Bacterial superglue generates a full-length circumsporozoite protein virus-like particle vaccine capable of inducing high and durable antibody responses

Malaria Journal

Research

Thor G. Theander¹  Morten A. Nielsen²  Adam F. Sander²  Christoph M. Janitzek²  Ali Salanti²  Susan Thrane²  Steve B. Mwakalinga³  Reginald Kavishe³  Sungwa Matondo³ 

[1] Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark;Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark;Kilimanjaro Christian Medical University College (KCMUCo), Moshi, Tanzania;

关键词: Virus-like particle;    VLP;    Pre-erythrocytic;    Malaria vaccine;    Circumsporozoite protein;    CSP;    Spycatcher;    Spytag;    Bacterial superglue;    Split-intein;   

DOI  :  10.1186/s12936-016-1574-1

 received in 2016-08-06, accepted in 2016-10-27,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundMalaria, caused by Plasmodium falciparum, continues to have a devastating impact on global health, emphasizing the great need for a malaria vaccine. The circumsporozoite protein (CSP) is an attractive target for a malaria vaccine, and forms a major component of RTS,S, the most clinically advanced malaria vaccine. The clinical efficacy of RTS,S has been moderate, yet has demonstrated the viability of a CSP-based malaria vaccine. In this study, a vaccine comprised of the full-length CSP antigen presented on a virus-like particle (VLP) is produced using a split-intein conjugation system (SpyTag/SpyCatcher) and the immunogenicity is tested in mice.MethodsFull-length 3d7 CSP protein was genetically fused at the C-terminus to SpyCatcher. The CSP-SpyCatcher antigen was then covalently attached (via the SpyTag/SpyCatcher interaction) to Acinetobacter phage AP205 VLPs which were modified to display one SpyTag per VLP subunit. To evaluate the VLP-display effect, the immunogenicity of the VLP vaccine was tested in mice and compared to a control vaccine containing AP205 VLPs plus unconjugated CSP.ResultsFull-length CSP was conjugated at high density (an average of 112 CSP molecules per VLP) to AP205 SpyTag-VLPs. Vaccination of mice with the CSP Spy-VLP vaccine resulted in significantly increased antibody titres over a course of 7 months as compared to the control group (2.6-fold higher at 7 months after immunization). Furthermore, the CSP Spy-VLP vaccine appears to stimulate production of IgG2a antibodies, which has been linked with a more efficient clearing of intracellular parasite infection.ConclusionThis study demonstrates that the high-density display of CSP on SpyTag-VLPs, significantly increases the level and quality of the vaccine-induced humoral response, compared to a control vaccine consisting of soluble CSP plus AP205 VLPs. The SpyTag-VLP platform utilized in this study constitutes a versatile and rapid method to develop highly immunogenic vaccines. It might serve as a generic tool for the cost-effective development of effective VLP-vaccines, e.g., against malaria.

【 授权许可】

CC BY   
© The Author(s) 2016