Experimental infection and protection against ... - TI Pharma

228 Chapter 11
only ~45 infected mosquito bites were needed to induce full protection.
Moreover, the follow-up study (Chapter 10) after 2.5 years proved that
protection was long-lasting in at least a proportion of volunteers. Moreover, the
CPS trial has led to the identification of pluripotent (IFNγ+IL-2+) effector memory
responses as a potential immunological correlate of protection (Chapter 9).
Serial in depth immunological analyses revealed that various lymphocyte subsets
contribute to the IFNγ response, including αβT cells, γδT and NK cells. Both γδT
cells and αβT cells were found to independently contribute to immunological
memory [107]. Interestingly, individual antigens responsible for the induction of
the IFNγ response (in vitro) could not be identified. Apparently, the induction of
IFNγ by Pf is complex, not only involving several cell types with a possible central
role for multifunctional T-cells, but also relying on a combination of multiple
antigens. Moreover, interindividual variation in the quantity and quality of IFNγ
responses reveals significant heterogeneity in Pf-induced immune responses.
The true correlate of protection may thus not be universal, but also display
diversity with several different immunological profiles correlating with
protection. Whether or not multifunctional T-cells form part of this correlate,
remains to be investigated. However, it seems likely that the true correlate of
protection will be a composite of multiple responses that form an individual
immunological fingerprint.
Although the CPS model is not a formal vaccine strategy, the CPS studies raised
the question of whether radiation alone produces the most efficient attenuated
parasites. One possible explanation for the greater efficiency of the CPSapproach
might be that the co-administration of chloroquine exhibits immune
modulating effects [108]. Alternatively, the exposure of the immune system to a
greater array of both pre-erythrocytic and intraerythrocytic antigens, while
restricting the development of symptomatic and potentially immunosuppressive
blood stage parasitemia may be critical to enhance the potency of wholesporozoite
immunization. Indeed, there is some evidence to support the notion
that late-liver stage arresting parasites might be more efficient in inducing
protection than early-liver stage arresting parasites [109]. In addition, recent
Plasmodium transcriptome and proteome analyses showed an increase in
shared antigens between late-liver stage parasites and blood-stage parasites,
supporting the use of late-liver stage arresting parasites as a tool to induce
cross-stage protection [110]. To dissect the immunomodulatory capacity of
chloroquine from its parasitocidal effect, it would be of interest to test the
potency of alternative drugs, such as azithromycin or mefloquine when coadministered
with live sporozoites in humans. Indeed, azithromycin has shown