GENDRIVAX

 

Central to the GENDRIVAX program is the concept that bacteria that infect humans are under strong selection pressure and that this has major impacts on vaccine strategies:

 

1. Vaccines design needs to address issues of antigenic diversity to ensure that a novel vaccine covers the major circulating serotypes of the pathogens.

2. Since target of protective immunity are under strong pressure, understanding the diversity of pathogen components gives important information about targets of natural immunity.

3. A successful vaccine will put new selection pressure on pathogens and understanding the population dynamics of pathogens will help design vaccines that minimize the risk of the emergence of vaccine resistant pathogens.

 

GENDRIVAX concentrates on vaccines for two major diseases of Africa: Infections caused by Salmonella enterica serovars (especially invasive non-typhoidal Salmonella infections) and bacterial meningitis caused by Neisseria meningitidis.

 

 

THE DISEASES

 

 

GENDRIVAX projects

 

The GENDRIVAX scientific program is comprised of three work packages. The aim and progress 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 non-typhoidal Salmonella in Africa. A particularly important part of this 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 and 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 non-typhoidal 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.

We (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 serogroup 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 bioinformatics studies from WSTI who 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. This information, with additional bioinformatics 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 a new direction: to examine the diversity of the O antigen of S. enterica serovars and this forms part of the work undertaken at NVGH by Robert Onsare, an exchange fellow from KEMRI. As summarized for the first work package, these studies have been critical in defining production lines for S. enterica serovars to form the basis of GMMA based vaccine, or alternatively conjugate vaccines based on O antigen.    This program has already achieved major goals that under pin the work do 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 has identified likely donors of genetic material coming from commensal Neisserial bacteria, including Neisseria lactamica and provides 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 are 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.