The development of effective vaccines against zoonotic pathogens represents a priority in public health protection programs. The design of clinical trials and appropriate data analysis of the experiments results are crucial for the assessment of vaccine effectiveness. This manuscript reviews important issues related to the assessment of the effectiveness of vaccines designed to obtain a quantitative reduction of the pathogen in animals or animal products. An effective vaccine will reduce the risk of human infections and therefore the number of human cases. Important considerations will be illustrated using a vaccination trial of a new campylobacter vaccine candidate developed to reduce the numbers of campylobacter in chickens and consequently the numbers of human campylobacteriosis cases. The design of the author's vaccination trial was based on the use of isolators, a parallel group design and several rotations. The effect of clustering or design effect was considered in the sample size calculations. Chickens were randomly assigned to different isolators (treatments) and challenged with Campylobacter jejuni. Samples were obtained at different intervals and processed in the laboratory. C. jejuni counts were determined as colony-forming unit-per-gram of chicken cecum or fecal mass in order to assess vaccine effectiveness. A desired vaccine effect of 2 logs reduction on the numbers of C. jejuni recovered from vaccinated chickens was selected. Sample-size calculations, desired vaccine effect, biological and epidemiological aspects, experimental design and appropriate statistical analysis of data considering group or clustering effects will be the focus of this manuscript.