A controlled effects approach to assessing immune correlates of protection.
Biostatistics
; 24(4): 850-865, 2023 10 18.
Article
em En
| MEDLINE
| ID: mdl-37850938
ABSTRACT
An immune correlate of risk (CoR) is an immunologic biomarker in vaccine recipients associated with an infectious disease clinical endpoint. An immune correlate of protection (CoP) is a CoR that can be used to reliably predict vaccine efficacy (VE) against the clinical endpoint and hence is accepted as a surrogate endpoint that can be used for accelerated approval or guide use of vaccines. In randomized, placebo-controlled trials, CoR analysis is limited by not assessing a causal vaccine effect. To address this limitation, we construct the controlled risk curve of a biomarker, which provides the causal risk of an endpoint if all participants are assigned vaccine and the biomarker is set to different levels. Furthermore, we propose a causal CoP analysis based on controlled effects, where for the important special case that the biomarker is constant in the placebo arm, we study the controlled vaccine efficacy curve that contrasts the controlled risk curve with placebo arm risk. We provide identification conditions and formulae that account for right censoring of the clinical endpoint and two-phase sampling of the biomarker, and consider G-computation estimation and inference under a semiparametric model such as the Cox model. We add modular approaches to sensitivity analysis that quantify robustness of CoP evidence to unmeasured confounding. We provide an application to two phase 3 trials of a dengue vaccine indicating that controlled risk of dengue strongly varies with 50$\%$ neutralizing antibody titer. Our work introduces controlled effects causal mediation analysis to immune CoP evaluation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vacinas
Limite:
Humans
Idioma:
En
Revista:
Biostatistics
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos