Periodic Report Summary 1 - GENDRIVAX (Genome-driven vaccine development for bacterial infections)
GENDRIVAX is a consortium of academic groups:
The Wellcome Trust Sanger Institute (WTSI), The Swiss Tropical Public Health Institute (STPHI) and the Kenyan Medical Research Institute (KEMRI) with an Industry Partner, The Novartis Vaccines Global Health institute (NGVH) aimed at strengthening industry-academic partnerships though working towards vaccines for Salmonella infections and Neisserial meningitis taking into account modern access to Genomics to design vaccines with high coverage of genetically variant strains of the bacteria. A key part of the program is the exchange of researchers between the industrial and academic partners. The R&D work is divided into 3 work packages as well as a planning, administrative and dissemination work package. Aims and progress for each is summarized below.
Outer membrane vaccines for Salmonella enterica and for Neisseria meningitidis.
We have developed a new platform for making vaccines for certain types of bacteria by introducing genetic changes into the bacteria that cause them to shed large quantities of pure outer membrane – the part of the bacteria most involved with generating protective immunity. Importantly, these are inexpensive to manufacture in large quantities and are highly immunogenic. These outer membrane fragments are called GMMA (Generalized Module for Membrane Antigens). We have now prepared GMMA from both Salmonella enterica and Neisseria meningitidis. Using information from the second work package we have selected S. enterica strains likely to form the basis for producing a vaccine for invasive nontyphoidal salmonella in Africa. A particularly important part of this work was identifying strains that produce an O antigen that induces antibodies to the current clones of S. enterica serovars, Typhimurium and Enteritidis, responsible for most of the disease; this has been done as a close collaboration between WSTI, KEMRI and NVGH. This project is now well towards its long term goal of developing a vaccine for nontyphoidal Salmonella, a disease particularly important in Africa with an annual mortality of at least 100,000 children and which places a considerable burden on health services.
STPHI and NVGH have also produced GMMA from Neisseria and have shown that GMMA induce substantial levels of antibody in mice. Importantly a single GMMA induces antibody that kills invasive lines of serogroups A, W135 and X from Africa. At a laboratory level this meets a major GENDRIVAX objective towards a prototype vaccine that covers different genotypes of Neisseria from Africa. This is also of major public health importance. The Menafrivac vaccine for serogroup A meningitis is being introduced into the meningitis belt of Africa. However, even as it was being introduced, the major serogroups responsible for meningitis were shifting and serogroup W135 and X are now of particular concern. This shift highlights the importance of the work in GENDRIVAX for developing a serogroup independent vaccine.
Analysis of the diversity and virulence of Salmonella enterica serovars.
Utilizing data from previous bioinformatics studies, WTSI researchers have studied the genetic diversity of iNTS serovars from Africa. They have mapped the evolution of the invasive strains of Typhimurium and Enteritidis over the past 30 years. With this information, and with additional bioinformatic studies from a range of other S. enterica serovars with reverse vaccinology expertise at NVGH, several outer membrane associated antigens have been identified that induce bactericidal activity against S. enterica serovars. We have also expanded into the new objective to examine the diversity of the O antigen of S. enterica serovars: this forms part of the work undertaken at NVGH by Robert Onsare, a seconded fellow from KEMRI. These studies have been critical in defining production lines for S. enterica serovars to form the basis of a GMMA based vaccine, or alternatively conjugate vaccines based on O antigen. This program has already achieved major goals that under pin the work done in work package 1 on the development of vaccines. It has been crucial for the design of these vaccines and will continue to be important in the future as the baseline for monitoring further evolution of invasive Salmonella.
Diversity of Neisseria and mathematical models of transmission and disease.
Major advances in our understanding of the evolution of Neisseria meningitidis in West Africa has come from a study undertaken by STPHI and WTSI on the genomics of successive waves of serogroup A. In particular, recombinations leading to evolution of the ST7 and ST2859 waves have identified likely donors of genetic material coming from commensal Neisserial bacteria, including Neisseria lactamica, and provide a plausible mechanism for selecting new surface antigenic specificities important for the replacement of sequence types within a single serogroup.
A major activity has been the further development of computer model for transmission and disease caused by S. enterica. This has been advanced through exchanges of Prof. T Smith and Dr. N. Maire from STPHI to NVGH and by Dr. A. Saul from NVGH to STPHI. While this model was specifically developed for S. enterica, it now appears that it will be applicable to many pathogens, and we are now looking at adapting it to Neisseria. The software package is now being tested for its ability to plan the most cost effective introduction of vaccines and ways of sustaining vaccine effectiveness in the longer term.
Administration and meetings.
GENDRIVAX has had 4 internal meetings involving all of the GENDRIVAX participants, a mid-term review in November 2012 and a scientific meeting in Nairobi in December 2012. The internal meetings have played a crucial role in the planning of work but also in the dissemination of information and as part of the training process of the Fellows. A highlight of the meeting program was the Scientific meeting held in Nairobi on the 8th to 10th December 2012.
In addition to GENDRIVAX members from each of the 4 participating Institutes, mid-career researchers from several African Countries (Malawi, Kenya, Uganda, Senegal, The Gambia) attended the meeting in Nairobi.
A particular focus of the meeting was on invasive nontyphoidal salmonella with updates from the work done in GENDRIVAX on the genetics of the organisms and on the development of a vaccine; Discussions from the African participants on the immunology, diagnosis and surveillance of the disease in the African setting were also included in the programme. The conference also provided a public opportunity to review the progress made in understanding the genetic variation underlying successive epidemics of Neisseria and on the progress towards a universal Neisseria vaccine. A similar conference is being planned for West Africa in late 2013.
Secondments and recruitments.
A key part of the IAPP program is the exchange of researchers between the industrial and academic partners. To date, exchanges have totaled 34.5 person months covering a wide range of interests and experiences ranging from newly enrolled PhD students to the heads of programs within the institutes. These have directly led to progress on vaccines but also have provided a valuable vehicle for exchanging knowledge. Due to the requirements that staff have at least one year at their home institute prior to being seconded, and because of unexpected problems with the ineligibility of exchange of Italian PhD students, the exchange program started slower than expected, but the pace has now quickened and the program will meet its overall objectives.