Shifts in the metabolic and virulence profiles of Streptococcus pneumoniae following the introduction of conjugate-polysaccharide vaccine in Malawi

It is estimated that in 2010-2011, there were 120 million episodes of pneumonia in young children worldwide, and 1.3 million pneumonia-related deaths. A microbe called Streptococcus pneumoniae or the pneumococcus, which frequently lives at the back of the nose in healthy children and adults, is a leading cause of childhood pneumonia in many African countries, and is also associated with a high burden of meningitis and severe blood infection. Reducing the burden of pneumococcal disease is therefore a major public health priority. Pneumococcal conjugate vaccines (PCV) are highly effective at reducing this disease and have been introduced into the routine infant immunisation programmes of several sub-Saharan African countries, including Malawi. We now have evidence from our ongoing work in Malawi that there has been a large direct benefit of vaccination occurring early after introduction. The critical question is whether this protection will be long-lasting and result in protection of individuals in the wider community who have not received or have responded poorly to the vaccine (so-called "herd immunity").

We have recently established a programme of surveillance in Malawi that is looking out for changes in the pneumococcus carried by otherwise healthy children and HIV-infected adults that may indicate that the vaccine will become less effective. In this proposed project we will exploit this ongoing work together with a wealth of data from pneumococci causing pneumonia, meningitis and blood poisoning to find out whether the introduction of PCV into the national childhood immunisation programme in Malawi leads to a change in the profile of carried pneumococci that has the potential to undermine vaccine impact; and then use a mathematical model to test potential strategies to prolong PCV effectiveness in Malawi and in other similar settings. This study will draw on expertise in Malawi, Liverpool and Oxford enabling us to exploit state-of-the-art genetic fingerprinting of these bacteria and new mathematical modelling approaches. Given that maintaining the effectiveness of pneumococcal vaccines is critical in resource constrained sub-Saharan African countries such as Malawi, this project is very timely in addressing the long term impact of these vaccines, particularly in vulnerable populations with a high burden of HIV, malnutrition and malaria.

Streptococcus pneumoniae is a leading cause of childhood pneumonia, meningitis and bacteraemia. Where PCV13 has been introduced in sub-Saharan Africa, including Malawi, a large direct benefit has been seen early after introduction. However, unlike some countries where there was an extensive catch-up campaign, we have not detected impact on unvaccinated populations and not observed herd immunity nearly four years after PCV13 introduction. Two questions remain: whether direct protection will be long-lasting or be undermined by progressive non-vaccine serotype replacement; and whether as the proportion of the population who have received PCV13 increases, there will be herd immunity.

We will exploit ongoing globally rare, carefully phenotyped pneumococcal strain collection, exploring the hypothesis that PCV introduction results in a reduction in vaccine serotype carriage and niche replacement by non-vaccine serotypes which have similar metabolic/ virulence profiles to the vaccine-serotypes, therefore undermining vaccine effectiveness. We speculate that non-vaccine carriage serotypes with a successful metabolic/ virulence profile will be increasingly identified in invasive disease. This hypothesis will be addressed through the following objectives:

a) Establish whether there is segregation of pneumococcal metabolic/ virulence profiles in geographically distinct human populations.
b) Determine whether there is segregation of metabolic/ virulence profiles in vaccine exposed and non-exposed individuals in Malawi.
c) Detect successful metabolic/ virulence pneumococcal profiles (identified above) amongst disease-associated isolates.
d) Further develop a theoretical framework to explore the effective use of vaccine.

Maintaining PCV impact is critical in resource constrained sub-Saharan African countries. This project will address long term vaccine effectiveness in vulnerable populations with a high prevalence of HIV, malnutrition and malaria.

In 2010-2011, it is estimated that there were 120 million episodes of pneumonia in children younger than 5 years worldwide, and 1.3 million pneumonia-related deaths. Streptococcus pneumoniae is a leading cause of childhood pneumonia, meningitis and bacteraemia in many African countries (18% of vaccine-preventable severe pneumonia), and is associated with a high burden of death and disability. Reducing the burden of pneumococcal disease is therefore a public health priority and critical to meeting Millennium Development Goals.

The benefits of this project will be through generation of new knowledge; the development of a strong partnership between internationally leading multidisciplinary group of multinational researchers focused on questions that address high-burden diseases in resource-poor countries; research capacity strengthening and the generation of new research independent researchers; and ultimately new approaches to pneumoccal vaccination. Thus our data will benefit the health and wealth of populations in Malawi and in other high pneumococcal carriage, high HIV seroprevelence countries across Africa.

To realise these benefits, we plan to engage with: (1) national policymakers (Ministry of Health, National Vaccine Programmes); (2) international opinion leaders and advocates (WHO, PATH, Bill & Melinda Gates Foundation, Clinton Foundation (with whom we have existing relationships); (3) pharmaceutical vaccine manufacturers who have existing or are generating new pneumococcal vaccines (with whom we have existing relationships); and (4) local academics and healthcare workers to discuss the aims of the study and disseminate the outputs and the research capacity benefits. These groups will benefit from our evidence based research, which aims to provide clear evidence of pneumococcal vaccine escape and suggest potential approach to overcome this obstacle. The work could shape the future approach to pneumococcal vaccination, attract additional investment from both the public and private sectors to this research area, and greatly improve the protective effects and the longevity of these vaccines. Once evaluated in larger trials, this would ultimately reduce the burden on overstretched, poorly resourced child health services in Africa and ensure a sustained reduction in childhood pneumonia.

To eventually influence policymakers and practitioners, we will also need to engage with academic audiences (who influence policy), and those training clinicians and researchers. Through new knowledge and scientific advancement, data from this study will provide new opportunities for research and academic discussion, knowledge and skills transfer, research training and the testing effective interventions to reduce pneumonia associated mortality. This would have considerable benefits for the development of academia in resource-poor settings, child-survival, health budgets and through a lower child mortality, ultimately a lower birth rate and maternal mortality, and a greater quality of life.

Finally, the impact on societal knowledge, public awareness and engagement with biomedical research in resource-poor settings will be realised through discussion and dissemination of our results in Malawi through our community engagement activities; science cafes; schools programme; national museums programme; and our national radio programme. These will be led by a dedicated science communication team at MLW.

To ensure progress in our knowledge exchange plans and the "pathways to impact", we will review these specifically at out investigator meetings and with our MLW community advisory groups every six months. We will also regularly monitor academic, policymaker and vaccine advocacy engagement with the project. Dr Charles Mwansambo, Chief of Health Services, Malawi Ministry of Health is an active member of the pneumococcal surveillance investigator team at MLW, and will take an active part in this process.