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


METHODS
Full-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.


RESULTS
Full-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.


CONCLUSIONS
This 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.
Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
Christoph M
CM
Janitzek
Kilimanjaro Christian Medical University College (KCMUCo), Moshi, Tanzania.
Sungwa
S
Matondo
Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
Susan
S
Thrane
Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark.
Morten A
MA
Nielsen
Kilimanjaro Christian Medical University College (KCMUCo), Moshi, Tanzania.
Reginald
R
Kavishe
Kilimanjaro Christian Medical University College (KCMUCo), Moshi, Tanzania.
Steve B
SB
Mwakalinga
Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Thor G
TG
Theander
Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. Salanti@sund.ku.dk.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark. Salanti@sund.ku.dk.
Ali
A
Salanti
Centre for Medical Parasitology, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. adamsander@gmail.com.|Department of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark. adamsander@gmail.com.
Adam F
AF
Sander
D000150:Acinetobacter / Q000821:virology; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood*; D000917:Antibody Formation; D001435:Bacteriophages / Q000737:chemistry; D061505:Cell Surface Display Techniques; D004337:Drug Carriers; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D008807:Mice, Inbred BALB C; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
D000913:Antibodies, Protozoan; D004337:Drug Carriers; D007074:Immunoglobulin G; D015800:Protozoan Proteins; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; D058425:Vaccines, Virus-Like Particle; C041595:circumsporozoite protein, Protozoan
Bacterial superglue; CSP; Circumsporozoite protein; Malaria vaccine; Pre-erythrocytic; Split-intein; Spycatcher; Spytag; VLP; Virus-like particle