A Hybrid Multistage Protein Vaccine Induces Protective Immunity against Murine Malaria

• Type of Material: Article
• Authors: Balwan Singh, Emory University; Monica Cabrera-Mora, Emory University; Jianlin Jiang, Emory University; C. Moreno, Emory University
• Language: English
• Date: 2012-04-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2012, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/IAI.05980-11
• Title of Journal or Parent Work: Infection and Immunity
• ISSN: 0019-9567
• Volume: 80
• Issue: 4
• Start Page: 1491
• End Page: 1501
• Grant/Funding Information: This research was supported by the U.S. National Institutes of Health, NIAID grant no. R01-AI064766, and the Yerkes National Primate Research Center, base grant no. RR00165, awarded by the National Center for Research Resources of the National Institutes of Health.
• Keywords: CANDIDATE; T-CELL; CRYSTAL-STRUCTURE; SPOROZOITE INOCULATION; ANTIBODY; Immunology; Infectious Diseases; INFECTIOUS DISEASES; PLASMODIUM-FALCIPARUM; STAGE; INFECTED HEPATOCYTES; MEROZOITE SURFACE PROTEIN-1; LINEAR PEPTIDE CHIMERA; Science & Technology; IMMUNOLOGY; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Pathology; Health Sciences, Immunology

Abstract

We have previously reported the design and expression of chimeric recombinant proteins as an effective platform to deliver malaria vaccines. The erythrocytic and exoerythrocytic protein chimeras described included autologous T helper epitopes genetically linked to defined B cell epitopes. Proof-of-principle studies using vaccine constructs based on the Plasmodium yoelii circumsporozoite protein (CSP) and P. yoelii merozoite surface protein-1 (MSP-1) showed encouraging results when tested individually in this mouse malaria model. To evaluate the potential synergistic or additive effect of combining these chimeric antigens, we constructed a synthetic gene encoding a hybrid protein that combined both polypeptides in a single immunogen. The multistage vaccine was expressed in soluble form in Escherichia coli at high yield. Here we report that the multistage protein induced robust immune responses to individual components, with no evidence of vaccine interference. Passive immunization using purified IgG from rabbits immunized with the hybrid protein conferred more robust protection against the experimental challenge with P. yoelii sporozoites than passive immunization with purified IgG from rabbits immunized with the individual proteins. High antibody titers and high frequencies of CD4(+)- and CD8(+)-specific cytokine-secreting T cells were elicited by vaccination. T cells were multifunctional and able to simultaneously produce interleukin-2 (IL-2), gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α). The mechanism of vaccine-induced protection involved neutralizing antibodies and effector CD4(+) T cells and resulted in the control of hyperparasitemia and protection against malarial anemia. These data support our strategy of using an array of autologous T helper epitopes to maximize the response to multistage malaria vaccines.