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A Nonadjuvanted Polypeptide Nanoparticle Vaccine Confers Long-Lasting Protection against Rodent Malaria¹

Stephen A. Kaba,^* Clara Brando,^* Qin Guo,^* Christian Mittelholzer, Senthilkumar Raman, David Tropel, Ueli Aebi, Peter Burkhard, and David E. Lanar^2*

^*Division of Malaria Vaccine Development, Walter Reed Army Institute of Research, Silver Spring, MD 20910; M.E. Müller Institut, Basel, Switzerland; and Institute of Materials Science, Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269

We have designed and produced a prototypic malaria vaccine based on a highly versatile self-assembling polypeptide nanoparticle (SAPN) platform that can repetitively display antigenic epitopes. We used this platform to display a tandem repeat of the B cell immunodominant repeat epitope (DPPPPNPN)₂D of the malaria parasite Plasmodium berghei circumsporozoite protein. Administered in saline, without the need for a heterologous adjuvant, the SAPN construct P4c-Mal conferred a long-lived, protective immune response to mice with a broad range of genetically distinct immune backgrounds including the H-2^b, H-2^d, and H-2^k alleles. Immunized mice produced a CD4⁺ T cell-dependent, high-titer, long-lasting, high-avidity Ab response against the B cell epitope. Mice were protected against an initial challenge of parasites up to 6 mo after the last immunization or for up to 15 mo against a second challenge after an initial challenge of parasites had successfully been cleared. Furthermore, we demonstrate that the SAPN platform not only functions to deliver an ordered repetitive array of B cell peptide epitopes but operates as a classical immunological carrier to provide cognate help to the P4c-Mal-specific B cells.

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 C.M., D.T., and S.R. were supported by the Grants 8433.1 and Peptide NP from the Kommission für Technologie und Innovation (Switzerland) and the Swiss Nanoscience Institute.

² Address correspondence and reprint requests to Dr. David E. Lanar, Division of Malaria Vaccine Development, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910. E-mail address: david.lanar{at}us.army.mil

³ Abbreviations used in this paper: VLP, virus-like particle; AI, avidity index; COMP, cartilage oligomeric matrix protein; DC, dendritic cell; DLS, dynamic light scattering; KO, knockout; LAL, Limulus amebocyte lysate; LP, linear polypeptide; MHC II, MHC class II; NaSCN, sodium isothiocyanate; P4c-Mal/M, P4c-Mal in Montanide ISA-720; PbCSP, Plasmodium berghei circumsporozoite protein; R-PbCSP, recombinant-PbCSP; R-PbCSP/M, R-PbCSP protein in Montanide ISA-720; SAPN, self-assembling polypeptide nanoparticle; TEM, transmission electron microscopy.