CAREPNEUMO - Combating Antibiotics Resistant Pneumococci by Novel Strategies Based on in vivo and in vitro Host-Pathogen Interactions

EC contribution: : € 2.999.999
Duration: : 36 months
Starting date: : 01/03/2009
Funding scheme: : Focused research project
Keywords: : Antibiotic resistance, S. pneumonia, epidemiology, host-pathogen interaction, virulence mechanisms, vaccine
Contract/Grant agreement number: : 223111
Project web-site: : http://www.helmholtz-hzi.de/en/carepneumo/home/

Summary:

The diseases caused by Streptococcus pneumoniae are a major public health problem all over the world. Children, elderly people and immuno-compromised individuals are the high-risk targets for pneumococcal diseases. In spite of the availability of a large number of antibiotics the mortality and morbidity due to S. pneumoniae infections remain very high. There are two reasons for this: Firstly, the increasing antibiotic resistance among pneumococcal strains, and secondly, a current vaccine, though effective for certain serotypes, leads to serotype replacement. For the development of combat strategies it is essential to identify new intervention strategies, for which an understanding of host-pathogen interaction is a prerequisite. This proposal would apply a multi-disciplinary approach that includes epidemiology, host-pathogen interactions, infection models and intervention strategies to combat antibiotic resistant S. pneumoniae. The consortium brings together 12 research organizations and 1 SME with expertise in the above-mentioned areas. The major objectives of this consortium will be 1. monitoring of prevalent S. pneumoniae serotypes and their resistance profiles in different countries, 2. analysis of host-pathogen interactions and identification of potential therapeutic targets and vaccine candidates, 3. providing a basis for the development of improved vaccine and intervention strategies. This joint international effort would contribute towards novel control strategies, especially of antibiotic resistant S. pneumoniae strains.

Problem:

There are currently two ways to limit the burden of pneumococcal infection: prevention by vaccination and treatment by the use of antibiotics. Vaccination of children is performed with a polysaccharide-protein conjugate, vaccination of adults is based on the use of a 23-valent polysaccharide vaccine. The limits of the currently used vaccines are the following: polysaccharide vaccines in young infants are poorly immunogenic, antibody levels rapidly decrease a few months after immunisation, and finally no immunological memory develops. Polysaccharide-protein conjugates have an overall higher efficacy, but are expensive and complicated to produce. This limits their use in developing countries, in which the burden of pneumococcal disease is enormous. Moreover, overall carriage rates are not affected by the conjugates and serotype replacement may will lead to the spread of other serotypes not covered by the vaccines.

Antibiotic treatment of pneumococcal disease is still a powerful tool to save lives. However, antibiotic consumption has led to a gradually increasing pneumococcal resistance against penicillin and cephalosporins, and to the emergence of multi-drug resistant strains. These strains pose a particular and increasing problem for the treatment of pneumococcal meningits. Since the entry of hydrophilic antibacterials (penicillin, cephalosporins, carbapenems, glycopeptides) into the CNS compartments is poor, pharmacokinetic and pharmacodynamic aspects of antibiotics in the central nervous compartments have to be considered. From a pharmacokinetic viewpoint, the ideal antibiotic to treat central nervous system infections possesses moderate lipophilicity, a low molecular weight, and a low binding to serum proteins. In addition to this, increasing the bactericidal activity of antibiotics in vivo by adjunctive compounds appears promising.

Aim:

The aims of this proposal were defined in order to obtain new knowledge on the molecular epidemiology of pneumococcal diseases and antibiotic resistance in different parts of the world, apply state-of-the-art technology to study host-pathogen interactions and apply innovative technologies for improving existing intervention strategies. Moreover, it would contribute towards the implementation of measures for prevention, control and treatment of pneumococcal diseases, especially those caused by multi-drug resistant strains. To achieve the purpose of this proposal, we have assembled a team with expertise required to fulfil the following objectives:

Aim 1: epidemiology of drug resistance and vaccine pressure replacement of S. pneumoniae

Aim 2: analysis of host-pathogen interactions and identification of potential therapeutic targets and vaccine candidates

Aim 3: development of improved vaccine and intervention strategies

Expected results: :

The overall strategy of this proposal is to generate knowledge based on epidemiology and host-pathogen interaction in order to control the diseases caused by antibiotic resistant strains of Streptococcus pneumoniae. In the wake of increasing antibiotic resistance among pneumococci and the fact that introduction of seven-valent vaccine has resulted in the replacement by non-vaccine serotypes, there is an urgent need to develop new strategies for combating pneumococcal diseases. The plan consists of activities such as research, technology development and project management. The structure of the implementation plan is designed in a way that all beneficiaries can achieve the scientific and technology objectives. The plan deals with the problem of drug resistant pneumococci in a systematic fashion involving epidemiology, host-pathogen interaction and intervention strategies. This proposal addresses a realistic set of objectives that require the coordinated efforts of multiple activities. The interdependence is a key feature of the work plan. WP1 to WP6 will primarily focus on epidemiology including drug resistance in pneumococci from different countries. This analysis would not only provide important information about the emergence and spread of antibiotic resistance, but would also generate strains which will be used in the work packages devoted to host-pathogen interaction. These are WP7 to WP12. WP13 to WP15 will focus on the validation of virulence factors in infection models. The information generated in epidemiology and host-pathogen interaction work packages will be used in WP16 to WP18 for generating knowledge required for the development of new prevention and intervention strategies.

Potential applications:

The project will deal with the development of novel therapeutic and vaccine strategies to combat antibiotic resistance in Streptococcus pneumoniae. The focus will be on the molecular approach for the development of a new generation of antimicrobials and on a novel polysaccharide-glycolipid conjugate pneumococcal vaccine. For this part of the project, the data generated on host-pathogen interactions will be crucial. The intervention strategies will also take into consideration important serotypes identified from epidemiological studies. Two groups from Spain and one from Switzerland are the major partners for this part. In addition, we have included one SME from Israel, which will focus on a protein-based universal vaccine for S. pneumoniae.

This coordinated working plan would yield scientific as well as technological knowledge essential for the improvement of current strategies for treatment and prevention of the diseases caused by antibiotic resistant pneumococci.

Coordinator:

Prof. Dr. G.S. Chhatwal
Dept. of Microbial Pathogenesis

Helmholtz-Zentrum für Infektionsforschung

Inhoffenstraße 7
38124 Braunschweig
Germany
gsc@helmholtz-hzi.de

European Commission