Abstract
Immunization with radiation attenuated Plasmodium sporozoites (RAS) elicits sterile protective immunity against sporozoite challenge in murine models and in humans. Similarly to RAS, the genetically attenuated sporozoites (GAPs) named uis3(-), uis4(-) and P36p(-) have arrested growth during the liver stage development, and generate a powerful protective immune response in mice. We compared the protective mechanisms in P. yoelii RAS, uis3(-) and uis4(-) in BALB/c mice. In RAS and GAPs, sterile immunity is only achieved after one or more booster injections. There were no differences in the immune responses to the circumsporozoite protein (CSP) generated by RAS and GAPs. To evaluate the role of non-CSP T-cell antigens we immunized antibody deficient, CSP-transgenic BALB/c mice, that are T cell tolerant to CSP, with P. yoelii RAS or with uis3(-) or uis4(-) GAPs, and challenged them with wild type sporozoites. In every instance the parasite liver stage burden was approximately 3 logs higher in antibody deficient CSP transgenic mice as compared to antibody deficient mice alone. We conclude that CSP is a powerful protective antigen in both RAS and GAPs viz., uis3(-) and uis4(-) and that the protective mechanisms are similar independently of the method of sporozoite attenuation.
Highlights
To date only vaccines containing radiation attenuated sporozoites (RAS) consistently induce sterile immunity in rodents [1], monkeys [2] and humans [3]
We found that the levels of protection elicited by RAS or genetically attenuated sporozoites (GAPs) vaccination were greater than 95% in all groups (Fig 1A)
Previous studies highlighted the central role of CD8+ T cells in protection of BALB/c mice after vaccination with P. yoelii uis3(-), uis4(-) [20], and of C57BL/6 mice with P. berghei uis3(-), uis4(-) [24] and P36p(-) [19] GAPS, but the respective protective antigen(s) have yet to be identified
Summary
To date only vaccines containing radiation attenuated sporozoites (RAS) consistently induce sterile immunity in rodents [1], monkeys [2] and humans [3]. Immunization of humans with Plasmodium falciparum sporozoites was accomplished by the bite of infected irradiated Anopheles mosquitoes, and after many booster injections a high degree of protection was obtained [3,4]. The RAS protective immunity is mediated by antibodies to sporozoites and by effector CD4+ and CD8+ T cells against livers stages (exoerythrocytic stages or EEFs) [5]. The antibodies are mostly or exclusively directed against the circumsporozoite protein (CSP) that covers the plasma membrane of the sporozoites [11]. These antibodies immobilize sporozoites [12], prevent their attachment to the host’s hepatocytes [13], and inhibit infection. CD4+ and/or CD8+ effector T cells that recognize the infected hepatocytes are required to obtain sterile immunity in the murine models of pre-erythrocytic vaccines [16]
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