A rationally designed flagellin-L2 fusion protein induced serum and mucosal neutralizing antibodies against multiple HPV types |
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| Institution: | 1. Department of Biophysics and Structural Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China;2. The Fifth Department of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, Yunnan, China;1. Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA;2. Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA;1. Defense Health Agency/Air Force Health Surveillance Branch-Air Force Satellite, United States;2. STS Systems Integration, LLC, San Antonio, TX, United States;1. Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy;2. Department of Biology and Biotechnology “Charles Darwin”, Sapienza University of Rome 00185 Rome, Italy;3. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, USA;4. Division of Virology, Department of Microbiology and Immunology, and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Japan;5. Infection-Induced Host Responses Project, Exploratory Research for Advanced Technology, Saitama 332-0012, Japan;1. Department of Pediatrics, Weill Cornell Medicine, New York, NY, United States;2. Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, United States;1. Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming 650118, China;2. National Institutes for Food and Drug Control, Beijing 100050, China |
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| Abstract: | The amino terminus of human papillomavirus (HPV) minor capsid protein L2 harbors several conserved neutralizing epitopes, including aa.17–36 (RG-1 epitope) and aa.65–85 consensus epitope (cL2 epitope), which are considered to be promising for the construction of cost-effective pan-HPV vaccine candidates. However, the immunogenicity of L2 epitope/peptide is rather weak, and the neutralizing spectrum induced by single type of L2 antigen is suboptimal. In this study, we constructed L2 concatemer with HPV18/33/58/59 RG-1 epitopes and 16L2 aa.11–88 peptide, and fused it with flagellin, a strong systemic and mucosal adjuvant, by hypervariable region replacement. A copy of cL2 epitope was also introduced to the C-terminus of the recombinant protein. The resultant Fla-5PcL2 protein can be produced in E. coli expression system with high yield and good stability. We assessed the immunogenicity of Fla-5PcL2 in mouse model via systemic and mucosal route, and found that subcutaneous immunization with Fla-5PcL2 induced robust serum neutralizing antibodies against divergent HPV types, while intranasal immunization with Fla-5PcL2 induced remarkable L2-specific IgA and cross-neutralizing antibodies in mucosal secretions, and medium titers of cross-neutralizing antibodies in sera. Moreover, Fla-5PcL2 induced full protection against vaginal HPV challenges. As mucosal antibodies provide the first-line defense at infection sites, and needle-free immunizations may increase vaccine compliance and require less public health resources, our results demonstrate that Fla-5PcL2 is a promising vaccine candidate which possibly meet the need in low-resource regions. |
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| Keywords: | Papillomavirus L2 Flagellin Neutralizing antibody Mucosal immunization |
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