Analysis of Studies to Evaluate Immune Response to Combination Vaccines

Abstract

The development and evaluation of new combination vaccines is an important public health endeavor. Trials to evaluate these vaccines are customarily designed and analyzed as noninferiority studies. We explain the concept of noninferiority and highlight important issues that can be challenging in the statistical evaluation of these vaccines. Topics covered include end points, hypotheses, and analyses for comparing geometric mean concentrations (or titers) of antibody and proportion of vaccine recipients responding; covariate adjustment; the problem of multiplicity and its impact on sample size; and choice of a meaningful difference to rule out.

Randomized, Controlled Trial of a 13-Valent Pneumococcal Conjugate Vaccine Administered Concomitantly with an Influenza Vaccine in Healthy Adults

“…Therefore, geometric mean immune response values that are within a 2-to 3-fold range are unlikely to manifest as a clinically significant change in the effectiveness of the vaccine. This noninferiority margin was consistent with those in relevant publications at the time of study design (10).…”

Diphtheria-tetanus-pertussis (DTP) combination vaccines and evaluation of pertussis immune responses

“…However, phase II immunogenicity/safety studies are sufficient to demonstrate noninferiority of the combined vaccine compared to their separately administered, licensed counterparts. The concept of non-inferiority vaccine evaluation was reviewed recently (Horne et al, 2001). In case of clearly defined correlates of protection, like for HepB, diphtheria, tetanus, Hib, and poliovirus protective thresholds can be used for non-inferiority analysis.…”

Combination vaccines in the South African setting

“…Evaluation of the efficacy of combination vaccines is typically conducted as a non-inferiority-based study format, thereby proving similar efficacy to individual component vaccines [44,45]. These studies need to be interpreted with clear consideration of what the final endpoint of evaluation is [46] as it can reflect in vivo models of antibody geometric mean concentrations [46,47], or epidemiological disease rates [41,48].…”