Clinical efficacy of casirivimab and imdevimab in preventing COVID-19 in the Omicron BA.5 subvariant epidemic: a retrospective study

Clinical efficacy of casirivimab and imdevimab in preventing COVID-19 in the Omicron BA.5 subvariant epidemic: a retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical efficacy of casirivimab and imdevimab in preventing COVID-19 in the Omicron BA.5 subvariant epidemic: a retrospective study Mariko Ohtani, Takuya Yokoo, Taito Miyazaki, Hiroshi Yasuda, Eriko Nishikawa, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6582593/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Oct, 2025 Read the published version in Journal of Pharmaceutical Health Care and Sciences → Version 1 posted You are reading this latest preprint version Abstract Background: The neutralizing monoclonal antibody combination of casirivimab and imdevimab (CAS + IMD) is the only therapy approved for preventing coronavirus disease 2019 (COVID-19) following exposure to severe acute respiratory syndrome coronavirus 2. However, the efficacy of CAS + IMD against Omicron variants remains uncertain, with in vitro studies indicating reduced neutralizing activity. This study aimed to evaluate the clinical efficacy of CAS + IMD in preventing COVID-19 among uninfected hospitalized contacts of patients with COVID-19. Methods: A retrospective chart review was conducted on 154 inpatients exposed to patients with COVID-19 between October and December 2022. Fifty-two uninfected participants who were unvaccinated or immunosuppressed and had risk factors for severe COVID-19 were included. The primary endpoint was the COVID-19 incidence rate. Statistical analyses included the chi-square test, Fisher's exact test, and Mann–Whitney U test, as appropriate. Factors associated with COVID-19 incidence ( p < 0.02) in univariate analysis were included in the multivariate logistic regression. Statistical significance was set at p < 0.05. Results: Among the 52 participants, 14 and 38 were included in the CAS + IMD and non-CAS + IMD groups, respectively. The COVID-19 incidence rate was significantly lower in the CAS + IMD group than in the non-CAS + IMD group (14.3% vs. 52.6%, p = 0.013). Multivariate analysis identified CAS + IMD administration as significantly associated with reduced COVID-19 incidence (adjusted odds ratio [OR], 0.121; 95% confidence interval [CI], 0.020–0.710; p = 0.019), whereas long-term use of immunosuppressive therapy was associated with increased incidence (adjusted OR, 4.320; 95% CI, 1.090–17.126; p = 0.037). Conclusions: CAS + IMD may be effective for post-exposure prophylaxis of COVID-19 during the Omicron BA.5 subvariant epidemic. However, prudent clinical use should consider the circulating variant profile. Further research is warranted to validate CAS + IMD’s role in COVID-19 post-exposure prophylaxis. COVID-19 casirivimab imdevimab post-exposure prophylaxis Omicron Figures Figure 1 Figure 2 Figure 3 Background Coronavirus disease 2019 (COVID-19) rapidly spread worldwide following its initial outbreak in Wuhan, China, in December 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19, is an enveloped virus with a large RNA genome of approximately 30,000 nucleotides. Since late 2020, numerous SARS-CoV-2 variants with genetic mutations have emerged ( 1 ). Following the emergence of the B.1.1.529 (Omicron) variant in late 2021, successive Omicron subvariants have replaced earlier epidemic strains, exhibiting immune evasion mechanisms such as increased transmissibility, vaccine resistance, and reduced susceptibility to neutralizing monoclonal antibodies. Although antiviral agents are frequently used to treat COVID-19, particularly Omicron lineages, none are indicated for prophylaxis. In contrast, in Japan, the only approved post-exposure prophylactic therapy is the neutralizing monoclonal antibody combination of casirivimab and imdevimab (CAS + IMD). A randomized, double-blind, placebo-controlled phase III trial assessed the efficacy of subcutaneous CAS + IMD in preventing SARS-CoV-2 infection among previously uninfected household contacts of infected individuals ( 2 ). During the 28-day assessment, symptomatic SARS-CoV-2 infection rates were 1.5% (11/753) and 7.8% (59/752) in the CAS + IMD and placebo groups, respectively, yielding a relative risk reduction of 81.4% (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.09–0.33; p < 0.001). A 7-month follow-up analysis confirmed a sustained prophylactic effect, with an 81.2% reduction in symptomatic SARS-CoV-2 infection compared to placebo (OR, 0.17; 95% CI, 0.10–0.27; p < 0.0001), demonstrating both pre- and post-exposure efficacy ( 3 ). However, these findings preceded the emergence of Omicron variants, and although CAS + IMD has shown reduced neutralizing activity against Omicron variants in vitro ( 4 – 9 ), its current effectiveness in preventing COVID-19 remains unclear. This study aimed to evaluate the clinical efficacy of CAS + IMD in preventing COVID-19 in uninfected hospitalized contacts of patients with COVID-19 during the Omicron BA.5 subvariant epidemic. Methods Patients A retrospective chart review was conducted at Toho University Omori Medical Center for inpatients who had contact with patients with COVID-19 between October and December 2022. Contacts were defined as patients admitted to the same hospital room as patients with COVID-19 within the 2 days preceding symptom onset. Those who remained hospitalized underwent a 7-day isolation period following their last exposure. Patients who had been discharged before the discovery of contact were followed up by telephone. To evaluate the clinical efficacy of CAS + IMD, we included uninfected patients who were unvaccinated or immunosuppressed and had risk factors for severe COVID-19, in accordance with the drug’s package insert. Patients were excluded if they were discharged during the isolation period and had no post-discharge clinical information available in their electronic medical records. Additionally, patients with asymptomatic SARS-CoV-2 infection at the time of CAS + IMD administration or who experienced treatment interruption due to adverse effects were excluded to ensure accurate assessment of prophylactic efficacy. The infection control team recommended CAS + IMD to eligible patients upon confirmation of contact with patients with COVID-19. The final decision regarding administration was made by the attending physician. CAS + IMD was administered as a single 1,200-mg dose (600 mg each of CAS and IMD). Nasopharyngeal samples were collected and tested for SARS-CoV-2 using either reverse transcription–polymerase chain reaction (Xpert Xpress SARS-CoV-2; Beckman Coulter, Tokyo, Japan) or antigen testing (Lumipulse SARS-CoV-2 Ag; Fujirebio, Tokyo, Japan) at the time of contact identification and between days 5 and 7 following exposure. Patients who developed symptoms suggestive of COVID-19 before the end of the isolation period were tested as clinically indicated. Research methods Using electronic medical records, we assessed the following characteristics during the study period: age, sex, height, weight, body mass index (BMI), estimated glomerular filtration rate (eGFR), CAS + IMD administration, dialysis, number of vaccinations, performance status, duration of contact with patients with COVID-19, isolation methods, and risk factors for severe COVID-19. These risk factors included age ≥ 50 years, obesity (BMI > 30 kg/m 2 ), cardiovascular disease (including hypertension), chronic lung disease (including asthma), diabetes, chronic kidney disease (eGFR < 60 mL/min/1.73 m 2 ), and immunosuppressed status. Immunosuppressed status encompassed malignancy treatment, bone marrow or organ transplant, end-stage renal failure (eGFR < 15 mL/min/1.73 m 2 or dialysis), and long-term use of immunosuppressive therapy. The primary endpoint was the COVID-19 incidence rate. Statistical analyses Participant characteristics were compared using the chi-square test, Fisher's exact test, or Mann–Whitney U test, as appropriate. COVID-19 incidence rates were compared using the chi-square test. Factors associated with COVID-19 incidence in univariate analysis ( p < 0.02) were included in the multivariate logistic regression analysis. The COVID-19 incidence rates in the CAS + IMD and non-CAS + IMD groups were analyzed using the Kaplan–Meier method and log-rank test. Data are presented as medians and interquartile ranges (IQR). Statistical significance was set at p < 0.05. Analyses were performed using SPSS version 24 (IBM Corp., Armonk, NY, USA). Results Patients' characteristics Of the 154 inpatients who had contact with patients with COVID-19 during the study period, 102 were excluded for the following reasons: 12 had no risk factors for severe COVID-19 or immunosuppression; 70 had ≥1 risk factor for severe COVID-19 but no immunosuppression; 17 had unknown outcomes after discharge; 2 received CAS + IMD for asymptomatic SARS-CoV-2 infection; 1 discontinued CAS + IMD due to adverse effects. The only adverse effect observed was in the excluded patient, who experienced neck-to-lumbar pain and nausea during administration, leading to discontinuation at half dose. The patient recovered thereafter. The final analysis included 52 patients: 14 in the CAS + IMD group and 38 in the non-CAS + IMD group ( Fig. 1 ). The CAS + IMD group had significantly more patients on dialysis than the non-CAS + IMD group (7 [50.0%] vs. 3 [7.9%] p = 0.002) ( Table 1 ). The duration of contact with patients with COVID-19 was significantly longer in the CAS + IMD group (median, 4 days; IQR, 3–5) than in the non-CAS + IMD group (median, 3 days; IQR, 3–3). No other significant differences in baseline characteristics were found between the groups. Regarding immunosuppressed status—a key risk factor for severe COVID- 19—the CAS + IMD group had more patients with end-stage renal failure than the non-CAS + IMD group (7 [50.0%] vs. 5 [13.2%], respectively; p = 0.010) ( Table 2 ). [Table 1 here] [Table 2 here] Clinical efficacy of CAS + IMD in preventing COVID-19 The COVID-19 incidence rates were 14.3% (2/14) in the CAS + IMD group and 52.6% (20/38) in the non–CAS + IMD group. The incidence was significantly lower in the CAS + IMD group ( p = 0.013) ( Fig. 2 ). Factors associated with COVID-19 incidence Among the 52 eligible patients, 22 developed COVID-19 and 30 did not ( Table 3 ). Univariate analyses indicated that patients in the COVID-19 group were significantly less likely to have received CAS + IMD and more likely to have undergone bone marrow or organ transplant or long-term immunosuppressive therapy than the non-COVID-19 group. Regarding isolation methods, fewer patients in the COVID-19 group were isolated in individual rooms (2 [9.1%] vs. 10 [33.3%], respectively; p = 0.010). Multivariate logistic regression showed that COVID-19 incidence was significantly associated with CAS + IMD administration (adjusted OR, 0.121; 95% CI, 0.020–0.710; p = 0.019) and long-term use of immunosuppressive therapy (adjusted OR, 4.320; 95% CI, 1.090–17.126; p = 0.037). The proportion of patients without COVID-19 was significantly lower in the CAS + IMD group than in the non-CAS + IMD group ( p = 0.023) ( Fig. 3 ). [Table 3 here] Discussion In this study, we evaluated the clinical efficacy of CAS + IMD in preventing COVID-19 among unvaccinated or immunosuppressed, uninfected inpatients with risk factors for severe COVID-19 who had been in contact with patients with COVID-19. The results demonstrated a significantly lower COVID-19 incidence rate in the CAS + IMD group than in the non-CAS + IMD group. Multivariate analysis identified CAS + IMD administration and long-term immunosuppressive therapy as significant factors associated with COVID-19 incidence. A phase III trial assessing the preventive efficacy of CAS + IMD was conducted prior to the Omicron variant epidemic ( 2 ). In contrast, the present study was conducted during the Omicron variant epidemic, involving different predominant strains. Although this study did not perform genetic sequencing of SARS-CoV-2 strains, national surveillance data from Japan during the study period indicated that BA.5 accounted for an average of 92.1% of infections, followed by BA.2 (6.2%) and BA.4 (0.2%) ( 10 ). Therefore, BA.5 was likely the dominant strain during the study period. CAS + IMD targets distinct, non-overlapping epitopes on the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, thereby inhibiting viral entry into host cells ( 11 ). Omicron variants possess multiple RBD mutations and various antigenic deletions and substitutions in the amino-terminal domain, enabling them to evade most therapeutic monoclonal antibodies ( 1 ). Takashita et al. evaluated in vitro neutralizing activity and reported that CAS + IMD was 317.8-fold less effective against BA.5 than against the ancestral strain and 43.0–143.6-fold less effective against BA.2 and other non-Omicron variants ( 4 , 5 ). Conversely, a retrospective study found no significant difference in the therapeutic efficacy of CAS + IMD between the Delta and Omicron variants. However, that study was conducted before the BA.5 subvariant became prevalent ( 12 , 13 ). In the present study, conducted during the BA.5 subvariant epidemic, the CAS + IMD group showed significantly lower COVID-19 incidence than the non-CAS + IMD group (Fig. 2 ), and CAS + IMD use was associated with reduced incidence (Table 3 ). These findings suggest that reduced neutralizing activity in vitro may not directly translate to diminished clinical efficacy. Hagihara et al. reported on patients with hematological malignancies and persistent SARS-CoV-2 infection despite prior antiviral treatment (remdesivir or molnupiravir) during the BA.5 epidemic. CAS + IMD was administered, and viral RNA became undetectable within 7 days in 5 of 9 patients, despite isolated viruses showing low or no sensitivity to CAS + IMD ( 14 ). One proposed explanation is that antibody-dependent cellular cytotoxicity (ADCC) activity against Omicron variants may have contributed to viral clearance. Wang et al. performed immunoprofiling in 46 participants from a single site in a multisite CAS + IMD trial using longitudinal blood samples collected before the emergence of Delta and Omicron variants and prior to widespread vaccination ( 15 ). Compared with placebo, CAS + IMD administration accelerated the transition from an acute inflammatory immunophenotype to a resolution phase characterized by reduced tissue injury, lower proinflammatory markers, and restoration of lymphocyte–monocyte balance, regardless of baseline serostatus. CAS + IMD also preserved host T-cell immunity to the SARS-CoV-2 spike protein. The observed ADCC activity and anti-inflammatory properties of CAS + IMD may help explain its role in reducing COVID-19 incidence, even amid BA.5 predominance. Timely detection of COVID-19 cases, isolation of patients, and identification and isolation of contacts are essential to prevent outbreaks in hospitals and nursing homes. Although private room isolation is preferable due to the potential for transmission among contacts, only 23.1% (12/52) of participants in this study were isolated in private rooms, whereas 71.2% (37/52) were isolated in shared rooms. This likely reflects the challenge of implementing ideal isolation protocols during cluster outbreaks across multiple wards. The COVID-19 group had a significantly lower rate of private room isolation than the non-COVID-19 group in the univariate analysis (Table 3 ). Notably, despite significantly longer exposure to patients with COVID-19, the CAS + IMD group experienced significantly lower COVID-19 incidence than the non-CAS + IMD group (Table 1 , Fig. 2 ). Many hospitalized patients are immunosuppressed and at elevated risk for severe COVID-19, and infection may delay treatment for underlying conditions. In this study, long-term immunosuppressive therapy was identified as a factor increasing COVID-19 incidence (Table 3 ). In such settings, post-exposure prophylaxis, alongside infection control, becomes especially important to prevent further transmission. Although in vitro studies suggest that CAS + IMD exhibits limited neutralizing activity against Omicron variants post-BA.5 ( 6 , 8 , 9 ), its ADCC activity and SARS-CoV-2–neutralizing anti-inflammatory effects may still contribute to reduced incidence. Therefore, its use should be carefully considered based on the prevalent variant. In Japan, all monoclonal antibodies for SARS-CoV-2 were previously government-distributed and free of charge, but distribution ended on May 31, 2024. Currently, there are virtually no agents available for post-exposure prophylaxis, despite recurring COVID-19 outbreaks. As with influenza, a strategic stockpile of agents for post-exposure prophylaxis is essential for COVID-19 preparedness. This study has several limitations, including its single-center, retrospective design, small sample size, and lack of randomization, which may introduce bias. The significantly higher number of dialysis patients in the CAS + IMD group may reflect selection bias, potentially due to greater willingness among renal center physicians to administer the agent. Although these findings suggest CAS + IMD is effective for post-exposure prophylaxis during the Omicron BA.5 subvariant epidemic, the current absence of suitable prophylactic agents poses a critical challenge. With emerging variants that may evade immunity, these results aim to inform future research on effective post-exposure prophylactic strategies. Conclusions The findings of this study suggest that CAS + IMD is effective for post-exposure prophylaxis of COVID-19 during the Omicron BA.5 subvariant epidemic. However, prudent decision-making should consider the prevalence of circulating variants. Further research is warranted to establish optimal strategies for post-exposure prophylaxis of COVID-19. Abbreviations ADCC, antibody-dependent cellular cytotoxicity; CAS, casirivimab; CI, confidence interval; COVID-19, coronavirus disease 2019; IMD, imdevimab; IQR, interquartile range; OR, odds ratio; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 Declarations Ethics approval and consent to participate This study adhered to the “Ethical Guidelines for Medical and Biological Research Involving Human Subjects” and was approved by the Ethics Committee of Toho University Omori Medical Center (approval number: M24037 22285). Patients were informed of their option to opt out, with details clearly outlined on the institutional website. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study did not receive specific grants from public, commercial, or non-profit funding agencies. Authors' contributions Study concept and design: MO, TY, TM, and HY. Investigation: MO, HY, EN, MT, MT, ES, and HM. Data acquisition: MO and HM. Data analysis and interpretation: MO, TY, and HY. Manuscript drafting: MO. Manuscript review and editing: TY, TM, HY, SH, SY, TM, and KT. Acknowledgements We would like to thank the Department of Pharmacy and Infection Control and Prevention members at our hospital for their assistance and suggestions regarding this study. We would like to thank Editage (www.editage.com) for the English language editing. References Carabelli AM, Peacock TP, Thorne LG, Harvey WT, Hughes J, de Silva TI, et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat Rev Microbiol. 2023;21(3):162–77. doi:10.1038/s41579-022-00841-7 O’Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan KC, Sarkar N, et al. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med. 2021;385(13):1184–95. doi:10.1056/NEJMoa2109682 Herman GA, O’Brien MP, Forleo-Neto E, Sarkar N, Isa F, Hou P, et al. Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2022;22(10):1444–54. doi:10.1016/S1473-3099(22)00416-9 Takashita E, Kinoshita N, Yamayoshi S, Sakai-Tagawa Y, Fujisaki S, Ito M, et al. Efficacy of antiviral agents against the SARS-CoV-2 Omicron subvariant BA.2. 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PLoS One. 2022;17(12):e0278770. doi:10.1371/journal.pone.0278770 Hagihara M, Hayashi H, Nakashima S, Imai Y, Nakano H, Uchida T, et al. Clinical efficacy of imdevimab/casirivimab for persistent Omicron SARS-CoV-2 infection in patients with hematological malignancies. Intern Med. 2024;63(16):2283–7. doi:10.2169/internalmedicine.2900-23 Wang B, Golubov J, Oswald EM, Poon P, Wei Q, Lett C, et al. Potential immunomodulatory effects of CAS+IMD monoclonal antibody cocktail in hospitalized patients with COVID-19. EBioMedicine. 2024;108:105334. doi:10.1016/j.ebiom.2024.105334. Tables Tables 1 to 3 are available in the Supplementary Files section Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6582593","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":454191483,"identity":"26d3c21d-e6df-47b5-be79-036d459aca33","order_by":0,"name":"Mariko 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07:23:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6582593/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6582593/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40780-025-00501-x","type":"published","date":"2025-10-27T15:58:33+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82604943,"identity":"fc2e0332-3eac-4d2c-b79a-cb0b2b6d7572","added_by":"auto","created_at":"2025-05-13 09:59:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34520,"visible":true,"origin":"","legend":"\u003cp\u003eParticipant selection flowchart.\u003c/p\u003e\n\u003cp\u003eCOVID-19, coronavirus disease 2019; CAS + IMD, casirivimab and imdevimab; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.\u003c/p\u003e","description":"","filename":"Figures1.png","url":"https://assets-eu.researchsquare.com/files/rs-6582593/v1/6df5fc829a9abe7b6501316b.png"},{"id":82602706,"identity":"1be26383-fb35-4d0f-b99f-04988daa3158","added_by":"auto","created_at":"2025-05-13 09:51:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":47476,"visible":true,"origin":"","legend":"\u003cp\u003eIncidence rate of COVID-19 in each group.\u003c/p\u003e\n\u003cp\u003eCOVID-19, coronavirus disease 2019; CAS + IMD, casirivimab and imdevimab.\u003c/p\u003e","description":"","filename":"Figures2.png","url":"https://assets-eu.researchsquare.com/files/rs-6582593/v1/3ce45976b3626c332ed5a21e.png"},{"id":82602723,"identity":"b33dc6b6-b729-4cf1-981c-94835e57bb5b","added_by":"auto","created_at":"2025-05-13 09:51:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":24403,"visible":true,"origin":"","legend":"\u003cp\u003eChanges over time in the proportion of patients without COVID-19. COVID-19, coronavirus disease 2019; CAS + IMD, casirivimab and imdevimab.\u003c/p\u003e","description":"","filename":"Figures3.png","url":"https://assets-eu.researchsquare.com/files/rs-6582593/v1/74f7d7b9c1d8e426e846d59c.png"},{"id":95040043,"identity":"846cac5e-664e-4eeb-a98c-4afe7331c056","added_by":"auto","created_at":"2025-11-03 16:07:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":694129,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6582593/v1/3ca4a3d4-48ba-48bd-a648-05d2ebd50272.pdf"},{"id":82604942,"identity":"e894d377-4d37-4a78-9b36-88bd8d0e62e1","added_by":"auto","created_at":"2025-05-13 09:59:32","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":126687,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6582593/v1/f10e01b7ce0e84807607f23d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical efficacy of casirivimab and imdevimab in preventing COVID-19 in the Omicron BA.5 subvariant epidemic: a retrospective study","fulltext":[{"header":"Background","content":"\u003cp\u003eCoronavirus disease 2019 (COVID-19) rapidly spread worldwide following its initial outbreak in Wuhan, China, in December 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19, is an enveloped virus with a large RNA genome of approximately 30,000 nucleotides. Since late 2020, numerous SARS-CoV-2 variants with genetic mutations have emerged (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Following the emergence of the B.1.1.529 (Omicron) variant in late 2021, successive Omicron subvariants have replaced earlier epidemic strains, exhibiting immune evasion mechanisms such as increased transmissibility, vaccine resistance, and reduced susceptibility to neutralizing monoclonal antibodies.\u003c/p\u003e \u003cp\u003eAlthough antiviral agents are frequently used to treat COVID-19, particularly Omicron lineages, none are indicated for prophylaxis. In contrast, in Japan, the only approved post-exposure prophylactic therapy is the neutralizing monoclonal antibody combination of casirivimab and imdevimab (CAS\u0026thinsp;+\u0026thinsp;IMD). A randomized, double-blind, placebo-controlled phase III trial assessed the efficacy of subcutaneous CAS\u0026thinsp;+\u0026thinsp;IMD in preventing SARS-CoV-2 infection among previously uninfected household contacts of infected individuals (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). During the 28-day assessment, symptomatic SARS-CoV-2 infection rates were 1.5% (11/753) and 7.8% (59/752) in the CAS\u0026thinsp;+\u0026thinsp;IMD and placebo groups, respectively, yielding a relative risk reduction of 81.4% (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.09\u0026ndash;0.33; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A 7-month follow-up analysis confirmed a sustained prophylactic effect, with an 81.2% reduction in symptomatic SARS-CoV-2 infection compared to placebo (OR, 0.17; 95% CI, 0.10\u0026ndash;0.27; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), demonstrating both pre- and post-exposure efficacy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). However, these findings preceded the emergence of Omicron variants, and although CAS\u0026thinsp;+\u0026thinsp;IMD has shown reduced neutralizing activity against Omicron variants \u003cem\u003ein vitro\u003c/em\u003e (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), its current effectiveness in preventing COVID-19 remains unclear.\u003c/p\u003e \u003cp\u003eThis study aimed to evaluate the clinical efficacy of CAS\u0026thinsp;+\u0026thinsp;IMD in preventing COVID-19 in uninfected hospitalized contacts of patients with COVID-19 during the Omicron BA.5 subvariant epidemic.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e A retrospective chart review was conducted at Toho University Omori Medical Center for inpatients who had contact with patients with COVID-19 between October and December 2022. Contacts were defined as patients admitted to the same hospital room as patients with COVID-19 within the 2 days preceding symptom onset. Those who remained hospitalized underwent a 7-day isolation period following their last exposure. Patients who had been discharged before the discovery of contact were followed up by telephone. To evaluate the clinical efficacy of CAS\u0026thinsp;+\u0026thinsp;IMD, we included uninfected patients who were unvaccinated or immunosuppressed and had risk factors for severe COVID-19, in accordance with the drug\u0026rsquo;s package insert. Patients were excluded if they were discharged during the isolation period and had no post-discharge clinical information available in their electronic medical records. Additionally, patients with asymptomatic SARS-CoV-2 infection at the time of CAS\u0026thinsp;+\u0026thinsp;IMD administration or who experienced treatment interruption due to adverse effects were excluded to ensure accurate assessment of prophylactic efficacy. The infection control team recommended CAS\u0026thinsp;+\u0026thinsp;IMD to eligible patients upon confirmation of contact with patients with COVID-19. The final decision regarding administration was made by the attending physician. CAS\u0026thinsp;+\u0026thinsp;IMD was administered as a single 1,200-mg dose (600 mg each of CAS and IMD). Nasopharyngeal samples were collected and tested for SARS-CoV-2 using either reverse transcription\u0026ndash;polymerase chain reaction (Xpert Xpress SARS-CoV-2; Beckman Coulter, Tokyo, Japan) or antigen testing (Lumipulse SARS-CoV-2 Ag; Fujirebio, Tokyo, Japan) at the time of contact identification and between days 5 and 7 following exposure. Patients who developed symptoms suggestive of COVID-19 before the end of the isolation period were tested as clinically indicated.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eResearch methods\u003c/h3\u003e\n\u003cp\u003eUsing electronic medical records, we assessed the following characteristics during the study period: age, sex, height, weight, body mass index (BMI), estimated glomerular filtration rate (eGFR), CAS\u0026thinsp;+\u0026thinsp;IMD administration, dialysis, number of vaccinations, performance status, duration of contact with patients with COVID-19, isolation methods, and risk factors for severe COVID-19. These risk factors included age\u0026thinsp;\u0026ge;\u0026thinsp;50 years, obesity (BMI\u0026thinsp;\u0026gt;\u0026thinsp;30 kg/m\u003csup\u003e2\u003c/sup\u003e), cardiovascular disease (including hypertension), chronic lung disease (including asthma), diabetes, chronic kidney disease (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e), and immunosuppressed status. Immunosuppressed status encompassed malignancy treatment, bone marrow or organ transplant, end-stage renal failure (eGFR\u0026thinsp;\u0026lt;\u0026thinsp;15 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e or dialysis), and long-term use of immunosuppressive therapy. The primary endpoint was the COVID-19 incidence rate.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eParticipant characteristics were compared using the chi-square test, Fisher's exact test, or Mann\u0026ndash;Whitney U test, as appropriate. COVID-19 incidence rates were compared using the chi-square test. Factors associated with COVID-19 incidence in univariate analysis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.02) were included in the multivariate logistic regression analysis. The COVID-19 incidence rates in the CAS\u0026thinsp;+\u0026thinsp;IMD and non-CAS\u0026thinsp;+\u0026thinsp;IMD groups were analyzed using the Kaplan\u0026ndash;Meier method and log-rank test. Data are presented as medians and interquartile ranges (IQR). Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Analyses were performed using SPSS version 24 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatients' characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;Of the 154 inpatients who had contact with patients with COVID-19 during the study period, 102 were excluded for the following reasons: 12 had no risk factors for severe COVID-19 or immunosuppression; 70 had ≥1 risk factor for severe COVID-19 but no immunosuppression; 17 had unknown outcomes after discharge; 2 received CAS + IMD for asymptomatic SARS-CoV-2 infection; 1 discontinued CAS + IMD due to adverse effects. The only adverse effect observed was in the excluded patient, who experienced neck-to-lumbar pain and nausea during administration, leading to discontinuation at half dose. The patient recovered thereafter. The final analysis included 52 patients: 14 in the CAS + IMD group and 38 in the non-CAS + IMD group (\u003cstrong\u003eFig. 1\u003c/strong\u003e). The CAS + IMD group had significantly more patients on dialysis than the non-CAS + IMD group (7 [50.0%] vs. 3 [7.9%]\u0026nbsp;\u003cem\u003ep\u003c/em\u003e = 0.002) (\u003cstrong\u003eTable 1\u003c/strong\u003e). The duration of contact with patients with COVID-19 was significantly longer in the CAS + IMD group (median, 4 days; IQR, 3–5) than in the non-CAS + IMD group (median, 3 days; IQR, 3–3). No other significant differences in baseline characteristics were found between the groups. Regarding immunosuppressed status—a key risk factor for severe COVID-\u003c/p\u003e\n\u003cp\u003e19—the CAS + IMD group had more patients with end-stage renal failure than the\u0026nbsp;\u003c/p\u003e\n\u003cp\u003enon-CAS + IMD group (7 [50.0%] vs. 5 [13.2%], respectively;\u0026nbsp;\u003cem\u003ep\u003c/em\u003e = 0.010) (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e[Table 1 here]\u003c/p\u003e\n\u003cp\u003e[Table 2 here]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical efficacy of CAS + IMD in preventing COVID-19\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;The COVID-19 incidence rates were 14.3% (2/14) in the CAS + IMD group and 52.6% (20/38) in the non–CAS + IMD group. The incidence was significantly lower in the CAS + IMD group (\u003cem\u003ep\u003c/em\u003e = 0.013) (\u003cstrong\u003eFig. 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFactors associated with COVID-19 incidence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;Among the 52 eligible patients, 22 developed COVID-19 and 30 did not (\u003cstrong\u003eTable 3\u003c/strong\u003e). Univariate analyses indicated that patients in the COVID-19 group were significantly less likely to have received CAS + IMD and more likely to have undergone bone marrow or organ transplant or long-term immunosuppressive therapy than the non-COVID-19 group. Regarding isolation methods, fewer patients in the COVID-19 group were isolated in individual rooms (2 [9.1%] vs. 10 [33.3%], respectively;\u0026nbsp;\u003cem\u003ep\u003c/em\u003e = 0.010). Multivariate logistic regression showed that COVID-19 incidence was significantly associated with CAS + IMD administration (adjusted OR, 0.121; 95% CI, 0.020–0.710;\u0026nbsp;\u003cem\u003ep\u003c/em\u003e = 0.019) and long-term use of immunosuppressive therapy (adjusted OR, 4.320; 95% CI, 1.090–17.126;\u0026nbsp;\u003cem\u003ep\u003c/em\u003e = 0.037). The proportion of patients without COVID-19 was significantly lower in the CAS + IMD group than in the non-CAS + IMD group (\u003cem\u003ep\u003c/em\u003e = 0.023) (\u003cstrong\u003eFig. 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e[Table 3 here]\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we evaluated the clinical efficacy of CAS\u0026thinsp;+\u0026thinsp;IMD in preventing COVID-19 among unvaccinated or immunosuppressed, uninfected inpatients with risk factors for severe COVID-19 who had been in contact with patients with COVID-19. The results demonstrated a significantly lower COVID-19 incidence rate in the CAS\u0026thinsp;+\u0026thinsp;IMD group than in the non-CAS\u0026thinsp;+\u0026thinsp;IMD group. Multivariate analysis identified CAS\u0026thinsp;+\u0026thinsp;IMD administration and long-term immunosuppressive therapy as significant factors associated with COVID-19 incidence.\u003c/p\u003e \u003cp\u003eA phase III trial assessing the preventive efficacy of CAS\u0026thinsp;+\u0026thinsp;IMD was conducted prior to the Omicron variant epidemic (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In contrast, the present study was conducted during the Omicron variant epidemic, involving different predominant strains. Although this study did not perform genetic sequencing of SARS-CoV-2 strains, national surveillance data from Japan during the study period indicated that BA.5 accounted for an average of 92.1% of infections, followed by BA.2 (6.2%) and BA.4 (0.2%) (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Therefore, BA.5 was likely the dominant strain during the study period.\u003c/p\u003e \u003cp\u003eCAS\u0026thinsp;+\u0026thinsp;IMD targets distinct, non-overlapping epitopes on the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, thereby inhibiting viral entry into host cells (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Omicron variants possess multiple RBD mutations and various antigenic deletions and substitutions in the amino-terminal domain, enabling them to evade most therapeutic monoclonal antibodies (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Takashita et al. evaluated \u003cem\u003ein vitro\u003c/em\u003e neutralizing activity and reported that CAS\u0026thinsp;+\u0026thinsp;IMD was 317.8-fold less effective against BA.5 than against the ancestral strain and 43.0\u0026ndash;143.6-fold less effective against BA.2 and other non-Omicron variants (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Conversely, a retrospective study found no significant difference in the therapeutic efficacy of CAS\u0026thinsp;+\u0026thinsp;IMD between the Delta and Omicron variants. However, that study was conducted before the BA.5 subvariant became prevalent (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In the present study, conducted during the BA.5 subvariant epidemic, the CAS\u0026thinsp;+\u0026thinsp;IMD group showed significantly lower COVID-19 incidence than the non-CAS\u0026thinsp;+\u0026thinsp;IMD group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and CAS\u0026thinsp;+\u0026thinsp;IMD use was associated with reduced incidence (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These findings suggest that reduced neutralizing activity \u003cem\u003ein vitro\u003c/em\u003e may not directly translate to diminished clinical efficacy. Hagihara et al. reported on patients with hematological malignancies and persistent SARS-CoV-2 infection despite prior antiviral treatment (remdesivir or molnupiravir) during the BA.5 epidemic. CAS\u0026thinsp;+\u0026thinsp;IMD was administered, and viral RNA became undetectable within 7 days in 5 of 9 patients, despite isolated viruses showing low or no sensitivity to CAS\u0026thinsp;+\u0026thinsp;IMD (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). One proposed explanation is that antibody-dependent cellular cytotoxicity (ADCC) activity against Omicron variants may have contributed to viral clearance. Wang et al. performed immunoprofiling in 46 participants from a single site in a multisite CAS\u0026thinsp;+\u0026thinsp;IMD trial using longitudinal blood samples collected before the emergence of Delta and Omicron variants and prior to widespread vaccination (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Compared with placebo, CAS\u0026thinsp;+\u0026thinsp;IMD administration accelerated the transition from an acute inflammatory immunophenotype to a resolution phase characterized by reduced tissue injury, lower proinflammatory markers, and restoration of lymphocyte\u0026ndash;monocyte balance, regardless of baseline serostatus. CAS\u0026thinsp;+\u0026thinsp;IMD also preserved host T-cell immunity to the SARS-CoV-2 spike protein. The observed ADCC activity and anti-inflammatory properties of CAS\u0026thinsp;+\u0026thinsp;IMD may help explain its role in reducing COVID-19 incidence, even amid BA.5 predominance.\u003c/p\u003e \u003cp\u003eTimely detection of COVID-19 cases, isolation of patients, and identification and isolation of contacts are essential to prevent outbreaks in hospitals and nursing homes. Although private room isolation is preferable due to the potential for transmission among contacts, only 23.1% (12/52) of participants in this study were isolated in private rooms, whereas 71.2% (37/52) were isolated in shared rooms. This likely reflects the challenge of implementing ideal isolation protocols during cluster outbreaks across multiple wards. The COVID-19 group had a significantly lower rate of private room isolation than the non-COVID-19 group in the univariate analysis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Notably, despite significantly longer exposure to patients with COVID-19, the CAS\u0026thinsp;+\u0026thinsp;IMD group experienced significantly lower COVID-19 incidence than the non-CAS\u0026thinsp;+\u0026thinsp;IMD group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMany hospitalized patients are immunosuppressed and at elevated risk for severe COVID-19, and infection may delay treatment for underlying conditions. In this study, long-term immunosuppressive therapy was identified as a factor increasing COVID-19 incidence (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In such settings, post-exposure prophylaxis, alongside infection control, becomes especially important to prevent further transmission. Although \u003cem\u003ein vitro\u003c/em\u003e studies suggest that CAS\u0026thinsp;+\u0026thinsp;IMD exhibits limited neutralizing activity against Omicron variants post-BA.5 (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), its ADCC activity and SARS-CoV-2\u0026ndash;neutralizing anti-inflammatory effects may still contribute to reduced incidence. Therefore, its use should be carefully considered based on the prevalent variant. In Japan, all monoclonal antibodies for SARS-CoV-2 were previously government-distributed and free of charge, but distribution ended on May 31, 2024. Currently, there are virtually no agents available for post-exposure prophylaxis, despite recurring COVID-19 outbreaks. As with influenza, a strategic stockpile of agents for post-exposure prophylaxis is essential for COVID-19 preparedness.\u003c/p\u003e \u003cp\u003eThis study has several limitations, including its single-center, retrospective design, small sample size, and lack of randomization, which may introduce bias. The significantly higher number of dialysis patients in the CAS\u0026thinsp;+\u0026thinsp;IMD group may reflect selection bias, potentially due to greater willingness among renal center physicians to administer the agent. Although these findings suggest CAS\u0026thinsp;+\u0026thinsp;IMD is effective for post-exposure prophylaxis during the Omicron BA.5 subvariant epidemic, the current absence of suitable prophylactic agents poses a critical challenge. With emerging variants that may evade immunity, these results aim to inform future research on effective post-exposure prophylactic strategies.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe findings of this study suggest that CAS\u0026thinsp;+\u0026thinsp;IMD is effective for post-exposure prophylaxis of COVID-19 during the Omicron BA.5 subvariant epidemic. However, prudent decision-making should consider the prevalence of circulating variants. Further research is warranted to establish optimal strategies for post-exposure prophylaxis of COVID-19.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADCC, antibody-dependent cellular cytotoxicity; CAS, casirivimab; CI, confidence interval; COVID-19, coronavirus disease 2019; IMD, imdevimab; IQR, interquartile range; OR, odds ratio; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study adhered to the “Ethical Guidelines for Medical and Biological Research Involving Human Subjects” and was approved by the Ethics Committee of Toho University Omori Medical Center (approval number: M24037 22285). Patients were informed of their option to opt out, with details clearly outlined on the institutional website.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive specific grants from public, commercial, or non-profit funding agencies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy concept and design: MO, TY, TM, and HY. Investigation: MO, HY, EN, MT, MT, ES, and HM. Data acquisition: MO and HM. Data analysis and interpretation: MO, TY, and HY. Manuscript drafting: MO. Manuscript review and editing: TY, TM, HY, SH, SY, TM, and KT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the Department of Pharmacy and Infection Control and Prevention members at our hospital for their assistance and suggestions regarding this study. We would like to thank Editage (www.editage.com) for the English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCarabelli AM, Peacock TP, Thorne LG, Harvey WT, Hughes J, de Silva TI, et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat Rev Microbiol. 2023;21(3):162\u0026ndash;77. doi:10.1038/s41579-022-00841-7\u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan KC, Sarkar N, et al. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med. 2021;385(13):1184\u0026ndash;95. doi:10.1056/NEJMoa2109682\u003c/li\u003e\n\u003cli\u003eHerman GA, O\u0026rsquo;Brien MP, Forleo-Neto E, Sarkar N, Isa F, Hou P, et al. Efficacy and safety of a single dose of casirivimab and imdevimab for the prevention of COVID-19 over an 8-month period: a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2022;22(10):1444\u0026ndash;54. doi:10.1016/S1473-3099(22)00416-9\u003c/li\u003e\n\u003cli\u003eTakashita E, Kinoshita N, Yamayoshi S, Sakai-Tagawa Y, Fujisaki S, Ito M, et al. Efficacy of antiviral agents against the SARS-CoV-2 Omicron subvariant BA.2. N Engl J Med. 2022;386(15):1475\u0026ndash;7. doi:10.1056/NEJMc2201933\u003c/li\u003e\n\u003cli\u003eTakashita E, Yamayoshi S, Simon V, van Bakel H, Sordillo EM, Pekosz A, et al. Efficacy of antibodies and antiviral drugs against Omicron BA.2.12.1, BA.4, and BA.5 subvariants. N Engl J Med. 2022;387(5):468\u0026ndash;70. doi:10.1056/NEJMc2207519\u003c/li\u003e\n\u003cli\u003eImai M, Ito M, Kiso M, Yamayoshi S, Uraki R, Fukushi S, et al. Efficacy of antiviral agents against Omicron subvariants BQ.1.1 and XBB. N Engl J Med. 2023;388(1):89\u0026ndash;91. doi:10.1056/NEJMc2214302\u003c/li\u003e\n\u003cli\u003eSyed AM, Ciling A, Taha TY, Chen IP, Khalid MM, Sreekumar B, et al. Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles. Proc Natl Acad Sci U S A. 2022;119(31):e2200592119. doi:10.1073/pnas.2200592119\u003c/li\u003e\n\u003cli\u003ePlanas D, Bruel T, Staropoli I, Guivel-Benhassine F, Porrot F, Maes P, et al. Resistance of Omicron subvariants BA.2.75.2, BA.4.6, and BQ.1.1 to neutralizing antibodies. Nat Commun. 2023;14(1):824. doi:10.1038/s41467-023-36561-6\u003c/li\u003e\n\u003cli\u003eWang Q, Iketani S, Li Z, Liu L, Guo Y, Huang Y, et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell. 2023;186(2):279-286. e8. doi:10.1016/j.cell.2022.12.018\u003c/li\u003e\n\u003cli\u003eJapan Institute for Health Security. The Infectious Disease Information Website. 2023. https://id-info.jihs.go.jp/diseases/sa/covid-19/170/cepr-topics-log.html. Accessed 3 Apr 2025.\u003c/li\u003e\n\u003cli\u003eDeeks ED. Casirivimab/imdevimab: first approval. Drugs. 2021;81(17):2047\u0026ndash;55. doi:10.1007/s40265-021-01620-z\u003c/li\u003e\n\u003cli\u003eSubhash Walinjkar R, Kumbhar M, Harihar Shinde R, Chaurasia E. Real-world effect of casirivimab and imdevimab cocktail in patients infected with SARS-CoV-2 delta and omicron variants. J Infect Dev Ctries. 2023;17(03):293\u0026ndash;301. doi:10.3855/jidc.17039\u003c/li\u003e\n\u003cli\u003eGershengorn HB, Patel S, Ferreira T, Das S, Parekh DJ, Shukla B. The clinical effectiveness of REGEN-COV in SARS-CoV-2 infection with Omicron versus Delta variants. PLoS One. 2022;17(12):e0278770. doi:10.1371/journal.pone.0278770\u003c/li\u003e\n\u003cli\u003eHagihara M, Hayashi H, Nakashima S, Imai Y, Nakano H, Uchida T, et al. Clinical efficacy of imdevimab/casirivimab for persistent Omicron SARS-CoV-2 infection in patients with hematological malignancies. Intern Med. 2024;63(16):2283\u0026ndash;7. doi:10.2169/internalmedicine.2900-23\u003c/li\u003e\n\u003cli\u003eWang B, Golubov J, Oswald EM, Poon P, Wei Q, Lett C, et al. Potential immunomodulatory effects of CAS+IMD monoclonal antibody cocktail in hospitalized patients with COVID-19. EBioMedicine. 2024;108:105334. doi:10.1016/j.ebiom.2024.105334.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, casirivimab, imdevimab, post-exposure prophylaxis, Omicron","lastPublishedDoi":"10.21203/rs.3.rs-6582593/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6582593/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e The neutralizing monoclonal antibody combination of casirivimab and imdevimab (CAS + IMD) is the only therapy approved for preventing coronavirus disease 2019 (COVID-19) following exposure to severe acute respiratory syndrome coronavirus 2. However, the efficacy of CAS + IMD against Omicron variants remains uncertain, with \u003cem\u003ein vitro\u003c/em\u003e studies indicating reduced neutralizing activity. This study aimed to evaluate the clinical efficacy of CAS + IMD in preventing COVID-19 among uninfected hospitalized contacts of patients with COVID-19.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A retrospective chart review was conducted on 154 inpatients exposed to patients with COVID-19 between October and December 2022. Fifty-two uninfected participants who were unvaccinated or immunosuppressed and had risk factors for severe COVID-19 were included. The primary endpoint was the COVID-19 incidence rate. Statistical analyses included the chi-square test, Fisher's exact test, and Mann–Whitney U test, as appropriate. Factors associated with COVID-19 incidence (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.02) in univariate analysis were included in the multivariate logistic regression. Statistical significance was set at \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Among the 52 participants, 14 and 38 were included in the CAS + IMD and non-CAS + IMD groups, respectively. The COVID-19 incidence rate was significantly lower in the CAS + IMD group than in the non-CAS + IMD group (14.3% vs. 52.6%, \u003cem\u003ep\u003c/em\u003e = 0.013). Multivariate analysis identified CAS + IMD administration as significantly associated with reduced COVID-19 incidence (adjusted odds ratio [OR], 0.121; 95% confidence interval [CI], 0.020–0.710; \u003cem\u003ep\u003c/em\u003e = 0.019), whereas long-term use of immunosuppressive therapy was associated with increased incidence (adjusted OR, 4.320; 95% CI, 1.090–17.126; \u003cem\u003ep\u003c/em\u003e = 0.037).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e CAS + IMD may be effective for post-exposure prophylaxis of COVID-19 during the Omicron BA.5 subvariant epidemic. However, prudent clinical use should consider the circulating variant profile. Further research is warranted to validate CAS + IMD’s role in COVID-19 post-exposure prophylaxis.\u003c/p\u003e","manuscriptTitle":"Clinical efficacy of casirivimab and imdevimab in preventing COVID-19 in the Omicron BA.5 subvariant epidemic: a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 09:51:27","doi":"10.21203/rs.3.rs-6582593/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6477763c-ef45-439d-8b1a-dd5265e31b95","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T16:03:20+00:00","versionOfRecord":{"articleIdentity":"rs-6582593","link":"https://doi.org/10.1186/s40780-025-00501-x","journal":{"identity":"journal-of-pharmaceutical-health-care-and-sciences","isVorOnly":false,"title":"Journal of Pharmaceutical Health Care and Sciences"},"publishedOn":"2025-10-27 15:58:33","publishedOnDateReadable":"October 27th, 2025"},"versionCreatedAt":"2025-05-13 09:51:27","video":"","vorDoi":"10.1186/s40780-025-00501-x","vorDoiUrl":"https://doi.org/10.1186/s40780-025-00501-x","workflowStages":[]},"version":"v1","identity":"rs-6582593","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6582593","identity":"rs-6582593","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}