Experimental infection and protection against ... - TI Pharma

General Discussion 229
to induce protection when co-administered with live sporozoites in a mouse
model [111]. Interestingly, both drugs also exhibit immunoregulatory properties
[112-114]. Alternatively, the passive transfer of antibodies directed against
blood-stage antigens could also prevent clinical disease and modulate the
immune response [115].
As an alternative to radiation, several other methods of attenuation, mainly in
rodent models, have been developed. Treatment of sporozoites with the DNA
alkylating agent centanamycin, a compound that particularly attenuates malaria
parasites because it exploits the AT-richness of the parasite genome, impairs the
infection of hepatocytes by sporozoites and arrests liver stage parasite
development. Mice inoculated with centanamycin-treated sporozoites failed to
produce blood stage infections and were protected against subsequent
challenge with wild-type sporozoites [116]. Moreover, cross-species protection
could be induced and parasite-specific antibodies and IFN-gamma-producing
CD8(+) T cells were induced that were not significantly different from radiationattenuated
sporozoites [116].
In fact, CPS immunisation also implies chemical attenuation, albeit in vivo. CPS as
currently presented is not a widely implementable vaccine strategy, but one
could envision the co-administration of a drug with a needle administered live
vaccine product for a selected group of subjects. However, safety requirements
for such in vivo attenuated product will likely be very stringent, e.g. full
attenuation must be independent from compliance and pharmacokinetics of the
drug. Moreover, in vivo attenuation precludes the ability to carry out viability
checks before the vaccine is administered, necessitating extensive postvaccination
follow-up.
In addition to the random genetic attenuation induced by radiation or chemicals,
targeted attenuation of sporozoites can be achieved by inactivation of specific
genes by molecular techniques. The main advantage of Genetically Attenuated
Parasites [GAP) over radiation and chemically attenuated parasites is the fact
that a homogeneous parasite population with a defined phenotype is obtained.
The recent availability of complete Plasmodium genome sequences permits the
development of live-attenuated parasites by more precise and defined genetic
manipulations [117]. Based on their expression profile and phenotype,
approximately seven genes have been selected for attenuation and knock-out
strains created primarily in rodent malaria parasites P. berghei and P. yoelii (p52,
p36, uis3, uis4, fabb/f, fabz, sap1 [118-126]). Immunisation of mice with GAP