@article{2bc7a45dcd6342e6b1ff1d5c286f88b4,
title = "Preclinical Development of a Stabilized RH5 Virus-Like Particle Vaccine that Induces Improved Anti-Malarial Antibodies",
abstract = "The development of a highly effective vaccine against the pathogenic blood-stage infection of human malaria will require a delivery platform that can induce an antibody response of both maximal quantity and functional quality. One strategy to achieve this includes presenting antigens to the immune system on virus-like particles (VLPs). Here we sought to improve the design and delivery of the blood-stage Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) antigen, which is currently in a Phase 2 clinical trial as a full-length soluble protein-in-adjuvant vaccine candidate called RH5.1/Matrix-M{\texttrademark}. We identify disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees, and a re-engineered and stabilized immunogen that includes just the alpha-helical core of RH5 induces a qualitatively superior growth-inhibitory antibody response in rats vaccinated with this protein formulated in Matrix-M{\texttrademark} adjuvant. In parallel, bioconjugation of this new immunogen, termed textquotedblleftRH5.2textquotedblright, to hepatitis B surface antigen VLPs using the textquotedblleftplug-and-displaytextquotedblright SpyTag-SpyCatcher platform technology also enabled superior quantitative antibody immunogenicity over soluble antigen/adjuvant in vaccinated mice and rats. These studies identify a new blood-stage malaria vaccine candidate that may improve upon the current leading soluble protein vaccine candidate RH5.1/Matrix-M{\texttrademark}. The RH5.2-VLP/Matrix-M{\texttrademark} vaccine candidate is now under evaluation in Phase 1a/b clinical trials.Competing Interest StatementSJD is an inventor on patent applications relating to RH5 malaria vaccines and antibodies; is a co-founder of and shareholder in SpyBiotech; and has been a consultant to GSK on malaria vaccines. AMM has been a consultant to GSK on malaria vaccines; and has an immediate family member who is an inventor on patent applications relating to RH5 malaria vaccines and antibodies and is a co-founder of and shareholder in SpyBiotech. MH is an inventor on patents relating to peptide targeting via spontaneous amide bond formation, and is a co-founder of and shareholder in SpyBiotech. SB is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and is a co-founder of, shareholder in and employee of SpyBiotech. JJ is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and is a co-founder of and shareholder in SpyBiotech. RAD is an inventor on patent applications relating to vaccines made using spontaneous amide bond formation and shareholder in SpyBiotech. LDWK, JRB, DQ, AML, SES, BGW, KMc, IC, SJF and DP are inventors on patent applications relating to RH5 malaria vaccines and/or antibodies. All other authors have declared that no conflict of interest exists.",
author = "King, \{Lloyd D. W.\} and David Pulido and Barrett, \{Jordan R.\} and Hannah Davies and Doris Quinkert and Lias, \{Amelia M.\} and Silk, \{Sarah E.\} and Pattinson, \{David J.\} and Ababacar Diouf and Williams, \{Barnabas G.\} and Kirsty McHugh and Ana Rodrigues and Rigby, \{Cassandra A.\} and Veronica Strazza and Jonathan Suurbaar and Chloe Rees-Spear and Dabbs, \{Rebecca A.\} and Ishizuka, \{Andrew S.\} and Yu Zhou and Gaurav Gupta and Jing Jin and Yuanyuan Li and Cecilia Carnrot and Minassian, \{Angela M.\} and Ivan Campeotto and Fleishman, \{Sarel J.\} and Noe, \{Amy R.\} and MacGill, \{Randall S.\} and King, \{C. Richter\} and Birkett, \{Ashley J.\} and Soisson, \{Lorraine A.\} and Long, \{Carole A.\} and Kazutoyo Miura and Rebecca Ashfield and Katherine Skinner and Mark Howarth and Sumi Biswas and Draper, \{Simon J.\}",
note = "The authors are grateful for the assistance of Julie Furze, Penelope Lane, Fay Nugent, Wendy Crocker, Charlotte Hague, Daniel Alanine, Robert Ragotte, Darren Leneghan, Genevi{\`e}ve Labb{\'e}, Carolyn Nielsen, Martino Bardelli, Jenny Bryant, Lana Strmecki and Matt Higgins (University of Oxford); Sally Pelling-Deeves for arranging contracts (University of Oxford); Colleen Woods (PATH-MVI); Jenny Reimer (Novavax); Ken Tucker, Timothy Phares, Jayne Christen, Cecille Browne and Vin Kotraiah (Leidos); Robin Miller (USAID); and all the VAC063 trial participants. This work was funded in part by the UK Medical Research Council (MRC) [MR/P001351/1] – this UK funded award was part of the EDCTP2 programme supported by the European Union; the European Union{\textquoteright}s Horizon 2020 research and innovation programme under a grant agreement for OptiMalVax (733273); the PATH Malaria Vaccine Initiative; the UK MRC Confidence in Concept (CiC) Tropical Infectious Disease Consortium [MC\_PC\_15040]; and the Wellcome Trust through a Translation Award [205981/Z/17/Z]. This work, as well as the VAC063 clinical trial, was made possible in part through support provided by the Infectious Disease Division, Bureau for Global Health, United States Agency for International Development (USAID), under the terms of the Malaria Vaccine Development Program (MVDP) (AID-OAA-C-15-00071) for which Leidos Inc. was the prime contractor, and under the terms of GH-BAA-2018-Addendum03 (7200AA20C00017), for which PATH is the prime contractor. The GIA assays were supported in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and by an Interagency Agreement (AID-GH-T-15-00001) between the USAID MVDP and NIAID, NIH. The findings and conclusions are those of the authors and do not necessarily represent the official position of USAID. This work was also supported in part by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) and NHS Blood \& Transplant (NHSBT; who provided material), the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care or NHSBT. GSK had the opportunity to review the manuscript but content is the sole responsibility of the authors. JS held a Wellcome/African Academy of Sciences DELTAS Africa Grant Master{\textquoteright}s Studentship [DEL-15-007: Awandare]. BGW held a UK MRC PhD Studentship [MR/N013468/1]. SB and SJD are Jenner Investigators and SJD held a Wellcome Trust Senior Fellowship [106917/Z/15/Z].",
year = "2024",
month = jan,
day = "5",
doi = "10.1101/2024.01.04.574181",
language = "الإنجليزيّة",
}