Vaccines can be extremely cost-effective public health measures. Unfortunately the research and development (R&D) of novel vaccines is suffering from rising costs and declining success rates. Because many vaccines target low- and middle income markets (LMIC), output needs to be maintained at a constrained budget. In addition, scientific neglect and political uncertainty around reimbursement decisions make it an unattractive arena for private investors. The vaccine development pipeline for LMIC thus is in need for a different, sustainable, and cost-effective development model. In conventional vaccine development, objectives for every clinical development phase have been predefined. However, given the scarcity of resources, the most efficient clinical development path should identify vaccine candidates with the highest potential impact as soon as possible. We argue for a custom-made question-based development path based on the scientific questions, success probabilities and investments required. One question can be addressed by several studies and one study can provide partial answers to multiple questions. An example of a question-based approach is the implementation of a controlled human malaria infection model (CHMI). Malaria vaccine R&D faces major scientific challenges and has limited resources. Therefore, early preliminary efficacy data needs to be obtained in order to reallocate resources as efficiently as possible and reduce clinical development costs. To meet this demand, novel malaria vaccines are tested for efficacy in so-called CHMI trials in which small groups of healthy volunteers are vaccinated and subsequently infected with malaria. Early evaluation studies of critical questions, such as CHMI, are highly rewarding, since they prevent expenditures on projects that are unlikely to succeed. Each set of estimated probabilities and costs (combined with market value) will have its own optimal priority sequence of questions to address. Algorithms can be designed to determine the optimal order in which questions should be addressed. Experimental infections of healthy volunteers is an example of how a question-based approach to vaccine development can be implemented and has the potential to change the arena of clinical vaccine development.