The effectiveness of a vaccine could refer to the reduced risk the vaccinated individual benefits from in the real world, or the population level impact of the vaccine that goes beyond the vaccinated individual. The individual’s protection is enhanced by herd immunity at the population level [6] and [36], where immunization Trametinib programs through reducing the prevalence of infection protect unvaccinated individuals. Vaccination against HPV in Australia and the US has generated rapid declines in the incidence of genital warts and the prevalence of high risk HPV infections,

including amongst those unvaccinated, which may be associated with herd protection [37] and [38]. This herd immunity adds to vaccine benefits and will be present to some extent regardless of coverage. In theory the greater the reduction in prevalence the greater

the protection remaining unvaccinated individuals will benefit from, until at a critical vaccination threshold infection is eliminated [6]. Fig. 1 illustrates the INK-128 difference between a vaccine providing herd immunity and one providing direct protection (this latter is achieved for illustration by assuming no change in exposure which is unreasonable). The critical vaccination threshold is 1 minus the inverse of the basic reproductive number – so the greater the basic reproductive number the greater the coverage needed to eliminate infection. The nature of herd immunity will depend upon another characteristic of vaccination that cannot easily be discerned in trials. This characteristic of the vaccine is whether the immunity it provides is an all or nothing effect (‘take’ type protection) or whether it protects against a fraction of challenges (‘degree’ type protection)[39]. The take and degree

categories are the two extremes of the frailty mixed models of vaccine efficacy described in the statistical literature [40] and [41] and have been explored in Linifanib (ABT-869) models of HIV vaccination where efficacy could be low [39], [42] and [43]. The effects of these properties are illustrated in Fig. 1 where degree type protection causes less herd protection until near the critical vaccination threshold. Fig. 2 illustrates a simulated trial of an STI vaccine with 60% efficacy comparing a vaccine with take and degree type protection. In a low incidence setting the difference in the impact of the two is indiscernible. In high incidence settings take type protection is maintained. This distinction is more of a concern for STIs than for other infections, because of the heterogeneity in risk and the potential for increased exposure and risk [44]. If vaccines are tested in populations with lower risk then the efficacy of the vaccine may be less in higher risk populations, or conversely if tested in higher risk populations more efficacious in lower risk populations.