Experimental Human Pneumococcal Carriage to determine optimal protection from carriage and mechanisms of mucosal immunisation against disease

Streptococcus pneumoniae is the most common bacterial cause of pneumonia, meningitis and otitis media in children world-wide. In adults, pneumococcal pneumonia is a common and increasing cause of hospital admission with substantial mortality in the elderly. In addition, pneumococcal infections cause exacerbations of chronic lung disease, particularly COPD and asthma. An important paradox in pneumococcal infection, however, is that in the vast majority of people these bacteria are occasionally found harmlessly inhabiting the naso-pharynx. This harmless state, termed pneumococcal carriage, boosts immunity to pneumococcal disease and is therefore of some benefit but can also be the means by which infection is transmitted. Pneumococcal carriage is considered to be the key to controlling disease as it is the means of transmission and the prerequisite of disease.

Vaccination is the most important and effective intervention in the prevention of pneumococcal disease but the weapons in this armoury are still far from optimal in terms of expense and coverage of pneumococcal types. Current vaccines have, however, demonstrated that effective prevention of both pneumococcal carriage and disease is possible in young children, with indirect benefit to unvaccinated adults resulting from reduction of circulating pneumococcal carriage. It is less clear how current vaccines should be used directly in adults, or those with chronic disease. It is also unclear by what mechanism vaccines alter carriage and which vaccines are most effective in this regard. There are many new vaccines at early stages of development and studies of how they influence carriage could be important in choosing between possible alternatives.

This Experimental Human Pneumococcal Carriage (EHPC) Programme Grant will make use of studies in healthy volunteers and patients with increased risk of pneumococcal disease to determine the immune responses in health that are protective against pneumococcal carriage. We have developed a method, unique in the world, for inoculating humans safely in order to establish carriage experimentally and have now tested it in over 300 subjects without adverse effects. This model of natural carriage can be used to (a) discover how healthy subjects make immune responses to carriage, (b) discover how subjects with risk factors (age, chronic lung disease) make responses to carriage and how this is different from healthy people, (c) test new vaccines for their effect in experimental carriage and (d) discover how the host alters the biology of the bacteria while it is being carried. Testing new vaccines using EHPC can be done more quickly and at a fraction of the cost of clinical studies (100 subjects rather than many thousands) and so several vaccines can be tested during this Programme, in parallel with the discovery science. This Programme also offers an opportunity for partnership with commercial entities or charities sponsoring particular new vaccines and these funding options will be explored with MRC.

In summary, This EHPC Programme will run and coordinate the maximum use of a unique human pneumococcal challenge model to study host/pathogen interactions critical to the prevention of pneumococcal disease by vaccination. We will use a variety of pneumococcal strains to challenge human volunteers, both healthy and with risk factors for pneumococcal disease, in order to determine factors underlying susceptibility and protection from disease. We will manage a portfolio of commercial vaccine development studies using the human challenge model in parallel with the science discovery programme.

Pneumococcal disease remains a research priority world-wide with high mortality from meningitis, pneumonia and sepsis and high morbidity and expense from otitis media. Conjugate vaccination programmes have shown that both carriage and disease can be prevented leading to substantial direct and additional very large herd benefits by reduction of carriage. There could be important additional gain, however, from bringing protein vaccines to licensure in order to gain from wide strain coverage, reduced production expense and potential combination with conjugates.

This Experimental Human Pneumococcal Carriage (EHPC) Programme will coordinate maximum use of a human pneumococcal challenge model to study host/pathogen interactions critical to the prevention of pneumococcal carriage and disease by vaccination. We will use a variety of pneumococcal strains to experimentally challenge human volunteers with bacteria. We will recruit both healthy subjects and those with risk factors for pneumococcal disease in order to determine both pathogen and host factors that determine susceptibility and correlates of protection. We will manage a portfolio of commercial vaccine development studies using the human challenge model in parallel with the science discovery programme.

The EHPC platform itself requires a complex, expensive integrated team including clinical, microbiological and immunological teams. In order to fully exploit the scientific potential of the platform, we have established collaborations with 20 other laboratories, predominantly in the UK. Our collaborators bring outstanding international expertise, a shared vision of global vaccination against pneumococcal disease and the offer of practical help in accessing the necessary additional resources to apply cutting-edge technology to the samples this model will generate.

This Programme is about vaccine development. The Programme will impact scientists, commercial partners and the public across the translational spectrum and will eventually benefit the most vulnerable populations that suffer with the high burden of pneumococcal disease.

1) Impact on scientists
See section above.

2) Impact on commercial sector
There is a logistic roadblock to novel vaccine testing as discussed in the Case for Support. This programme will make early clinical testing of novel vaccines a reasonable prospect and so alter the risk-benefit balance for companies considering novel vaccine programmes. Commercial partners will be able to investigate whether their vaccine candidates can protect against carriage in a phase 1-2 trial involving a relative small number of subjects. The information on increased susceptibility of the elderly and asthmatics to pneumococcal diseases will also be very relevant for the development of novel vaccines that will benefit these groups.

3) Impact on susceptible populations and vulnerable minorities
The development of a novel and more effective pneumococcal vaccine will benefit susceptible populations. The most susceptible groups of adults, particularly the elderly and patients with asthma and COPD will benefit from a more direct vaccine discovery approach. The global burden of pneumococcal disease and carriage is highest in vulnerable least-economically-developed-countries (LEDC) due to malnutrition, HIV burden and co-infections. This Programme does not directly address these populations but progress in vaccine discovery will alter the prospects for countries currently lacking a pneumococcal vaccine strategy.

3) Impact on vaccine policy
There is current controversy regarding the efficacy of current polysaccharide-based vaccines, particularly in adults. Preferred vaccines would prevent transmission by blocking carriage; some of the data required in these decisions could be obtained by focused studies using EHPC to determine the prevention of carriage by new vaccines.

4) Impact on general public
Public involvement. Our public engagement programme will disseminate knowledge on pneumonia and benefits of vaccination during news releases from our group, school talks, and social media (twitter and facebook). LSTM have a strong past record of successful public engagement and are committed to improving the public understanding of science. We will encourage our collaborators on this programme grant to take part in our public engagement activities.

5) Impact on all staff and students
Students: Samples and data generated during this programme grant will enable several PhD projects to be developed both at the Respiratory Infection group at LSTM and in our collaborators laboratories.
Staff: The parallel commercial Work Package in the Programme will allow staff ordinarily in an academic environment to learn more of the regulatory and other challenges that form part of bringing a new vaccine to licensure. This Programme will also give the opportunity for short-term internship and exchange visits between collaborators laboratories and the Respiratory Infection group at LSTM.