Evaluating the immunogenicity and protective efficacy of peptide mimotope MP13, a pneumococcal candidate vaccine antigen
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
Streptococcus pneumoniae, pneumococcus, is a bacteria causing death and disease worldwide, with over one million deaths annually in children alone. By triggering the body to produce antibodies against surface sugar molecules on the bacteria, vaccines can protect against pneumococcal disease. Sugar based vaccines are very expensive to manufacture and are not affordable in the developing world where the burden of disease is highest. In addition, only a few types of bacteria can be covered by these vaccines, limiting their usefulness. In the search for new, affordable and effective vaccine strategies, we have developed a protein which mimics the structure of a pneumococcal sugar and can protect in vivo against pneumococcal infection. To determine whether this approach is likely to represent a useful alternative to current immunisation strategy in man, we now need to understand in more detail how this protein works.
By the end of this project we hope to understand how the protein protects against pneumococcal infection and what advantages, in addition to low cost, it offers over conventional vaccines in protection against pneumococcal disease. If the potential advantages look significant, we will then look to developing this vaccine strategy for clinical trials in man
By the end of this project we hope to understand how the protein protects against pneumococcal infection and what advantages, in addition to low cost, it offers over conventional vaccines in protection against pneumococcal disease. If the potential advantages look significant, we will then look to developing this vaccine strategy for clinical trials in man
Technical Summary
Background
Streptococcus pneumoniae, a major bacterial pathogen, accounts for millions of deaths globally each year. Anti-capsular polysaccharide antibodies protect against invasive pneumococcal disease, however polysaccharide-based vaccines, although efficacious, are expensive, provide limited serotype coverage and in their current form, and do not represent a realistic long term preventative strategy for the developing world where disease burden is highest.
Using mimotope technology to identify peptides which mimic the conformation of pneumococcal polysccharides (PncPS) and induce anticapsular antibodies, we have identified MP13, the first immunogenic peptide of type 6B PncPS, which induces significant protection against invasive Pnc disease. We now propose to investigate the mechanisms of MP13 induced immune protection to ascertain whether mimotope based vaccines represent a realistic alternative to polysaccharide vaccines for global protection against invasive Pnc disease.
Aims
To characterise the immune mechanisms involved in MP13 induced protection against invasive Pnc disease. To identify correlates of protection for mimotope based Pnc vaccines.
Objectives
A detailed evaluation of the cellular and humoral immune responses to MP13 including assessment of the ability of the peptide to prime for immunological memory.
Design
The following questions will be addressed:
1. Does vaccination with MP13 prime for B-cell memory affording enhanced protection against invasive Pnc disease?
2. Does MP13-induced antibody alone protect against invasive Pnc6B disease?
3. Does vaccination with MP13 prime for CD4 and/or CD8 memory responses?
4. What is the contribution of cellular immunity to vaccine efficacy?
Methods
1. With a series of prime/boost experiments and subsequent bacterial challenge in an established model of invasive Pnc disease, the ability of MP13 to prime for B cell memory with enhanced immune protection will be investigated using serological assays to document anamnestic responses and in vivo challenge to assess protective efficacy.
2. Passive transfer of MP13 induced immune serum to assess the potential of MP13 induced antibody alone to protect against invasive Pnc disease.
3. Prime/boost immunisation with MP13, in vitro analysis of T cell memory responses to MP13 using established ELISPOT-based cytokine assays.
4. T cell depletion and subsequent immunisation/bacterial challenge experiments to assess the relative contribution of cellular immunity to MP13 induced immune protection.
Scientific/Medical Opportunities
This information will be used to evaluate whether MP13 should be developed further for phase one clinical trials in man and whether investment in the search for new candidate mimics of other pneumococcal serotypes is likely to be worthwhile.
Streptococcus pneumoniae, a major bacterial pathogen, accounts for millions of deaths globally each year. Anti-capsular polysaccharide antibodies protect against invasive pneumococcal disease, however polysaccharide-based vaccines, although efficacious, are expensive, provide limited serotype coverage and in their current form, and do not represent a realistic long term preventative strategy for the developing world where disease burden is highest.
Using mimotope technology to identify peptides which mimic the conformation of pneumococcal polysccharides (PncPS) and induce anticapsular antibodies, we have identified MP13, the first immunogenic peptide of type 6B PncPS, which induces significant protection against invasive Pnc disease. We now propose to investigate the mechanisms of MP13 induced immune protection to ascertain whether mimotope based vaccines represent a realistic alternative to polysaccharide vaccines for global protection against invasive Pnc disease.
Aims
To characterise the immune mechanisms involved in MP13 induced protection against invasive Pnc disease. To identify correlates of protection for mimotope based Pnc vaccines.
Objectives
A detailed evaluation of the cellular and humoral immune responses to MP13 including assessment of the ability of the peptide to prime for immunological memory.
Design
The following questions will be addressed:
1. Does vaccination with MP13 prime for B-cell memory affording enhanced protection against invasive Pnc disease?
2. Does MP13-induced antibody alone protect against invasive Pnc6B disease?
3. Does vaccination with MP13 prime for CD4 and/or CD8 memory responses?
4. What is the contribution of cellular immunity to vaccine efficacy?
Methods
1. With a series of prime/boost experiments and subsequent bacterial challenge in an established model of invasive Pnc disease, the ability of MP13 to prime for B cell memory with enhanced immune protection will be investigated using serological assays to document anamnestic responses and in vivo challenge to assess protective efficacy.
2. Passive transfer of MP13 induced immune serum to assess the potential of MP13 induced antibody alone to protect against invasive Pnc disease.
3. Prime/boost immunisation with MP13, in vitro analysis of T cell memory responses to MP13 using established ELISPOT-based cytokine assays.
4. T cell depletion and subsequent immunisation/bacterial challenge experiments to assess the relative contribution of cellular immunity to MP13 induced immune protection.
Scientific/Medical Opportunities
This information will be used to evaluate whether MP13 should be developed further for phase one clinical trials in man and whether investment in the search for new candidate mimics of other pneumococcal serotypes is likely to be worthwhile.
