U.S. Federal Malaria Vaccine Programs: FMVCC's Role
Malaria vaccine development programs exist in several different agencies in the U.S. Government. 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 discovery as well as the capability for clinical trials through its extramural program. The Division of Parasitic Diseases (DPD) at the Centers for Disease Control and Prevention (CDC), another element of DHHS, contributes to malaria vaccine development through evaluation of investigational vaccines in non-human primates, through the development of multistage and multicomponent vaccines, and through malaria vaccine related field activities. Most actual human testing of malaria vaccines has been done by the Department of Defense's (DOD) Walter Reed Army Institute of Research (WRAIR), and more recently the Naval Medical Research Center (NMRC). The U.S. Agency for International Development (USAID) has supported vaccine development for many years, shifting emphasis in recent years from discovery to vaccine production and evaluation. 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 and the name FMVCC is about a decade old. 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. The goals are 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, time limited objectives are derived from this list. But the most important work of FMVCC member agencies is the ongoing malaria vaccine development effort within each agency.
Each of the U.S. Federal Agencies has its own separate mission and strategy based on two quite different vaccine approaches based on the biology of the parasite and on the intended uses of the product. Whereas the ideal vaccine for travelers would be one which completely prevents all manifestations of malaria which might otherwise result from transient exposure (see next paragraph), there is broad agreement that a different approach is more prudent for residents of endemic areas which are exposed repeatedly. Natural acquisition of malaria develops during repeated attacks over a number of years. In highly endemic areas, malaria due to Plasmodium falciparum has a case fatality rate in excess of 1% and is responsible for up to 25% of the deaths of young children; fatal disease 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 is previously relative immune individuals. This phenomenon is most frequently encountered in pregnancy, especially in primaparous women. One major objective of the malaria vaccine development effort is the prevention of life threatening disease without prevention of infection, thus enabling the acquisition of natural immunity through repeated infection. Consequently, antigens expressed in the erythrocytic stages of malaria parasites have an important role in vaccine development efforts.
Artificial immunization against P. falciparum resulting in abortion of infection prior to invasion of erythrocytes, a second major objective, has been achieved in an experimental setting through the administration of sporozoites, the stages through which malaria is transmitted from mosquito to human, which 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 which develop from sporozoites. However, this method of immunization does not serve as a basis for vaccine development since sporozoites can only be produced in mosquitoes and can only be delivered by mosquito bite! In the experiments cited, intact living mosquitoes were irradiated and allowed to bite the volunteers. Up to 1000 bites were necessary to induce immunity to subsequent challenge by non-irradiated malaria infected mosquitoes. Consequently, there has been much effort to identify the (preerythrocytic) antigens responsible for the induction of immunity by irradiated sporozoites and their use in vaccine development.
A third approach to malaria vaccine development is the targeting of the sexual stages of the parasite. In a vaccine of this type, based on antigens of the gametocytes or gametes, would operate through the induction of antibodies which 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.
These three approaches to vaccine development merge in consideration of a multistage vaccine which would have the advantages of each. Preerythrocytic components of the vaccine could result in abortion of infection before bloodstage invasion, thus preventing morbidity. However, breakthroughs after immunization with these components only are not unexpected, raising the specter of delay of onset of disease which, however, when it eventually occurs might be very sever, perhaps as severe as if no immunization has taken place. In a multicomponent 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. Thus mutant parasites might escape which display alternate antigenic targets, thus making the vaccine ineffective. The addition of a vaccine based on the antigens of these 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. This letter approach is being addressed using DNA plasmids to deliver the individual antigenic stimuli. This combination of approaches, if implemented properly, will minimize the time until a practical vaccine is available.
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