Abstract
BackgroundIntravenous injection of mice with attenuated Plasmodium berghei sporozoites induces sterile immunity to challenge with viable sporozoites. Non-intravenous routes have been reported to yield poor immunity. Because intravenous immunization has been considered to be unacceptable for large scale vaccination of humans, assessment was made of the results of intradermal immunization of mice with Plasmodium yoelii, a rodent malaria parasite whose infectivity resembles that of human malaria.MethodsMice were immunized with two injections of isolated, radiation-attenuated P. yoelii sporozoites, either by intravenous (IV) or intradermal (ID) inoculation. In an attempt to enhance protective immunogenicity of ID-injections, one group of experimental mice received topical application of an adjuvant, Imiquimod, while another group had their injections accompanied by local "tape-stripping" of the skin, a procedure known to disrupt the stratum corneum and activate local immunocytes. Challenge of immunized and non-immunized control mice was by bite of sporozoite-infected mosquitoes. Degree of protection among the various groups of mice was determined by microscopic examination of stained blood smears. Statistical significance of protection was determined by a one-way ANOVA followed by Tukey's post hoc test.ResultsTwo intravenous immunizations produced 94% protection to mosquito bite challenge; intradermal immunization produced 78% protection, while intradermal immunization accompanied by "tape-stripping" produced 94% protection. There were no statistically significant differences in degree of protective immunity between immunizations done by intravenous versus intradermal injection.ConclusionsThe use of a sub-microlitre syringe for intradermal injections yielded excellent protective immunity. ID-immunization with large numbers of radiation-attenuated P. yoelii sporozoites led to levels of protective immunity comparable to those achieved by IV-immunization. It remains to be determined whether an adjuvant treatment can be found to substantially reduce the numbers of attenuated sporozoites required to achieve a strong protective immunity with as few doses as possible for possible extension to immunization of humans.
Highlights
Intravenous injection of mice with attenuated Plasmodium berghei sporozoites induces sterile immunity to challenge with viable sporozoites
Studies on immunization against sporozoite-induced rodent malaria resulted in close to 100% protection when mice were immunized with Plasmodium berghei sporozoites irradiated to sufficient levels and the immunized mice
Even after five immunizations, mice immunized by intramuscular (IM), intraperitoneal (IP) or intradermal (ID) routes were protected only 32%, 26% and 24%, respectively, in contrast to 95% protection after IV immunization [3]. In another P. berghei study done with similar protocols, IM immunization resulted in only 11% protection, addition of albumin to the immunizing inoculum raised this to 42%; in contrast, IV immunization yielded 100% protection [4]
Summary
Intravenous injection of mice with attenuated Plasmodium berghei sporozoites induces sterile immunity to challenge with viable sporozoites. An alternate approach allowed irradiated mosquitoes to directly inoculate attenuated sporozoites into hosts, the mosquitoes thereby acting as vehicles of immunization This approach was first established with rodent malaria [5] and extended to the first successful human vaccination trial against P falciparum malaria [6]. A compendium of subsequent human vaccination trials with this approach showed that when sufficient numbers of mosquitoes were used for immunization, greater than 90% of volunteers were completely protected against challenge by bite of infected mosquitoes [7,8] Recent progress by this group, under the auspices of the biopharmaceutical company Sanaria, has permitted the raising of large numbers of mosquitoes infected with Plasmodium falciparum sporozoites, the purification of these sporozoites sufficient to render them acceptable for human vaccination, and the successful freeze-preservation of the attenuated sporozoites. Trials are currently underway to attempt to vaccinate humans by syringe injection of these sporozoites [9,10]
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