New interventions are needed to reduce morbidity and mortality associated with malaria, as well as to accelerate elimination and eventual eradication. Interventions that can break the cycle of parasite transmission, and prevent its reintroduction, will be of particular importance in achieving the eradication goal. In this regard, vaccines that interrupt malaria transmission (VIMT) have been highlighted as an important intervention, including transmission-blocking vaccines that prevent human-to-mosquito transmission by targeting the sexual, sporogonic, or mosquito stages of the parasite (SSM-VIMT). While the significant potential of this vaccine approach has been appreciated for decades, the development and licensure pathways for vaccines that target transmission and the incidence of infection, as opposed to prevention of clinical malaria disease, remain ill-defined. This article describes the progress made in critical areas since 2010, highlights key challenges that remain, and outlines important next steps to maximize the potential for SSM-VIMTs to contribute to the broader malaria elimination and eradication objectives.

Many new interventions are being created to address health problems of the developing world. However, many developing countries have fragile health systems and find it difficult to accommodate change. Consequently, it is essential that new interventions are well aligned with health systems and their users. Establishing target product profiles (TPPs) is a critical, early step towards tailoring interventions to suit both of these constituencies. Specific analyses can help identify and establish relevant TPP criteria such as optimal formulation, presentation and packaging. Clinical trials for a new intervention should be designed to address both TPP-specific questions and anticipated use of the intervention in target countries. Examples are provided from research on malaria vaccines that are also applicable to other new public health interventions.

BackgroundEfforts to develop malaria vaccines show promise. Mathematical model-based estimates of the potential demand, public health impact, and cost and financing requirements can be used to inform investment and adoption decisions by vaccine developers and policymakers on the use of malaria vaccines as complements to existing interventions. However, the complexity of such models may make their outputs inaccessible to non-modeling specialists. This paper describes a Malaria Vaccine Model (MVM) developed to address the specific needs of developers and policymakers, who need to access sophisticated modeling results and to test various scenarios in a user-friendly interface. The model’s functionality is demonstrated through a hypothetical vaccine.MethodsThe MVM has three modules: supply and demand forecast; public health impact; and implementation cost and financing requirements. These modules include pre-entered reference data and also allow for user-defined inputs. The model includes an integrated sensitivity analysis function. Model functionality was demonstrated by estimating the public health impact of a hypothetical pre-erythrocytic malaria vaccine with 85% efficacy against uncomplicated disease and a vaccine efficacy decay rate of four years, based on internationally-established targets. Demand for this hypothetical vaccine was estimated based on historical vaccine implementation rates for routine infant immunization in 40 African countries over a 10-year period. Assumed purchase price was $5 per dose and injection equipment and delivery costs were $0.40 per dose.ResultsThe model projects the number of doses needed, uncomplicated and severe cases averted, deaths and disability-adjusted life years (DALYs) averted, and cost to avert each. In the demonstration scenario, based on a projected demand of 532 million doses, the MVM estimated that 150 million uncomplicated cases of malaria and 1.1 million deaths would be averted over 10 years. This is equivalent to 943 uncomplicated cases and 7 deaths averted per 1,000 vaccinees. In discounted 2011 US dollars, this represents $11 per uncomplicated case averted and $1,482 per death averted. If vaccine efficacy were reduced to 75%, the estimated uncomplicated cases and deaths averted over 10 years would decrease by 14% and 19%, respectively.ConclusionsThe MVM can provide valuable information to assist decision-making by vaccine developers and policymakers, information which will be refined and strengthened as field studies progress allowing further validation of modeling assumptions.

Infection with Plasmodium berghei is lethal to mice, causing high levels of parasitemia, severe anemia, and death. However, when mice are treated with antimalarial drugs during acute infection, they have enhanced immunity to subsequent infections. With this infection and cure model of immunity, we systematically examined the basis of adaptive immunity to infection using immunodeficient mice. In order to induce adaptive immunity, mice were infected with blood-stage parasites. When the mice developed 2 to 3% parasitemia, they were treated with chloroquine to cure the infection. These convalescent mice were then challenged with homologous blood-stage parasites. Immunized wild-type mice were able to control the level of infection. In contrast, mice lacking mature B cells and T cells were unable to control a challenge infection, indicating the critical role of lymphocytes in immunity to P. berghei. Furthermore, mice lacking secreted antibody were unable to control the level of parasitemia following a challenge infection. Our results indicate that secreted antibody is a requirement for immunity to P. berghei.Each year there are approximately 500 million cases of malaria worldwide, resulting in 2 to 3 million deaths, primarily in children in sub-Saharan Africa (42). Malaria is caused by infection with one of four protozoan Plasmodium species: P. falciparum, P. vivax, P. malariae, and P. ovale. P. falciparum is responsible for the majority of severe disease, which can manifest itself in anemia, cerebral malaria, organ failure, and death. Repeated infection and treatment of individuals in areas of malaria endemicity eventually induce a level of immunity that limits morbidity and results in chronic infection with low levels of parasitemia (41). A fully effective vaccine that reduces parasite burden and severe disease has not been developed.Murine models of malaria have long been used to examine the immune response to Plasmodium parasites and to understand the host factors required for the development of immunity. P. berghei infection in mice is lethal, causing high levels of parasitemia, severe anemia, and body weight loss. However, mice can become resistant to subsequent infections by treatment with antimalarial drugs during acute infection (27). This is known as the infection and cure model, and mice that develop this immunity mimic the human experience of disease in that they are reinfected but experience low-level patent parasitemia and survive. However, it takes years to establish this level of immunity in humans (36), while in mice it is accomplished by only one infection and drug cure, which provides long-lasting protection (12,13,48). An understanding of the basis of rodent immunity to blood-stage infection will help to direct future vaccine approaches.The fact that immunity induced by infection and cure is long-lasting suggests that the adaptive immune system is required for immunity. Evidence from previous work indicates a role for B and T cells in immunity. Mice lacking both mature B and T cells (SCID mice) (6)...

With approximately 225 million new cases and 800,000 deaths annually, malaria exacts a tremendous toll--mostly on African children under the age of five. Late-stage trials of an advanced malaria vaccine candidate--which, if approved, would become the world's first malaria vaccine--are under way, and it may be ready for use by 2015. This article recounts the pivotal roles in that achievement played by collaborations of nonprofit organizations, pharmaceutical companies, private and public donors, and countries whose citizens would benefit most directly from a vaccine. Just as it takes a village to raise a child, it has taken a huge number of stakeholders around the world to reach this point. Developing even more effective vaccines for malaria and other diseases will require continued hard work and creative thinking from scientists, regulators, and policy makers.