Experimental infection and protection against ... - TI Pharma

226 Chapter 11
were also tried at that time, sometimes accompanied by an intramuscular
injection of penicillin to prevent bacterial co-infection [92-94]. The practice of
malariatherapy stopped with the advent of antibiotics. Techniques to induce
malaria were subsequently used in the vaccine research field, when the first
available malaria vaccine candidates were tested [95, 96]. However, by that
time, Pf gametocytes could be produced in culture and Anopheles mosquitoes
were infected by feeding on culture material [97, 98]. Because these methods
were safer and less costly, mosquitoes bites have been used for controlled
infections ever since.
The translation of mosquito-delivered inoculations into whole-sporozoite needle
administration is a technical challenge because of difficulties to isolate, purify
and cryopreserve sporozoites according to current regulatory standards. Recent
progress has been made by Sanaria Inc., which has developed technology for the
purification and cryopreservation of aseptic sporozoites for use in humans
according to the current safety standards [99]. Initially developed as an
attenuated sporozoite vaccine, these sporozoites were irradiated and tested for
safety, immunogenicity and efficacy in a clinical vaccine trial. Unfortunately,
although safe, the trial showed limited protectivity and immunogenicity [100].
We subsequently tested the unattenuated cryopreserved sporozoites for
infectiousness by intradermal injection, proving their potency in five of six
volunteers from each of three dose groups (Chapter 8). Future studies will focus
on improving the administration of these sporozoites in order to achieve 100%
infection rates. Results of these studies will not only attribute to the
development of a standardized controlled human malaria infection model, but
also advance the development of a whole-sporozoite vaccine. However, one
must bear in mind that needle and syringe administration of a bolus of
sporozoites is clearly different from mosquito bite delivery. Mosquitoes deliver a
proportion of sporozoites intracapillary and a proportion intradermally [101].
Sporozoites are embedded in mosquito saliva when inoculated, components of
which may possibly improve infectivity [102]. The volume of injection by
mosquito is also considerably smaller than will ever be reached by needle and
syringe. These factors may be important to consider particularly if sporozoites
are injected for the testing sporozoite vaccines that aim to induce antibodies to
immobilize sporozoites.
Murine studies indicate that the intramuscular administration of sporozoites by
needle may be more efficient than the intradermal delivery, possible due to
better circulation of the muscular tissue (Ploemen pers comm.). The