Our study is the first that addresses the problem of suboptimal vaccines in the case of smallpox. We show that a network-based vaccination strategy strongly depends on a very high vaccine efficacy and on a high eligibility and compliance of the people selected for vaccination. It can quickly lose its effect if some of the most highly connected individuals cannot be vaccinated or if vaccination fails protect them ( Figure 5 ). If only a few of them are left unprotected, they can fuel a super-spreading event (cf. [1] ) multiplying the infection in the population.