Structure-guided design of malaria and rabies vaccines

Project Overview

Rabies virions, responsible for the only 100% fatal human viral disease.

‘Structural vaccinology’ is one of the most exciting novel approaches to vaccine development. The term describes the rational design of improved vaccine antigens using information from 3-dimensional protein structures (eg from protein crystallography). For example, the structure may be used to select targeted mutations to stabilise a particular conformation of the protein, favouring the induction of antibodies with some desirable property (for example, the ability to neutralise the pathogen at a very low antibody concentration, or to neutralise multiple genetically diverse strains of the pathogen). The approach has displayed promising results against a range of pathogens including malaria (PMID: 25132548 & further unpublished results from work by Oxford investigators including Dr Douglas & Prof Higgins; for reviews see https://www.ncbi.nlm.nih.gov/pubmed/23806515https://www.ncbi.nlm.nih.gov/pubmed/23154260)). This project will apply similar approaches to the development of improved antigens for rabies and/or malaria vaccines.

Rabies kills nearly 60,000 people every year- more than 10% of the number killed by malaria- and yet receives a tiny fraction of the research expenditure & effort invested in other diseases. As a result, we believe there are some ‘low-hanging fruit’ in the field- opportunities for an intelligent & motivated student to have major impact, both scientifically  and practically i.e. by contributing to the development of tools with a real chance of reducing this death toll.

Rabies is a relatively straightforward vaccine target: an effective vaccine against rabies was developed by Pasteur in the 19th century, and it is known that neutralising antibody against the rabies glycoprotein is the mechanism of vaccine-induced protection. The reason rabies continues to kill people is largely that current vaccines still use essentially the same technology as that used by Pasteur, i.e. inactivated rabies virions, which are expensive to manufacture & requires multiple doses. It is therefore not cost-effective for mass vaccination in developing countries where most cases occur. Dr Douglas is leading a project to conduct a clinical trial of a cheap novel single-dose thermostable rabies vaccine which has shown outstanding efficacy against rabies challenge in pre-clinical studies (PMID: 24503087). This PhD project seeks to build upon that effort by using a structural vaccinology approach to design a second-generation candidate antigen. The approach is motivated by preliminary data suggesting that, although the efficacy of the new vaccine is excellent, there is scope for further improvement in the proportion of the vaccine-induced antibody which is function in virus neutralisation- in other words, we have data to suggest that a structure-guided approach could enable the novel vaccine to get ‘more bang for its buck’. The approach has a good chance of generating high impact publications and leading to the development of a vaccine which enters clinical trials. 

In the case of malaria, it is known that antibodies against Plasmodium falciparum’s  circumsporozoite protein (CSP) can protect humans against infection with the parasite- a fragment of CSP is used in the partially effective RTS,S vaccine recently licensed by GSK. There is data to suggest that antibodies against regions of CSP which are not included in RTS,S can be more effective, but at present, structural understanding of the way in which these antibodies bind the CSP antigen is insufficient. This project will aim to improve that understanding and hence to rationally design vaccines which favour the induction of similar antibodies.

Training Opportunities

The Jenner Institute is Europe’s largest academic translational vaccinology research centre, with activity extending from basic microbiological and immunological research into first-time-in-human clinical trials and subsequent international field trials. The Institute’s close integration of pre-clinical and clinical activities offers near-unique opportunities for students to be involved throughout this process. With other active programmes within the Institute targeting diseases including HIV, TB, dengue, cancer and influenza, DPhil students have the opportunity to interact with senior researchers with a wide variety of expertise, and to develop a broad skill-set to support a career in 21st century translational medicine.

Close attention is paid to the generation of a stimulating, productive and collaborative learning environment, with a regular programme of informal lab meetings and ‘journal club’ in addition to more formal Jenner Institute seminars. All students are expected to present their research internally and at relevant conferences, and to work towards publications. A student pursuing this project could expect to learn a broad range of transferable practical techniques in molecular biology, virology, parasitology and immunology.

This cross-disciplinary project will involve working in close collaboration with the University of Oxford’s Department of Biochemistry (South Parks Road). A student pursuing this project would thus also have access to the outstanding facilities, environment and seminar programmes offered by that department.

Theme

Protein Science & Structural Biology and Immunology & Infectious Disease

Admissions

Project reference number: 924

Funding and admissions information

Supervisors

Name Department Institution Country Email
Dr Alexander (Sandy) D Douglas MRCP Jenner Institute Oxford University, Henry Wellcome Building for Molecular Physiology GBR sandy.douglas@ndm.ox.ac.uk
Professor Matthew K Higgins Department of Biochemistry University of Oxford GBR matthew.higgins@bioch.ox.ac.uk

Xiang ZQ, Greenberg L, Ertl HC, Rupprecht CE. 2014. Protection of non-human primates against rabies with an adenovirus recombinant vaccine. Virology, 450-451 pp. 243-9. Read abstract | Read more

Rabies remains a major neglected global zoonosis. New vaccine strategies are needed for human rabies prophylaxis. A single intramuscular immunization with a moderate dose of an experimental chimpanzee adenovirus (Ad) vector serotype SAd-V24, also termed AdC68, expressing the rabies virus glycoprotein, resulted in sustained titers of rabies virus neutralizing antibodies and protection against a lethal rabies virus challenge infection in a non-human primate model. Taken together, these data demonstrate the safety, immunogenicity, and efficacy of the recombinant Ad-rabies vector for further consideration in human clinical trials. Hide abstract

Wright KE, Hjerrild KA, Bartlett J, Douglas AD, Jin J, Brown RE, Illingworth JJ, Ashfield R, Clemmensen SB, de Jongh WA, Draper SJ, Higgins MK. 2014. Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies. Nature, 515 (7527), pp. 427-30. Read abstract | Read more

Invasion of host erythrocytes is essential to the life cycle of Plasmodium parasites and development of the pathology of malaria. The stages of erythrocyte invasion, including initial contact, apical reorientation, junction formation, and active invagination, are directed by coordinated release of specialized apical organelles and their parasite protein contents. Among these proteins, and central to invasion by all species, are two parasite protein families, the reticulocyte-binding protein homologue (RH) and erythrocyte-binding like proteins, which mediate host-parasite interactions. RH5 from Plasmodium falciparum (PfRH5) is the only member of either family demonstrated to be necessary for erythrocyte invasion in all tested strains, through its interaction with the erythrocyte surface protein basigin (also known as CD147 and EMMPRIN). Antibodies targeting PfRH5 or basigin efficiently block parasite invasion in vitro, making PfRH5 an excellent vaccine candidate. Here we present crystal structures of PfRH5 in complex with basigin and two distinct inhibitory antibodies. PfRH5 adopts a novel fold in which two three-helical bundles come together in a kite-like architecture, presenting binding sites for basigin and inhibitory antibodies at one tip. This provides the first structural insight into erythrocyte binding by the Plasmodium RH protein family and identifies novel inhibitory epitopes to guide design of a new generation of vaccines against the blood-stage parasite. Hide abstract

Dormitzer PR, Grandi G, Rappuoli R. 2012. Structural vaccinology starts to deliver. Nat. Rev. Microbiol., 10 (12), pp. 807-13. Read abstract | Read more

Following the impact of the genomics revolution on vaccine research and the development of reverse vaccinology, it was predicted that another new approach, structure-based antigen design, would become a driving force for vaccine innovation. Now, 5 years on, there are several examples of how structure-based design, or structural vaccinology, can deliver new vaccine antigens that were not possible before. Here, we discuss some of these examples and the contribution of structural vaccinology to our understanding of the protective epitopes of important bacterial and viral pathogens. Hide abstract

Kulp DW, Schief WR. 2013. Advances in structure-based vaccine design. Curr Opin Virol, 3 (3), pp. 322-31. Read abstract | Read more

Despite the tremendous successes of current vaccines, infectious diseases still take a heavy toll on the global population, and that provides strong rationale for broadening our vaccine development repertoire. Structural vaccinology, in which protein structure information is utilized to design immunogens, has promise to provide new vaccines against traditionally difficult targets. Crystal structures of antigens containing one or more protection epitopes, especially when in complex with a protective antibody, are the launching point for immunogen design. Integrating structure and sequence information for families of broadly neutralizing antibodies (bNAbs) has recently enabled the creation of germline-targeting immunogens that bind and activate germline B-cells in order to initiate the elicitation of such antibodies. The contacts between antigen and neutralizing antibody define a structural epitope, and methods have been developed to transplant epitopes to scaffold proteins for structural stabilization, and to design minimized antigens that retain one or more key epitopes while eliminating other potentially distracting or unnecessary features. To develop vaccines that protect against antigenically variable pathogens, pioneering structure-based work demonstrated that multiple strain-specific epitopes could be engineered onto a single immunogen. We review these recent structural vaccinology efforts to engineer germline-targeting, epitope-specific, and/or broad coverage immunogens. Hide abstract