Preethrocytic Stage Erythrocytic Stage Sexual Stage Multi-Stage Approach

Malaria vaccine development programs exist in several different agencies in the U.S. Government. Coordination of these efforts is essential if optimum use of resources is to be accomplished. The federal malaria vaccine development community has addressed this need through the formation of an ad hoc Federal Malaria Vaccine Coordinating Committee (FMVCC).

Federal coordination in malaria vaccine development has been in existence in various forms for many years. The name FMVCC dates to about 1990, at which time previously ad hoc collaborations were further organized. FMVCC has now evolved into a consortium in which each agency is cognizant of the activities of the others, thus enabling complementary program planning, collaboration, and concerted action on common problems. While remaining an ad hoc group, FMVCC has developed a mission statement and formalized its goals: to exchange information, identify and develop priorities, and coordinate efforts among the member agencies. For each goal there is a series of general objectives and specific, from which time-limited objectives are derived. But the most important work of FMVCC members is the ongoing malaria vaccine development effort within each agency.

Within the Department of Health and Human Services (DHHS), the Laboratory of Parasitic Diseases (LPD) in the National Institute of Allergy and Infectious Diseases (NIAID) has for many years made major contributions to the discovery phase of malaria vaccine development, while the Division of Microbiology and Infectious Diseases (DMID) has supported malaria vaccine discovery as well as the capability for clinical trials through its extramural program. More recently the Malaria Vaccine Development Branch (MVDB) has made a concerted effort towards development of malaria vaccines and the newly formed Laboratory of Malaria Vaccine Immunology and Vaccines LMVI) and the Laboratory of Malaria and Vector Research (LMVR) promise to continue this effort. The Division of Parasitic Diseases (DPD) in the Centers for Disease Control and Prevention (CDC), Center for Global Health (CGH), another element of DHHS, contributes to malaria vaccine development through evaluation of investigational vaccines in non-human primates, and through malaria vaccine-related field activities. Most human testing of malaria vaccines has been done by the Department of Defense's (DOD) Walter Reed Army Institute of Research (WRAIR), the Naval Medical Research Center (NMRC), and NIAID programs. In addition to clinical testing of malaria vaccines, the Military Malaria Vaccine Program, which is implemented by WRAIR and NMRC, has focused on new antigen discovery, production, and formulation for clinical studies. Trials have been conducted both in the U.S. and in field sites in endemic areas through collaboration with partner organizations. The U.S. Agency for International Development (USAID) has supported vaccine development for many years, for the last two decades focusing on vaccine production and evaluation.

Each of the U.S. Federal Agencies has its own separate mission and strategy based on the intended uses of the product. However, the same biological approaches to malaria vaccine development are being used by each agency to accomplish its mission.

Preerythrocytic Stage Vaccine

Artificial immunization against Plasmodium falciparum resulting in abortion of infection prior to invasion of erythrocytes has been achieved in an experimental setting through the administration of sporozoites (the stages through which malaria is transmitted from mosquito to human) that have been attenuated by irradiation. In this instance infection is aborted either through neutralization of sporozoite infectivity immediately after introduction or by arrest of development of liver stages of the parasite that develop from sporozoites. This seminal finding led to the development of the currently most advanced vaccine by WRAIR and GlaxoSmithKline Biologicals, which is now in phase 3 trials under support and management by the Malaria Vaccine Initiative at PATH (MVI). The basis for the vaccine is the circumsporozoite protein (CSP), a major antigen of the sporozoite. In addition, there is currently also an effort to exploit the immunogenicity of sporozoites directly by producing a vaccine consisting of purified irradiated sporozoites.

|Back to Top|

Erythrocytic Stage Vaccine

Although the ideal vaccine for travelers would be one that completely prevents all manifestations of malaria that could result from transient exposure, there is also a point of view that there are advantages in a different approach for residents of endemic areas who are exposed repeatedly. Natural acquisition of malaria develops during repeated attacks over a number of years. In highly endemic areas, malaria due to P. falciparum has a case fatality rate in excess of 1% and is responsible for up to 25% of the deaths of young children. However, malaria is much less frequent in older children and adults who survive the early years. In the resulting state of relative immunity, infection is not prevented, but replication of parasite blood stages, which are responsible for symptomatology, is restrained. The exception to this is the occasional unexplained occurrence of cerebral malaria, a severe life threatening complication, which occurs in previously relatively immune individuals. This phenomenon is most frequently encountered in pregnancy, especially in primaparous women. Thus in addition to efforts to prevent infection entirely, a second objective of the malaria vaccine development effort is the prevention of life-threatening disease without prevention of infection. Consequently, antigens expressed in the erythrocytic stages of malaria parasites have an important role in vaccine development efforts.

|Back to Top|

Sexual Stage Vaccine

A third approach to malaria vaccine development is the targeting of the sexual stages of the parasite. A vaccine of this type, based on antigens of the gametocytes or gametes, would operate through the induction of antibodies that arrest the development of sexual stage parasites either in the blood or in the mosquito after the insect takes blood containing both the parasites and the antibodies. This approach has recently gained considerable support as a technology that could be useful in future malaria elimination and eradication efforts.

|Back to Top|

Multi-Stage Approach

These three approaches to vaccine development merge in consideration of a multistage vaccine that would have the advantages of each. Preerythrocytic components of the vaccine could result in abortion of infection before blood-stage invasion, thus preventing morbidity. However, breakthroughs after immunization with only these components would not be unexpected. In a multi-component vaccine with erythrocytic components as a "second line of defense," severe disease could be prevented. However, this second vaccine might not prevent transmission to mosquitoes since the sexual stages have an antigenic composition different from both preerythrocytic and erythrocytic forms. As such, mutant parasites might escape that display alternate antigenic targets, making the vaccine ineffective. The addition of a vaccine based on the antigens of this sexual stage which resulted in blocking of transmission to the mosquito vectors would prevent this escape.

A cogent argument can also be made for the combination of more than a single antigen of each of the three stages. First, synergy can be expected when immune effector mechanisms are operative against multiple targets, resulting in a more robust defense. Second, both the polymorphism of malaria antigens in nature and the heterogeneity of the major histocompatibility complex provide opportunities for the complete failure of some antigens to contribute to the protective immune response. Antigen redundancy mitigates against this.

In practice,the eventual development of a multistage multicomponent malaria vaccine is proceeding along two lines. On the one hand, individual antigens are being evaluated as vaccine constituents to either be used alone, if this proves to be efficacious, or to serve as constituents of a vaccine along with other antigens. A second approach is the formulation of vaccines containing multiple components and evaluation of the mixture for efficacy. A third approach is the use of heterologous prime-boost strategies, in which the same antigen(s) is(are) use to prime and boost the immune response, but in different carrier platforms, thus minimizing retardation of the response by immunity to non-malaria antigens present in the carrier portion of the vaccine.

The complexity of malaria vaccine development mandates that the effort is a collaborative one, allowing each partner to contribute its unique strengths to the benefit of the entire enterprise. This is the basis for FMVCC’s role.

|Back to Top|