Forward and reverse translational approaches to predict efficacy of neutralizing respiratory syncytial virus (RSV) antibody prophylaxis

• Published in: EBioMedicine Vol. 73; p. 103651
• Main Authors: Maas, Brian M., Lommerse, Jos, Plock, Nele, Railkar, Radha A., Cheung, S.Y. Amy, Caro, Luzelena, Chen, Jingxian, Liu, Wen, Zhang, Ying, Huang, Qinlei, Gao, Wei, Qin, Li, Meng, Jie, Witjes, Han, Schindler, Emilie, Guiastrennec, Benjamin, Bellanti, Francesco, Spellman, Daniel S., Roadcap, Brad, Kalinova, Mariya, Fok-Seang, Juin, Catchpole, Andrew P., Espeseth, Amy S., Stoch, S. Aubrey, Lai, Eseng, Vora, Kalpit A., Aliprantis, Antonios O., Sachs, Jeffrey R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2021; Elsevier
• Subjects: Adolescent; Adult; Advanced Basic Science; Aged; Algorithms; Antibodies, Monoclonal; Antibodies, Neutralizing - administration & dosage; Antibodies, Neutralizing - immunology; Antibodies, Viral - administration & dosage; Antibodies, Viral - immunology; Clinical Trials as Topic; Female; Human Challenge Study; Humans; Incidence; Internal Medicine; Male; Middle Aged; Modelling and Simulation; Models, Theoretical; Monoclonal Antibody; Premedication; Research paper; Respiratory Syncytial Virus; Respiratory Syncytial Virus Infections - epidemiology; Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Virus Infections - prevention & control; Respiratory Syncytial Virus, Human - immunology; RSV, Meta-analysis; Seasons; Translational Research, Biomedical - methods; Young Adult; RSV, Meta-analysis; Modelling and Simulation; Human Challenge Study; Respiratory Syncytial Virus; Monoclonal Antibody
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2021.103651

Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary. Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population. The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants. An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.