Experimental infection and protection against ... - TI Pharma

216 Chapter 11
The development of a highly efficacious malaria vaccine faces many hurdles, key
to which is our limited knowledge of what exactly constitutes protection against
Plasmodium falciparum malaria in humans. Malaria vaccine development relies
on a trial-and-error approach, with many candidates in (pre-)clinical
development awaiting efficacy testing in the field. This thesis focuses on the
development of research tools that facilitate immunological and vaccine
research into human protection against Plasmodium falciparum malaria in early
stages of clinical development. We used the following approaches:
Firstly, we tested an asexual erythrocytic stage subunit vaccine candidate (Apical
Membrane Antigen 1) for its safety and immunogenicity in humans and
performed in depth analysis of the humoral immune response following
immunization.
Secondly, we assessed and optimized an important tool for malaria vaccine and
immunological research: controlled human malaria infections. In these trials,
healthy malaria-naïve volunteers are exposed to infectious mosquito bites in
order to test the preliminary efficacy of vaccine candidates or in order to
perform immunological research.
Thirdly, we developed a human model for protection against Plasmodium
falciparum malaria to facilitate immunological research and facilitate the
development of a whole-sporozoite vaccine for malaria.
Apical Membrane Antigen 1 (AMA1)
AMA1 is considered a promising vaccine candidate, primarily due to a large body
of data from animal studies indicating that AMA1 can induce immune responses
capable of inhibiting the blood stage parasite multiplication in vitro and in vivo
(reviewed in [1]). Specifically, protection can be conveyed by transferring anti-
AMA1 antibodies [2-5] and epidemiological studies in malaria endemic areas
show that the presence of AMA1 antibodies correlate with malaria protection [6,
7]. Subsequently, AMA1 has been produced as recombinant protein both in
Pichia pastoris and E. Coli. Animal studies showed satisfactory pharmacotoxicity,
so the whole-length (amino acid 25 to 545) Pichia pastoris-expressed AMA1
from the FVO strain has been taken forward into the first phase of clinical
testing. We showed that PfAMA1[25-545] FVO can be safely administered to
humans and is immunogenic (Chapter 2). We also showed that both
reactogenicity and immunogenicity are dependent on the adjuvant, with the