Real-world effectiveness of sotrovimab for the treatment of SARS-CoV-2 infection during Omicron BA.2 subvariant predominance: a systematic literature review

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Following its initial emergence in December 2019 and the subsequent declaration of a pandemic by the World Health Organization (WHO) in March 2020 [1], the virus has continued to evolve and continues to place pressure on healthcare systems globally. Some individuals, such as older patients, immunocompromised patients, or those with advanced renal or liver disease, diabetes, cancer, chronic obstructive pulmonary disease, or cardiovascular disease, are at a higher risk of developing severe COVID-19 [2‐4].

Clinical outcomes of COVID-19 are influenced by country-level factors such as healthcare system capacity and policies for disease prevention and management, as well as individual-level factors such as age, pre-existing illnesses, and immune status [2, 3, 5, 6]. Moreover, new SARS-CoV-2 variants continue to emerge globally, affecting viral transmissibility, pathogenicity, and antigenic capacity, thus potentially impacting the spectrum and severity of clinical outcomes, immune evasion, and treatment effectiveness in infected individuals [7].

Sotrovimab is a dual-action engineered human IgG1κ monoclonal antibody (mAb) derived from the parental mAb S309, a potent neutralizing mAb that targets the spike protein of SARS-CoV-2 [8‐11]. In a randomized clinical trial (COMET-ICE, NCT04545060) conducted during the period of the pandemic predominated by the original “wild-type” variant, a single intravenous (IV) infusion of sotrovimab (500 mg) was found to significantly reduce the risk of all-cause hospitalization (of > 24-h duration) or death by 79% compared with placebo in high-risk patients with COVID-19 [12, 13]. Consequently, sotrovimab (IV 500 mg) was first granted Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (≥ 12 years of age and ≥ 40 kg) who tested positive for SARS-CoV-2 and were at a high risk of progression to severe COVID-19, including hospitalization or death [14]. Sotrovimab was then authorized by several regulatory agencies across the world, including the European Medicines Agency [15].

Since the COMET-ICE trial was undertaken, the original “wild-type” virus has evolved, leading to the emergence and establishment of new variants, with the Alpha variant being the first recognized by the WHO as a variant of concern at the end of 2020 [16]. A number of other recognized variants subsequently emerged, including the Omicron BA.2 subvariant that became predominant globally in March 2022 [7, 17]. In vitro neutralization assays demonstrated that sotrovimab retained its neutralization capacity against Omicron BA.1 (3.8-fold reduction in activity relative to wild-type SARS-CoV-2), but showed reduced neutralization against Omicron BA.2, BA.4, BA.5, and BA.2.12.1, with 16-, 21.3-, 22.6-, and 16.6-fold changes in EC₅₀ values, respectively, relative to wild-type SARS-CoV-2 using a pseudotyped virus assay [18]. In lieu of evidence supporting the efficacy of sotrovimab against BA.2, sotrovimab was deauthorized in the US on a state-by-state basis from the end of March 2022, with a national deauthorization occurring on April 5, 2022 [19]. In the absence of clinical trials to assess the efficacy of sotrovimab against these emerging variants, the clinical relevance of the reduction in in vitro neutralization was unknown. It should be noted that direct virus neutralization is not the only antiviral mechanism of action expected for sotrovimab in vivo, given it has also been demonstrated to mediate Fc-effector functions like antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. However, since these effector functions are not measured by standard neutralization assays, changes in in vitro neutralization potency against different variants may not accurately represent the true change in sotrovimab’s antiviral potency in vivo.

Considering the ever-evolving SARS-CoV-2 variant landscape, the growing body of published real-world evidence is a key source of information with which to assess the effectiveness of sotrovimab on newer variants outside of clinical trials. A published systematic literature review (SLR) and meta-analysis of 17 studies including 27,429 patients concluded that sotrovimab is an effective and well-tolerated therapy that can reduce mortality and hospitalization rates in patients infected with both the Delta (odds ratio [OR] 0.07; 95% CI 0.01–0.51) and Omicron BA.1 (OR 0.27; 95% CI 0.14–0.51) circulating variants [20].

Despite deauthorization in the US, sotrovimab remained authorized in other countries [15], and use continued for early treatment of COVID-19 in high-risk populations during BA.2 predominance. To address some of the questions regarding the use of sotrovimab against emerging variants, this SLR was undertaken to evaluate the totality of evidence on the clinical effectiveness of sotrovimab (IV 500 mg) during the Omicron BA.2 predominance period and onwards.

This SLR included observational studies investigating clinical outcomes and viral load in patients treated with sotrovimab published in peer-reviewed journal articles, preprint articles, and conference abstracts between January 1, 2022 and November 3, 2022. Although we originally sought to investigate both clinical and viral outcomes, we subsequently decided to focus on clinical outcomes in this paper as these are most useful for those considering the use of sotrovimab in clinical practice. The SLR was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO registration number: CRD42022376733) [21]. The decision to focus on clinical outcomes and omitting viral load distinguishes this SLR from the original PROSPERO protocol.

The publication period covered by the systematic review was selected to identify data on Omicron BA.2 and subsequent subvariants. Where available, data on other circulating variants were also extracted for potential comparison between periods of variant predominance.

This SLR identified and assessed all observational studies in the published literature available as of November 3, 2022, which reported clinical outcomes for patients treated with sotrovimab during Omicron BA.2 subvariant predominance and onwards circulating variants. In this context, real-world evidence is potentially a more agile source of evidence than randomized clinical trials.

A recently published SLR and meta-analysis by Amani et al. demonstrated the real-world effectiveness of sotrovimab in terms of reducing hospitalization and mortality during both the Delta and Omicron BA.1 periods of predominance [20]. The findings of the current SLR build on the work of Amani et al. and demonstrate the real-world benefit of sotrovimab for the treatment of COVID-19 during the Omicron BA.2 predominance period. The studies included in our review consistently reported low proportions of severe clinical outcomes (such as all-cause or COVID-19-related hospitalization or mortality) in patients treated with sotrovimab during the predominant period of Omicron BA.2. In addition, although only a limited number of studies evaluated the clinical outcomes of sotrovimab during both the Omicron BA.1 and BA.2 periods, these demonstrated that clinical outcomes in patients with COVID-19 treated with sotrovimab were consistently low across Omicron BA.1 and BA.2 predominance periods. Furthermore, one large study by Harman et al. found no evidence of a difference in clinical outcomes when directly comparing patients treated with sotrovimab with sequencing-confirmed BA.1 and BA.2 [26]. Together, these findings provide no evidence to indicate that the neutralization fold change reported in vitro led to a commensurate change in the effectiveness of sotrovimab.

The low proportions of severe clinical outcomes summarized in the current SLR closely align with the 1% all-cause hospitalization or mortality through day 29 reported for sotrovimab in the randomized COMET-ICE trial conducted when the wild-type strain was predominant [13]. These real-world clinical effectiveness data were generated from the recent use of sotrovimab in patient populations as recommended by country-specific guidelines, and hence reflect the clinical risk and immunological characteristics of the patient population more closely than clinical trials. In particular, population-level immunity resulting from both vaccination and prior infection means these effectiveness results provide important information for prescribers, as the COMET-ICE population was unvaccinated and likely immunologically naïve.

In the current SLR, two high-quality studies from England were included [26, 29]. The observational cohort study by Zheng et al. leveraged the substantial size of the OpenSAFELY platform database to examine the effectiveness of sotrovimab in preventing severe COVID-19 outcomes across both the Omicron BA.1 and BA.2 periods of predominance using propensity scoring methodology and a number of sensitivity analyses to confirm the robustness of the analyses [29]. This study demonstrated that sotrovimab was associated with a substantially lower risk of 28-day COVID-19-related hospitalization or mortality during the Omicron BA.2 subvariant surge compared with molnupiravir after adjustment. The proportions of COVID-19-related hospitalization or mortality for sotrovimab were also comparable across Omicron BA.1 and BA.2. Lower mortality in patients treated with sotrovimab vs molnupiravir was also reported during both Omicron periods of predominance. Zheng et al. concluded that these data support a persistent protective role for sotrovimab against the Omicron BA.2 subvariant [29]. It should be noted, however, that guidance in England for molnupiravir was changed from a second- to third-line treatment option between the Omicron BA.1 and BA.2 periods of predominance, while sotrovimab remained a first-line option during both periods [33]. Although the impact of this change in national recommendations is unclear, it may have altered the baseline characteristics of patients who received molnupiravir in the Zheng et al. study, and the analysis of the BA.2 period was considered exploratory by the authors. Multiple sensitivity analyses were undertaken as part of this study, and the consistency of the results was maintained.

The results from Zheng et al. are supported by Harman et al. [26]. This large retrospective cohort study of SARS-CoV-2-sequenced patients in England assessed the risk of hospital admission or mortality within 14 days in patients treated with sotrovimab and infected with Omicron BA.2, compared with Omicron BA.1. No evidence of a difference between the Omicron BA.2 and BA.1 subvariants was observed. However, it should be noted that testing guidance in England varied during Omicron predominance, and free community testing was restricted from April 1, 2022. This reduced sequencing capacity and thus impacted the overall number of cases available for inclusion in Harman et al.; possible selection bias may have been introduced after this date as a result. In addition, the absence of a comparator-treated control group, and the limited information on comorbidities and severity, limit the utility of the study in assessing the effectiveness of sotrovimab during the Omicron BA.2 period. Nevertheless, the fact that the results of both the Zheng et al. and Harman et al. studies are consistent across different clinical outcomes further supports the robustness of these findings. In addition, the findings of the ecological study conducted by Zheng et al. are aligned with the findings of Harman et al., where a variant of infection was confirmed by sequencing. The remainder of the studies identified in the SLR are consistent in reporting low rates of severe clinical outcomes in sotrovimab-treated patients during periods of Omicron BA.1 and BA.2 predominance.

A single study from Zaqout et al., however, reported a point estimate for the main finding of progression to severe, critical, or fatal COVID-19 in favor of the comparator group who received no treatment [28]. These results had wide CIs and were non-significant, and it is notable that the point estimate is favorable for sotrovimab when the analysis population is limited to those only at higher risk. It should be noted that a selection bias toward patients less likely to progress to severe disease was expected for the control group in this point estimate, as patients were excluded from the control group if they showed signs or symptoms of severe COVID-19 within 7 days of diagnosis.

Two additional studies that did not meet the inclusion criteria of this SLR but support its findings (consistent clinical benefit with sotrovimab during the Omicron BA.2 subvariant predominant period) were identified. Interim results of the French multicenter, prospective, observational cohort study, COCOPREV, were published as a Letter to the Editor at the time of the review and were, therefore, out of scope [35]. These results indicated low and similar proportions of hospitalization or mortality within 28 days of sotrovimab treatment in patients infected with Omicron BA.1 (n = 125; 2.4%; 95% CI 1–7) and BA.2 (n = 42; 2.4%; 95% CI 0–13) viral variants, as confirmed by sequencing. No patients died in either group. In addition, there was no evidence of a difference in the slope of the change over time in the cycle threshold values between Omicron BA.1 or BA.2 infected patients (p = 0.87), indicating that time to virus resolution was similar between the two groups. It should be noted that the sample size of Omicron BA.2 infected patients in COCOPREV was comparatively small [35]. Secondly, the results of an interim report of a Japanese post-marketing study were only published in Japanese at the time our SLR was conducted and were thus excluded. Results were subsequently published in English and demonstrate a similarity in clinical outcomes for sotrovimab-treated patients infected with both Omicron BA.1 and BA.2 [36]. Progression (defined as needing oxygen or ventilation, needing ICU for exacerbation, hospitalization for exacerbation, or death due to exacerbation) within 29 days of sotrovimab administration or discharge/transfer date was assessed in hospitalized patients with mild-to-moderate COVID-19 (n = 246 for clinical outcomes). The rate of progression was found to be similar between the groups: 0.8% (95% CI 0.02–4.63; n = 1/118) in Omicron BA.1 (January 31, 2022 to March 27, 2022) and 0% (95% CI 0.00–2.84; n = 0/128) during BA.2 (March 28, 2022 to June 19, 2022). While many patient characteristics were similar across the periods, small differences in sex, age, weight, comorbidity status, vaccination status, and body temperature were reported, and not corrected for. It should also be noted that hospitalization in Japan was not only for clinical reasons, which may have affected these findings [36].

Results from this SLR suggest continued clinical effectiveness of sotrovimab (IV 500 mg) in preventing severe clinical outcomes related to COVID-19 infections during the period of Omicron BA.2 predominance vs control/comparator and compared with the period of Omicron BA.1 predominance, despite reduced in vitro neutralization activity. The studies included in this review were consistent in reporting low proportions of severe clinical outcomes (such as hospitalization and mortality) in sotrovimab-treated patients during the periods of Omicron BA.1 and Omicron BA.2 subvariant predominance. It is important to consider these findings with a degree of caution due to the inherent heterogeneity (e.g., population of interest, target outcomes, study design, and analytical methods applied) across the studies identified. It is expected that future real-world observational studies will further increase our understanding of sotrovimab’s effectiveness during Omicron BA.2 predominance.