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BRIEFING PAPER Southern Hemisphere Influenza Vaccine Effectiveness Research and Surveillance (SHIVERS) DOCUMENT EMBARGOED UNTIL 5 OCTOBER 2011 INTRODUCTION: In December 2010, the Influenza Division of the National Center for Immunization and Respiratory Diseases (NCIRD) of the United States Centers for Disease Control and Prevention (CDC) called for cooperative applications from organisations working in the Southern Hemisphere to provide Southern Hemisphere Influenza Vaccine Effectiveness Research and Surveilllance (SHIVERS) over a five year period. An application was made by ESR working with a team of collaborators consisting of leading influenza researchers in New Zealand and abroad including the University of Otago, The University of Auckland, the Auckland District Health Board (ADHB) and the WHO Collaborating Centre at St Jude Children’s Hospital in the USA. ESR has received formal confirmation from CDC that the application for the five year multi‐ million dollar study was successful. The study will commence end of September 2011 with funding allocated on an annual appropriation basis by the US Department of Health and Human Services. The Award is a significant achievement for ESR and their collaborators and the resulting research will generate new knowledge to underpin the public health strategies and policies needed to address the many factors influencing the impact of influenza locally, nationally, and globally. Combating seasonal and pandemic influenza and other respiratory pathogens relies on being able to accurately identify the disease in all its forms, from mild infection though to severe disease causing hospitalisation and death. We also need to understand how immune systems respond to this virus, monitor the effectiveness of influenza vaccines, and know how disease can be prevented through improvements in housing, nutrition, personal behaviour and other factors. 1 www.esr.cri.nz The SHIVERS project will consider all of these questions in a southern hemisphere setting, New Zealand, which has high quality public health surveillance systems and a proven track record in early detection and characterisation of pandemic influenza viruses. The SHIVERS project proposes to extend New Zealand’s existing influenza surveillance systems by establishing two (hospital‐based and community‐based) enhanced real‐time surveillance systems in the Auckland region. The Award is the start of a process that will see the project team and collaborators consulting widely with primary and secondary care networks across the Auckland region about how to collectively work together to achieve the study’s objectives. In addition to the benefits envisaged by CDC (in provision of information to support northern hemisphere influenza planning), the SHIVERS project is intended to provide New Zealand with: • Robust information for national influenza response planning; • Development and integration of existing surveillance systems; • Further development of relationships with overseas collaborators and funders; • Models for organising collaborative activity within New Zealand; • An innovative model for surveillance research collaboration within New Zealand; and • Establish New Zealand as a centre for research excellence at a population level; and • Position New Zealand‐based collaborating organisations for future collaborative overseas bids SHIVERS OBJECTIVES The two primary research objectives of SHIVERS, commencing in the first year, are: Objective 1: Estimate the incidence rate, prevalence, clinical spectrum, pathogenesis and outcomes of severe pneumonia and severe acute respiratory infection (SARI) caused by influenza and other respiratory pathogens in population and subpopulations. Expected outcomes: - Guide improved methods for disease surveillance - Assist early detection and prediction - Optimise clinical case management - Optimise laboratory diagnosis 2 www.esr.cri.nz Objective 2: Assess the annual effectiveness and/or efficacy of influenza vaccines in preventing laboratory‐confirmed influenza in population and subpopulations. Expected outcomes: - Guide better vaccine design - Guide targeted vaccination strategies for population and subgroups - Understand host immune response - Identify better immune diagnostic markers - Optimise laboratory diagnosis In addition to the above primary objectives, additional studies are to be conducted on interaction between influenza infection and other infections, aetiologies and causes of respiratory mortality, non‐severe illness due to influenza and other respiratory pathogens, serological studies of annual infection risk, impact of various risk factors for influenza infection or severe disease, immune response to influenza, healthcare and societal economic burden of influenza disease, and assessment of cost‐effectiveness of influenza vaccination. These additional studies are provided for in the additional objectives below, which will be conducted in the second to fifth years of the project: Objective 3 Investigate the interaction between influenza and other respiratory/non‐ respiratory infections Objective 4 Understand aetiologies and causes of respiratory mortality Objective 5 Estimate annual incidence and attack rates of non‐severe illness due to influenza and other respiratory pathogens in population and subpopulations Objective 6 Estimate annual risk of infection with influenza among population subgroups using serologic methods Objective 7 Identify and quantify the impact of various risk factors for influenza infection or severe disease Objective 8 Describe immune response to influenza infection /vaccination and compare the level, duration and cross‐reactivity of immune response in subgroups with risk factors for influenza disease. Objective 9 Estimate healthcare and societal economic burden of influenza and other respiratory pathogens and cost‐effectiveness of influenza vaccination among different subpopulations 3 www.esr.cri.nz WHY NEW ZEALAND? A number of powerful factors combined to give the ESR‐led research team the competitive advantage to win the CDC tender against tough international competition, these include: (1) New Zealand’s Location New Zealand is a temperate southern hemisphere country that lies entirely below the Tropic of Capricorn. Its influenza season occurs predominantly during the northern hemisphere summer (June to September) and what is observed in New Zealand often predicts the subsequent northern hemisphere experience. (2) New Zealand’s Unique Healthcare System • A number of critical logistical factors combine to make New Zealand a unique location for ground‐breaking, population‐based research, including its predominantly publicly funded healthcare system and associated health information systems: o All New Zealanders have a unique identifier ‐ the National Health Index number ‐ that allows tracking of individual healthcare utilisation over time and linkage to multiple data sources (e.g. notifiable diseases, primary care, hospitalisation, mortality, pharmaceuticals and geographically referenced data). o Additionally, patients are registered with primary care providers who maintain highly computerised records with detailed demographic, risk factor and immunisation status information. o The NZ population is extremely well characterised according to demographic structure, particularly by ethnicity and socioeconomic group. Indigenous Maori and Pacific immigrant populations (collectively 20% of the population) are vulnerable to influenza and other respiratory infections and will be of particular interest in this proposed research. (3) World class National Influenza Surveillance system New Zealand operates a number of surveillance systems which will be employed to provide real‐time strategic information to New Zealand and to northern hemisphere countries during inter‐pandemic and pandemic periods. 4 www.esr.cri.nz • • Inter‐pandemic period - Sentinel GP‐based surveillance - Virological surveillance of outpatients and inpatients - ICD code‐based morbidity and mortality surveillance Pandemic period - National notification - Border‐related public health surveillance - ICU utilisation - Pandemic sero‐survey - Transmission dynamic study Over 21 papers on pandemic influenza (2009‐11) • The programme will expand New Zealand’s existing influenza surveillance systems by establishing two surveillance systems in Auckland ‐ hospital‐based and community‐based. (4) Collaboration of World Leading Influenza Researchers on a single national application New Zealand gained a ‘best in class’ international reputation for its response to the pandemic influenza A(H1N1)09, and this credibility was further extended as a result of a subsequent seroprevalence study and over 20 related publications. For the SHIVERS application, as for the earlier seroprevalence study, ESR assembled a multi‐ disciplinary, multi‐centre team consisting of leading influenza researchers in New Zealand and abroad. This type of productive collaboration also led to the success of this CDC award. To undertake the proposed research and surveillance programme ESR’s science staff from its WHO National Influenza Centre based at the Wallaceville National centre for Biosecurity and Infectious Disease (NCBID) and its Health Intelligence Team (led by Dr Sue Huang and Dr Graham Mackereth) will collaborate with numerous researchers and clinicians including: • Dr Michael Baker, University of Otago • Dr Nikki Turner, The University of Auckland • Dr Sally Roberts, Auckland District Health Board (ADHB) • Dr Colin McArthur, Auckland City Hospital • Dr Cameron Grant, Starship Children’s Hospital • Dr Richard Webby, Collaborating Centre at St Jude Children’s hospital in the USA. 5 www.esr.cri.nz ABOUT CDC The Centers for Disease Control and Prevention (CDC) collaborate to create the expertise, information and tools that people and communities need to protect their health through: • Health promotion; • Prevention of disease; • Injury and disability; and • Preparedness for new health treatments CDC seeks to accomplish its mission by working with partners throughout the US and the world to: • Monitor health; • Detect and investigate health problems; • Conduct research to enhance prevention; • Develop and advocate sound public health policies; • Implement prevention strategies; • Promote healthy behaviours; • Foster safe and healthful environments; and • Provide leadership and training. THE RESEARCH TEAM & COLLABORATORS The SHIVERS research team has been carefully selected to have the skills, knowledge and experience to address the objectives, meet the scientific and design criteria, and deliver results that will make a difference to the way influenza is managed in the future in New Zealand and globally. Most importantly, the research team has successfully collaborated on influenza‐related research for several years and has published numerous joint papers and reports on both seasonal and pandemic influenza. ESR ESR is the host institute for the SHIVERS project and one of eight Crown Research Institutes owned by the government on behalf of the people of New Zealand. ESR’s work underpins the health and justice systems in New Zealand through the provision of science services and research, primarily to government clients. 6 www.esr.cri.nz The Health Programme in ESR includes the public health reference laboratory, disease surveillance and the National Influenza Centre (NIC). The NIC was recognised by the WHO in 1954 and serves as the key point of contact for both the WHO and the New Zealand Ministry of Health for the virology and epidemiologic surveillance of influenza. The NIC provides influenza virus isolates to the WHO Global Influenza Surveillance Network on a regular basis. ESR has made a recent and very significant investment in infrastructure that will support this research, in particular the newly built and refurbished laboratories, a new laboratory information management system (StarLIMS), a platform for web‐based surveillance of notifiable infectious diseases, and other information management and surveillance tools and systems. The NIC is situated at a newly purpose‐built PC2 facility attached to a PC3+ facility and is fully equipped to conduct the proposed laboratory testing. ESR is also linked to the Kiwi Advanced Research and Education Network (KAREN) enabling the transfer of large datasets between research and education organisations involved in this study. ESR is committed to ethical research and the research team has considerable experience with ethics and privacy issues, processes and compliance. All ESR laboratories are IANZ accredited to the ISO 15189 quality standard. Health and safety are organisational priorities. ESR operations have not been halted by the recent Christchurch earthquake and the research forming this proposal will be unaffected. Programme Leader ‐ Dr Virginia Hope Dr Hope joined ESR in 2006 to lead the development of its National Centre for Biosecurity and Infectious Disease (ESR NCBID) Programme. She has subsequently merged this with the Communicable Diseases and Population and Environmental Health Programmes to form the current Health Programme. Dr Hope is a specialist in both public health medicine and in medical administration. She was formerly a Medical Officer of Health in Auckland and a lecturer in Environmental Health at the School of Population Health in Auckland. Dr Hope has been involved in research on the epidemiology of infectious disease, the transmission of water‐borne disease, and biosecurity, and has been involved in numerous emergency responses to food or water‐borne pathogens and environmental hazards. 7 www.esr.cri.nz She was previously a member of the Biosecurity Ministerial Advisory Committee and Deputy Chair of the National Health Board and currently serves on the Capital and Coast and Hutt Valley District Boards as Chair. Principal Investigator – Dr Sue Huang The Principal Investigator for the study is Dr Sue Huang from the Institute of Environmental Science and Research (ESR), which is based in a new purpose ‐built facility at the National Centre for Biosecurity and Infectious Disease (NCBID) in Upper Hutt, Wellington. Dr Huang is a virologist and WHO National Influenza Centre (NIC) Director. As the principal investigator of the SHIVERS project, Dr Huang is responsible for scientific oversight of the project including active leadership and involvement in several objectives. As the Director of the WHO National Influenza Center (NIC), Dr Huang is responsible for the virological surveillance of influenza, providing reference services for hospital laboratories within the New Zealand Virus Laboratory Network and some Pacific Island countries, as well as providing primary diagnostic services for some sentinel general practitioners (GPs). She is also responsible for the national sentinel GP surveillance for influenza, overseeing the operation of the system, providing detailed analysis of influenza epidemiological and virological data for New Zealand. As a member of the Australia Influenza Vaccine Committee, Dr Huang works with other international leading experts to provide the annual recommendation for influenza vaccine composition for New Zealand, Australia and South Africa. In addition to routine virological and epidemiological surveillance, Dr Huang has published extensively on influenza virology and epidemiology and has successfully attracted multi‐million dollar research funding for previous studies. Dr Graham Mackereth is a veterinary epidemiologist with ESR and NCBID and will be the Project Manager of this research. During the A(H1N1) 2009 pandemic Dr Mackereth worked as an epidemiologist in the response centre for the New Zealand Ministry of Health. His responsibility during the response was to work on improving and collating surveillance information and designed a serological study to assess the level of population exposure to the pandemic virus. 8 www.esr.cri.nz Dr Mackereth now manages the Health Intelligence Team for ESR. The Team manages the public health informatics associated with influenza sentinel surveillance and notifiable diseases. Co‐Principal Investigator Dr Don Bandaranayake is a Public Health Physician at ESR. He was a principal investigator for the NZ pandemic Influenza sero‐prevalence study and has published widely on communicable disease and public health issues in international journals. Since coming back to NZ after eight years with the WHO, Dr Bandaranayake worked as a senior advisor at the Ministry of Health before joining ESR two years ago. He will co‐lead the serology component of the project with Dr Sue Huang. Dr Richard Hall is a Molecular Virologist with ESR at NCBID. Universities of Otago and Auckland The University of Otago and University of Auckland host New Zealand’s two medical schools and New Zealand’s leading research universities (ranked first and second for research excellence in the last New Zealand review). Contributors from the University of Otago are based in the Department of Public Health at the University’s clinical school in Wellington. Contributors from the University of Auckland are based in the University’s Immunisation Advisory Centre and Department of Pediatrics: Child and Youth Health. Co‐Principal Investigator Dr Michael Baker is an epidemiologist and Associate Professor at the University of Otago, Wellington. As most of the goals of the proposed research are concerned with aspects of the epidemiology of influenza, notably its incidence, distribution, impact, risk factors, and prevention (through vaccination), Dr Baker will co‐lead the project with Dr Sue Huang. He will also lead specific components concerned with how influenza interacts to cause other illnesses and to identify risk factors for this infection, particularly the role of household crowding. Through Dr Baker’s involvement as the Co‐director of the Housing and Health Research Programme at the University of Otago, he has researched factors associated with transmission of infectious diseases in the domestic environment. Dr Baker has researched and published extensively on the epidemiology of influenza, and infectious diseases more generally. He is currently the principal investigator on a Health Research Council funded project investigating causes for ethnic and socioeconomic inequalities in pandemic influenza infection rates in New Zealand. He was the principal investigator for a previous (2006‐09) CDC funded research project which investigated how influenza crosses borders and how such spread might be contained. 9 www.esr.cri.nz Dr Heath Kelly is an Australian epidemiologist and adjunct Associate Professor at the University of Otago whose interests and outputs are well aligned with the projects aim of assessing the burden of influenza in a southern hemisphere country and estimating influenza vaccine effectiveness in community and hospital settings. For more than a decade Dr Kelly has had responsibility for laboratory‐supported surveillance of influenza‐like illness (ILI) in sentinel general practices in the Australian state of Victoria. In addition to reporting surveillance findings on an annual basis, the surveillance scheme has been used to explore seasonal thresholds for influenza, the adequacy of the ILI case definition and the optimal distribution and number of sentinel general practice sites. More recently the Victorian sentinel surveillance network has been used to estimate influenza vaccine effectiveness (VE) using the relatively novel approach of the test‐negative design, where cases are sentinel patients with ILI who test positive for influenza by RT‐PCR and controls are sentinel patients who test negative. Des O’Dea is an Economist at the University of Otago and will lead Objective 9. Co‐Principal Investigator Dr Nikki Turner is a General Practitioner and Director of the Immunisation Advisory Centre (IMAC) and a Senior Lecturer at The University of Auckland. She will also co‐lead the project with Dr Huang and lead specific components concerned with vaccine effectiveness. IMAC is a national service delivery organisation that focuses on immunisation coverage, communication and coordination, which includes an active research division that utilises effective service delivery networks to translational research. Dr Turner’s areas of interest academically are in general practice and child health, with a major specialty interest in immunisation and she runs a research unit within the Immunisation Advisory Centre. This unit is focused on translational research around all aspects of improving immunisation uptake in New Zealand, vaccine delivery quality issues, matching coverage to disease surveillance and adverse events following immunisation, and overall reducing the impact of vaccine preventable diseases. 10 www.esr.cri.nz Auckland District Health Board (ADHB) Auckland District Health Board (ADHB) operates NZ’s largest public hospital with almost two million patient contacts, serving more than 449,440 people. ADHB provides a tertiary and quaternary referral service for the rest of NZ and for other pacific nations. There are over 10,000 staff or approximately 7,750 full‐time equivalent positions including bureau staff. The clinical staff is fully committed to ethical research when collecting respiratory and blood specimens. LabPLUS is the IANZ accredited (ISO 15189) medical laboratory of ADHB. The Clinical Microbiology and Virology Laboratories provides a wide range of services and are well supplied with modern processing equipment, work practices and test systems and supported by highly qualified and experienced clinical and technical staff. Co‐Principal Investigator Dr Sally Roberts is a Clinical Microbiologist and Infectious Diseases physician and she is the Clinical Head of Microbiology at Auckland City Hospital. Co‐Principal Investigator Dr Colin McArthur is an Intensivist and Clinical Director of Critical Care Medicine at Auckland City Hospital. He co‐ordinated the national intensive care response to pandemic influenza in 2009 and has been the New Zealand intensive care representative for several international severe influenza research projects. Co‐Principal Investigator Dr Cameron Grant is a paediatrician at Starship Children’s Hospital, Associate Professor at the University of Auckland, and Associate Director of Growing Up in New Zealand. His research is focused on child health problems that are common, affect New Zealand children disproportionately, and are preventable either by immunisation or improved nutrition. They will also co‐lead the project with Dr Huang and lead specific components on hospital based surveillance. Dr Mark O’Carroll is a Respiratory Disease Specialist at Auckland City Hospital. Dr Craig Thornley is a Public Health Physician with Auckland District Health Board. 11 www.esr.cri.nz WHO Collaborating Centre at St Jude’s Children’s hospital in the USA St. Jude Children’s Research Hospital is a premier research center that has 112 faculty‐level basic science investigators and 165 postdoctoral research associates. Faculty has appointments and direct graduate students at the University of Tennessee, Memphis, Colleges of Medicine and Pharmacy. Each area of research has fully equipped, state‐of‐the‐art laboratories, with additional common areas allocated for tissue culture, cold room storage, ultracentrifuges, and other shared equipment. Shared resources in bioinformatics and biotechnology, biostatistics, central data management, molecular resources, and others are available to all investigators. Dr Richard Webby is a virologist and Immunologist, and WHO Collaborating Center (WHOCC) Director at St. Jude Children’s Research Hospital, USA. His role in the SHIVERS project is to describe components of the immune response to influenza infection and/or influenza vaccination and compare the level, duration and cross‐reactivity of immune response in subgroups with risk factors for influenza disease. Over the past 11 years Dr Webby has been involved in laboratory and clinical research on influenza pathogenesis and vaccinology, all of which will provide the reagents and expertise needed for this study. Other SHIVERS collaborators The SHIVERS project will be undertaken in the Auckland region with extensive engagement with Auckland based DHBs and Primary Health Organisations (PHOs). THE INFLUENZA VIRUS Influenza is a significant public health issue worldwide with tens of thousands infected, many thousands every year die from influenza or seasonal flu‐related deaths, and billions of dollars are spent on vaccine preventative measures. In New Zealand, each year it has a large impact on our community, with approximately 10‐20% of New Zealanders infected. Some of these people become so ill they need hospital care, and a small number die. It also has a financial impact, particularly in workplaces, and can potentially overwhelm both primary care and hospital services during winter epidemics. The Ministry of 12 www.esr.cri.nz Health undertakes a “Don’t let the flu get you” vaccination awareness programme and funds free vaccinations for higher risk groups. Influenza viruses frequently undergo antigenic changes, thus evading the host immune response. This poses a real challenge in the prevention and control of influenza. Infection with the influenza virus can be asymptomatic, mild, severe or fatal, and can pave the way for severe secondary bacterial infections. The recent pandemic A(H1N1) 2009 fortunately caused generally mild disease compared with previous pandemics but it showed very clearly that we do not know enough about this virus, its interactions with the host or ways to minimise its health, social and economic impacts. INFLUENZA AND OTHER RESPIRATORY DISEASES IN THE SOUTHERN HEMISPHERE (NEW ZEALAND) New Zealand has a well‐established national influenza surveillance system, comprising four information sources: 1) a national sentinel general practitioner (GP) virology and epidemiologic surveillance component 2) virology surveillance of outpatients and hospital inpatients 3) international classification of diseases (ICD) coded data for influenza hospitalization and mortality; and 4) an estimate of immunisation coverage based on medical practitioners’ reimbursement claims for immunisations. During the recent pandemic A(H1N1) 2009 it was necessary to establish other surveillance tools such as border‐related public health surveillance, notifiable disease surveillance, intensive care unit (ICU) utilisation reporting and the Pandemic Influenza Mortality and Morbidity Review Group. These initiatives helped contain the spread of the disease and manage the pandemic response. The influenza season in New Zealand occurs during the northern hemisphere summer, and can therefore provide critical information on the epidemiology, burden, strains and effectiveness of prevention measures of influenza and other respiratory pathogens at a time when study sites in the northern hemisphere cannot. In addition, understanding the epidemiology of influenza and the effectiveness of annual vaccines in the southern hemisphere will provide needed data for influenza control strategies in other parts of the world. 13 www.esr.cri.nz PUBLIC HEALTH IMPACTS OF THE SHIVERS PROJECT The SHIVERS research will provide an extended evidence base for future health investment and policy development relevant to New Zealand and globally and will answer many unresolved questions regarding the epidemiology of influenza. These include but are not limited to: • understanding the ‘true’ contribution of influenza to serious disease • understanding the independent contributions of chronic diseases, raised BMI, ethnicity and socioeconomic deprivation to disease risk; • measuring vaccine effectiveness (VE) in population and subgroups in relation to vaccine formulation and variations in the virus over time. • assisting the timely identification of known and unknown etiological organisms causing respiratory diseases. • assessing influenza‐specific humoral and cellular immune response among well characterised individuals with varying disease spectrum. The research will also deliver a tested model for efficient, sustainable surveillance that could be applied in multiple settings to assist early detection of influenza epidemics and pandemics, and respiratory illness more generally. Studies on the epidemiology and aetiology of respiratory illness will guide improved methods for laboratory diagnosis and clinical case management. Studies on VE in the population and subgroups with various risk factors will inform population‐ wide and subgroup‐targeted vaccine strategies. Understanding of host immune responses will guide better vaccine design and immune diagnostic markers. Finally, studies on risk factors will guide non‐pharmaceutical interventions and preventive measures. ESR believes that in addition to providing an extended evidence base and providing further answers on the epidemiology of influenza, the SHIVERS research will improve the health of New Zealanders by informing: • the development of health policy in New Zealand and elsewhere; • public health initiatives; • strategies (diagnostic and treatment) to manage patients admitted with Severe Community‐Acquired Pneumonia (severe CAP) ; and • influenza response planning within New Zealand. 14 www.esr.cri.nz