Malaria is a disease affecting millions of people in Africa, Asia, Central and South America . It has its highest frequency, morbidity, and mortality in infants and young children. For many reasons, a vaccine that would prevent this disease is sought.
Plasmodium falciparum and Plasmodium vivax, the most common and severe forms of malaria, have host and stage specific proteins that can induce immunity to disease caused by this pathogen. Surprisingly, vaccines against stages that infect mosquitos will prevent the spread of malaria (transmission-blocking). We have developed a vaccine composed of a single protein, denoted as Pfs25, to induce transmission-blocking antibodies in the human host. These transmission-blocking antibodies will be ingested by the mosquito and inactivate the sexual forms of the plasmodia (ookinetes) as they develop in the midgut of the mosquito. Because Pfs25 is present only in the mosquito, humans do not develop antibody to this antigen even in endemic areas. No antibodies were detected against Pfs25, a 21-kD protein expressed on zygotes and ookinetes of P. falciparum and known to be a sensitive target of transmission-blocking antibodies. Theoretically, frequent boosting with this antigen, as is required for the other experimental malarial vaccines, would be necessary.
Our investigational vaccine is based upon the following:
1. Pfs25 is a low molecular weight protein and a poor immunogen.
Bharti et al showed the protective action of antibodies to Pvs25 raised by intensive immunization of rabbits and mice (these regimes are not suitable for humans) to the recombinant protein. These findings have been confirmed;
2. Transmission of Plasmodia to mosquitos is mediated by their ingestion of gametocytes in the human bloodstream.
Within 10 minutes, these gametocytes transform into gametes in the midgut of the mosquito. The male gametocyte fertilizes the female to form a zygote. Twenty four hours later ookinetes pierce the epithelium of the midgut and differentiates into an oocyst. This cell type forms the sporozoite that lodges in the salivary gland and is the infective form injected by the mosquito into the human host. Pfs25 may also be involved in survival of the ookinete in the midgut and its transformation into the oocyst;
3. The immunogenicity of poor immunogens is increased, especially in infants, by covalently binding them to medically-acceptable carrier proteins to form conjugates.
The Pfs25 was bound to itself by the synthetic scheme used for Haemophilus influenzae type b and other polysaccharides to proteins. The resultant conjugate was immunogenic and, unexpectedly, antibodies elicited by this vaccine continued to rise 3 months and 7 months after the second and third injections. The property of the Pfs25 conjugate to elicit long-lived antibody at high levels is unique to this construct. Our data from Pfs25 conjugate in mice suggest that administration of this vaccine to the whole population including infants along with their routine immunizations may be sufficient to elicit long-lived, effective transmission-blocking activity.
Our plan is to evaluate clinical lots of this conjugate for P. falciparum and for P. vivax, for their safety and immunogenicity in adults, children and infants, and then to establish a clinical site to test their efficacy.
