Vaccine effects and trial designs for nontypeable <italic>Haemophilus influenzae</italic>.

Abstract

Vaccines against nontypeable <italic>Haemophilus influenzae </italic> (NTHi) that could be medically and economically important in preventing respiratory infections are under active development. Issues of what vaccine effects need to be assessed and how trials to assess those effects should be designed have not, however, been adequately addressed. To address these issues, we constructed a series of NTHi transmission models. The first was a deterministic compartmental (DC) model. Analysis of this model indicated that colonization-induced immunity that alters susceptibility to and contagiousness of NTHi colonization has larger effects on disease occurrence than immunity against pathogenicity (disease rates given colonization). This led to an elaboration of this DC model to examine the effects of vaccines that altered susceptibility, contagiousness and/or pathogenicity. Analysis of that model demonstrated that without effects on transmission, NTHi vaccines would inadequately protect against disease. Thus vaccine trials that assess effects on transmission are essential. Due to NTHi transmission and immunity, standard design methods for group randomized trials (GRTs) are not applicable to NTHi vaccines. To explore GRT designs for NTHi, a discrete individual stochastic model based on the DC model was constructed and power to detect vaccine effects on the prevalence of NTHi nasopharyngeal colonization was simulated and compared between different designs. Trials in populations with lower NTHi prevalence have higher power than those with higher prevalence. When the interval between subsequent follow-ups was larger than 3 months, power was significantly increased by increasing follow-up frequency. Recruiting newly enrolled daycare children during trials also increased power. A hybrid GRT design, which further randomized subjects into vaccine and placebo among each daycare center in the arm offering vaccine, significantly compromises power, but it separately specifies direct and indirect effects. In larger daycare centers, larger sample sizes were not needed to attain the same power attained in smaller ones. This is unlike the case for non-infectious diseases. NTHi transmission and immunity, which are unique to infectious diseases, are responsible for the difference. Taken together, these findings provide a basis for designing GRTs of future NTHi vaccines and more general insights about how GRT designs differ between infectious and non-infectious diseases.