Daniel Orosco

Background: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in children worldwide, contributes to millions of hospitalizations, and nearly 100,000 deaths annually in children under five years of age.¹ Current management of RSV is mainly supportive, with limited drug options available for prevention and treatment. Monoclonal antibodies (mAbs) such as nirsevimab and clesrovimab have emerged as important prophylactic agents targeting the RSV F protein.² Both antibodies contain YTE Fc-region modifications that extend serum half-life and allow once-seasonal dosing. Even with these antibodies, RSV continues to have a large overall disease burden. This led to an investigation into improved antibody engineering strategies that enhance efficacy and airway mucosal activity.³

Objective: To evaluate current and innovative mAb strategies for RSV prevention and treatment with an emphasis on antibody functionality, clinical outcomes, and novel approaches designed to improve airway mucosal concentration.

Search Methods:  A review of research articles in the PubMed database from 2018-2026 was conducted using keywords such as “respiratory syncytial virus,” “monoclonal antibodies,” “clesrovimab,” “nirsevimab,” and “Fc effector.”

Results: Current RSV mAbs primarily function through direct viral neutralization rather than Fc-mediated immune effector activity. In a cotton rat challenge study, nirsevimab analogs lacking Fc effector function provided similar protection against RSV compared to antibodies with intact Fc activity, suggesting that direct neutralization is the main protective mechanism. These findings support prioritization of antibody concentration and half-life for long term protection in future RSV mAb development.⁴  A phase 1b/2a clinical trial in infants demonstrated that clesrovimab is a promising prophylactic therapy for RSV, showing good tolerance and reduced RSV-related clinical endpoints. The antibody exhibited an approximate 45-day half-life, comparable to nirsevimab and much longer than palivizumab, the older monthly-dosed RSV mAb.⁵  Standard and effective clesrovimab dosages were measured in the nasal epithelial lining fluid at only 1.4–3.3% of serum concentrations. Because RSV primarily infects airway mucosal tissue, increasing antibody deposition at mucosal surfaces may improve antiviral effectiveness, particularly during early infection or post-exposure prophylaxis.⁶  Two engineering approaches were identified to address this low airway mucosal limitation. The first approach used bispecific antibodies containing both anti-RSV IgG functionality and anti-pIgR single-domain antibody regions to facilitate transcytosis into airway mucosa, utilizing IgA transport mechanisms. Experimental models showed that RSV neutralization was preserved with added mucosal transport.⁷ The second approach used inhaled “muco-trapping” mAbs designed to bind both RSV particles and airway mucins. Administration of the nebulized engineered antibody Mota-MT significantly reduced RSV viral load in animal models by trapping viral particles within mucus for physiologic clearance.⁸

Conclusion: mAbs currently provide strong prophylactic protection against RSV, with nirsevimab and clesrovimab representing major advances in long-acting immunoprophylaxis. New evidence suggests that direct viral neutralization is the primary protective mechanism of these therapies. Future RSV antibody development could benefit from enhanced airway mucosal deposition and acute antiviral activity. Bispecific antibodies and inhaled muco-trapping antibodies are promising innovations that could improve both prevention and treatment of RSV and potentially other respiratory viral infections.

Works Cited:

1. Asseri AA. Respiratory Syncytial Virus: A Narrative Review of Updates and Recent Advances in Epidemiology, Pathogenesis, Diagnosis, Management and Prevention. J Clin Med. 2025;14(11):3880. Published 2025 May 30. doi:10.3390/jcm14113880
2. Sevendal ATK, Hurley S, Bartlett AW, Rawlinson W, Walker GJ. Systematic Review of the Efficacy and Safety of RSV-Specific Monoclonal Antibodies and Antivirals in Development. Rev Med Virol. 2024;34(5):e2576. doi:10.1002/rmv.2576
3. Abdeldaim DT, Schindowski K. Fc-Engineered Therapeutic Antibodies: Recent Advances and Future Directions. Pharmaceutics. 2023;15(10):2402. Published 2023 Sep 28. doi:10.3390/pharmaceutics15102402
4. Brady T, Cayatte C, Roe TL, et al. Fc-mediated functions of nirsevimab complement direct respiratory syncytial virus neutralization but are not required for optimal prophylactic protection. Front Immunol. 2023;14:1283120. Published 2023 Oct 11. doi:10.3389/fimmu.2023.1283120
5. Madhi SA, Simões EAF, Acevedo A, et al. A Phase 1b/2a Trial of a Half-life Extended Respiratory Syncytial Virus Neutralizing Antibody, Clesrovimab, in Healthy Preterm and Full-term Infants. J Infect Dis. 2025;231(3):e478-e487. doi:10.1093/infdis/jiae581
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7. McSweeney MD, Alnajjar S, Schaefer AM, et al. Inhaled “Muco-Trapping” Monoclonal Antibody Effectively Treats Established Respiratory Syncytial Virus (RSV) Infections. Adv Sci (Weinh). 2024;11(12):e2306729. doi:10.1002/advs.202306729
8. Liu J, Jung J, Zhou S, et al. Unlocking binding properties of single-domain antibodies targeting the polymeric immunoglobulin receptor to enhance mucosal enrichment of IgG against respiratory syncytial virus. Front Immunol. 2026;16:1739562. Published 2026 Feb 9. doi:10.3389/fimmu.2025.1739562