Experimental infection and protection against ... - TI Pharma

186 Chapter 9
protective role in other infectious diseases [33,34]. Further detailed
investigations will be necessary to ascertain the longevity of this immunological
response, its association with central memory-type T cell activity and its ability
to serve as a true correlate of protection.
Since the magnitude of the first wave of parasitemia is thought to directly reflect
the burden of erupting mature liver schizonts, the step-wise decrease of such
following each subsequent immunizing infection, culminating in the total
absence of PCR-detectable parasitemia following challenge, would suggest that
the protection in our model is primarily due to pre-erythrocytic immunity.
However, a component of blood-stage immunity, i.e. the inhibition of
erythrocyte invasion and maturation of sub-PCR liver-derived merozoite inocula,
is also possible. Indeed we found cellular responses to asexual blood-stage
parasites [PfRBC) prior to challenge to be an excellent discriminative marker of
exposure and protection in our volunteers and similar immune responses may
have contributed to protection in the rodent model [12]. It must be borne in
mind, however, that many of the best-studied P. falciparum antigens conferring
protective immunity are shared between sporozoite, liver-stage and blood-stage
parasites [35,36]. Thus it is plausible that our findings represent the response to
a broad antigenic repertoire that transcends parasite developmental stages [37],
making a dichotomy into pre-erythrocytic or intra-erythrocytic immunity
inappropriate. At present the stage-specificity of the protective immune
response must thus remain formally unresolved, although one way to further
address this issue in future studies would be a blood-stage challenge.
Whereas the methodology described here does not itself represent a widely
implementable vaccine strategy, the induction of sterile protection against an
homologous malaria challenge suggests that the concept of a whole parasite
malaria vaccine warrants further consideration. In addition, this model allows
the nature of protective immune responses against malaria, both stage- and
antigen-specific, to be further investigated.
Acknowledgements
Foremost, we are indebted to the study volunteers for their participation. We
thank K. Nganou Makamdop for help with RT-PCR, J. Bakkers & W. Melchers for
parasite genotyping, W. Arts, N. Huibers & P. Beckers for blood slide reading, P.
Houze & D. Mazier for chloroquine measurements and J. Klaassen, L. Pelser-
Posthumus, J. Kuhnen & A. Pouwelsen for technical assistance generating