The COVID-19 pandemic is the most significant global public health crisis of this generation, resulting in a high estimated excess mortality rate across the globe (1). Older adults and individuals with multimorbidity are predominantly vulnerable to the severe clinical course of COVID-19, in-hospital complications, and death (2). While several vaccines have been proven to be highly effective in reducing the incidence of hospitalization and death attributed to numerous causative SARS-CoV-2 variants (3), there has been significant hesitancy among the population with vaccine uptake, thus hampering the attainment of vaccination coverage required for population immunity (4). Furthermore, given the increased risks of COVID-19 infection and severe disease associated with inactivated whole-virus vaccines (5), the widespread use in many countries worldwide, particularly in crowded low- and middle-income countries that bear potentially higher risks of emerging SARS-CoV-2 variants becoming the epicenter for further spread and health care crisis warrants the need of effective therapeutic interventions to prevent severe disease progression, hospitalization, and mortality.

A growing body of evidence shows that monoclonal antibody therapies significantly reduce the risk of hospitalization of COVID-19 when administered early (6). Monoclonal antibodies are the largest class of biologicals for use in clinical practice, comprising a myriad of structures, ranging from small fragments to intact, modified, or unmodified immunoglobulins, all of which possess an antigen-binding domain (7). The emergence and proliferation of SARS-CoV-2 variants have been demonstrated to impair the efficacy of monoclonal antibody therapies due to the occurrence of mutations in the antigenic supersite of N-terminal domain or the ACE2-binding site (receptor-binding motif) of SARS-CoV-2, both major binding targets of the neutralizing monoclonal antibodies (8). To date, five types of anti-SARS-CoV-2 antibody drugs have been developed, namely bebtelovimab, bamlanivimab plus etesevimab, casirivimab plus imdevimab, sotrovimab, and tixagevimab-cilgavimab (9).

Of note, circulating variants of concern in the communities affect the effectiveness of each anti-SARS-CoV-2 monoclonal antibody therapy. The emergence and proliferation of SARS-CoV-2 B.1.1.529 Omicron virus has rendered specific monoclonal antibodies ineffective due to a marked reduction in neutralizing activity (10). A live virus focus reduction neutralization test depicts that combinations of monoclonal antibodies, including bamlanivimab plus etesevimab, casirivimab plus imdevimab, as well as tixagevimab-cilgavimab have neutralizing activity against early strain and the Alpha and Delta variants. Nonetheless, etesevimab plus bamlanivimab exhibits dramatically decreased activity against Gamma variant and exerts no inhibitory effect against Omicron and Beta variants. On the other hand, casirivimab plus imdevimab shows efficacy against Beta and Gamma variants, whilst losing neutralizing activity against Omicron. Tixagevimab-cilgavimab elicits inhibitory activity against Beta, Gamma, and Omicron variants, but the titer of monoclonal antibodies required for a 50% reduction in the number of infectious foci (FRNT₅₀ or sometimes also referred to as IC₅₀) is 24.8 to 142.9 higher for Omicron than for Beta or Gamma. Likewise, sotrovimab remains to have neutralizing activity against Beta, Gamma, and Omicron variants, but nevertheless, the FRNT₅₀ value is 3.7 to 198.2 higher for Omicron than for Beta or Gamma (11).

In another experiment, etesevimab plus bamlanivimab is found to have no neutralizing activity against Omicron/BA.2. Casirivimab plus imdevimab can inhibit Omicron/BA.2, but no neutralizing activity is demonstrated against Omicron/BA.1 or Omicron/BA.1.1. Tixagevimab-cilgavimab retains activity against Omicron/BA.2. Sotrovimab has been depicted to have lower neutralizing activity against Omicron/BA.2 compared to Omicron/BA.1, Omicron/BA.1.1, and the ancestral strain. The FRNT₅₀ value of each of these monoclonal antibodies is considerably higher for Omicron/BA.2 in comparison with the ancestral strain and other variants of concern (12).

In view of the global dominance of the Omicron variant and the diminished therapeutic effect against the newly emerged variant, the United States National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel no longer recommends the use of bamlanivimab plus etesevimab, casirivimab plus imdevimab, or sotrovimab for the treatment of COVID-19. At present, tixagevimab-cilgavimab is shown to be safe and efficacious as pre-exposure prophylaxis and potential treatment for mild to moderate COVID-19 (13). On the other hand, bebtelovimab, being the sole monoclonal antibody that remains effective in vitro against all circulating Omicron subvariants (14), is approved by the United States Food and Drug Administration (FDA) and the NIH COVID-19 Treatment Guidelines Panel as a therapeutic option in high-risk patients with COVID-19 (9, 15).

One of the strategies to ascertain the role of bebtelovimab in mild to moderate COVID-19 infection is evidence synthesis using existing literature to inform and design studies of this promising therapy. Recognizing this gap, a scoping review is performed to identify and delineate of the current state of research evidence on the effect of bebtelovimab on COVID-19. The findings of the review will be utilized to inform future research within the theme of human IgG1 monoclonal SARS-CoV-2 antibody and possibly other research groups examining biologic drugs and lay a cornerstone of the foundation for formulating laboratory guidance and clinical tools for biomedical researchers to work on therapeutic options for COVID-19 patients.

The database search yielded 66 records, of which 24 duplicate records were removed. 23 additional articles were identified by manual searching. Hence, 65 full-text articles were assessed for eligibility, of which 39 were included in the review ( Figure 1 ). 34 studies were non-clinical research (19–52), encompassing in vitro virus neutralization experiments (19–50), immunoinformatic analysis (51), and deep mutational scanning (52). The remaining 5 studies were clinical research (18, 53–56), comprising randomized controlled trial (53) and retrospective cohort studies (18, 54–56). 17 studies were conducted in the United States (28, 30, 34, 35, 38, 42, 45, 49, 50, 56), 8 in China (19, 23–26, 31, 48), 7 in Europe (20–22, 29, 36, 37, 41), 4 in Japan (39, 40, 46, 47), 2 in India (32, 51), and 1 across three countries, namely United States, Argentina, and Puerto Rico (53). A summary of the main characteristics of each individual study is outlined in Tables 1 , 2 .

The rapid evolution of the SARS-CoV-2 virus continues to challenge our global effort to curb the COVID-19 pandemic. Several clinically available monoclonal antibodies, such as bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab are no longer recommended as the treatment for COVID-19 due to a lack of effectiveness against the widely circulating Omicron subvariants. Up till November 2022, bebtelovimab is the sole monoclonal antibody authorized as a treatment for mild to moderate COVID-19 in non-hospitalized patients (9). Our evidence synthesis highlights the therapeutic role of bebtelovimab in COVID-19 infection based on preclinical data depicting its retained potent neutralization against all currently known variants of concern (VOC), along with studies that have demonstrated its clinical safety and efficacy in association with a greater viral clearance and shorter period for symptom resolution. The rate and severity of treatment-emergent adverse events resulting from the use of bebtelovimab are evidenced to be similar to those of placebo and existing monoclonal antibodies in treating both low-risk and high-risk patients. Meta-analyses of clinical studies show no significant differences in risks of COVID-19 hospitalization, ICU admission, or death between patients treated with bebtelovimab and other COVID-19 therapies.

Bebtelovimab, a fully human immunoglobulin G1 (IgG1) monoclonal SARS-CoV-2 antibody, works by targeting the SARS-CoV-2 spike (S) protein’s receptor-binding domain, thereby hindering the spike protein interaction with ACE2 and subsequent viral entry into host cells (45). The in vitro efficacy of bebtelovimab is conferred by its ability to bind to an epitope of the SARS-CoV-2 S protein with amino acids that are rarely mutated, as documented in the Global Initiative on Sharing All Influenza Data (GISAID) EpiCoV database (45, 49). Bebtelovimab overcomes mutation-induced structural alterations of the COVID-19 variants by exploiting loop mobility and by minimizing side-chain interactions (49). Overall, there are also consistent findings from clinical studies that demonstrate the effectiveness of bebtelovimab for the treatment of patients infected with SARS-CoV-2 variants (18, 53–56). The collated significant data of this review, in the context of laboratory research and clinical trials, indicate that bebtelovimab is a promising therapeutic option against COVID-19 and newly emerging Omicron sublineages. Our results broadly concur with a recent prediction analysis that bebtelovimab can maintain detectable in vitro neutralization against Omicron subvariants such as BA.1, BA.2, BA.4, and BA.5, as well as have a 70.1% (95% CI: 61.9 – 76.8, p < 0.0001) therapeutic efficacy when administered to ambulant COVID-19 positive individuals in preventing illness progression to hospitalization (57).

Monoclonal antibodies have propelled to the forefront in the investigations of pharmacological approaches to treating COVID-19 infection as they are the only appropriate options for clinical use in pediatric patients. Several existing anti-SARS-CoV-2 monoclonal antibodies have been reported to be well-tolerated and raise no safety concerns in children of age between 24 days and 18 years old (58). Whilst bebtelovimab is approved for use in non-hospitalized patients aged 12 years or older, the therapeutic decision to use it across all age pediatric groups should be individualized by incorporating risk factors of progression to severe COVID-19 in the risk-benefit judgment (59). Its indication for a broad population of patients across age groups renders it to be a potential therapeutic strategy to vaccinations and other COVID-19 therapies, especially among those who have underlying immunocompromising condition or multimorbidity, have intolerable adverse effects to COVID-19 vaccination, or are not yet eligible for COVID-19 vaccination.

In tandem with the appearance of multi-mutational SARS-CoV-2 variants such as Delta and Omicron lineages, it is important to enhance the efficacy of bebtelovimab and other potential monoclonal antibodies to overcome new variants that evade natural immunity responses (60). During the period of Delta variant predominance, an existing neutralizing monoclonal antibody sotrovimab resulted in 89% reduction in all-cause mortality and 63% in hospitalization at 28 days compared to untreated patients (61). However, during the period in which Omicron BA.2 was the dominant variant, individuals receiving sotrovimab were associated with higher rates of progression to severe, critical, or fatal COVID-19 (62). Collectively, these real-world findings stand in concurrence with in vitro evidence that sotrovimab potently neutralized Omicron B.1.1.529 and BA.1 variants but had low neutralizing activity against Omicron BA.2 and its sublineages (12, 30). Concerning bebtelovimab, the best in vitro and clinical data available at present highlight its substantial neutralizing activity against all known SARS-CoV-2 variants, including the Omicron and its new subvariants such as BA.2.75, BA.4, and BA.5, and patients administering bebtelovimab have shown a faster decay in virus titer than placebo. The time frames for clinical studies included in this review comprise pre-Omicron era (53) and Omicron variant (BA.1, BA.2, and BA.5) predominance period (18, 54–56). We could reasonably anticipate that the data carry prominent clinical implications for curbing severe COVID-19 illnesses arising from the current sublineages of the Omicron variant and are likely to resonate with growing evidence from future large-scale randomized controlled trials and real-world studies to recommend the use of bebtelovimab in a broader range of patients. Whilst bebtelovimab appears to be well tolerated in our review, case reports have documented that a patient experienced sinus bradycardia-mediated cardiac arrest immediately following infusion of bebtelovimab (63) and another patient developed colitis 10 days after the use of bebtelovimab (64). Post-marketing surveillance for adverse events and ad hoc safety studies are henceforth crucial for earlier detection of safety issues and preventing patients from unnecessary harm (65). Besides, continued laboratory investigations are critical to develop anti-SARS-CoV-2 monoclonal antibodies with better efficacy, safety, and developability features (66). Albeit dedicated wet-lab preclinical research is warranted, this gap can be addressed more rapidly by adding a bioengineering and viral molecular evolution lens to existing lines of research. Instead of just combining different neutralizing monoclonal antibodies, targeting mutated S protein with multivalent nanobody conjugates that can precisely display neutralizing antibodies against SARS-CoV-2 variants has been suggested to have the potential for enhancing the antiviral efficacy (67). However, a recent retrospective cohort study revealed evidence of lack of treatment efficacy among patients infected with SARS-CoV-2 Omicron BA.2, BA.2.12.1, and BA.5 subvariants (68). Hence, well-designed real-world evidence observational studies are important to confirm the efficacy and usage of bebtelovimab. Of note, a next-generation monoclonal antibody may play a pivotal role in inducing rapid immunomodulation and limiting the course of illness, for instance, in debilitating multisystem inflammatory syndrome in children associated with COVID-19 considering the vast potential for improved outcomes with the use of single or combination immunotherapies (69, 70).

Key strengths of our study encompass adherence to scoping review methods, comprehensive search strategy, and inclusion criteria without restrictions on publication status. Limitations of our review are the inclusion of articles published in English only. Supplementary preclinical research is needed to develop neutralizing monoclonal antibodies with optimized clinical efficacy against the evolving variants. The evidence synthesized by this review and the gaps in knowledge reveal that future clinical studies are necessary to foster a deeper understanding of the safety and efficacy of bebtelovimab across different age groups or clinical characteristics, particularly pediatric population and persons with multiple high-risk conditions or comorbidities, the optimal time to initiate treatment, the impact of bebtelovimab on clinical outcomes among patients having previously immunized with different vaccine types or heterologous vaccination regimens, and how Immunocompromised individuals would benefit from additional doses of bebtelovimab in the event of COVID-19 breakthrough infection. The clinical trial included in our review was limited by the exclusive geographical enrollment of patients in North and Latin America, collection of placebo-controlled data among patients at low risk for severe COVID-19, lack of power to assess improvements in clinical outcomes among patients with active treatment before the emergence of Omicron subvariants, use of viral surrogate markers in low-risk younger or healthier subjects for efficacy evaluation, and absence of patient-level clinical data to determine the efficacy of bebtelovimab in patients with symptomatic Omicron infection (53). The retrospective cohort studies had inherent limitations, such as inability to account for sources of residual confounding and selection bias, absence of an untreated control group, and the potential of misclassification bias resulting from administrative data ascertainment, variation in completeness of documentation, inclusion of patients solely in the United States, and lack of laboratory values and biomarkers to better characterize the disease severity. Therefore, further large multinational clinical studies are warranted to resolve these limitations, increase generalizability and evaluate the clinical efficacy and safety of bebtelovimab in diverse patient populations.

The currently available evidence supports the clinical use of bebtelovimab for patients with SARS-CoV-2 infection who are at increased risk of progression to severe illnesses. With relatively similar pharmacological properties as other previously approved anti-SARS-CoV-2 monoclonal antibodies, bebtelovimab possesses superiority in terms of the ability to neutralize presently circulating Omicron subvariants and different variants of interest. The favorable preclinical and clinical results justify its potential to reserve an active therapeutic role despite the evolutionary trajectories of SARS-CoV-2.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

ML – Article selection, data analysis, data interpretation, validation, and writing the original draft. KK – Literature search, study design, article selection, data analysis, data interpretation, validation, and writing the original draft. SL – Literature search, study design, and writing the review & editing. KW – Conceptualization, provision of funding for open-access publishing, project administration, resources, and review. All authors contributed to the article and approved the submitted version.