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

Lead Research Organisation: University College London
Department Name: Infection

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Obolski U (2018) Vaccination can drive an increase in frequencies of antibiotic resistance among nonvaccine serotypes of Streptococcus pneumoniae. in Proceedings of the National Academy of Sciences of the United States of America

 
Description This work provides new insights into the impact of vaccines on the population biology of S. pneumoniae and the emergence of antimicrobial resistance. Analysis of geospatial is informing our understanding of the emergence of pneumococcal genotypes.
Exploitation Route See other grants which are a direct continuation of this work.
Sectors Healthcare,Government, Democracy and Justice,Pharmaceuticals and Medical Biotechnology

 
Description Assessment of a vaccine schedule shift (3+0 to 2+1) in partnership with government
Geographic Reach Africa 
Policy Influence Type Gave evidence to a government review
 
Description WHO Defeating Meningitis by 2030 Task Force
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact A global strategy to defeat meningitis by 2030 is being developed by a WHO-led multi-organization partnership assembled into a Technical Taskforce (Heyderman a member). This strategy, integrated into a global roadmap, covers the organisms responsible for most of acute bacterial meningitis. The development of this roadmap involves a wide range of stakeholders and experts.
URL https://www.who.int/immunization/research/development/meningitis/en/index1.html
 
Description Evaluation of the impact of a PCV13 schedule change from 3+0 to a 2+1 schedule in Malawi, to accelerate reduction in vaccine serotype population carriage in high disease burden countries
Amount $2,800,000 (USD)
Funding ID OPP1208803 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 03/2019 
End 07/2023
 
Description Long terms effects of Azithromycin Mass Treatment in Malawi
Amount $338,000 (USD)
Funding ID INV-004301 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2020 
End 01/2021
 
Description Population Pneumococcal Serology Profiling to Understand the Impact of Vaccine-Induced Anti-Pneumococcal Antibody on Pneumococcal Carriage in Malawi
Amount $391,555 (USD)
Funding ID OPP1185516 
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 11/2018 
End 04/2020
 
Description The Impact of Pneumococcal and Malaria Vaccines on Bacterial Resistance, Febrile Illness and Antibiotic Usage in Young Children In Malawi
Amount £764,996 (GBP)
Funding ID 219900/Z/19/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2020 
End 02/2023
 
Description Antibiotic resistome analysis 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Collaborative project to refine the methods and then test samples derived from this project.
Collaborator Contribution Development of analytical techniques
Impact None so far
Start Year 2019
 
Description Field Epidemiology Collaboration (Liverpool) 
Organisation University of Liverpool
Department Institute of Infection and Global Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Weekly teleconferences and numerous face-to-face meetings
Collaborator Contribution Visits to Malawi; discussion of data; statistical analysis
Impact Clinical research; epidemiology; genomics; statistics; modelling. Three abstracts at the 11th International Symposium on Pneumonia and Pneumococcal Disease 2018.
Start Year 2017
 
Description Field Epidemiology and sample Collection (Liverpool School of Tropical Medicine) 
Organisation Liverpool School of Tropical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Weekly teleconferences and numerous face-to-face meetings during site visits, including both the PI and post-doc.
Collaborator Contribution Sample collection; field epidemiology
Impact Clinical research; epidemiology; genomics; statistics; modelling. Three abstracts at the 11th International Symposium on Pneumonia and Pneumococcal Disease 2018.
Start Year 2017
 
Description Modelling and Genomics Collaboration (Oxford) 
Organisation University of Oxford
Department Department of Zoology
Country United Kingdom 
Sector Academic/University 
PI Contribution Frequent discussions, meetings and visits to Oxford. Joint working between Oxford team and UCL post doc
Collaborator Contribution Advice and guidance on genomic analysis. Generation of a mathematical model.
Impact Clinical research; epidemiology; genomics; statistics; modelling. Three abstracts at the 11th International Symposium on Pneumonia and Pneumococcal Disease 2018. Four peer reviewed publications.
Start Year 2017
 
Description Pneumococcal DNA Microarray (St George's) 
Organisation St George's University of London
Department Bacterial Microarray Group at St George's (BµG@S)
Country United Kingdom 
Sector Academic/University 
PI Contribution Discussion and face to face visits
Collaborator Contribution DNA Microarray of culture samples
Impact Abstracts at ISPPD 2018, 2020
Start Year 2017
 
Description All for one, one for all project 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Funderd by the Wellcome Trust. "One for All?' explores herd immunity related to vaccination and engages multiple audiences in the global South and North. Working with an artist, the project aims to increase awareness, dialogue and informed choice about immunisation, amongst community leaders, parents (and/or guardians), firstly in two African countries then in the UK. We will increase capacity to 'do' public engagement focused on herd immunity, using the 'One for All?' engagement outputs, amongst researchers, community fieldworkers, health professionals, national policymakers and engagement practitioners in Africa and the UK. We will also empower community leaders, parents and guardians, older children and patients through peer-to-peer approaches to promote a dialogue around her immunity. Ultimately, through enhanced stakeholder ownership of vaccine engagement, the project will contribute to decreased vaccine hesitancy and improved vaccine uptake; increased mutual understanding and trust amongst citizens, scientists and policymakers about immunisation; and promote responsible vaccine research and engagement.
Year(s) Of Engagement Activity 2019,2020
URL http://www.mpru.org
 
Description Community Engagement (Malawi) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Meeting with Community advisory Groups in Malawi
Year(s) Of Engagement Activity 2017
 
Description Football to engage men on vaccines 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Football matches to engage men on vaccines (video documentation)
Year(s) Of Engagement Activity 2018
 
Description School visit of research activities for schools and communities (video of event) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact Visit by schools and communities to MLW lab facilities and video documentation
Year(s) Of Engagement Activity 2018