Forward and reverse translational approaches to predict efficacy of neutralizing respiratory syncytial virus (RSV) antibody prophylaxis
- Resource Type
- Authors
- Francesco Bellanti; Antonios O. Aliprantis; Juin Fok-Seang; Wen Liu; Jeffrey R. Sachs; Radha Railkar; Brad Roadcap; Kalpit A. Vora; Qinlei Huang; Li Qin; Nele Plock; W. Gao; Eseng Lai; Daniel S. Spellman; Jingxian Chen; Andrew P. Catchpole; Emilie Schindler; Mariya Kalinova; Amy S. Espeseth; Jie Meng; S. Y. Amy Cheung; Luzelena Caro; S. Aubrey Stoch; Benjamin Guiastrennec; Jos Lommerse; Brian M. Maas; Ying Zhang; Han Witjes
- Source
- EBioMedicine, Vol 73, Iss, Pp 103651-(2021)
EBioMedicine
- Subject
- Adult
Male
Medicine (General)
Research paper
Adolescent
medicine.drug_class
Premedication
Monoclonal Antibody
Force of infection
Respiratory Syncytial Virus Infections
Antibodies, Viral
Monoclonal antibody
medicine.disease_cause
Placebo
General Biochemistry, Genetics and Molecular Biology
Virus
Translational Research, Biomedical
Young Adult
R5-920
Modelling and Simulation
Clinical endpoint
Humans
Medicine
Aged
RSV, Meta-analysis
Clinical Trials as Topic
biology
business.industry
Incidence
Antibodies, Monoclonal
Human Challenge Study
General Medicine
Middle Aged
Models, Theoretical
Antibodies, Neutralizing
Clinical trial
Respiratory syncytial virus (RSV)
Respiratory Syncytial Virus, Human
Immunology
biology.protein
Female
Seasons
Respiratory Syncytial Virus
Antibody
business
Algorithms
- Language
- ISSN
- 2352-3964
Background 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. Methods 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. Findings 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. Interpretation An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.