Experimental infection and protection against ... - TI Pharma

Introduction 13
pipeline of clinical development will ultimately be licensed for clinical use.
Clinical development is time-consuming and costly and starts with safety and
immunogenicity trials. If satisfactory, clinical trials aimed at obtaining efficacy
profiles will be undertaken. Whereas the first two criteria can generally be
assessed in a small initial Phase I trial, vaccine efficacy in the field can only be
assessed in larger study cohorts with at least a few hundred volunteers in
malaria-endemic areas (Phase IIb trials). With only a limited number of
competent field trial sites and a downward trend in malaria incidence in several
endemic areas, the size and costs of Phase IIb trials are rising [12], underpinning
the need to develop tools for downstream selection of vaccine candidates.
Conventional vaccine technologies rely on the production of a single
recombinant or synthetic subunit protein or peptide vaccine in a yeast or
bacterial vector or administer (attenuated) whole organisms [13]. Proteins may
also be combined together to enhance protection or increase the breath of the
immune response. Alternatively, DNA vaccines have been tried, but they proved
to be less immunogenic [14]. In order to increase or modify the vaccine-elicited
immune response, vaccines are often administered in conjunction with an
adjuvant. Adjuvants can consist of many different materials that are either
mixed with or linked to the vaccine. Moreover, delivery platforms can deliver a
vaccine to a certain site, such as (Adeno-)viral vectors or liposomes that can take
care of intracellular delivery of the vaccine. In such cases, the DNA-sequence
vaccine is expressed by the host cell. Particularly combinations of a viralvectored
DNA prime and protein booster injections have proven to be successful
[15].
Malaria vaccine candidates
The vaccine candidates currently under pre-clinical or clinical development are
categorized according to the life cycle stage of antigen expression (Figure 3). The
pre-erythrocytic stage begins when a female Anopheles mosquito inoculates Pf
sporozoites into the human skin. These sporozoites travel to the human liver
and invade hepatocytes, where they develop into thousands of asexual parasites
called merozoites. This process takes approximately one week and is clinically
silent. Pre-erythrocytic stage vaccines aim to prevent the passage of parasites
through the human liver and subsequent blood-stage infection. Ideally, such
vaccines should be 100% effective to prevent disease, since any merozoite
released from the liver is potentially capable of exponential growth by invasion