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Ex Vivo Cytokine and Memory T Cell Responses to the 42-kDa Fragment of Plasmodium falciparum Merozoite Surface Protein-1 in Vaccinated Volunteers¹

Maria Cecilia Huaman^*,, Laura B. Martin^*, Elissa Malkin^2,*, David L. Narum^*, Louis H. Miller^*, Siddhartha Mahanty^*, and Carole A. Long^3,*,

^* Malaria Vaccine Development Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; Laboratory of Malaria and Vector Research, and Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

A number of blood-stage malaria Ags are under development as vaccine candidates, but knowledge of the cellular responses to these vaccines in humans is limited. We evaluated the nature and specificity of cellular responses in healthy American volunteers vaccinated with a portion of the major merozoite surface protein-1 (MSP1) of Plasmodium falciparum, MSP1₄₂, formulated on Alhydrogel. Volunteers were vaccinated three times with 80 µg of either MSP1₄₂-FVO/Alhydrogel or MSP1₄₂-3D7/Alhydrogel. Cells collected 2 wk after the third vaccination produced Th1 cytokines, including IFN- and IL-2 following Ag stimulation, and greater levels of the Th2 cytokines IL-5 and IL-13; the anti-inflammatory cytokine IL-10 and the molecule CD25 (IL-2R) were also detected. The volunteers were evaluated for the MSP1₄₂–FVO or MSP1₄₂-3D7 specificity of their T cell responses. Comparison of their responses to homologous and heterologous Ags showed ex vivo IFN- and IL-5 levels that were significantly higher to homologous rather than to heterologous Ags. The epitopes involved in this stimulation were shown to be present in the dimorphic MSP1₃₃ portion of the larger MSP1₄₂-3D7 polypeptide, and indirect experiment suggests the same for the MSP1₄₂–FVO polypeptide. This contrasts with B cell responses, which were primarily directed to the conserved MSP1₁₉ portion. Furthermore, we explored the maturation of memory T cells and found that 46% of vaccinees showed specific memory T cells defined as CD4⁺CD45RO⁺CD40L⁺ after long-term in vitro culture. The identification of human-specific CD4⁺ memory T cells provides the foundation for future studies of these cells both after vaccination and in field studies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by The Intramural Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Support for the phase I clinical trial of MSP1₄₂-FVO/Alhydrogel and MSP1₄₂-3D7/Alhydrogel was obtained from the Program for Appropriate Technology in Health (PATH)/Malaria Vaccine Initiative.

² Current address: PATH Malaria Vaccine Initiative, 7500 Old Georgetown Road, Bethesda, MD 20814.

³ Address correspondence and reprint requests to Dr. Carole A. Long, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook 3, 12735 Twinbrook Parkway, Rockville, MD 20852. E-mail address: calong{at}niaid.nih.gov

⁴ Abbreviations used in this paper: MSP1, merozoite surface protein-1; SFU, spot-forming unit; FoxP3, forkhead box P3 transcriptional repressor; Treg, regulatory T cell.