Experimental infection and protection against ... - TI Pharma

16 Chapter 1
allowed to bite on human volunteers. Irradiation attenuated the sporozoites
located in the mosquito salivary gland. It was shown that more than a 1000 of
such bites could protect humans from subsequent challenge [35]. The technical
challenge of whole-sporozoite immunization is the manufacturing process, since
the sporozoite parasite forms cannot be cultured outside their mosquito host.
The production of whole-sporozoite vaccines that comply with current vaccine
regulations for registration thus requires the standardized isolation, purification
and preservation of parasites from mosquito salivary glands. This procedure
meets numerous technical hurdles [36].
Blood stage vaccine candidates
Despite the fact that blood stage parasite multiplication is the only parasite
developmental stage that causes disease, relatively few blood-stage antigens are
in clinical development as vaccines thus far. Nevertheless, erythrocytic stage
vaccines are considered valuable, because they may not only be used as single
antigen vaccines but also protect against break-through infections in a multistage
vaccine with pre-erythrocytic vaccine components [37]. Erythrocytic stage
malaria vaccine candidates include Apical Membrane Antigen 1, (AMA1),
Erythrocyte-Binding Antigen-175 (EBA-175), Glutamate-Rich Protein (GLURP),
Merozoite Surface Protein 1 (MSP1), MSP2, MSP3 and Serine-Repeat Antigen 5
(SERA5), all of which are highly expressed on the merozoite surface [11]. To
date, none of these candidates have demonstrated protection against clinical
outcomes [37]. Efficacy of these candidates may be hampered by the genetic
diversity of the parasite surface proteins, which is likely due to the selective
pressure exerted by the human immune response [37].
AMA1 is one of the most advanced blood stage malaria vaccine candidates.
Animal data consistently show that AMA1 antibodies alone can protect mice and
monkeys against subsequent challenge, raising high hopes for the vaccine [38-
40]. The protein is maximally expressed in late schizony of erythrocytic
development and relocates from the parasite microneme to the merozoite
surface, where it plays a role in erythrocyte invasion [41]. Possibly, AMA1 is also
involved in liver cell invasion [42], making the antigen an attractive target
particularly for antibodies. Unfortunately, AMA1 is also highly polymorphic with
hundreds of haplotypes identified [43]. Another potential target for blood-stage
vaccines is the Pf erythrocyte membrane protein 1 (PfEMP1) family, a highly
polymorphic protein encoded by a great number of genes. The PfEMP1s are