GLOBAL INFLUENZA PROGRAMME BACKGROUND DOCUMENT STREAM WHO PUBLIC HEALTH RESEARCH

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s d AGENDA FOR d v a e 3 n INFLUENZA e c n e h s lt c a ie e nc c h e li to a pub ddress unmet

MINIMIZING IMPACT Minimizing the impact of pandemic,

2017 UPDATE zoonotic, and seasonal epidemic influenza WHO/WHE/IHM/GIP/2017.6 © World Health Organization 2017

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WHO Public Health Research Agenda for Influenza 2017 Update Contents

Abbreviations 3.0 INTRODUCTION 1 Substream 3.1 DETERMINING DISEASE BURDEN AND SOCIAL IMPACT 2

RESEARCH RECOMMENDATION 3.1.1, 3.1.2 AND 3.1.4 Summary of key accomplishments 3.1.1, 3.1.2 and 3.1.4 Knowledge gaps 3.1.1, 3.1.2 and 3.1.4 RESEARCH RECOMMENDATION 3.1.3 Summary of key accomplishments 3.1.3 Unmet public health needs 3.1.3 Knowledge gaps 3.1.3 RESEARCH RECOMMENDATION 3.1.5 Summary of key accomplishments 3.1.5 Unmet public health needs 3.1.5 Knowledge gaps 3.1.5 RESEARCH RECOMMENDATION 3.1.6 Summary of key accomplishments 3.1.6 Unmet public health needs 3.1.6 Knowledge gaps 3.1.6 Key research questions 3.1

Substream 3.2 IMPROVE IMMUNOGENICITY, AVAILABILITY AND DELIVERY OF INFLUENZA VACCINE 7

RESEARCH RECOMMENDATION 3.2.1 Summary of key accomplishments 3.2.1 Unmet public health needs 3.2.1 Knowledge gaps 3.2.1 RESEARCH RECOMMENDATION 3.2.2 Summary of key accomplishments 3.2.2 Unmet public health needs 3.2.2 Knowledge gaps 3.2.2 RESEARCH RECOMMENDATION 3.2.3 Summary of key accomplishments 3.2.3 Unmet public health needs 3.2.3 knowledge gaps 3.2.3 RESEARCH RECOMMENDATION 3.2.4 Summary of key accomplishments 3.2.4 Unmet public health needs 3.2.4 Knowledge gaps 3.2.4 RESEARCH RECOMMENDATION 3.2.5 Summary of key accomplishments 3.2.5 Unmet public health needs 3.2.5 Knowledge gaps 3.2.5 RESEARCH RECOMMENDATION 3.2.6 Summary of key accomplishments 3.2.6 Unmet public health needs 3.2.6 Knowledge gaps 3.2.6 RESEARCH RECOMMENDATION 3.2.7 Summary of key accomplishments 3.2.7 Unmet public health needs 3.2.7 Knowledge gaps 3.2.7 RESEARCH RECOMMENDATION 3.2.8 Summary of key accomplishments 3.2.8 Unmet public health needs 3.2.8 Knowledge gaps 3.2.8 RESEARCH RECOMMENDATION 3.2.9 Summary of key accomplishments Unmet public health needs 3.2.9 Knowledge gaps 3.2.9 Key research questions 3.2

Substream 3.3 PUBLIC HEALTH POLICIES TO REDUCE THE IMPACT OF DISEASE 19 RESEARCH RECOMMENDATION 3.3.1 Summary of key accomplishments 3.3.1 Unmet public health needs 3.3.1 Knowledge gaps 3.3.1 RESEARCH RECOMMENDATION 3.3.2 Summary of key accomplishments 3.3.2 Unmet public health needs 3.3.2 Knowledge gaps 3.3.2 RESEARCH RECOMMENDATION 3.3.3 Summary of key accomplishments 3.3.3 Unmet public health needs 3.3.3 Knowledge gaps 3.3.3

REFERENCES 22 Abbrevations

ADCC Antibody Dependent Cellular Cytotoxicity

AESI Adverse Events of Special Interest

BARDA Biomedical Advanced Research and Development Authority

CDC Centers for Disease Control and Prevention

CHMP Committee for Medicinal Products for Human Use

CMI Cell-mediated Immunity

CVV candidate vaccines virus

EMA’s European Medical Agency’s

EU European Union

FACS Fluorescent Activated Cell Sorting

GACVS Global Advisory Committee on Vaccine Safety GAP WHO Global Pandemic Influenza Action Plan to Increase Vaccine Supply

GIVE Global Influenza Vaccine Effectiveness

HA Haemagglutinin

HI Haemagglutination inhibition

HLA Human Leukocyte Antigen HPLC High-performance Liquid Chromatography

HPV Human Papillomavirus

ICTRP International Clinical Trials Registry Platform

IFPMA International Federation of Pharmaceutical Manufacturers & Associations

ILI Influenza-like Illness

IVS ITF Influenza Vaccine Supply International Task Force

KAP Knowledge, Attitude and Practices

LAIVs Live Attenuated Influenza Vaccines

LMICs Low and Middle Income Countries

MDCK Madin Darby Canine Kidney

NA Neuraminidase NAI Neuraminidase Inhibitor

NGS Next-generation Sequencing

NI neuraminidase inhibiting

NIH National Institutes of Health

RG Reverse Genetics BACKGROUND SAES Serious Adverse Events DOCUMENT SAGE Strategic Advisory Group of Experts (WHO) Minimizing the impact of pandemic,zoonotic, and seasonal epidemic influenza SDS-PAGE Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis STREAM SPR Surface Plasmon Resonance SRD Single Radial Immunodiffusion

SRH single radial haemolysis 3 TB Tuberculosis TIP Tailoring Immunization Programmes

VE Vaccine Effectiveness

VLP Virus-like Particle

WHO World Health Organization STREAM 3.0 Introduction 3

Immunization against influenza is an essential public health intervention to control both seasonal epidemics and pandemic influenza. The WHO Global Pandemic Influenza Action Plan to Increase Vaccine Supply (GAP) – in 2006 with GAP-I (World Health Organization, 2006) and in 2011 with GAP-II (World Health Organization, 2011) – articulated a multifaceted strategy to increase vaccine production and use.

The WHO Public Health Research Agenda for Influenza in 2009 outlined research recommendations for minimizing the impact of pandemic, zoonotic and seasonal epidemic influenza (Stream 3) and identified three major topics: • Substream 3.1 Determining disease burden and social impact; • Substream 3.2 Improve immunogenicity, availability and delivery of influenza vaccines; and • Substream 3.3 Public health policies to reduce the impact of disease by immunization.

With the global pandemic of A(H1N1)pdm09 influenza virus in 2009 and subsequent extensive research reports published relating to the pandemic, a review of the research recommendations in the 2009 WHO Public Health Research Agenda for Influenza was deemed necessary. In 2013, WHO published a progress review and report (World Health Organization, 2013a).

Much progress has been made since the last update of 2009, especially with respect to publications, workshops, international collaborations and the generation of various websites on specific topics from some stakeholders. However, there have been many parallel activities, and although these often represent excellent approaches, they urgently need to be aligned and harmonized, then accepted by global regulatory authorities.

For Substream 3.1, major achievements have included the establishment and provision of WHO documents, especially the WHO manual for estimating disease burden (World Health Organization, 2015a), and standardized protocols for surveillance of influenza (World Health Organization, 2012).

For Substream 3.2, a range of resources are now available. For example, there is WHO guidance on deployment of pandemic influenza vaccine (World Health Organization, 2013b), and programmes such as GAP (World Health Organization, 2006) and the pandemic influenza preparedness (PIP) framework1 have been established to improve pandemic preparedness. Additional source documents that relate to Recommendation 3.2.3 have been provided by the United States (US) Biomedical Advanced Research and Development Authority (BARDA), 2 the European Union (EU) influenza virus tracker 3 and industry – via the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Influenza Vaccine Supply International Task Force (IVS ITF) .4 In relation to Recommendation 3.2.9, various websites bring together

1 http://www.who.int/influenza/pip/en/ 2 http://www.phe.gov/about/BARDA/Pages/default.aspx 3 www.who.int/fluvrius_tracker 4 http://www.ifpma.org/tag/ivs/

1 important clinical studies; for example, WHO’s International Clinical Trials Registry Platform (ICTRP) 5 and the US National Institutes of Health’s (NIH’s) clinical trials platform.6 Other websites are focusing on vaccine safety; for example, the US Vaccine Adverse Event Reporting System (VAERS)7 and WHO’s Global Advisory Committee on Vaccine Safety (GACVS). 8

Major progress has been achieved with the development of alternative potency assays (related to Recommendations 3.2.3 and 3.2.9), and the identification of bottlenecks during two WHO workshops (related to Recommendation 3.2.3). Also, serological assays have been developed and established to provide alternatives to haemagglutination inhibition (HI) – such as neuraminidase (NA) inhibiting (NI) antibodies, neutralizing antibodies and cell-mediated immunity (CMI) – to better address the immunogenicity of conventional and novel influenza vaccines and production platforms. Progress has been also made with respect to novel vaccine technologies, including universal influenza vaccine approaches (related to Recommendation 3.2.5).

Several programmes and tools have been developed for Substream 3.3. They include tailoring immunization programmes (TIP) (related to Recommendation 3.3.1) and knowledge, attitude and practices (KAP) (related to Recommendation 3.3.2). Progress has also been made with social science research for influenza vaccine acceptance and uptake (related to Recommendation 3.3.3). Another important accomplishment was the successful completion of Recommendation 3.3.2.

The main issues identified were the recognition and acceptance of alternative potency assays, international databases for pharmacovigilance (especially in risk groups and different socioeconomic settings), clinical study designs, immunological parameters and immune correlates, and vaccine effectiveness (VE) studies, especially in risk groups and different socioeconomic settings, by public health and scientific organizations and regulatory bodies.

Substream 3.1 Determining disease burden and social impact

Research recommendation 3.1.1, 3.1.2 and 3.1.4 This section summarizes the accomplishments related to the following three recommendations: 3.1.1 Conduct epidemiological projects to determine disease burden among WHO recommended influenza vaccine target groups including incidence of influenza disease, interactions with co-morbidities, and the role of seasonality in countries seeking to expand coverage. 3.1.2 Assess the timeliness, quality, and sustainability of influenza disease surveillance and explore its utility towards estimating annual vaccine coverage, effectiveness and averted illnesses. 3.1.4 Establish the economic burden of seasonal and pandemic influenza.

5 http://www.who.int/ictrp/en/ 6 https://clinicaltrials.gov/ct2/search 7 http://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vaers/index.html 8 http://www.who.int/vaccine_safety/committee/en/

2 Summary of key accomplishments 3.1.1, 3.1.2 and 3.1.4 Much data on disease burden – as defined by influenza-like illness (ILI) and other outpatient rates – is available; for example: • modelling and observational data from selected countries (Azziz-Baumgartner et al., 2012; Dawood et al., 2010b; Emukule et al., 2014a; Emukule et al., 2015; Feikin et al., 2012a; Fowler et al., 2013; Fowlkes et al., 2013a; Fowlkes et al., 2013b; Gindler et al., 2011; Gresh et al., 2016; Katz et al., 2012; Marcone et al., 2015; McMorrow et al., 2015; Nair et al., 2011; Poehling et al., 2013; Shrestha et al., 2011; Steffen et al., 2011; Szilagyi et al., 2016; Talaat et al., 2011; Thompson et al., 2011; Tsai, Zhou & Kim, 2014; Van Kerkhove et al., 2013; World Health Organization, 2015a; Zhang et al., 2016; Zimmerman et al., 2016); • hospitalization rates (Al-Awaidy et al., 2015; Baggett et al., 2012; Broor et al., 2014; Chadha et al., 2013; Chaves et al., 2014; Clara et al., 2012; Cox et al., 2012; Dawood et al., 2010a; Descalzo et al., 2016; Deutscher et al., 2012; Feikin et al., 2012b; Fry et al., 2010; Fuller et al., 2013; Gurley et al., 2010; Hasan et al., 2014; Hirve et al., 2015; Homaira et al., 2012; Jules et al., 2012; Lafond et al., 2016; Millman et al., 2015; Moorthy et al., 2012; Murray et al., 2015; Nasreen et al., 2014; Nelson et al., 2014; Olsen et al., 2010; Ortiz et al., 2014a; Ortiz et al., 2013; Ortiz et al., 2014b; Reed et al., 2015; Rowlinson et al., 2017; Thompson et al., 2012; Yu et al., 2014); and • mortality rates using data from about 33 countries through at least two models (Aungkulanon et al., 2012; Azziz‐Baumgartner et al., 2013; Cheng et al., 2015; Emukule et al., 2014b; Feng et al., 2012; Garg et al., 2014; Greenbaum et al., 2014; Meerhoff et al., 2015; Saborío et al., 2014; Simmerman et al., 2009; Walaza et al., 2015) have been published and were summarized in the WHO disease burden manual in September 2015 (World Health Organization, 2015a).

The WHO disease burden manual also describes the use of three methods to analyse data from 70 tropical and subtropical countries on the seasonality of influenza during the 2016 season (Hirve et al., 2016; World Health Organization, 2015a). WHO also provided standardized protocols (World Health Organization, 2012) aligned with regional offices, probe studies (Gessner et al., 2013) and studies on economic burden piloted in three Latin American countries (Bhuiyan et al., 2014; Tinoco et al., 2016; Wang et al., 2013).

Unmet public health needs and knowledge gaps 3.1.1, 3.1.2 and 3.1.4 There is insufficient information on ILI and other outpatient rates, on hospitalization and mortality rates, on seasonality of epidemics, and on disease and economic burden.

Research recommendation 3.1.3 Evaluate the influenza vaccine preventable disease burden and the potential impact of immuni- zation programmes (e.g. vaccine demonstration project).

Summary of key accomplishments 3.1.3 In 2009, understanding of the potential impact of influenza immunization in many settings was limited, owing to the lack of robust national influenza immunization programmes from which to measure the disease burden prevented. Since then, countries’ interest in expanding influenza vaccine use has also increased as a result of recommendations from the WHO Strategic Advisory Group of Experts (SAGE) on the use of influenza vaccines (SAGE Working Group, 2012). The recommendations provided clearer and more operationally feasible guidance on the use of influenza vaccines (SAGE Working Group, 2012). Finally, the use of monovalent influenza vaccine in 2009–2010 was, for many countries, the first time that an influenza vaccine had been used in a large

3 public health programme. This experience has also led some countries to consider further refining or expanding the use of seasonal vaccination as part of their effort towards influenza pandemic preparedness.

Substantial information on influenza disease burden, both at country and global levels, has also been collected. This has led to a greater appreciation of the value of influenza prevention and of vaccination. The PIP framework has catalysed progress in this area. In addition, data on vaccine efficacy have been collected in key settings (e.g. tropical countries or populations with underlying diseases of importance in developing countries, such as HIV infection), and in key risk groups (e.g. pregnant women or children). Finally, global public health and academic partners have created the Global Influenza Vaccine Effectiveness (GIVE) project to provide timely and robust estimates of annual VE, and have driven the creation of consensus methods to measure VE (Feikin, Scott & Gessner, 2014; Hanquet et al., 2013; Molinari et al., 2007; Nair et al., 2011; Osterholm et al., 2012; Saadatian-Elahi et al., 2016; SAGE Working Group, 2012).

Unmet public health needs 3.1.3 There will be a need to estimate the reduction in illness associated with influenza vaccination programmes in key representative settings, over multiple years and among outcomes of public health interest. The work should focus on severe disease outcomes because these would be of most interest to policy makers. This work should be paired with a communications plan to ensure that the results are effectively provided to key stakeholders.

Knowledge gaps 3.1.3 Further consensus is needed on the best methods to use in estimating impact. In addition, work to define optimal strategies for vaccination in settings in which influenza circulates year-round or semi-annually will be important (e.g. year-round vaccination versus annual campaigns). Further understanding of the appropriate target groups for vaccination in low- and middle-income settings will be critical to using resources most efficiently. Finally, data on whether influenza vaccination can reduce severity of illness may be helpful in models of impact.

Research recommendation 3.1.5 Determine best approaches for applying influenza disease burden data, coupled with cost– effectiveness data, to inform development or expansion of influenza control programmes in the context of competing priorities.

Summary of key accomplishments 3.1.5 Substantial data have been collected on the disease burden among pregnant women since the 2012 SAGE recommendations. However, most of these data were collected during the 2009 pandemic, and therefore may not be representative of disease burden during seasonal epidemics. Also, WHO has produced reviews of disease among pregnant women (Fell et al., 2017), and the United States of America (USA) has developed models to estimate the averted burden annually and communicates this averted burden in annual reports. A US model (Kostova et al., 2013) is now being tried in Kenya and is planned for other countries, to determine whether routine surveillance data can be used in low- and middle-income countries (LMICs) to estimate the potential impact of vaccination strategies. In addition, some LMICs are working on models to understand which

4 strategy will produce the greatest impact with respect to planned expansion of vaccine use (e.g. year-round vaccination versus annual campaigns). These early data will be useful to other countries making vaccine investment decisions.

Relevant references for this recommendation are the following: (Ahmed et al., 2014; Ahmed et al., 2015; Canelle et al., 2016; Foppa et al., 2015; Gessner & Feikin, 2014; Hajjeh et al., 2010; Hanquet et al., 2013; International Federation of Pharmaceutical Manufacturers & Associations; Janusz et al., 2012; Jauregui et al., 2011; Kostova et al., 2013; Leung & Nicoll, 2010; Levine & Levine, 1997; Liang et al., 2011; Lyytikainen et al., 2011; Molinari et al., 2007; Moro et al., 2016; Reed et al., 2014; Ropero-Álvarez et al., 2009; Samaan, McPherson & Partridge, 2013; Weycker et al., 2005; World Health Organization, 2006; World Health Organization, 2013b; World Health Organization, 2014).

Unmet public health needs 3.1.5 One product of the introduction of several new vaccines into national immunization programmes over the past two decades is the gain of substantial experience and the formulation of best practices in building and communicating the evidence base for vaccine introduction to stakeholders. WHO developed a roadmap for vaccine introduction that outlines the key concepts and data needs (World Health Organization, 2014).

These principles have been applied to the introduction of new Expanded Programme on Vaccination (EPI) vaccines, such as pneumococcal and Haemophilus influenzae type b (Hib) conjugate vaccines, and rotavirus vaccines. Influenza vaccine expansion or introduction is unique in many ways (e.g. the need for yearly vaccination due to the year-to-year variability of circulating influenza viruses and their associated disease burden and of VE). However, the basic principle of estimating and communicating the disease burden of influenza, and understanding the relative disease burden compared with other interventions, is relevant to stakeholders considering the value of investing in influenza vaccination programmes and considering competing public health needs.

Knowledge gaps 3.1.5 Work in three areas would be of value in determining the best approaches to the use of disease burden data to inform vaccination programme development: • Substantial data have been collected on the burden among pregnant women since the 2012 SAGE recommendations. However, data are still needed for other SAGE risk groups, and it might be useful to pay particular attention to collecting data on young children and on specific groups with higher risks of severe influenza that are of public health significance in some settings in developing countries; for example, individuals with HIV and tuberculosis (TB), haemoglobinopathies, diabetes, and chronic lung and heart disease. • Targeted vaccination programmes addressing these groups might prove cost-effective in some settings, but data are needed to assess their utility. • A process to collect best practices in the use of such data for decision-making would be valuable.

5 Research recommendation 3.1.6 Assess social determinants of health under different epidemiological settings (such as socially disadvantaged, indigenous populations etc.) and evaluation of the social impact (such as disruptions in commerce, health care systems, public safety, social and political fabrics etc.) of influenza outbreaks and pandemics based on such determinants.

Summary of key accomplishments 3.1.6 There has been an expansion of knowledge on broad social determinants of influenza. For example, a recent review (de Francisco Shapovalova et al., 2015) encompassed the years 1950–2013, and identified 62 relevant articles, of which 32 were published between 2008 and 2014. Social outcomes included the following: • security if influenza pandemics were to become an existential threat, nationally and internationally; • medical insurance policies; • legal frameworks; • impact of disruption (e.g. economic disruption, social disruption and health system disruption); and • lack of appropriate legal frameworks and investments to address public health measures during a pandemic; for example, in India, this led to economic disruption (Kakkar et al., 2010).

A systematic review of paediatric hospitalizations reported that 96% of 895 000 influenza-associated hospitalizations occurred in developing countries, with a threefold higher incidence (Lafond et al., 2016). The highest incidences and greatest burden occurred in the WHO African Region and South- East Asia Region.

Data from Canada (Charland et al., 2011) and from a modelling study (Hyder & Leung, 2015) showed that individuals and neighbourhoods with a lower social deprivation index had higher influenza attack rates. In addition, a case–control study reported that H1N1pdm09 infection in Canada was associated with minority race or ethnicity, but not with social deprivation, education or poverty (Navaranjan et al., 2014). The US Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, reported an increased risk of H1N1pdm09-associated hospitalizations among minority groups compared with white persons (Dee et al., 2011). Beyond illness, lower socioeconomic status was significantly associated with barriers to information access and processing, resulting in people adopting incorrect protective behaviours against H1N1pdm09 (Lin et al., 2014).

Unmet public health needs 3.1.6 Numerous studies from diverse populations have documented medical risk factors for severe influenza disease (e.g. pregnancy, underlying illness and age), but few studies have examined social determinants and outcomes of influenza infection. For example, in a major systematic review (de Francisco Shapovalova et al., 2015), studies were not geographically representative – there were 15 studies from China; five to seven each from the Russian Federation and several Latin American countries (Argentina, Brazil and Colombia); one to three each from many other Latin American and Asian countries; and only four countries represented from Africa (Madagascar, Rwanda, South Africa and Zimbabwe, with one to three studies from each).

6 The key unmet public health need is to better define the broad array of social outcomes resulting from seasonal and pandemic influenza, including disruptions in commerce, health-care systems, public safety, social and political fabrics, family functioning and social well-being issues. Only through such an assessment can the public health value of vaccination and other intervention strategies be adequately assessed and prioritized for endemic and pandemic influenza control.

Knowledge gaps 3.1.6 Social determinants of health to be assessed should include illness, hospitalization and death in resource-poor settings, and the social outcomes of seasonal and pandemic influenza and modelling studies.

Key research questions 3.1 3.1.1 Conduct epidemiological projects to determine disease burden among WHO recommended influenza vaccine target groups including incidence of influenza disease, interactions with co-morbidities, and the role of seasonality in countries seeking to expand coverage. 3.1.2 Assess the timeliness, quality, and sustainability of influenza disease surveillance and explore its utility towards estimating annual vaccine coverage, effectiveness and averted illnesses. 3.1.3 Evaluate the influenza vaccine preventable disease burden and the potential impact of immunization programs (e.g. vaccine demonstration project). 3.1.4 Establish the economic burden of seasonal and pandemic influenza. • What is the actual disease and economic burden caused by influenza among vaccine target groups identified by WHO/SAGE, such as pregnant women, health-care workers and individuals with pre-existing conditions? • In particular, what is the burden of severe illness among LMICs? 3.1.5 Determine best approaches for applying influenza disease burden data, coupled with cost- effectiveness data, to inform development or expansion of influenza control programs in the context of competing priorities. • How could the estimation of the cost–benefit of influenza vaccination be improved? • What are the drivers for policy decisions? • Which processes are used by ministries of health to adopt national influenza vaccination programmes, and can they be harmonized?

Substream 3.2 Improve immunogenicity, availability and delivery of influenza vaccines

Research recommendation 3.2.1 Investigate methods to improve the vaccine strain selection process and to characterize optimal vaccine strains including the establishment of vaccine strain libraries.

7 Summary of key accomplishments 3.2.1 Many different factors are involved in the current vaccine strain selection process. Some of these factors have been refined or improved since 2009; for example, VE studies (Omer & Yildirim, 2016; Sullivan, Feng & Cowling, 2014; Zimmerman et al., 2016) and virus evolution modelling (Luksza & Lassig, 2014; Neher et al., 2016). In addition, new technologies have been introduced; for example, next-generation sequencing (NGS) (Dinis et al., 2016; McGinnis et al., 2016), improved methods such as addition of oseltamivir carboxylate to A(H3N2) HI assays (Lin et al., 2012) and additional assays (e.g. virus neutralization) (Lin et al., 2015). These technologies are now integral to selecting new candidate vaccine viruses (CVVs), and of the overall assessment of existing vaccine performance. Relevant references for the vaccine strain selection process are the following: (Ahmed et al., 2014; Ahmed et al., 2015; Bedford et al., 2014; Canelle et al., 2016; Chan & Rabadan, 2013; Crowcroft, Rosella & Pakes, 2014; Dorjee et al., 2013; Eichelberger et al., 2016; Eurosurveillance editorial team, 2011; Houser & Subbarao, 2015; Impagliazzo et al., 2015; International Federation of Pharmaceutical Manufacturers & Associations; Klimov et al., 2012; Laurie et al., 2015; Leung & Nicoll, 2010; Liang et al., 2011; Lin et al., 2012; Lyytikainen et al., 2011; Monto et al., 2015; Moro et al., 2016; Neher & Bedford, 2015; Nolte et al., 2015; Ovsyannikova et al., 2016; Pereyaslov et al., 2016; Ren et al., 2015; Schmeisser et al., 2013; Shcherbik et al., 2014; Sun et al., 2013; Suphaphiphat et al., 2016; Visher et al., 2016; Westgeest et al., 2014; Wong & Ross, 2016; World Health Organization, 2006; World Health Organization, 2013b; Yassine et al., 2015; Zhao et al., 2016; Zou et al., 2016).

The new methodologies and technical advancements have been discussed extensively at several WHO workshops on this topic: on 14–16 June 2010 (Ampofo et al., 2012), on 7–9 December 2011 (Ampofo et al., 2013), on 1–3 April 2014 (Ampofo et al., 2015) and on 18–20 November 2015 (Alan et al., 2017). For all of these meetings, full reports are available and a series of action items have been identified and initiated. For example, at the Hong Kong Special Administrative Region (SAR) meeting (in 2015), there were 28 individual proposed action points grouped into seven categories covering near- and mid-term time frames. Completion of these tasks over time will improve the accuracy and robustness of the influenza vaccine strain selection process.

Since 2009, extensive progress has been made in the establishment of influenza vaccine strain libraries in order to have seed vaccine viruses available for rapid deployment in the event of a pandemic. These CVVs have been made using conventional reassortment methods, various reverse genetics (RG) technologies and, more recently, a combination of synthetic DNA and RG methods (Dormitzer et al., 2013). The list of potential pandemic CVVs made and distributed is continually being updated as new subtypes and variance emerge, causing infection in animals and humans, even though only a small number of these potential pandemic CVVs have been tested in clinical studies. There is much room for further improvement of the process of timely generation and testing of CVVs, and for improvements in virus yields and immunogenicity against the circulating wild type viruses in nature.

Unmet public health needs 3.2.1 The influenza vaccine remains a moderately effective vaccine in its various current forms, and it is important to have a close match between the vaccine virus and the viruses circulating during the season. The challenge is even greater in the elderly – one of the major targets of the influenza vaccine – where influenza vaccines are generally less effective due to immune senescence. Other factors include the dependency on eggs, long lead times, requirement for annual vaccination and cost.

8 Knowledge gaps 3.2.1 Many gaps have been identified in the vaccine strain selection process; for example, high- throughput assays for antigenic characteristics of CVVs, human serology studies, improved predictive modelling algorithms and the need for observational effectiveness studies to support the CVV selection process.

Research recommendation 3.2.2 Conduct studies to enhance the clinical applications of existing vaccines including improvements in the production; duration and breadth of protection; safety and immunogenicity profiles and dose-sparing formulations, especially for high-risk groups.

Summary of key accomplishments 3.2.2 Seasonal vaccines that are based on egg-independent production platforms have been licensed in recent years. They include the first baculovirus-based recombinant haemagglutinin (HA) vaccine as well as cell-based vaccines, produced either in Madin Darby canine kidney (MDCK) or in Vero cells. Progress has also been made with other vaccine production platforms (e.g. recombinant vaccine technologies) for both seasonal and pandemic vaccines. The synthetic generation of influenza vaccine virus, which requires only the genetic sequence of HA and NA genes, is an important step towards acceleration of vaccine development against potential pandemic threats, as demonstrated with the emergence of H7N9 viruses in humans in 2013. Numerous studies have demonstrated that the use of oil-in-water adjuvants allows considerable antigen dose sparing for novel subtypes such as H5N1 or H7N9, against which humans are serologically naive. Adjuvants can also broaden antibody responses, resulting in an extended cross-reactivity against heterologous viruses within the same subtype (Berlanda Scorza, Tsvetnitsky & Donnelly, 2016). However, safety concerns emerged following the use of ASO3-adjuvanted H1N1pdm09 vaccine in Europe. An increased risk for childhood narcolepsy was associated with a certain human leukocyte antigen (HLA) genotype (Bomfim et al., 2017).

Heterologous prime-boost vaccination has emerged as a powerful strategy to stimulate antibody responses to avian influenza viruses with pandemic potential, and suggests a new vaccination approach for pandemic preparedness. Evaluation of cellular responses elicited by influenza vaccination have become more routine. In particular, it has provided evidence for the immunogenicity of live attenuated influenza vaccines (LAIVs) in children. The latest achievement was the licensing of two seasonal vaccines in the US with enhanced immunogenicity and protective efficacy in the elderly.

Relevant references for this recommendation are the following: (Ahmed et al., 2015; Aichinger et al., 2015; Bart et al., 2014; Benowitz et al., 2010; Chen et al., 2014; Chen et al., 2015; Coughlan & Lambe, 2015; DiazGranados et al., 2015; Dormitzer et al., 2013; Eick et al., 2011; Fries, Smith & Glenn, 2013; Gillard et al., 2014; Hartvickson et al., 2015; Izurieta et al., 2015; Jacob et al., 2015; Khurana et al., 2011; Langley et al., 2015; McLean et al., 2014; Mohn et al., 2015; Nakaya et al., 2016; Partinen et al., 2012; Ping et al., 2015; Schuind et al., 2015; Soema et al., 2015; Suzuki et al., 2016; Talaat et al., 2014; Thompson et al., 2016; Treanor et al., 2011; Van Buynder et al., 2013; Wijnans et al., 2013; Winokur et al., 2015).

9 Unmet public health needs 3.2.2 Post-marketing surveillance studies of A(H1N1)pdm09 vaccines was limited in some regions, but a large cohort study (Wijnans et al., 2013) revealed safety concerns with adjuvanted A(H1N1)pdm09 vaccines. Routine evaluation of both humoral and cellular immune responses will be important for the development of improved or new influenza vaccines. It is also essential to address the needs and costs associated with monitoring of medium and longer term SAEs of novel vaccines and formulations, particularly in some high-risk groups (e.g. young children or subjects with underlying chronic medical conditions).

Knowledge gaps 3.2.2 Optimal vaccination strategies that elicit improved breadth and durability of immunity to seasonal and pandemic influenza need additional investigation.

Frequent annual seasonal vaccination has, in some studies, resulted in blunting of the post- vaccination antibody response and reduced VE in adults. However, the consistency and the immunological basis of these observations remain poorly understood, and require further urgent study. This also has implications for childhood annual vaccination campaigns in some countries.

Research recommendation 3.2.3 Evaluate systematically the steps in vaccine production to reduce bottlenecks in the production of vaccines and to improve the processes of rapid response, surge capacity, rapid deployment and tracking of vaccine usage.

Summary of key accomplishments 3.2.3 The initial stages of the 2009 A(H1N1) pandemic identified the bottlenecks that affect the rapid production and deployment of pandemic influenza vaccines. Although recombinant (RG) CVVs became available quickly, most vaccine manufacturers relied on CVVs produced by classical reassortment for vaccine manufacturing, because of potential patent conflicts. Instead of committing full manufacturing capacity for the pandemic vaccine immediately, vaccine producers were obliged to complete contracted orders of seasonal vaccines before starting production of pandemic vaccines. These unexpected delays, together with already anticipated bottlenecks (e.g. the production of CVV and the respective reagents) contributed to the delay in pandemic vaccine supply globally. A library of CVVs and reagents against potential pandemic influenza strains was available (via the FLUSECURE consortium1), but lacked a suitable H1N1pdm09 CVV at that time. Cell-based culture was able to provide pandemic vaccine at an early stage in the pandemic (Barrett, Portsmouth & Ehrlich, 2013), but total cell-based vaccine manufacturing capacity was limited. Alternative production platforms (e.g. a recombinant virus-like particle [VLP] candidate vaccine produced in plants) were able to produce large quantities of pandemic vaccine candidates, but lacked regulatory approval or “mock-up2 ” dossiers. In summary, production of pandemic A(H1N1) vaccine using the standard production strategies employed by the major vaccine manufacturers was limited and late. In addition, many LMICs lacked the capacity for regulatory approval, importation and distribution of the A(H1N1) pandemic vaccines; this resulted in delays in implementing vaccination for pandemic control. 1 www.who.int/fluvrius_tracker 2 “A mock-up pandemic influenza vaccine is a vaccine that mimics the future pandemic influenza vaccine in terms of its composition and manufacturing method. However, because the virus strain causing the pandemic is not known, the mock-up vaccine contains another flu strain instead. This is a strain that is not circulating in humans, and to which humans have not been exposed in the past. This enables the company to test its vaccine in preparation for any flu pandemic that may occur in the future, by carrying out studies with the mock-up vaccine that predict how people will react to the vaccine when the strain causing a pandemic is included.” (European Medicines Agency, 2006) 10 In addition to and as a consequence of the lessons learned from the 2009 A(H1N1) pandemic, most of the bottlenecks have been identified and addressed by WHO, research institutions, government programmes and industry. For example, WHO has produced guidance on deployment of pandemic influenza (World Health Organization, 2013b), and programmes such as GAP (World Health Organization, 2006) and the PIP framework1 have been established to improve pandemic preparedness. Additional source documents have been provided by the US BARDA,2 the EU influenza virus tracker3 and industry (via the IVS ITF4).

Unmet public health needs 3.2.3 National governments competed at an early stage of the pandemic for delivery contracts from vaccine manufacturers. This created an unbalanced situation between private companies and public interests. As a result, most of the vaccine was distributed to high-income and some middle- income countries, with only marginal supplies available for LMICs, although WHO distributed 78 million doses to LMICs through the WHO pandemic influenza vaccine deployment initiative.

Knowledge gaps 3.2.3 The main bottlenecks to vaccine production are the timely availability of suitable CVVs, especially in cases of pandemic (or pandemic-like) attenuated CVVs, where there is a need for rapid biosafety risk assessment to initiate timely vaccine production.

Another bottleneck is the long development of SRD standard reagents and their calibration. Again, especially in a pandemic situation, there is an urgent need for alternative potency assays for timely vaccine release.

Research recommendation 3.2.4 Conduct studies to optimize and standardize animal models to be used in pre-clinical evaluation of new vaccines.

Summary of key accomplishments 3.2.4 The mouse model continues to be a primary tool for proof-of-concept studies to assess influenza vaccine strategies and to identify the immunological mechanism(s) contributing to protection. Given the diversity of strains available, the contributions of host factors (e.g. gender and obesity) can also be assessed.

The elucidation of the ferret genome, and the development of reagents and methods to measure both innate and adaptive responses to infection or vaccination in ferrets, represent major advances in the use of the ferret model. The model can be used for further evaluation of efficacy and immune correlates of traditional and next-generation influenza vaccines.

Non-human primates have been used to evaluate the pathogenesis of the H1N1pdm09 virus as well as multiple avian influenza virus subtypes. Also, the development of bioluminescent and fluorescent reporter viruses and improved imaging methods offer a new approach to tracking disease processes, and provide a tool for assessment of vaccine efficacy in the different animal models. Relevant references for this recommendation are the following: (Carolan et al., 2014; Cheng et

1 http://www.who.int/influenza/pip/en/ 2 http://www.phe.gov/about/BARDA/Pages/default.aspx 3 www.who.int/fluvrius_tracker 4 http://www.ifpma.org/tag/ivs/ 11 al., 2013; Davis, Taubenberger & Bray, 2015; DiPiazza et al., 2016; Enkirch & von Messling, 2015; Fukuyama et al., 2015; Graham et al., 2016; Itoh, 2016; Jonsson et al., 2012; Karlsson et al., 2016; Karlsson et al., 2015; Krammer et al., 2014; Lorenzo et al., 2011; Margine & Krammer, 2014; Marriott et al., 2014; Matsuoka et al., 2014; Memoli et al., 2015; Moore et al., 2014; Nakayama et al., 2013; Nohynek et al., 2012; Pan et al., 2013; Peng et al., 2014; Skinner et al., 2014; Song et al., 2015; Wikramaratna & Rambaut, 2015).

Unmet public health needs 3.2.4 Standardized protocols for study of animal infections would make it easier to compare across studies. Although some studies have modelled the effects of pre-existing immunity in animal models, a broader understanding of the impact of pre-existing immunity on the immunogenicity and protective efficacy of vaccines in pre-clinical studies is needed.

Knowledge gaps 3.2.4 Restricted availability of standard reagents for the ferret continues to limit the assessment of immunological and biochemical properties of infection in this model.

Research recommendation 3.2.5 Develop new vaccines, vaccine platforms and formulations that are safe and have enhanced immunogenicity; vaccine delivery systems with improved ease of storage and administration especially for use in under-resourced settings.

Summary of key accomplishments 3.2.5 Since 2009, much progress has been made in the development of new vaccines, platforms and formulations, and their delivery. Hence, this section lists the different approaches but does not give details as that would be beyond the scope of this report (the details can be found in the accompanying references). Developments include: • universal influenza vaccines development; for example: o headless HA: induction of stalk-specific antibodies (de Vries & Rimmelzwaan, 2016; Impagliazzo et al., 2015; Krammer, 2016; Krammer & Palese, 2013; Yassine et al., 2015); o M2-based vaccines (Kolpe et al., 2016); o NP/M1-based vaccines: induction of cell-mediated immunity (Altenburg, Rimmelzwaan & de Vries, 2015; Hayward et al., 2015; Sridhar, 2016; Sridhar et al., 2013; Wang et al., 2015); o NA-based vaccines (Wohlbold & Krammer, 2014); • new technologies, such as mammalian cells, plants and recombinant approaches (de Vries & Rimmelzwaan, 2016; Kreijtz et al., 2014); • LAIV, such as deltaNS (Mössler et al., 2013), DeltaM2 (FluGen) (Hatta et al., 2011) and Codon Deoptimized (Codagenix) (Mueller et al., 2010); • heterologous prime-boost strategies (Babu et al., 2014; Belshe et al., 2014; Czako & Subbarao, 2015; Ledgerwood et al., 2013); and • alternative delivery systems, such as intradermal, intranasal, dry formulations, gold nanoparticles, microneedles and nanopatches (Arakane et al., 2015; Belshe, 2007; Camilloni et al., 2015; Gill et al., 2014; Osterholm et al., 2012).

12 Unmet public health needs 3.2.5 Although much progress has been made since 2009, there are still many issues with respect to new technologies (e.g. cells, plants and recombinant approaches), improved LAIVs, alternative delivery systems, heterologous prime-boost strategies and various universal influenza vaccines.

Knowledge gaps 3.2.5 A careful assessment of the current status of new technologies (e.g. cell culture, plant and VLP technologies) is needed. In addition, novel and safe adjuvants need to be evaluated. Finally, the potential of heterologous prime-boost strategies for increased vaccine efficacy and effectiveness should be studied.

Research recommendation 3.2.6 Identify correlates of protection for different vaccines and correlates of priming, including development and standardization of methodologies.

Summary of key accomplishments 3.2.6 HI antibody levels have most often been used as a correlate of protection or surrogate marker for vaccine efficacy, especially as part of the approval criteria for some regulatory processes. However, there are other immunological parameters that contribute to protective immunity to influenza viruses. Alternative correlates of protection beyond HI include HA-specific antibodies that have virus neutralizing activity or that display other modes of action, such as antibody dependent cellular cytotoxicity (ADCC), NA-specific antibodies that inhibit the enzymatic activity of NA (i.e. NA inhibitors [NAIs]) or antibodies to the ectodomain of M2. In addition, the cellular arm of the adaptive immune system contributes to protective immunity and comprises virus-specific CD4+ and CD8+ T cells (Coughlan & Lambe, 2015; Li, Rappuoli & Xu, 2013; Reber & Katz, 2013; Wohlbold & Krammer, 2014).

Various assays have been developed for the detection of non-HI antibodies; for example, virus neutralization, enzyme-linked immunoassay (ELISA) using chimeric HA with the head domain of an irrelevant subtype, and ADCC assays (Laurie et al., 2015). The enzyme-linked lectin assay (ELLA) has become the gold standard assay for the detection antibodies against NA (Eichelberger et al., 2016). For the detection of virus-specific T cells, various methods are available, including interferon gamma (IFN-γ) ELISpot assays, tetramer staining or intracellular cytokine staining followed by flowcytometry (Coughlan & Lambe, 2015).

Unmet public health needs 3.2.6 Many assays have been available for some time, including HI, NAI/ELLA, single radial haemolysis (SRH), ELISA isotyping, ADCC and cell-mediated immunity assays such as EliSpot or multi-parametric cytokine fluorescent activated cell sorting (FACS) analysis. However, well-standardized assays for the detection of these (potentially) alternative correlates of protection are not available, and there is still a need for better standardization of the well-accepted HI assay and development of standard HI-like assays that are not based on the use of animal red blood cells. Harmonization and standardization are important issues that are currently being addressed by various international collaborations (Klimov et al., 2012).

13 Knowledge gaps 3.2.6 The minimal requirements of the various correlates of protection to afford protective immunity, to prevent infection or to reduce disease severity remain largely unknown. This situation constitutes a major gap in our understanding of immunity to influenza virus infections.

Filling the knowledge gaps about how to improve measurement of correlates of protection is a challenge (Eichelberger et al., 2016) that will require clinical efficacy and effectiveness studies. It will also require validated and standardized assays for the detection and quantification of the various correlates of protection.

Research recommendation 3.2.7 Develop innovative clinical trial methodologies to study the effectiveness and safety of novel vaccines for pre-licensure and post-licensure vaccine evaluation and vaccine effectiveness studies.

Summary of key accomplishments 3.2.7 A new generation of influenza vaccines is reaching the market. Although hens’ eggs remain the major production platform for seasonal and pandemic influenza vaccines, new production platforms (e.g. cell culture and plants) and vaccine formulations (adjuvanted or quadrivalent seasonal vaccines) are reaching the market. In addition, recombinant influenza vaccines, such as Flublok (Protein Science), are now licensed and commercially available. Many different universal influenza vaccines (i.e. those giving broad and long-lasting protection) are being developed, and some of these have already completed Phase IIB clinical studies.

Measuring and reporting of the immune response to these new and already existing influenza vaccines is held back by the lack of robust criteria for the prediction of the efficacy of these vaccines. The introduction of novel and non-HA-based vaccines, in combination with the abolition of the European Medical Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) criteria in Europe for licensing of traditional influenza vaccines, means that new guidelines will have to be developed and new and validated immune correlates generated. The generation of such data depends on diligently planned clinical studies that address all immune responses, including neutralizing antibodies, NI antibodies, cell-mediated immunity and so on. In addition, comparative evaluation of clinical study samples in independent specialized test laboratories is vital for evaluation of new correlates of protection (Liu et al., 2016; Wijnans & Voordouw, 2016).

Unmet public health needs 3.2.7 Specific influenza vaccines for specific target groups is the future in developed countries, whereas access to seasonal and pandemic influenza vaccines in general remains the major topic for LMICs. Although egg-based production capacity in LMICs has increased substantially, there is still a lack of availability of affordable influenza vaccines. The new generations of influenza vaccines that are under development might fill all these gaps. Comparative evaluation of existing and newly developed vaccines, to identify the best vaccine candidate for each application, is lacking; however, in a first attempt, different universal influenza vaccine candidates have been tested in comparative Phase II trial studies (UNISEC1).

1 http://cordis.europa.eu/project/rcn/110139_en.html

14 Knowledge gaps 3.2.7 Cellular and humoral correlates of protection for new and existing influenza vaccines need to be developed, validated and implemented by regulatory authorities. It is expected that niche vaccines (e.g. those targeted to specific groups such as the elderly with reduced immune system, or young children) will become the preferred strategies for seasonal vaccination, in combination with new methods of vaccine application.

Broadness of protection and duration of immunological responses are important issues for next- generation vaccines. Although protection of the individual is the primary focus of studies after vaccination, experimental data on the reduction of shedding after vaccination is a topic that is often overlooked. In the case of pandemics, this might be important in relation to containing the infection rate and assisting herd immunity.

Research recommendation 3.2.8 Expand studies on pharmacovigilance and reduction of disease burden for post licensure vaccine evaluation in a wider range of settings that likely vary by geography and in at-risk groups including children.

Summary of key accomplishments 3.2.8 The 2009 pandemic has resulted in the large-scale application of A(H1N1) pandemic vaccine worldwide. Europe has been following the existing WHO guidelines on adjuvanted vaccine and two doses for vaccination; however, the USA has been applying a single non-adjuvanted dose of A(H1N1)pdm09 vaccine. Both approaches appear to have resulted in sufficient protection in the target populations, but some adverse effects were observed with adjuvanted vaccines. For example, a cohort study in Finland found a correlation between narcolepsy in children and an AS03-adjuvanted pandemic vaccine (Ahmed et al., 2014; Lyytikainen et al., 2011). Also, the second vaccination in children with a MF59-adjuvanted pandemic vaccine resulted in high fever in a large subpopulation of the vaccinated children. These side-effects had not been mentioned in the available mock-up dossiers.

Relevant references for this recommendation are the following: (Ahmed et al., 2014; Ahmed et al., 2015; Canelle et al., 2016; International Federation of Pharmaceutical Manufacturers & Associations; Leung & Nicoll, 2010; Liang et al., 2011; Lyytikainen et al., 2011; Moro et al., 2016; World Health Organization, 2006; World Health Organization, 2013b).

Unmet public health needs 3.2.8 Mock-up dossiers of pandemic influenza vaccines should be complete, including extensive safety and efficacy studies. Both humoral and cellular immune responses of mock-up vaccines should be available in order to define effectiveness in target populations. Monitoring of adverse effects after vaccination has mainly been performed by national organizations, whereas international coordination and standardization of these efforts would have provided bigger data sets with less effort.

Knowledge gaps 3.2.8 There are challenges in establishing active versus passive pharmacovigilance, especially in LMICs.

15 Research recommendation 3.2.9 Examine and develop ways to harmonize the regulatory processes, especially for rapid international safety monitoring and standardized evaluation of vaccine potency.

Summary of key accomplishments 3.2.9 The EMA initiated the concept of mock-up procedures for rapid and harmonized licensure of vaccines in the EU in case of a pandemic, and has used the 2009 A(H1N1) pandemic to accelerate the licensing of the A(H1N1)pdm09 vaccines. The experience over recent years with newly emerging animal influenza virus subtypes in the human population or seasonal strain variations that result in changes to the vaccine strain recommendations has shown that such mock-up procedures should be introduced globally, for rapid and harmonized licensing of traditional and improved next-generation vaccines.

Global harmonization of vaccines should include the establishment of a global database for safety evaluation, based on the huge amount and variety of clinical data. Promising infrastructures for documentation and outcomes of clinical studies has been established in recent years; for example, WHO’s ICTRP 1 and the US NIH’s clinical trials platform. 2 In addition, the safety of vaccines is being evaluated by the US VAERS3 and WHO’s GACVS.4 However, the data provided lack the harmonization and independent evaluations that would allow a general comparison of the different vaccines in different population groups and subgroups, with respect to vaccine safety and tolerability.

Another important topic for general acceptance of seasonal and pandemic vaccines is the diligent analysis of vaccine-related and (in particular) vaccine-unrelated serious adverse events (SAEs), adverse events of special interest (AESIs) or rare events (e.g. Guillain-Barré syndrome in the 1976 US mass immunization programme against swine flu or narcolepsy in the 2009 A(H1N1) pandemic (Nohynek et al., 2012)). Of particular concern in relation to such events are the use of adjuvants (e.g. Al(OH)3, AS03 and MF59) and different formulations (e.g. subunit, split, whole virus, virosomes, VLPs and new universal flu vaccine approaches), especially for pandemic influenza vaccines. This deficiency has been acknowledged by the US CDC and Food and Drug Administration (FDA), who have stated that “It is generally not possible to find out from VAERS data if a vaccine caused the adverse event”. 5

A promising approach has been published in a study addressing the risks of increasing cases of autoimmune diseases with temporal association with vaccination, after the large-scale implementation of human papillomavirus (HPV) immunization. It is difficult to distinguish between adverse reactions caused by the HPV vaccine and events only observed by chance in temporal association during a mass vaccination programme. Therefore, the authors used a database of female adolescents (n = 214 896) and young adults (n = 221 472) before the introduction of HPV vaccination when calculating rates of emergency consultations, hospitalizations and outpatient consultations, and estimating risks of coincident associations. The authors concluded that “prior use of population-based data allows for identification of issues of potential concern, for monitoring the impact of large-scale interventions and for addressing rapidly vaccine-safety issues that may

1 http://www.who.int/ictrp/en/ 2 https://clinicaltrials.gov/ct2/search 3 http://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vaers/index.html 4 http://www.who.int/vaccine_safety/committee/en/ 5 http://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vaers/index.html 16 compromise vaccine programs” (Siegrist et al., 2007). This approach would help to avoid discussion of vaccine safety after the start of mass vaccination in a potential or real pandemic event, as happened in the pandemics of 1976 and 2009.

WHO has developed a website – “Immunization, vaccines and biologicals: tables on clinical evaluation of influenza vaccines1” – that provides information on immunogenicity as well as efficacy or effectiveness (when available) of human influenza vaccines for pandemic (or pandemic- like) and seasonal influenza vaccines. However, these data sets provide little information on safety and tolerability.

Another important topic for evaluation is the use of the single radial immunodiffusion (SRD) assay for potency testing of inactivated influenza vaccines. The SRD assay was developed in the 1970s, and measures the quantity of HA antigen present in a vaccine, using an immunological reaction between specific antibodies and the respective test antigen. In 1978, WHO recommended the SRD assay for use in batch release of influenza vaccines, and it is still the gold standard method for the potency determination of inactivated influenza vaccines, as detailed by the National Institute for Biological Standards and Control.2

There are considerable issues with the SRD, such as the time required for generation of the standard reagents (i.e. specific antiserum and antigen) and the calibration of the assay, which often causes delay in seasonal vaccine availability and is a major bottleneck in the approval of pandemic vaccines. Therefore, alternative assays are under development. Those that are most likely to replace the conventional SRD assay and will overcome the issues of time constraints and high throughput are high-performance liquid chromatography (HPLC), ELISA, surface plasmon resonance (SPR), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometry. For reviews of these methods, see the report of the EMA/European Directorate for the Quality of Medicines workshop (European Medicines Agency UK, 2012), a review by Minor (2015), a study by Siegrist et al. (2007) and various online resources: the ICTRP, 3 the NIH list of clinical trials,4 the VAERS,5 the GACVS6 and the WHO Tables on clinical evaluation of influenza vaccines.7

Unmet public health needs 3.2.9 Mock-up procedures, as initiated by the EMA for rapid and harmonized licensure of vaccines in the EU in case of a pandemic, should be introduced globally for rapid and harmonized licensing of traditional and improved vaccines. This procedure should include the establishment of a global database for safety evaluation.

Knowledge gaps 3.2.9 The huge variety of clinical data requires careful analyses and evaluations for a general comparison of the different vaccines in different population groups and subgroups, with respect to vaccine safety and tolerability. Also required is the diligent analysis of vaccine-related and vaccine-unrelated SAEs, AESI and rare events.

1 http://www.who.int/immunization/diseases/influenza/clinical_evaluation_tables/en/ 2 http://www.nibsc.org/science_and_research/virology/influenza_resource_/influenza_potency_testing.aspx 3 http://www.who.int/ictrp/en/ 4 https://clinicaltrials.gov/ct2/search 5 http://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vaers/index.html 6 http://www.who.int/vaccine_safety/committee/en/ 7 http://www.who.int/immunization/diseases/influenza/clinical_evaluation_tables/en/

17 Conclusions and decisions are needed on which alternative assay (e.g. HPLC, ELISA, SPR, SDS-PAGE or mass spectrometry) has the best potential to replace the conventional SRD assay. However, regulatory authorities may require final confirmation by clinical studies.

Key research questions 3.2 3.2.1 Investigate methods to improve the vaccine strain selection process and to characterize optimal vaccine strains including the establishment of vaccine strain libraries. • How can the CVV selection process be further improved to identify optimal CVVs? • Is there a need for generation of non-egg-based CVVs for novel vaccine approaches? • Is there a need for inclusion of human serology and VE studies for further improvement of the CVV selection process?

3.2.2 Conduct studies to enhance the clinical applications of existing vaccines including improvements in the production; duration and breadth of protection; safety and immunogenicity profiles and dose-sparing formulations, especially for high-risk groups. • Is there a need for optimization of vaccination strategies, especially with respect to immunological priming and repeated booster vaccinations? 3.2.3 Evaluate systematically the steps in vaccine production to reduce bottlenecks in the production of vaccines and to improve the processes of rapid response, surge capacity, rapid deployment and tracking of vaccine usage. • What are the major bottlenecks? • Which activities and policies can be implemented to overcome these bottlenecks or at least reduce their impact on vaccine production and delivery?

3.2.6 Identify correlates of protection for different vaccines and correlates of priming, including development and standardization of methodologies.

Recent experience with pandemic (or pandemic-like) influenza vaccines (especially of avian origin) and novel candidate vaccines has shown that there is an urgent need to define and validate correlates of protection other than HI antibodies for novel vaccine candidates. Questions that need to be answered are: • What assays should be evaluated, established or validated; for example, neutralizing antibodies, NI antibodies, other functional antibodies, CMI or systems biology? • What measurements can be used to identify novel correlates of protection?

3.2.9 Examine and develop ways to harmonize the regulatory processes, especially for rapid international safety monitoring and standardized evaluation of vaccine potency.

The question that needs to be answered is, what are the main activities required for harmonization? Are they: • mock-up procedures for rapid and harmonized licensing of traditional and improved vaccines globally; • establishment of a global database for safety evaluation; or • identification and agreement of an alternative potency assay that will be accepted by regulatory authorities and used globally?

18 Substream 3.3 Public health policies to reduce the impact of disease

Research recommendation 3.3.1 Evaluate existing and new policies and strategies to optimize vaccine uptake and improve vaccine acceptability (e.g. policies targeting risk groups versus the general population).

Summary of key accomplishments 3.3.1 Vaccine hesitancy has increasingly been recognized as a threat to immunization programmes. In relation to influenza, concerns over the safety and effectiveness of influenza vaccines have resulted in some decrease in vaccine coverage in Europe and, to a lesser extent, in the Americas. SAGE identified vaccine acceptance as a key priority in 2011, undertook a survey to understand reasons for individual and community reluctance to be vaccinated, and produced a report in 2014 that defined the problem and reviewed available data on causes.1 Especially concerning for influenza vaccination usage was the finding that vaccine hesitancy is of greater importance with vaccines delivered through campaigns and with “new” vaccines (influenza might be considered as such). The report recommended that regular monitoring be undertaken, and that tools for monitoring be developed.

Previous publications have looked at influenza vaccine acceptance in general (Advisory Committee for Ontario’s Immunization System Review, 2014; Directorate-General for Health and Food Safety, 2015; Dubé et al., 2015; Nguyen et al., 2011), or among specific groups such as health-care workers (Hollmeyer et al., 2012; Wada & Smith, 2013; Wallace, 2015; World Health Organization, 2015b), the elderly (Bradley, 2013; Li et al., 2016; Nagata et al., 2013; Zhang, 2012), pregnant women (Lohiniva et al., 2014) or those with underlying diseases (Gopal & Davis, 2005; Hofstetter, LaRussa & Rosenthal, 2015; Wigham et al., 2014).

Tools specific for understanding this issue for influenza have been developed. For example, the TIP tool was developed in 2013, and was modified for use for influenza vaccination programmes in pregnant women and health-care workers (TIP-FLU) by the WHO Regional Office for Europe (World Health Organization, 2015b; World Health Organization, 2016). These tools have been piloted and are being rolled out to new countries through the Partnership for Influenza Vaccine.2

Unmet public health needs 3.3.1 Influenza vaccination programmes have been in place for decades in many countries. Even so, in many countries, vaccine coverage in key target groups has been relatively low, highlighting the challenges in realizing the promise of influenza prevention. Two relevant examples are the cases of pregnant women and health-care workers. Substantial increases in vaccine coverage in pregnant women in the USA were observed during and after the 2009 pandemic, driven by the evidence of severe disease and deaths among pregnant women during that time. Doctors caring for pregnant women became advocates for vaccination, and began offering vaccination in their clinics. However, in most parts of the world, fears of adverse events associated with vaccination of pregnant women remain an impediment to vaccination of this group.

1 http://www.who.int/immunization/sage/meetings/2014/october/1_Report_WORKING_GROUP_vaccine_hesitancy_final.pdf 1 https://pivipartners.org/

19 Health-care workers have also often been historically sceptical of vaccination. They tend to be less concerned about adverse events, but voice uncertainty about the risk of disease and doubts about the effectiveness of vaccine. Successful increases in vaccine coverage have been demonstrated in settings where influenza vaccination mandates for employment have been installed, with rates increasing to over 90%.

These examples illustrate that each group will have unique reasons for getting vaccinated or not, and that solutions that target these reasons may be successful in raising coverage and increasing acceptance. Hence, data are needed in target populations in any country interested in vaccination, to best address the information needs relevant to the population. Reports on successful immunization programmes of health-care workers (other than making it mandatory for employment) would provide needed evidence for those taking the voluntary approach.

Knowledge gaps 3.3.1 Information to understand vaccine attitudes and reasons for reluctance to undergo vaccination has been collected in several countries. In addition, WHO has created tools for countries to collect these data and to develop programmes to increase vaccine uptake. These tools have been piloted in some countries and are available for any country interested in using them. Technical support for the use of these tools needs to be provided to willing countries, and experience collected and analysed to refine the approach for future vaccination programmes. As the SAGE report (SAGE Working Group, 2012) illustrated, reasons for low uptake will be complex and need to be understood at the local level if interventions are to be designed successfully. Key gaps will be to pair efforts to monitor vaccine acceptance with vaccine programmes, especially in countries introducing influenza vaccines to new risk groups.

Research recommendation 3.3.2 Develop effective immunization policies using community-based input.

Summary of key accomplishments 3.3.2 Since 2009, there has been increasing recognition of the importance of community opinion in influenza vaccine policy development and implementation. There has been advocacy for public input into influenza vaccination policy, particularly for policies addressing pandemic preparedness (World Health Organization, 2007) and specific risk groups such as paediatric, the elderly and health-care workers. With the introduction of universal influenza vaccine policy in the USA, proven measures to improve vaccine compliance can be undertaken by health-care professionals (including retail and health system pharmacists), government programmes and community organizations.

Engaging the public in pandemic planning can provide vital information about local values and beliefs that may ultimately lead to increased acceptability, feasibility and implementation of pandemic preparedness plans. An example is the successful integration of community input into pandemic vaccine planning in a Canadian study (Charania & Tsuji, 2012) that aimed to elicit and address First Nations community members’ suggested modifications to their community level pandemic plans after the 2009 A(H1N1) influenza pandemic.

20 Surveys on KAP, to inform influenza vaccination police and implementation, have been conducted in many countries and in various vaccination targeted groups for both seasonal and pandemic vaccines.

Relevant references for this recommendation are the following: (Atkins et al., 2016; Bali et al., 2013; Centers for Disease Control and Prevention, 2015; Charania & Tsuji, 2012; Lin et al., 2011; Nagata et al., 2013; Ompad, Galea & Vlahov, 2006; Person et al., 2013; Pickering et al., 2009; Prematunge et al., 2012; Shen, Fields & McQuestion, 2014; Smith, Snider & Pickering, 2009; Trostle & Shen, 2014; UPMC McKeesport, 2016; Ventola, 2016a; Ventola, 2016b; World Health Organization, 2007).

Unmet public health needs 3.3.2 Much of the discussion on community input has taken place in high-income countries; thus, there is still a lack of information on community input and influenza vaccine policy development and implementation in LMICs.

Knowledge gaps 3.3.2 No relevant gaps were identified for this recommendation.

Research recommendation 3.3.3 Study the role of social science research such as its involvement in establishing social, ethical and legal standards in public health policy application; the public perception of influenza and its impact on societies particularly in under-resourced populations.

Summary of key accomplishments 3.3.3 One major area of progress since 2009 has been the role of social science research in prospectively planning and retrospectively assessing pandemic influenza policies (Danforth et al., 2010; Lurie et al., 2008). For example, in the Australian Aboriginal population, social science research led to a variety of recommendations for risk reduction, mainly centred around communication, health-care access and cultural integration (Massey et al., 2011; Massey et al., 2009). These findings were similar to those from Mexico (Del Rio & Hernandez-Avila, 2009). Additional research has focused on the importance of ethics in pandemic planning (Chakraborti, 2010; Derpmann, 2011).

The other major arm of progress has been social science research into influenza vaccine acceptance. Reviews have identified numerous factors for vaccine acceptance associated with populations (Bish et al., 2011) or health-care workers (Prematunge et al., 2012). Some studies have sought to disentangle social factors associated with pandemic and seasonal influenza vaccination (Bonaccorsi et al., 2013; Prematunge et al., 2014). Studies also have occurred in developing country settings and have focused on new methods (Sundaram et al., 2017).

Unmet public health needs 3.3.3 The primary unmet public health need is to move beyond descriptive studies, and instead to use social science research to define interventions for prospective acceptance of immunization and design of pandemic preparedness plans. In resource-poor settings, there is an additional need to define issues (e.g. social, ethical and legal issues) related to decisions about whether to implement national influenza immunization programmes.

21 Knowledge gaps 3.3.3 The following knowledge gaps have been identified: • use of research on social determinants to design interventional studies and impact assessments; • social science research into reasons for implementation or non-implementation of national influenza immunization programmes; and • development of social science research methods and tools.

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