Malaria Clinical Trial
Official title:
Malaria Transmission-Blocking Pfs25-Pfs25 Conjugate Vaccine
Background:
- Malaria, a disease transmitted by mosquitoes, affects millions of people with the
highest frequency, morbidity, and mortality in infants and young children. Plasmodium
falciparum and Plasmodium vivax, the most common and severe forms of malaria, have host-
and stage-specific proteins that can induce immunity to the disease.
- Vaccines against stages that infect mosquitoes will prevent the spread of malaria.
Researchers have developed a vaccine composed of a single protein, Pfs25, to induce
antibodies in the human host that will be ingested by the mosquito and prevent the
malaria parasite from reproducing and stop transmission of the disease. Because Pfs25 is
present only in the mosquito, humans do not develop antibodies to this antigen even in
endemic areas. Repeated injections of this vaccine may be necessary.
Objectives:
- To establish the safety and optimal dosage of a malaria vaccine developed with the Pfs25
protein.
Eligibility:
- Healthy adults between 18 and 49 years of age who have never had malaria or received a
malaria vaccine.
Design:
- Two doses of Pfs25 conjugate (10 micrograms and 25 micrograms) will be evaluated in this
study. Participants will receive only one of these doses in order to provide the best
scientific data for evaluation.
- To determine eligibility, participants will provide a medical history and have a
physical examination, and will provide blood and urine samples to test for HIV/AIDS,
hepatitis, and other conditions that would prevent them from participating.
- Eligible participants will receive one injection of the vaccine. The injection will be
followed 30 minutes later with a temperature reading and an inspection of the vaccine
site.
- Upon leaving the clinic, participants will receive diary forms, a digital thermometer, a
ruler, and instructions about how to take their temperature and to measure redness and
swelling (if any) at the injection site. About 6 hours later, and daily for 3 days,
participants will take their temperature at home and examine the injection site.
Participants will be examined at the clinic at 48 to 72 hours and on day 7 after an
injection. A blood sample will be taken 1 week after immunization. - Participants will
receive a second and third injection of the same vaccine at 6-week intervals, and will
follow the same recording procedure given above. Further blood samples will be taken at
regular intervals for up to 12 months after the vaccination, as directed by the study
researchers.
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.
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