Development of a malaria vaccine candidate based on virosome technology

Malaria is an infectious disease caused by protozoan pathogens of the genus
Plasmodium. The most important species affecting humans is P. falciparum
transmitted by the bite of female Anopheles mosquitoes during a blood meal. About
40% of the world’s population is exposed to the parasite and 350 to 500 million cases
of disease and more than one millions deaths are reported every year. Almost 80%
of these cases occur in sub-Saharan Africa, where mainly children younger than five
years and pregnant women are affected. Due to problems with arising resistance of
mosquitoes against insecticides and parasites against drugs, the development of a
malaria vaccine is an urgent need. It has been shown more than 30 years ago that
sterile protection against malaria infection is feasible by vaccination with irradiated
sporozoites. Since then many malaria vaccine candidates have been developed but
there is no vaccine on the market to date.
We have established a strategy to develop synthetic peptides of P. falciparum
antigens for inclusion in a multi-stage multivalent malaria subunit vaccine based on
the immunopotentiating reconstituted influenza virosome (IRIV) technology. IRIVs are
an already registered delivery/adjuvant system based on liposomes incorporating
influenza surface proteins hemagglutinin and neuraminidase. IRIVs enhance and
facilitate the delivery of antigens to antigen presenting cells. This technology allows a
stepwise lead peptide optimization based on parasite-binding properties of antibodies
elicited after immunization of experimental animals with virosomally-formulated
peptide-phospholipid conjugates. In this thesis the development steps of three
peptide antigens are described: UK-39 a peptide derived from the sporozoite antigen
circumsporozoite protein (CSP), AMA49-CPE derived from the blood-stage protein
apical membrane antigen 1 (AMA-1) and FB-23 derived from the blood-stage protein
serine repeat antigen 5 (SERA5). All optimized peptides induced parasite crossreactive
antibodies in experimental animals. Virosomal formulations of the antigens
UK-39 and AMA49-CPE were carried into a phase 1 clinical trial. Both vaccine
components were safe and immunogenic in malaria-naïve volunteers. Two
immunizations with appropriate doses of UK-39 or AMA49-CPE were enough to
induce high titers of parasite-binding antibodies. Combined delivery of the two
peptides did not interfere with the development of an antibody response to either of
the two antigens. The antibody responses were affinity maturated and long-lived,
indicating the formation of B cell memory. Purified total IgG from UK-39 immunized
volunteers inhibited sporozoite migration, invasion and development in a dose
dependent manner. Further clinical trials with this two-component vaccine candidate
are ongoing and new peptide candidates like FB-23 have been developed and are
now ready for preclinical and clinical profiling.