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Novel Virus-Like Particle Vaccine Encoding the Circumsporozoite

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Novel Virus-Like Particle Vaccine Encoding the Circumsporozoite bioRxiv preprint doi: https://doi.org/10.1101/2020.12.14.422617; this version posted December 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Novel virus-like particle vaccine encoding the circumsporozoite 2 protein of Plasmodium falciparum is immunogenic and induces 3 functional antibody responses 4 AUTHORS AND AFFILIATIONS 5 Liriye Kurtovic1,2#, David Wetzel3#, Linda Reiling1, Damien R. Drew1, Catherine Palmer1, 6 Betty Kouskousis1, Eric Hanssen4, Bruce D. Wines1,2,5, P. Mark Hogarth1,2,5, Manfred 7 Suckow3, Volker Jenzelewski3, Michael Piontek3, Jo-Anne Chan1,2,6#*, James G. Beeson1,2,6,7#* 8 1Burnet Institute, Melbourne, Australia. 9 2Departments of Immunology and Pathology and Infectious Diseases, Central Clinical School, 10 Monash University, Melbourne, Australia. 11 3ARTES Biotechnology GmbH, Langenfeld, Germany. 12 4The Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 13 Parkville, Australia. 14 5Clinical Pathology, The University of Melbourne, Parkville, Australia 15 6Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, 16 Australia 17 7Department of Microbiology, Monash University, Clayton, Australia. 18 #Authors contributed equally (co-first and co-senior authors) 19 *Corresponding authors: James Beeson & Jo-Anne Chan; 85 Commercial Road, Melbourne, 20 Australia; +61 3 9282 2111; [email protected] & [email protected] 21 22 23 24 25 26 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.14.422617; this version posted December 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 27 ABSTRACT 28 RTS,S is the leading malaria vaccine in development, but has demonstrated only moderate 29 protective efficacy in clinical trials. RTS,S is a virus-like particle (VLP) that uses the human 30 hepatitis B virus as scaffold to display the malaria sporozoite antigen, circumsporozoite protein 31 (CSP). Particle formation requires fourfold excess scaffold antigen, and as a result, CSP 32 represents only a small portion of the final vaccine construct. Alternative VLP or nanoparticle 33 platforms that reduce the amount of scaffold antigen and increase the amount of the target CSP 34 antigen present in particles may enhance vaccine immunogenicity and efficacy. Here, we 35 describe the production and characterization of a novel VLP that uses the small surface antigen 36 (dS) of duck hepatitis B virus to display CSP. The CSP-dS fusion protein successfully formed 37 VLPs without the need for excess scaffold antigen, and thus CSP represented a larger portion 38 of the vaccine construct. Importantly, this is the first report of a dS-based vaccine that formed 39 particles without excess scaffold protein. CSP-dS formed large particles approximately 31-74 40 nm in size and were confirmed to display CSP on the surface. The CSP-dS VLP was highly 41 immunogenic in mice and induced antibodies to multiple regions of CSP, even when 42 administered at a lower vaccine dosage. Vaccine-induced antibodies demonstrated functional 43 activity, including the ability to interact with complement and Fcγ-receptors, both previously 44 identified as important in malaria immunity. Our novel platform to produce VLPs without 45 excess scaffold protein has wide implications for the future development of innovative vaccines 46 for malaria and other infectious diseases. 47 Key words 48 Circumsporozoite protein; Duck hepatitis B surface antigen; Malaria; Plasmodium falciparum; 49 RTS,S; Vaccines; Virus-like particles 50 51 52 53 54 2 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.14.422617; this version posted December 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 55 INTRODUCTION 56 There were an estimated 228 million cases of malaria and 405,000 deaths in 2018, largely 57 attributed to infection with Plasmodium falciparum (1). Various antimalarial interventions are 58 currently available, including vector control measures to prevent transmission of the malaria- 59 causing parasite from mosquitoes to humans, and drugs to clear infection and treat clinical 60 illness. However, the effectiveness of these tools are threatened by the emergence and spread 61 of drug and insecticide resistance (2), and disruptions to and gaps in public health interventions 62 (3). A critical step towards reducing malaria burden and achieving global malaria elimination 63 will require innovative research to develop new interventions, including efficacious malaria 64 vaccines (4). 65 The most advanced malaria vaccine in development is RTS,S, which is based on the major 66 surface antigen expressed by P. falciparum sporozoites, the circumsporozoite protein (CSP). 67 This vaccine approach targets the initial asymptomatic stage of infection in the liver and 68 therefore aims to prevent parasite replication in the blood and subsequent onset of clinical 69 disease (5). The RTS,S vaccine construct is a fusion protein of a domain derived from the CSP 70 (including the central-repeat and C-terminal regions of the protein) and the human hepatitis B 71 surface antigen (HBsAg), which is co-expressed with excess HBsAg to self-assemble into 72 virus-like particles (VLPs) (6). These particles are ~20 nm in size and co-administered with the 73 potent AS01 adjuvant to enhance vaccine immunogenicity (7). RTS,S/AS01 is the only malaria 74 vaccine to complete phase III clinical trials, which were conducted at 11 study sites in sub- 75 Saharan Africa. RTS,S vaccination conferred ~30-50% protective efficacy against clinical 76 malaria in young children and infants depending on the age group and duration of follow-up 77 (8). However, vaccine efficacy waned substantially in the 12 months after completion of 78 primary vaccination of three doses (9). To further evaluate vaccine safety and efficacy, pilot 79 implementation of RTS,S recently commenced in Ghana, Kenya and Malawi as recommended 80 by the World Health Organization (WHO) (10). 81 While RTS,S is the leading malaria vaccine candidate, it is an imperfect vaccine that is unlikely 82 to drive malaria elimination as a stand-alone tool. Strategies to modify RTS,S could lead to the 83 development of RTS,S-like or next-generation vaccines with improved immunogenicity, 84 efficacy and longevity in target populations. An important limitation of the RTS,S vaccine 85 construct is the need for excess HBsAg for particle formation to occur and thus, the resulting 86 VLP is comprised of only ~20% CSP-HBsAg fusion protein and ~80% unfused HBsAg 3 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.14.422617; this version posted December 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 87 scaffold protein (11). A novel CSP-based particle vaccine was recently described known as 88 R21, which did not require excess unfused HBsAg for particle formation, and therefore had an 89 increased proportion of CSP compared to RTS,S. R21 was immunogenic and efficacious in a 90 pre-clinical murine vaccine study, and may improve upon current vaccine approaches (12). 91 Another consideration is the VLP scaffold protein used to display the CSP antigen, which can 92 influence particle size and structure, and therefore influence the induction of protective immune 93 responses (13). 94 Here we describe the production and characterization of a novel VLP-based vaccine candidate 95 that displays CSP on the surface (Figure 1). We used the membrane integral small surface 96 protein (dS) of the duck hepatitis B virus (DHBV) as a VLP scaffold protein (14-16). As a 97 proof-of-concept for this vaccine platform, the same portion of CSP that is included in RTS,S 98 (central-repeat and C-terminal regions of the protein) was selected as the malaria vaccine 99 antigen and was genetically fused to the dS. The resulting CSP-dS fusion protein was 100 overexpressed in recombinant yeast Hansenula polymorpha, which is a cell line suitable for 101 large-scale vaccine manufacturing. This approach resulted in the formation of VLPs with the 102 CSP-dS fusion protein alone, without the need for excess dS as a scaffold protein, thereby 103 achieving a higher ratio of the CSP vaccine antigen compared to the approach used for RTS,S 104 and other VLP-based vaccines. The biophysical properties of these VLPs were characterized 105 and the expression of CSP confirmed through Western blotting, transmission electron 106 microscopy and super resolution microscopy. We performed an immunogenicity study of the 107 CSP-dS VLPs in mice and measured the ability of vaccine-induced antibodies to mediate 108 effector functions that have been associated with RTS,S vaccine efficacy (17), such as 109 interacting with complement and Fcγ-receptors (FcγRs) that are expressed on immune cells. 110 111 112 113 114 4 bioRxiv preprint doi: https://doi.org/10.1101/2020.12.14.422617; this version posted December 15, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
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