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Strains Used in Whole Organism Plasmodium Falciparum Vaccine Trials Differ in 2 Genome Structure, Sequence, and Immunogenic Potential 3 4 Authors: Kara A

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bioRxiv preprint doi: https://doi.org/10.1101/684175; this version posted June 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Title: Strains used in whole organism Plasmodium falciparum vaccine trials differ in 2 genome structure, sequence, and immunogenic potential 3 4 Authors: Kara A. Moser1‡, Elliott F. Drábek1, Ankit Dwivedi1, Jonathan Crabtree1, Emily 5 M. Stucke2, Antoine Dara2, Zalak Shah2, Matthew Adams2, Tao Li3, Priscila T. 6 Rodrigues4, Sergey Koren5, Adam M. Phillippy5, Amed Ouattara2, Kirsten E. Lyke2, Lisa 7 Sadzewicz1, Luke J. Tallon1, Michele D. Spring6, Krisada Jongsakul6, Chanthap Lon6, 8 David L. Saunders6¶, Marcelo U. Ferreira4, Myaing M. Nyunt2§, Miriam K. Laufer2, Mark 9 A. Travassos2, Robert W. Sauerwein7, Shannon Takala-Harrison2, Claire M. Fraser1, B. 10 Kim Lee Sim3, Stephen L. Hoffman3, Christopher V. Plowe2§, Joana C. Silva1,8 11 12 Corresponding author: Joana C. Silva, [email protected] 13 Affiliations: 14 1 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, 15 MD, 21201 16 2 Center for Vaccine Development and Global Health, University of Maryland School of 17 Medicine, Baltimore, MD, 21201 18 3 Sanaria, Inc. Rockville, Maryland, 20850 19 4 Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, 20 São Paulo, Brazil 21 5 Genome Informatics Section, Computational and Statistical Genomics Branch, 22 National Human Genome Research Institute, Bethesda, Maryland, USA 20892 23 6 Armed Forces Research Institute of Medical Sciences, Department of Bacterial and 24 Parasitic Diseases, Bangkok, Thailand 25 7 Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, 26 Netherlands 27 8 Department of Microbiology and Immunology, University of Maryland School of 28 Medicine, Baltimore, MD, 21201 29 30 ‡Current address: Institute for Global Health and Infectious Diseases, University of 31 North Carolina Chapel Hill 32 ¶Current address: Warfighter Expeditionary Medicine and Treatment, US Army Medical 33 Material Development Activity 34 §Current address: Duke Global Health Institute, Duke University, Durham, North 35 Carolina, 27708 36 37 Author emails (in order of author list above): 38 [email protected], [email protected], [email protected], 39 [email protected], [email protected], [email protected], 40 [email protected], [email protected], [email protected], 41 [email protected] , [email protected], [email protected], 42 [email protected], [email protected], 43 [email protected], [email protected], 44 [email protected], [email protected], [email protected], 45 [email protected], [email protected], [email protected], 1 bioRxiv preprint doi: https://doi.org/10.1101/684175; this version posted June 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 46 [email protected] , [email protected], 47 [email protected], [email protected], 48 [email protected], [email protected], [email protected], 49 [email protected], [email protected] 50 51 52 53 Abstract 54 Background: Plasmodium falciparum (Pf) whole-organism sporozoite vaccines have 55 provided excellent protection against controlled human malaria infection (CHMI) and 56 naturally transmitted heterogeneous Pf in the field. Initial CHMI studies showed 57 significantly higher durable protection against homologous than heterologous strains, 58 suggesting the presence of strain-specific vaccine-induced protection. However, 59 interpretation of these results and understanding of their relevance to vaccine efficacy 60 (VE) have been hampered by the lack of knowledge on genetic differences between 61 vaccine and CHMI strains, and how these strains are related to parasites in malaria 62 endemic regions. 63 Methods: Whole genome sequencing using long-read (Pacific Biosciences) and short- 64 read (Illumina) sequencing platforms was conducted to generate de novo genome 65 assemblies for the vaccine strain, NF54, and for strains used in heterologous CHMI (7G8 66 from Brazil, NF166.C8 from Guinea, and NF135.C10 from Cambodia). The assemblies 67 were used to characterize sequence polymorphisms and structural variants in each strain 68 relative to the reference Pf 3D7 (a clone of NF54) genome. Strains were compared to 69 each other and to clinical isolates from South America, Sub-Saharan Africa, and 70 Southeast Asia. 2 bioRxiv preprint doi: https://doi.org/10.1101/684175; this version posted June 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 71 Results: While few variants were detected between 3D7 and NF54, we identified tens of 72 thousands of variants between NF54 and the three heterologous strains both genome- 73 wide and within regulatory and immunologically important regions, including in pre- 74 erythrocytic antigens that may be key for sporozoite vaccine-induced protection. 75 Additionally, these variants directly contribute to diversity in immunologically important 76 regions of the genomes as detected through in silico CD8+ T cell epitope predictions. Of 77 all heterologous strains, NF135.C10 consistently had the highest number of unique 78 predicted epitope sequences when compared to NF54, while NF166.C8 had the lowest. 79 Comparison to global clinical isolates revealed that these four strains are representative 80 of their geographic region of origin despite long-term culture adaptation; of note, 81 NF135.C10 is from an admixed population, and not part of recently-formed drug resistant 82 subpopulations present in the Greater Mekong Sub-region. 83 Conclusions: These results are assisting the interpretation of VE of whole-organism 84 vaccines against homologous and heterologous CHMI, and may be useful in informing 85 the choice of strains for inclusion in region-specific or multi-strain vaccines. 86 87 Keywords: P. falciparum, malaria, genome assembly, PfSPZ Vaccine, whole-sporozoite 88 vaccine 89 90 3 bioRxiv preprint doi: https://doi.org/10.1101/684175; this version posted June 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 91 Main Text 92 Introduction 93 The flattening levels of mortality and morbidity due to malaria in recent years (1), 94 which follow a decade in which malaria mortality was cut in half (2), highlight the pressing 95 need for new tools to control the disease. A highly efficacious vaccine against 96 Plasmodium falciparum, the deadliest malaria parasite, would be a critical development 97 for control and elimination efforts. Several variations of a highly promising pre- 98 erythrocytic, whole organism malaria vaccine based on P. falciparum sporozoites (PfSPZ) 99 are under development, all based on the same P. falciparum strain, NF54 (3), thought to 100 be of West African origin, and which use different mechanisms for attenuation of PfSPZ. 101 Of these vaccine candidates, Sanaria® PfSPZ Vaccine, based on radiation-attenuated 102 sporozoites, has progressed furthest in clinical trial testing (4–10). Other whole-organism 103 vaccine candidates, including chemo-attenuated (Sanaria® PfSPZ-CVac), transgenic 104 and genetically attenuated sporozoites, are in earlier stages of development (11–13). 105 PfSPZ Vaccine showed 100% short-term protection against homologous 106 controlled human malaria infection (CHMI) in an initial phase 1 clinical trial (6), and 107 subsequent trials have confirmed that high levels of protection can be achieved against 108 both short-term (8) and long-term (7) homologous CHMI. However, depending on the 109 immunization regimen, sterile protection can be significantly lower (8-83%) against 110 heterologous CHMI using the 7G8 Brazilian clone (8,9), and against infection in malaria- 111 endemic regions with intense seasonal malaria transmission (29% and 52% by 112 proportional and time to event analysis, respectively) (10). Heterologous CHMI in 113 chemoprophylaxis with sporozoite (CPS) studies, in which immunization is by infected 4 bioRxiv preprint doi: https://doi.org/10.1101/684175; this version posted June 27, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 114 mosquito bite of individuals undergoing malaria chemoprophylaxis, have been conducted 115 with NF135.C10 from Cambodia (14) and NF166.C8 from Guinea (15), and have had 116 lower efficacy than against homologous CHMI (16,17). One explanation for the lower 117 efficacy seen against heterologous P. falciparum strains is the extensive genetic diversity 118 in this parasite species, which is particularly high in genes encoding antigens (18), which 119 combined with low vaccine efficacy against non-vaccine alleles (19–21) reduces overall 120 protective efficacy and complicates the design of broadly efficacious vaccines (22,23). 121 The lack of a detailed genomic characterization of the P. falciparum strains used in CHMI 122 studies, and the unknown genetic basis of the parasite
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  • Capture-Based Enrichment of Theileria Parva DNA

    Capture-Based Enrichment of Theileria Parva DNA

    bioRxiv preprint doi: https://doi.org/10.1101/2020.04.11.037309; this version posted April 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Capture-based enrichment of Theileria parva DNA enables full genome assembly of first buffalo- derived strain and reveals exceptional intra-specific genetic diversity Nicholas C Palmateer1, Kyle Tretina1, Joshua Orvis1, Olukemi O Ifeonu1, Jonathan Crabtree1, Elliott Drabék1, Roger Pelle2, Elias Awino3, Hanzel T Gotia1, James B Munro1, Luke Tallon1, W Ivan Morrison4, Claudia A Daubenberger5,6, Vish Nene3, Donald P Knowles7, Richard P Bishop7, Joana C Silva1,8§ 1Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA 2Biosciences eastern and central Africa-International Livestock Research Institute, Nairobi, Kenya 3International Livestock Research Institute, Nairobi, Kenya 4The Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Roslin, Midlothian EH25 9RG, UK 5Swiss Tropical and Public Health Institute, 4002 Basel, Switzerland 6University of Basel, Basel, Switzerland 7Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99163, USA 8Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA §Corresponding author: [email protected] Running title: “Apicomplexan Theileria parva is exceptionally polymorphic” Keywords: Theileria parva, lawrencei, DNA enrichment, genome assembly, polymorphism 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.04.11.037309; this version posted April 13, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.