Low doses of killed parasite in CpG elicit vigorous CD4+ T cell responses against blood-stage malaria in mice
Alberto Pinzon-Charry, … , James McCarthy, Michael F. Good
Alberto Pinzon-Charry, … , James McCarthy, Michael F. Good
Published July 12, 2010
Citation Information: J Clin Invest. 2010;120(8):2967-2978. https://doi.org/10.1172/JCI39222.
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Low doses of killed parasite in CpG elicit vigorous CD4+ T cell responses against blood-stage malaria in mice

Abstract

Development of a vaccine that targets blood-stage malaria parasites is imperative if we are to sustainably reduce the morbidity and mortality caused by this infection. Such a vaccine should elicit long-lasting immune responses against conserved determinants in the parasite population. Most blood-stage vaccines, however, induce protective antibodies against surface antigens, which tend to be polymorphic. Cell-mediated responses, on the other hand, offer the theoretical advantage of targeting internal antigens that are more likely to be conserved. Nonetheless, few of the current blood-stage vaccine candidates are able to harness vigorous T cell immunity. Here, we present what we believe to be a novel blood-stage whole-organism vaccine that, by combining low doses of killed parasite with CpG-oligodeoxynucleotide (CpG-ODN) adjuvant, was able to elicit strong and cross-reactive T cell responses in mice. Our data demonstrate that immunization of mice with 1,000 killed parasites in CpG-ODN engendered durable and cross-strain protection by inducing a vigorous response that was dependent on CD4+ T cells, IFN-γ, and nitric oxide. If applicable to humans, this approach should facilitate the generation of robust, cross-reactive T cell responses against malaria as well as antigen availability for vaccine manufacture.

Authors

Alberto Pinzon-Charry, Virginia McPhun, Vivian Kienzle, Chakrit Hirunpetcharat, Christian Engwerda, James McCarthy, Michael F. Good

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Figure 1

Definition of a low-dose whole-parasite vaccine.

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Definition of a low-dose whole-parasite vaccine. (A) To define the low-d...
(A) To define the low-dose vaccine, A/J mice were immunized with decreasing doses of P. c. chabaudi AS (AS) antigen equivalent to 108, 103, 102, or 0 (adjuvant alone) prbc in CpG-ODN or control ODN. 2 weeks after immunization, mice were challenged i.v. with 105 homologous (AS) prbc and the outcome of infection monitored as parasitemia. Disease severity is also described in Supplemental Figure 1. Data for individual mice are shown. †Animals that succumbed to infection. (B) To assess cellular immune responses induced by vaccination, antigen-specific proliferation of splenic lymphocytes was assessed at the time of challenge infection. Spleen cells were cultured for 96 hours in the presence of fresh (AS) parasitized rbc (P), normal rbc (N), medium (M), or ConA (C) and proliferation assessed by thymidine uptake. Results show mean ± SEM. (C) To assess vaccine-induced antibody responses, parasite-specific IgG titers against homologous (AS) antigen were assessed by ELISA at the time of challenge. Reciprocal median total IgG titers and interquartile ranges are shown. All results are representative of 5 mice per group of 3 independent experiments performed. Significant differences compared with adjuvant alone (control ODN or CpG-ODN) are shown. *P < 0.05; **P < 0.01. HIS, hyperimmune sera.