Experimental infection and protection against ... - TI Pharma

General Discussion 227
immunological consequences of dermal versus intramuscular administration are
currently being investigated (Nganou-Makamdop pers comm.). Whether or not
the administration of local vasodilators or the use of smaller injection volumes
improves the immunogenicity or infectivity of sporozoites will also be
investigated. In any case, it will likely take several years before the needle
administration of sporozoites has been optimized for human use. However
elaborate, these studies are not only important to the development of a
standardized controlled malaria infection model, but will also prove to be crucial
to the translation of mosquito-delivered sporozoites into a vaccine strategy.
Whole sporozoite vaccines
The concept of whole-parasite immunisation originates from studies in which
humans were immunized by irradiated infected mosquito bite and proved to be
protected against subsequent Pf challenge (summarized in [103]). Irradiation of
infectious mosquitoes disrupts the gene expression of sporozoites, which remain
capable of hepatocyte invasion but are no longer capable of complete liver-stage
maturation or progression to the pathogenic blood stage [104]. Exposure of
humans to the antigen repertoire of the irradiated sporozoites proved to be
sufficient to induce protection against subsequent challenge with viable
sporozoites, which was shown to last 14 months in several instances [103]. The
radiation dose was crucial: too much radiation reduced potency while too low
radiation doses caused break-through infections [105].
Although these results were published already in the 1960’s they were not
considered a vaccine strategy, because the production of a whole-sporozoite
vaccine that would comply with regulatory standards seemed technically
impossible. Moreover, the potency of these attenuated sporozoites was limited:
high doses [> 1000 mosquito bites) were needed to achieve full protection [103].
This requirement for large immunisation doses might reflect the lack of normal
intrahepatocytic differentiation of irradiated sporozoites into thousands of
hepatic merozoites, an amplification process that is expected to result in an
expanded antigen repertoire and thus drive immune responses qualitatively and
quantitatively [106].
The protection of human volunteers from Pf challenge by mosquito-delivered
whole sporozoite inoculation under chloroquine prophylaxis (CPS, Chapter 9)
shed new light on the concept of whole-parasite immunisation, because this
strategy proved to be much more efficient at inducing protection. In this case,