vs. 57% in test group48% vs. 52% in Placebo	Mild-to-moderate SARS-CoV-2 patients at risk of progressing to severe disease	Single 500 mg infusion of sotrovimab (n = 528)	Placebo (n = 529)	Primary Proportion of patients with COVID-19 progression through day 29	1% (sotrovimab) vs. 6% (placebo)Absolute difference, −4.53% (95% CI, −6.70% to −2.37%); p < 0.001
								Secondary Percent of ED visit, hospitalization OR death	2% (sotrovimab) vs. 7% (placebo)Absolute difference, −4.91% (95% CI, −7.50% to −2.32%); p < 0.001
								Percent of patients with disease progression to requiring supplemental oxygen	<1% (sotrovimab) vs. 5% (placebo)Absolute difference, −3.97% (95% CI, −6.11% to −1.82%); p = 0.002
(18)	Dougan et al.³⁶BLAZE-4 trial	Phase 2, double blind randomized placebo-controlled trial	Low-risk 35 yearsHigh-risk cohorts 48.5–52.5 years		Mild-to-moderate COVID-19 within 3 days (≤3 days) of laboratory diagnosis of SARS-CoV-2 infection	175 mg BEB (n = 125), 700 mg B + E (700 + 1400 mg; n = 127) IV infusion	N = 128	Time to sustained symptom resolution, median days (95% CI)COVID-19 hospitalization and all-cause mortality through day 29, n/N (%)	Low risk: BEB vs. +BEB+B+E vs. placebo (6 vs. 7 vs. 8)High risk: BEB vs. +BEB+B+E (7 vs. 6)Low risk: BEB vs. +BEB+B+E vs. placebo (1.6% vs. 2.4% vs. 1.6%)High risk: BEB vs. +BEB+B+E (6% vs. 6%)
(19)	Levin et al.³⁷PROVENT trial	Phase 3, double blind randomized placebo-controlled trial	53.5	53.9%/46.1%	Pre-exposure prophylaxis	Tixagevimab+Cilgavimab (AZD7442) (N = 3460)	Placebo (n = 1737)	Primary (1) Symptomatic COVID-19 occurring after giving test drug or placebo by day 183(2) Incidence of AEs after a single dose of AZD7442	AZD7442 group (0.2%) vs. placebo (1.0%)RRR, 76.7%; 95% CI, 46.0 to 90.0; p < 0.001Extended follow-up at 6 months 82% RRRAZD7442 group (35.3%) vs. placebo (34.2%)Five cases of severe or critical COVID-19Two COVID-19–related deaths in placebo group
(20)	TACKLE trial³⁸	Phase 3, double blind randomized placebo-controlled trial	≥18 Years	NA	Nonhospitalized, mild-to-moderate COVID-19 patients	Tixagevimab–cilgavimab (AZD7442) 600 mg intramuscular (N = 452)	Placebo (n = 451)	Primary Severe COVID-19 or death from any cause by day 29	50% risk reduction compared with placebo

AE, adverse event; ARR, absolute risk ratio; B, bamlanivimab; B+E, bamlanivimab plus etesevimab; BEB, bebtelovimab; C+I, casirivimab plus imdevimab; CI, confidence interval; ED, emergency department; ICU, intensive care unit; IQR, interquartile range; OR, odds ratio; ; RCT, randomized controlled trials; RR, rate ratio; RRR, relative risk reduction; RT-PCR, real time-polymerase chain reaction; SD, standard deviation; SAE, serious adverse event.

Others

T+CG was studied in the TACKLE COVID-19 treatment trial and results showed 50% reduction in the risk of developing severe COVID-19 or death (from any cause) compared with placebo in mild-to-moderate symptomatic COVID-19 patients. The findings of this study were released through the media by Astra Zeneca after primary analysis of 822 participants data.³⁸

Safety outcomes: Proportion of patients experiencing AEs and SAEs were shown

Prophylaxis

Phase 3 RCT was conducted with C + I as PEP in 214 asymptomatic COVID-19 adults and adolescents (Table 4). Study results reported that the proportion of participants developing symptomatic COVID-19 on day 28 was 29.0% (C+I) versus 42.3% (placebo) with ARR, −13.3% (95% CI, −26.3% to −0.3%).²⁹

Table 4.

Safety Outcomes of Anti-SARS-CoV-2 Monoclonal Antibodies

Author Ref.	Study drug	AEs	SAE
Gottlieb et al.¹⁹	Bamlanivimab monotherapy, bamlanivimab 2800 mg + etesevimab 2800 mg	Nausea 3.0% (700 mg), 3.7% (2800 mg), 5.0% (7000 mg), 3.6% (combination therapy), 3.8% (placebo group)Diarrhea 1.0% (700 mg), 1.9% (2800 mg), 5.9% (7000 mg), 0.9% (combination therapy), 4.5% (placebo group)Infusion-related reactions 1.5% (monotherapy), 1.7% (combination), 0.6% (placebo group)	UTI (0.9%) (combination therapy)Upper abdominal pain (placebo group)0% (monotherapy)
Dougan et al.²⁰	Bamlanivimab 2800 mg + tesevimab 2800 mg	Overall incidence: 13.3% (bamlanivimab+etesevimab), 11.6% (placebo)Most common AEs: GI upset (nausea, loose stools) skin rash, dizziness increase in BP (0.4% in both the groups)	1.4% (bamlanivimab+etesevimab), 1.0% (placebo)
Study group²¹	Bamlanivimab 7000 mg	—	Type III hypersensitivity
Rainwater-Lovett et al.²²	Bamlanivimab (n = 270)	No AEs	—
Ganesh et al.²³	Bamlanivimab (n = 2335)	Fever (0.2%), nausea (0.2%), and lightheadedness (0.1%)	—
Webb et al.²⁸	Bamlanivimab (n = 157)	Chest pain, oral tingling, itching (0.8%)Infusion-associated AEs Any 6 (1.3) (B) vs. 1 (0.9) (C+I) Severed 2 (0.4) (B) vs. 0 (0) (C+I)	Chest pain (0.3%)
O'Brien et al.²⁹	Casirivimab/imdevimab (600 + 600 mg) (n = 158)	At least one TEAE: 33.5% (casirivimab/imdevimab)48.1% (placebo)	0% (casirivimab/imdevimab)2.6% (placebo)
Dougan et al.³⁶	Bebtelovimab	TEAEs were comparable between the BEB (8.8%) and BEB+BAM+ETE groups (12.6%), and placebo (7.8%)Infusion-related reactions −2 (BEB+B+E)	One death—high risk patient received BEB+B+E
Levin et al.³⁷ (PROVENT Trial)	300 mg of AZD7442 (tixagevimab+cilgavimab)	Injection site reaction (most common AE): 2.4% (AZD7442)2.1% (placebo)AE of special interest: 2.7% (AZD7442)2.1% (placebo)	1.4% (AZD7442)1.3% (placebo)AE leading to death: 0.1% (AZD7442) 0.2% (placebo)
TACKLE trial³⁸	600 mg of AZD7442 (tixagevimab+cilgavimab)	4.4% (AZD7442) vs. 8.9% (placebo)	NA

BP, blood pressure; ETE, etesevimab; GI, gastrointestinal; TEAE, treatment emergent adverse events; UTI, urinary tract infections.

PROVENT trial studied the single dose of AZD7442 (T+CG) for PrEP against COVID-19 in adults who were at an increased risk of exposure to SARS-CoV-2 COVID-19 and an inadequate response to COVID-19 vaccination. The results showed that AZD7442 reduced the incidence of infection by 77% (95% CI, 46% to 90%; p < 0.001) after median follow-up of 183 days and 82% after post hoc analysis.

Discussion

The present review was done to know the efficacy and safety of neutralizing anti-SARS CoV-2 mAbs against COVID-19. REGEN COV mAb (C+I) was the first drug received EUA and it was most commonly used during third wave in India. A total of 20 studies were included for review, and in these studies, mAbs were tested either alone or combination of mAbs. The combination was used mainly to decrease the loss of antiviral activity on different variants and escape mutants.

Bamlanivimab, and T+CG were derived from B lymphocytes of a convalescent naturally SARS-CoV-2-infected person. The EUA given to bamlanivimab was revoked by U.S, FDA on April 17, 2021, due to an increase in virus variants that are resistant to viral neutralization.³⁹ The efficacy of these mAbs against various variants of SARS CoV-2 was tested in in vitro through pseudo type neutralization assays.⁴⁰

Efficacy and safety of the neutralizing anti-SARS CoV-2 mAbs varied across the studies. Proportion of patients with hospitalization, change in viral load, and symptom resolution were the common efficacy end points evaluated in nonhospitalized mild COVID-19 patients, and 28-day mortality or all-cause mortality was the primary end point in hospitalized patients. ACTIV-3 and RECOVERY trial were conducted in hospitalized patients, whereas other studies were conducted in mild COVID-19 nonhospitalized patients.

Rate of hospitalization within 30 days was ranging from 2% to 6% with treatment of these neutralizing mAbs. The other drugs that received EUA for mild COVID-19 nonhospitalized patients were oral antiviral preparations such as molupiravir and paxlovid (combination of nirmatrelvir and ritonavir). These drugs should be administered within 3–5 days of symptom onset. Phase 3 clinical MOVe-OUT trial conducted with molnupirvair in mild-to-moderate non-hospitalized patients with at least one risk factor showed 7.3% hospitalization for any cause or had died through day 29 compared with 14.1% in placebo group. The difference was significant and it was reported −6.8 percentage (95% CI, −11.3 to −2.4; p = 0.001).⁴¹

With paxlovid, significant difference (−5.81% [95% CI, −7.78 to −3.84]; p < 0.001) was observed in the incidence of COVID-19–related hospitalization or death by day 28 and it was 0.72% and 6.45% in paxlovid and placebo group, respectively.⁴²

The C + I combination (REGEN-COV) is available as prefilled syringe subcutaneous injection and also for IV infusion. This drug was approved for both mild-to-moderate COVID-19 patients who are at high risk for progression to severe COVID-19, including hospitalization or death and PEP of COVID-19 in individuals who are at high risk for progression to severe COVID-19 and not fully vaccinated or who are not able to induce an adequate immune response to COVID-19 vaccination. It has been mentioned in the U.S. FDA prescriber information that mAbs, such as REGEN-COV, may be associated with worse clinical outcomes when administered to hospitalized patients with COVID-19 requiring high flow oxygen or mechanical ventilation.

This drug was tested in the RECOVERY trial in hospitalized patients. About 6% of hospitalized patients were on invasive mechanical ventilation at the base line. It has been reported that fever, sudden hypotension, and thrombotic events were numerically high in the C + I group than in the usual care group. Seven SAEs were reported in these trials in the test group. The dose used in this trial was high and it was casirivimab 4 g and imdevimab 4 g.

In the PROVENT trial, T+CG had shown protective effect against COVID-19 in unvaccinated individuals, and during the testing with drug, the variants identified in the study population were Alpha, Beta, and Delta variants. The results of this trial will be applicable to people infected with these variants but not to Omicron variant. The same situation was observed when C + I combination was tested as PEP.

The National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel recommends the use of tixagevimab/cilgavimab as PrEP and recommends against the use of the combinations bamlanivimab/etesevimab and casirivimab/imdevimab as PEP (NIH).⁴³

There is only one study reporting the effectiveness of these mAbs against Alpha and Gamma variants. The C + I combination showed significant decreases in hospitalization or ICU admission or faster virological cure of mild-to-moderate COVID-19–infected patients with Gamma variant. At present, Omicron variant is the major variant of concern, and efficacy against this variant is not known.

Bruel et al. reported noticeable differences in the sensitivity of BA.1 and BA.2 Omicron variants to therapeutic neutralizing mAbs. They compared the sensitivity of BA.1 and BA.2 variants to neutralization by nine therapeutic mAbs. The BA.2 variant showed sensitivity to cilgavimab, inhibition partly by imdevimab, and resistance to sotrovimab. In patients' sera, this anti-Omicron neutralizing activity was reduced when C + I and T+CG were given to immunocompromised individuals.⁴⁴

More clinical studies need to be conducted to know the effectiveness of these mAbs against variants of Omicron for either treatment or disease prevention. The U.S. FDA has revised its EUA in April 2022 on sotrovimab and mentioned that sotrovimab is no longer authorized to treat COVID-19 in any U.S. region due to the majority of COVID-19 cases were caused by the Omicron BA.2 subvariant. In in vitro assays, sotrovimab has not shown neutralization against Omicron variant.⁹

The significant reduction in viral load was observed more with B + E than with C + I on day 7. The broad-spectrum antiviral drug aprotinin was tested in phase 3 clinical trial, ATAC (aprotinin treatment against COVID-19), and results showed that aprotinin nebulization caused significant reduction (p = 0.016) in viral load levels on day 5 in hospitalized moderate COVID-19 patients. Reduction was 3.9 log₁₀ copies/mL compare with base line. Aprotinin is a host proteases inhibitor and proteases are used by the virus to cleave the viral “spike” protein and subsequently be able to recognize surface receptors on epithelial cells to infect. Neutralizing mAbs and aprotonin target the viral spike protein.⁴⁵

In a phase 2a trial, administration of 800 mg of molnupiravir in mild COVID-19 patients showed significant difference in the least squares mean viral load change from baseline n day 7 compared with the placebo group (−0.534 log₁₀ copies/mL [p = 0.006])⁴⁶

In the RECOVERY trial, the primary efficacy was all-cause mortality and it was less in seropositive (16%) patients than in seronegative (24%) patients, and other outcomes were better in seronegative patients.

Among the AEs reported, gastrointestinal-related AEs were most commonly reported followed by infusion-related reactions. SAEs were reported in majority of the studies included. Most of these mAbs are available as injection for IV route of administration and requires hospital setup for administration of these drugs. Infusion-related reactions were the most common AEs reported in these studies

Most of the studies conducted with mAbs for treatment of nonhospitalized COVID-19 patients observed the outcomes for 1 month maximum and it was 6 months in prophylaxis studies. No study has reported the duration of protection of these mAbs against COVID-19. For PrEP, T+CG is authorized to be administered every 6 months and with advisory note that the combination is not a substitute for COVID-19 vaccination.¹¹

Conclusion

The anti-SARS CoV-2 mAbs with EUA by U.S. FDA have shown reduced hospitalization in mild-to-moderate patients with infusion-related reactions as common adverse effects. When these mAbs were given as prophylactic agents, the occurrence of symptomatic COVID-19 decreased. As the response to mAbs in seropositive COVID-19 patients could not be assessed, further studies in this cohort is required.

The important limiting factor for wider use of these mAbs is their cost. Most of these studies were conducted in unvaccinated individuals and against Alpha, Gamma, and Delta variants. There are unanswerable questions regarding the use of these drugs such as duration of protection, efficacy in immune disorder patients, and against the emerging variants.

Limitations

Meta analysis was not done due to difference in interventional drugs, drug combination, dosage, and multiple arms in the studies reported.

Footnotes

Acknowledgment

The authors are very thankful to Dr. Bhavani Sankara Bagepally Scientist D, ICMR-NIE, Chennai, Tamilnadu, India, for his help during article collection.

Authors' Contributions

Concept design of the study was carried out by M.E. and V.R.K. Methodology was by M.E. and G.R. Articles collection was by G.R. and K.R.M. Figure was drawn by L.F.C. Article draft was taken care by G.R., M.E., and V.R.K. Article review was by D.B., G.M.R., and R.P.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Shereen

, Khan

, Kazmi

, et al. COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. J Adv Res, 2020; 24:91–98; doi: 10.1016/j.jare.2020.03.005

Cascella

, Rajnik

, Aleem

, et al. Features, Evaluation, and Treatment of Coronavirus (COVID-19). StatPearls Publishing: Treasure Island, FL; 2022.

Frediansyah

, Nainu

, Dhama

, et al. Remdesivir and its antiviral activity against COVID-19: A systematic review. Clin Epidemiol Glob Health, 2021; 9:123–127; doi: 10.1016/j.cegh.2020.07.011

Tanni

, Silvinato

, Floriano

, et al. Use of remdesivir in patients with COVID-19: A systematic review and meta-analysis. J Bras Pneumol, 2022; 48(1):e20210393; doi: 10.36416/1806-3756/e20210393

U.S. Food and Drug Administration. FDA News Release. Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19. Silver Spring, MD; 2021. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19 [Last accessed: December 19, 2022].

U.S. Food and Drug Administration. FDA News Release. Coronavirus (COVID-19) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 in Certain Adults. Silver Spring, MD; 2021. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-oral-antiviral-treatment-covid-19-certain [Last accessed: December 20, 2022].

U.S. Food and Drug Administration. Drug Safety and Availability. FDA Authorizes REGEN-COV Monoclonal Antibody Therapy for Post-Exposure Prophylaxis (Prevention) for COVID-19. Silver Spring, MD; 2021. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-regen-cov-monoclonal-antibody-therapy-post-exposure-prophylaxis-prevention-covid-19 [Last accessed: December 19, 2022].

U.S. Food and Drug Administration. Drug Safety and Availability. FDA Authorizes Bamlanivimab and Etesevimab Monoclonal Antibody Therapy for Post-Exposure Prophylaxis (Prevention) for COVID-19. Silver Spring, MD; 2021. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-bamlanivimab-and-etesevimab-monoclonal-antibody-therapy-post-exposure-prophylaxis [Last accessed: December 19, 2022].

U.S. Food and Drug Administration. Drug Safety and Availability. FDA Updates Sotrovimab Emergency Use Authorization. Silver Spring, MD; 2022. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-sotrovimab-emergency-use-authorization [Last accessed: December 19, 2022].

10.

U.S. Food and Drug Administration. FDA News Release. Coronavirus (COVID-19) Update: FDA Authorizes New Monoclonal Antibody for Treatment of COVID-19 That Retains Activity Against Omicron Variant. Silver Spring, MD; 2021. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-monoclonal-antibody-treatment-covid-19-retains [Last accessed: December 19, 2022].

11.

U.S. Food and Drug Administration. Drug Safety and Availability. FDA Releases Important Information About Risk of COVID-19 Due to Certain Variants Not Neutralized by Evusheld. Silver Spring, MD; 2022. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-releases-important-information-about-risk-covid-19-due-certain-variants-not-neutralized-evusheld [Last accessed: December 19, 2022].

12.

Deeks

. Casirivimab/imdevimab: First approval. Drugs, 2021; 81(17):2047–2055; doi: 10.1007/s40265-021-01620-z

13.

U.S. Food and Drug Administration. Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Bamlanivimab and Etesevimab. Silver Spring, MD; 2022. Available from: https://www.fda.gov/media/145802/download [Last accessed: December 19, 2022].

14.

Westendorf

, Žentelis

, Wang

, et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. Cell Rep. 2022:17;39(7):110812. doi: 10.1016/j.celrep.2022.110812.

15.

Kreuzberger

, Hirsch

, Chai

, et al. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev, 2021; 9(9):CD013825; doi: 10.1002/14651858.CD013825.pub2

16.

Cao

, Yisimayi

, Jian

, et al. BA.4 and BA.5 escape antibodies elicited by Omicron infection. Nature, 2022; 608(7923):593–602; doi: 10.1038/s41586-022-04980-y

17.

Wang

, Guo

, Iketani

, et al. Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5. Nature, 2022; 608(7923):603–608; doi: 10.1038/s41586-022-05053-w

18.

Yamasoba

, Kosugi

, Kimura

, et al. Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to therapeutic monoclonal antibodies. Lancet Infect Dis, 2022; 22(7):942–943; doi: 10.1016/S1473-3099(22)00365-6

19.

Gottlieb

, Nirula

, Chen

, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: A randomized clinical trial. JAMA, 2021; 325(7):632–644; doi: 10.1001/jama.2021.0202

20.

Dougan

, Nirula

, Azizad

, et al. Bamlanivimab plus etesevimab in mild or moderate Covid-19. N Engl J Med, 2021; 385(15):1382–1392; doi: 10.1056/NEJMoa2102685

21.

Lundgren

, Grund

, Barkauskas

, et al. Responses to a neutralizing monoclonal antibody for hospitalized patients with COVID-19 according to baseline antibody and antigen levels: A randomized controlled trial. Ann Intern Med, 2022; 175(2):234–243; doi: 10.7326/M21-3507

22.

Rainwater-Lovett

, Redd

, Stewart

, et al. Real-world effect of monoclonal antibody treatment in COVID-19 patients in a diverse population in the United States. Open Forum Infect Dis, 2021; 8(8):ofab398; doi: 10.1093/ofid/ofab398

23.

Ganesh

, Pawlowski

, O'Horo

, et al. Intravenous bamlanivimab use associates with reduced hospitalization in high-risk patients with mild to moderate COVID-19. J Clin Invest, 2021; 131(19):e151697; doi: 10.1172/JCI151697

24.

Kumar

, Wu

, Stosor

, et al. Real-world experience of bamlanivimab for coronavirus disease 2019 (COVID-19): A case-control study. Clin Infect Dis, 2022; 74(1):24–31; doi: 10.1093/cid/ciab305

25.

Iqbal

, Terlau

, Hernandez

, et al. Efficacy of bamlanivimab in reducing hospitalization and mortality rates in COVID-19 patients in a rural community. Cureus, 2021; 13(7):e16477; doi: 10.7759/cureus.16477

26.

Bariola

, McCreary

, Wadas

, et al. Impact of bamlanivimab monoclonal antibody treatment on hospitalization and mortality among nonhospitalized adults with severe acute respiratory syndrome coronavirus 2 infection. Open Forum Infect Dis, 2021; 8(7):ofab254; doi: 10.1093/ofid/ofab254

27.

Destache

, Aurit

, Schmidt

, et al. Bamlanivimab use in mild-to-moderate COVID-19 disease: A matched cohort design. Pharmacotherapy, 2021; 41(9):743–747; doi: 10.1002/phar.2613

28.

Webb

, Buckel

, Vento

, et al. Real-world effectiveness and tolerability of monoclonal antibody therapy for ambulatory patients with early COVID-19. Open Forum Infect Dis, 2021; 8(7):ofab331; doi: 10.1093/ofid/ofab331

29.

O'Brien

, Forleo-Neto

, Sarkar

, et al. Effect of subcutaneous casirivimab and imdevimab antibody combination vs placebo on development of symptomatic COVID-19 in early asymptomatic SARS-CoV-2 infection: A randomized clinical trial. JAMA, 2022; 327(5):432–441; doi: 10.1001/jama.2021.24939

30.

Weinreich

, Sivapalasingam

, Norton

, et al. REGEN-COV antibody combination and outcomes in outpatients with Covid-19. N Engl J Med, 2021; 385(23):e81; doi: 10.1056/NEJMoa2108163

31.

RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet, 2022; 399(10325):665–676; doi: 10.1016/S0140-6736(22)00163-5

32.

Falcone

, Tiseo

, Valoriani

, et al. Efficacy of bamlanivimab/etesevimab and casirivimab/imdevimab in preventing progression to severe COVID-19 and role of variants of concern. Infect Dis Ther, 2021; 10(4):2479–2488; doi: 10.1007/s40121-021-00525-4

33.

Razonable

, Pawlowski

, O'Horo

, et al. Casirivimab-imdevimab treatment is associated with reduced rates of hospitalization among high-risk patients with mild to moderate coronavirus disease-19. EClinicalMedicine, 2021; 40:101102; doi: 10.1016/j.eclinm.2021.101102

34.

Bierle

, Ganesh

, Razonable

. Breakthrough COVID-19 and casirivimab-imdevimab treatment during a SARS-CoV-2 B1.617.2 (Delta) surge. J Clin Virol, 2021; 145:105026; doi: 10.1016/j.jcv.2021.105026

35.

Gupta

, Gonzalez-Rojas

, Juarez

, et al. Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate COVID-19: A randomized clinical trial. JAMA, 2022; 327(13):1236–1246; doi: 10.1001/jama.2022.2832

36.

Dougan

, Azizad

, Chen

, et al. Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19. medRxiv;, 2022; doi: 10.1101/2022.03.10.22272100v1

37.

Levin

, Ustianowski

, De Wit

, et al. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of Covid-19. N Engl J Med, 2022; 386(23):2188–2200; doi: 10.1056/NEJMoa2116620

38.

AstraZeneca. AZD7442 Reduced Risk of Developing Severe COVID-19 or Death in TACKLE Phase 3 Outpatient Treatment Trial. Available from: https://www.astrazeneca.com/media-centre/press-releases/2021/azd7442-phiii-trial-positive-in-covid-outpatients.html [Last accessed: December 19, 2022].

39.

U.S. Food and Drug Administration. FDA News Release. Coronavirus (COVID-19) Update: FDA Authorizes New Long-Acting Monoclonal Antibodies for Pre-Exposure Prevention of COVID-19 in Certain Individuals. Silver Spring, MD; 2022. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-long-acting-monoclonal-antibodies-pre-exposure [Last accessed: December 19, 2022].

40.

Cantoni

, Mayora-Neto

, Temperton

. The role of pseudotype neutralization assays in understanding SARS CoV-2. Oxf Open Immunol, 2021; 2(1):iqab005; doi: 10.1093/oxfimm/iqab005

41.

Jayk Bernal

, Gomes da Silva

, Musungaie

, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med, 2022; 386(6):509–520; doi: 10.1056/NEJMoa2116044

42.

Hammond

, Leister-Tebbe

, Gardner

, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with Covid-19. N Engl J Med, 2022:386(15):1397–1408; doi: 10.1056/NEJMoa2118542

43.

National Institutes of Health (NIH). COVID-19 Treatment Guidelines. Antiviral Agents, Including Antibody Products. Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/summary-recommendations [Last accessed: December 19, 2022].

44.

Bruel

, Hadjadj

, Maes

, et al. Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies. Nat Med, 2022; 28(6):1297–1302; doi: 10.1038/s41591-022-01792-5

45.

Redondo- Calvo

, Padín

, Martínez- Alarcón

, et al. Inhaled aprotinin reduces viral load in mild- to- moderate in patients with SARS- CoV-2 infection. Eur J Clin Invest, 2022; 52:e13850; doi: 10.1111/eci.13850

46.

Fischer

, 2nd, Eron

Jr ., Holman

, et al. A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl Med, 2022; 14(628):eabl7430; doi: 10.1126/scitranslmed.abl7430