SEASONAL INFLUENZA VACCINES: An overview for decision-makers

SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS A B SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS SEASONAL INFLUENZA VACCINES: An overview for decision-makers Seasonal influenza vaccines: an overview for decision-makers

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All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. CONTENTS 1. Executive Summary iv 5. Seasonal influenza vaccine coverage 11 5.1. Estimates of global coverage 11 2. Introduction 1 5.2. Estimates of regional coverage 13 2.1 Seasonal influenza 1 2.2 Why is having a seasonal influenza 6. Other prevention and control measures 14 vaccination programme important? 1 6.1. Antivirals 14 3. Burden of disease 2 6.2. Public Health Measures (PHMs) 15

3.1 Monitoring influenza 2 7. Seasonal influenza vaccines for 3.2 The burden of seasonal influenza 3 preparedness 16 3.3 Vaccine cost effectiveness 4 8. Introducing seasonal influenza vaccines 18 4. About seasonal influenza vaccines 5 8.1. Is seasonal influenza vaccination a 4.1. Vaccine types 5 public health priority? 18 4.2. Vaccine composition 6 8.2. How to Develop a Seasonal Influenza Vaccination Programme 18 4.3. Vaccine production 7 4.4. Vaccine storage 7 References 19 4.5. Vaccine costs 7 Annex 1. Example costs for different 4.6. Vaccine effectiveness, safety and uptake 8 influenza vaccines 24

LIST OF FIGURES, TABLES AND BOXES Figure 1. The benefits of having a seasonal influenza vaccination programme. 1 Table 1. WHO case definitions for ILI and SARI. 2 Box 1. Vulnerable populations 3 Figure 2. Global estimates for the burden of seasonal influenza. 3 Box 2. Value of Seasonal Influenza Vaccination 4 Box 3. Trivalent and quadrivalent vaccines 5 Box 4. What makes influenza vaccines unique? 6 Figure 3. Range of cost per dose (in US$) for seasonal influenza vaccines. 8 Box 5. Adverse events 8 Box 6. Coverage challenges 11 Figure 4. Proportion of countries with national influenza immunization policies, as reported through the 2018 JRF.* 12 Table 2. Influenza antiviral treatments. 14 Figure 5. Recommended PHMs for use during influenza outbreaks. 15 Table. Examples of seasonal influenza vaccine costs. 24

iii 1. EXECUTIVE SUMMARY Influenza causes 3-5 million cases of severe illness and up to 650,000 respiratory deaths a year globally. Lower respiratory infections are the leading cause of death in low income countries annually.1 Influenza vaccine are the leading public health tool for prevention and control of influenza.

This document presents a summary of the evidence and know-how on seasonal influenza vaccines; where relevant, it includes links to the latest WHO guidance. It has been written to support Ministries of Health and other key stakeholders in their decision-making around designing and implementing seasonal influenza interventions.

Key points include:

Seasonal influenza vaccines are safe, effective, and cost-effective.

WHO recommends annual seasonal influenza vaccination for five target groups (health workers, pregnant women, children, elderly, and people living with chronic conditions) to protect these vulnerable populations.

Vaccination against seasonal influenza has been shown to reduce the substantial national, regional, and global health and economic burden of influenza.

Seasonal influenza programmes contribute to pandemic preparedness by annually using global and national systems that would be needed during a response. These include: sustaining manufacturing facilities, developing delivery capacities, increasing acceptance of vaccine, training health workers, strengthening decision making, and exercising systems annually.

Throughout this document, additional information can be found on seasonal influenza vaccine types, costs, and target groups. This Seasonal influenza vaccines: An overview for decision-makers also includes resources, guidance, and key questions for Ministries to review as they consider how to introduce a seasonal influenza vaccination programme.

iv 2. INTRODUCTION

2.1 Seasonal influenza Seasonal influenza can be deadly. To protect against • influenza, WHO recommends annual vaccination of the five Seasonal influenza is an acute respiratory infection that is target groups (health workers, pregnant women, children, caused by two types of influenza virus (types A and B), which elderly, and people living with chronic conditions). circulate in all parts of the world. In recognition of the significant health threat posed by this disease, public health authorities in The burden of seasonal influenza is likely to be higher than high- and low-income countries alike are increasingly prioritizing • you think because current estimates tend not to include influenza prevention and control. influenza-related deaths from other diseases such as cardiovascular diseases. WHO advises that the best way for people to avoid getting seasonal influenza is to get vaccinated once a year. Vaccination reduces the need for antiviral treatments, which • can lose effectiveness when over-prescribed (because of Influenza vaccines: drug resistance). are safe and generally well tolerated; • Having a seasonal influenza vaccination programme could are key to reducing the health and economic burden of • help strengthen health systems by adding capacities (such • influenza; as cold chain storage and health worker skills).

can prevent illness and death, and reduce disease It could also save money: several studies show that • transmission and severity; • vaccinating against seasonal influenza reduces costs for the health system. do not cause influenza disease and very rarely have serious • side effects. Having a seasonal influenza vaccination programme also • helps prepare health systems for public health emergencies by building the systems for timely delivery of vaccines. 2.2 Why is having a seasonal influenza vaccination Seasonal influenza vaccination campaigns can build on, and • build up, other ongoing immunization programmes such as programme important? adult, health worker, and other non-traditional target group vaccination programmes.

Figure 1. The benefits of having a seasonal influenza vaccination programme.

SEASONAL INFLUENZA VACCINAION OAE

deaths cold chain facilities systems for delivery

hospitalizations trained staff regulatory pathways

disease transmission cost savings operational capacity

missed work days integration vaccine awareness

Reduced burden Strong health Better prepared of disease system for pandemic

1 3. BURDEN OF DISEASE

3.1 Monitoring influenza In this context, WHO has developed two standard case definitions for use in national influenza surveillance Seasonal influenza is characterized by the sudden onset of programmes: one for influenza-like-illness (ILI) and one for fever and cough. Other symptoms can include headache, muscle severe acute respiratory infection (SARI) (see Table 1).3 All 2 and joint pain, sore throat and a runny nose. In many cases, countries are encouraged to use these case definitions; and to it is not clinically easy to distinguish seasonal influenza from support their use with laboratory testing of samples obtained other respiratory infections; and a definitive diagnosis requires a from all, or a systematic proportion of, case patients. diagnostic test.

Table 1. WHO case definitions for ILI and SARI.

ILI case definition SARI case definition

An acute respiratory infection with: An acute respiratory infection with: • measured fever of ≥ 38°C; • history of fever or measured fever of ≥ 38°C; • and cough; • and cough; • with onset within the last ten days. • with onset within the last ten days; • and requires hospitalization.

Table source: WHO surveillance case definitions for ILI and SARI. Geneva: World Health Organization; 2014 (https://www.who.int/influenza/surveillance_monitoring/ili_sari_surveillance_case_definition, accessed 26 February 2020).

At a global level, influenza surveillance is conducted by the WHO- coordinated Global Influenza Surveillance and Response System (GISRS), through country collaboration and sharing of viruses, data and benefits. GISRS data provide the basis for:

identifying and tracking the constant changes in influenza • epidemiology and disease; • alerting countries to novel influenza viruses; recommending the composition of seasonal influenza • vaccines twice a year; Data from influenza surveillance programmes are essential to • supplying virus samples and potency reagents for vaccine inform local, national and global burden of disease estimates. At production; and all levels, they are useful for driving action and decision making. researching and developing new diagnostic tools, vaccines • 4 At a local level, surveillance data can help alert healthcare and other treatments. providers of emerging outbreaks and inform and improve clinical management in high-risk patients.

At a national level, surveillance data can help allocate resources WHO GUIDANCE for response; and be used to develop and revise influenza WHO has developed Global epidemiological surveillance prevention and treatment policies. These policies include standards for influenza and encourages all countries to deciding whether and when to use pharmaceutical and/or conduct their own national epidemiological surveillance in non-pharmaceutical interventions to control spread as well as line with these international standards; and to report their choosing when and who to vaccinate. data to global surveillance systems.5

2 3.2 The burden of seasonal influenza Developing reliable national and global estimates of the burden of disease (BoD) for seasonal influenza can inform activities to mitigate influenza’s public health and economic consequences. Governments, health systems, donors, partners and pharmaceutical manufacturers can all use BoD estimates to inform their decision-making.6

In 2018, WHO estimated that up to 650,000 people may die from respiratory-related effects of seasonal influenza each year (see 7 Figure 2). Box 1. Vulnerable populations These global figures reflect illness and death in the general Some populations are at higher risk of severe health population. But some groups are known to be more vulnerable outcomes from influenza than others. to severe health outcomes than others (see Box 1. Vulnerable populations). Reporting BoD for high-risk groups can drive Since 2012, the WHO has identified five groups that appropriate targeted interventions and provide cost-effective are particularly vulnerable to seasonal influenza, either options to reduce the influenza disease burden. because they have a greater risk of exposure or because they have a greater risk of developing severe disease:9 • pregnant women; • health workers; • people with chronic health conditions (such as diabetes, HIV, asthma, heart or lung disease); • people over the age of 65 years; and • children from 6 months to 5 years.

In all cases, global estimates of influenza BoD currently The WHO recommends annual vaccination for these groups. only include respiratory deaths (not influenza derived There is some additional evidence to suggest that: cardiovascular or diabetes deaths) and as such are likely to be an underestimate. Recent advances in estimation methods children with neurological conditions are at higher risk of and national efforts to calculate BoD have yielded significant • severe outcomes, especially in LMICs; insights into the burden of seasonal influenza in several LMICs.8 But disease burden information is still sparse in regions such • adults are more likely than children to suffer severe outcomes as Africa, Asia and South America. There is also a relative lack if they have certain comorbidities, including diabetes, obesity of data from the tropics. Many LMICs do not have any seasonal and liver disease; and influenza surveillance system in place, making burden estimation asthma is a risk factor for hospitalization but not for severe difficult. And in other LMICs, healthcare access and use are low, • influenza outcomes.10 so surveillance systems can miss large numbers of cases.

Figure 2. Global estimates for the burden of seasonal influenza.

3-5 290,000- ILLION 650,000 cases of severe respiratory deaths illness

Figure source: Influenza (Seasonal) In: WHO/Newsroom [website]. Geneva: World Health Organization; 2018 (https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal), accessed 26 February 2020).

BURDEN OF DISEASE 3 Box 2. Value of Seasonal Influenza WHO GUIDANCE Vaccination WHO has several resources designed to support Influenza vaccination was cost saving in two-thirds countries to calculate the burden of seasonal influenza • (12/18) of studies for children, one-third (8/27) of in their countries and to continue strengthening the studies for elderly and one-third (2/6) of studies for evidence base for seasonal influenza vaccination and pregnant women.11 other interventions. • A 2017 study found vaccinating children was cost- The WHO Manual for estimating disease burden saving for the health system.12 associated with influenza provides guidance and Influenza vaccination in South Africa found that standardized approaches for estimating influenza BoD. • vaccinating people with active tuberculosis, adults It is particularly aimed at supporting BoD estimates in living with HIV and pregnant women was the most LMICs using ILI and SARI data. cost effective.13 WHO’s Global epidemiological surveillance standards • about US$500 per DALY saved.14 for influenza is also useful for estimating BoD, in that it recommends how to stratify BoD analysis by age. Importantly, the standards suggest including an age General consensus grouping of under-two-year-olds if feasible. The WHO Given the available evidence, influenza vaccinations for children guidance suggests that BoD estimates should ideally and other vulnerable populations are likely to be cost effective. be based on data covering three to five years; but even Vaccinating children is often cost saving in HICs, and may be a single year’s worth of data can serve as a valuable cost saving in LMICs, especially if it is integrated into existing starting point. immunization programmes. Such integration requires evidence- based decision making on the appropriate vaccine type and timing, and can be facilitated by SAGE recommendations.

It is important that influenza vaccination does not divert money, time, attention or other resources away from routine immunization or vaccination programmes for diseases like measles, yellow fever, meningitis A, Haemophilus influenzae b (Hib), hepatitis B, Streptococcus pneumoniae, Japanese encephalitis, or human papillomavirus, which have all been demonstrated to be both cost-effective and life-saving.

More research and analysis are needed to inform cost effectiveness analyses of influenza vaccine campaigns in LMICs. Still, it is likely that LMICs with a sufficiently robust and well- funded childhood vaccination programme will find a targeted 3.3 Vaccine cost effectiveness influenza vaccination programme to be a good use of resources. Given BoD estimates, vaccine costs and vaccine effectiveness, Across all income settings, cost effectiveness studies of it is possible to analyse the cost effectiveness of implementing seasonal influenza vaccination programmes have not considered a seasonal influenza vaccination programme. Such analyses the benefits of preparing countries for pandemic response. also enable decision-makers to compare the value of influenza vaccination with other public health interventions, and to consider how and why an influenza vaccination campaign should WHO GUIDANCE fit into a national budget (see Box 2. Value of Seasonal Influenza Vaccination). The WHO Guidance on the economic evaluation of influenza vaccination is a helpful resource for countries Influenza vaccination cost effectiveness has been demonstrated conducting cost effectiveness analyses.15 in LMICs and HICs.

4 SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS 4. ABOUT SEASONAL INFLUENZA VACCINES

Trivalent influenza vaccines (TIVs) protect against two influenza A viruses and one influenza B virus. WHO notes that there are three main types of TIV: whole virus vaccines, split virus vaccines, and subunit vaccines.

Quadrivalent influenza vaccines (QIVs) target two influenza A viruses and both influenza B viruses. Originally licensed in the United States of America (USA) in 2012, QIVs have since been increasingly incorporated into other countries’ national immunization programmes. They provide wider protection against influenza B disease.

4.1. Vaccine types There is considerable debate about the pros and cons of using trivalent versus quadrivalent vaccines to combat influenza. Seasonal influenza vaccines are available and have been used for more than 60 years, although they remain largely underused Some scholars favour the use of QIVs because it can be in many LMICs.16 They target the three or four influenza virus difficult to predict which influenza B strain will circulate during a 18 strains that are likely to be the most circulating for the season season. QIVs reduce the risk of a mismatch in the vaccine and (see Box 3. Trivalent and quadrivalent vaccines). seasonal strains which can increase the vaccine effectiveness and boost public confidence in influenza vaccination.19 WHO WHO convenes the Vaccine Composition Meeting (VCM) twice notes that TIVs appear to be less efficacious among people a year to review the latest influenza surveillance data, predict living in tropical regions. which strains of the virus are most likely to be circulating during the next influenza season, and recommend the composition of However, TIVs tend to be cheaper. Countries can procure both trivalent and quadrivalent vaccines (see Section 3.2 Vaccine more TIV doses with smaller budgets, protecting more people composition). from seasonal influenza. The cost effectiveness of TIVs or QIVs depends on the influenza B burden as well as on patient comorbidities and contraindications.20 Box 3. Trivalent and quadrivalent vaccines WHO does not provide a preferential recommendation. Countries • Trivalent influenza vaccines (TIVs) protect against can review the respective costs, benefits, and context-specific two influenza A viruses and one influenza B virus. evidence to inform their decisions about which type of vaccine WHO notes that there are three main types of TIV: to choose. whole virus vaccines, split virus vaccines, and subunit vaccines. Inactivated versus live attenuated • Quadrivalent influenza vaccines (QIVs) target two influenza vaccines influenza A viruses and both influenza B viruses. Both TIVs and QIVs can be made using a weakened form of the Originally licensed in the United States of America virus (live attenuated vaccines) or using a protein or other small (USA) in 2012, QIVs have since been increasingly piece of the dead virus (inactivated vaccines). incorporated into other countries’ national immunization programmes. They provide wider Inactivated vaccines are recommended for pregnant women, protection against influenza B disease.17 • the elderly, health workers, and immuno compromised people.21 Older adults may require the use of more antigen, multiple doses, or adjuvants to achieve the efficacy comparable to younger adults.

5 Live attenuated influenza vaccines (LAIVs) can be delivered • through a nasal spray and can induce a more protective and Box 4. What makes influenza vaccines longer-lasting immune response in naive populations (i.e. unique? children) because they are more similar to the real virus.22 Studies have shown that LAIVs are particularly effective in Two things in particular differentiate seasonal influenza children above two years of age.23 However, for seasonal vaccines from most other vaccines: influenza vaccines, LAIV have lower efficacy in adolescents 1 Annual re-vaccination. Unlike most other vaccines, and adults. Because they contain a small amount of live seasonal influenza vaccines must be re-formulated virus, they are not recommended for people with weakened and re-administered every year to account for the immune systems or long-term health problems. constant changes in circulating strains and rapid evolution of the virus. Vaccine formulations can also Most influenza vaccines (both TIVs and QIVs) that are licensed differ between northern and southern hemispheres, for use are inactivated vaccines; although some LAIVs are which may have different circulating strains. available. The efficacy and effectiveness of both LAIV and inactivated vaccines vary considerably with season and age 2 Variable effectiveness. Because influenza viruses group. For example, LAIV is recommended for children in change so quickly, the effectiveness of seasonal Germany and the United Kingdom.24,25 vaccines depends, in part, on the match between the circulating viral strains and the strains included in the Universal vaccines: Research is underway to develop vaccines vaccine. If the match is poor, then the vaccine is less that do not need to be changed every year to match the effective. Individual immune response to influenza circulating strains. Numerous clinical trials are ongoing but no vaccination also influences effectiveness of the vaccine has yet been approved that achieves this goal. vaccine and differs by target group. Past exposure to influenza may also influence individuals’ immune response to the vaccine and so impact vaccine 4.2. Vaccine composition effectiveness. Circulating influenza virus strains change and evolve rapidly so seasonal influenza vaccines must be regularly reformulated Because there can be different influenza strains circulating in to ensure they cover the strains with the highest probability of northern and southern hemispheres, and because peak influenza circulation (see Box 4. What makes influenza vaccines unique?). seasons occur at different times of the year, the VCM is Twice a year, the VCM reviews the latest surveillance data so convened twice a year: in February and September.27 The timing that WHO can be confident in its recommendation for which of the meeting is designed to provide at least 6–8 months for virus strains to include in the seasonal influenza northern and the vaccine to be produced and distributed before the next peak southern hemisphere vaccines.26 influenza season.

These data are generated by the GISRS network of WHO Tropical and subtropical regions may experience multiple peaks Collaborating Centres, National Influenza Centres, WHO of influenza, or year-round activity. This means that regional and Essential Regulatory Laboratories and WHO H5 Reference national surveillance data should be reviewed to identify which Laboratories. They include information on: seasonal influenza vaccine to use and when to vaccinate.28 • the antigenic and genetic characteristics of circulating viruses; and WHO GUIDANCE vaccine effectiveness and antiviral resistant strains. • To support public health authorities in these regions in At the VCM, experts use the data to forecast the strains likely to deciding whether to use northern or southern hemisphere circulate and make recommendations on how to optimize the seasonal influenza vaccine, WHO has developed a next vaccine. The recommendations inform the development of series of maps and tables that identify, for each country, candidate vaccine viruses, for use in manufacturing the vaccine. whether the primary influenza activity starts in April or October.29 This information can be used by countries to decide which type of vaccine to use and when to vaccinate against seasonal influenza.

In addition, WHO recommends countries in the tropics and subtropics use local surveillance data to establish seasonality patterns and influenza transmission levels.

6 SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS 4.3. Vaccine production 4.4. Vaccine storage In 2015, the global production capacity for seasonal influenza Influenza vaccines are typically not heat stable and require cold vaccines was estimated to be 1.5 billion doses with the ability chain storage from the time they are manufactured until the to expand, in a best-case scenario, to 6.4 billion doses in the time they are administered.38 Specific storage requirements for event of an influenza pandemic.30 Seasonal influenza vaccination different seasonal influenza vaccines are included in the vaccine programmes maintain seasonal influenza and pandemic vaccine package inserts. production capacity. Without sufficient seasonal influenza vaccination, vaccine production capacity would be drastically reduced, impacting accessibility of the pandemic vaccine (see WHO GUIDANCE Section 6). WHO’s training module on vaccine cold chain provides The full timeline for moving a vaccine from bench to bedside— guidance for workers in health facilities on how to use including strain selection, production, testing, formulation, cold chain and temperature monitoring equipment to packaging, shipping and vaccination—can take as long as a safely transport and store vaccines that require cold 31 full calendar year. Most seasonal influenza vaccines licensed chain.39 for use are produced using egg-based methods, which rely on supplies of eggs and candidate vaccine viruses (CVVs). Egg- WHO’s Guidelines for establishing or improving primary based vaccines can take as long as 5 to 8 months to produce, and intermediate vaccine stores, which apply to all may be prone to changes in antigenicity, and can pose health vaccines, provide guidance on vaccine storage locations risks to people with egg allergies.32,33 and refrigeration equipment, site and building selection, space planning and equipment procurement for cold Other ways of producing influenza vaccines that do not rely chain.40 on using eggs tend to be faster but have limited production capacity. Increasing availability of other production technologies could enable quicker scale-up and expansion of manufacturing 4.5. Vaccine costs during a pandemic. The cost of influenza vaccines varies considerably depending on Cell-culture is one example of a new technology that could be a broad range of factors, which include but are not limited to: used for influenza manufacturing. The advantage of cell-culture vaccines could be to reduce dependence on egg supply (a how the vaccine is being procured (self-procurement key concern in particular for influenza strains that impact • vs. UNICEF or group purchasing); poultry) and to potentially avoid egg-derived changes in the virus strain. But, cell-based technologies still rely on CVVs and • who is buying the vaccine (government agency vs. are particularly vulnerable to contamination. In most cases private sector entity); switching to cell-based or other vaccine production technologies what type of vaccine is being sought (trivalent vs. 34,35 would require an overhaul of existing manufacturing facilities. • quadrivalent);

Another type of vaccine production uses recombinant how the vaccine is presented (pre-filled syringe vs. 36 technology. Recombinant vaccines could potentially • injector vs. vials or ampoules); and be produced more quickly than vaccines from traditional technologies. These vaccines do not need CVVs. They are how many doses are being purchased. produced synthetically by taking a small piece of DNA made • from the virus sequence and inserting it into other cells to It is cheaper to procure vaccines through UNICEF than to self- produce large quantities of active ingredient for the vaccine. procure them. For example, in 2017, the same adult influenza vaccine that was sold to an LMIC in Europe for US$1.51 per dose Other next-generation vaccines—based on the use of virus-like through UNICEF was sold to an upper middle-income country particles or viral vectors – remain in relatively early stages of in Africa for US$11.44 per dose through self-procurement. That development but show considerable promise for further reducing same vaccine was also self-procured by a high-income country production times.37 (HIC) in the Eastern Mediterranean for US$2.90 per dose and by another HIC in the Western Pacific for US$5.82 per dose.41

ABOUT SEASONAL INFLUENZA VACCINES 7 Trivalent vaccines also tend to be cheaper than quadrivalent 4.6. Vaccine effectiveness, ones. For example, the 2019 weighted average price per dose safety and uptake for the southern hemisphere trivalent vaccine was US$3.29, compared with US$5.40 for the quadrivalent one.42 From Seasonal influenza vaccines are considered globally to be safe available data, replacing TIV with QIV could result in a more than and well tolerated, with few serious side effects or complications 25% budget increase for seasonal influenza vaccination in low- (see Box 5. Adverse events).44 and middle-income countries.43

The more doses a country procures, the cheaper the vaccine Box 5. Adverse events tends to be. For example, countries tend to receive better Common side effects from seasonal influenza vaccination prices when they procure through multi-year contracts or as include soreness, tenderness, redness and swelling; as part of a group (i.e. the Gulf Cooperation Council). But this well as systemic effects such as general malaise, fever, requires demand forecasting and coordination, which can be headache, nausea, and muscle aches. These side effects difficult because demand for seasonal influenza vaccine can are generally mild and go away on their own within a few vary by year. days. Overall, the cost of seasonal influenza vaccines in recent years Serious complications from seasonal influenza has ranged from US$1.08–24.05, with a median cost of $4.56 vaccination are rare. In particular, concerns about Guillain- (see Figure 3; and Annex 1 for more information). Barr Syndrome (GBS) are not supported by the latest research. Evidence indicates that a person is more likely to get GBS from influenza than from the vaccine.45 Figure 3. Range of cost per dose (in US$) for seasonal influenza vaccines. The effectiveness of seasonal influenza vaccines, however, 30 varies depending on the age and immune status of the person receiving it (as well as the match between vaccine composition and circulating strains).

Vaccine uptake is similarly variable, shaped by a mix of: 25 $24.05 Maximum cost structural social determinants, such as age, gender, marital • status, education, ethnicity, socio-economic status and cultural values; 20 intermediary determinants, including place of residence, • behavioral beliefs, social influences, previous vaccine experiences, perceived susceptibility and health status and $15.77 Fourth quartile 15 sources of information; 46 and

factors related to the healthcare system, including • accessibility, affordability and health workers’ knowledge, 10 attitudes and advice.47

$8.08 Third quartile Importantly, effectiveness and uptake can vary across target groups. The rest of this section looks at the effectiveness, safety 5 and uptake of seasonal influenza vaccines in each of the WHO- $4.56 Median cost recommended priority groups. $2.90 First quartile Historically, many estimates of influenza vaccine efficacy came $1.08 Minimum cost from randomized controlled trials (RCTs) held in wealthier 0 countries with temperate climates, leaving LMICs to rely on their own local epidemiological data—or data from neighbouring or epidemiologically similar countries–to develop their vaccine policy. But efforts to include LMICs in influenza vaccine RCTs are rising and are anticipated to diversify and strengthen the evidence base for vaccine policy-making in these countries (and elsewhere).

8 SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS Health workers represent an attractive option for building influenza vaccination capacity in LMICs as they are typically the smallest of the five SAGE-recommended target groups. Health worker infections in Ebola, MERS, SARS and COVID-19 outbreaks provide reminders of the importance of protecting health workers, our first line of defense for responding to disease outbreaks. Annual health worker vaccination programmes for seasonal influenza build capacity for efficient and timely delivery of epidemic/pandemic vaccines.

Finally, health workers serve as educators and trusted advisors for the population. Vaccinated health workers who receive a Pregnant women vaccine are more likely to recommend vaccination to other high- 60,61 In 2012, the WHO Strategic Advisory Group of Experts on risk groups. Immunization (SAGE) identified pregnant women as the highest Uptake of influenza vaccines by health workers is low.62 priority group for vaccination against seasonal influenza. Mandatory influenza vaccination programmes exist in some Influenza infection during pregnancy can also cause negative healthcare settings and have shown to be effective at increasing outcomes in fetal development. vaccine uptake. But there are legal and ethical issues to be Pregnant women should receive inactivated vaccines.48 Both considered; and the decision to use mandatory vaccination is TIVs and QIVs are considered safe and effective; and neither are highly context dependent. associated with adverse effects in mothers or infants. In addition Children to protecting mothers against severe disease, vaccination during pregnancy also protects fetuses via transplacental transfer of All over the world, children under five years of age have a antibodies.49,50,51 high burden of influenza and a high risk of hospitalization. Vaccinating children against influenza is important to: There is no evidence of negative pregnancy outcomes with 63 inactivated influenza vaccines.52 • prevent severe illness and deaths; and Studies show that vaccine acceptance and uptake in pregnant • reduce transmission of influenza (because children shed women is driven by recommendations from healthcare more virus, for longer periods of time, compared with adults). 53,54 providers. The biggest barriers to uptake by pregnant women Building seasonal influenza vaccination into existing schedules include lack of knowledge about the vaccine and its safety for expanded programmes on immunization (EPI) can increase profile. coverage among children and reduce the disease burden in this Health workers high-risk population. WHO recommends health workers receive seasonal influenza Infants younger than six months of age should not receive vaccinations and are prioritized for pandemic vaccination to influenza vaccines. But vaccinating mothers during or shortly protect health workers, maintain healthcare services during after pregnancy can protect these infants by transferring influenza epidemics, and reduce the spread of influenza to antibodies through breast milk.64 Vaccination of close contacts vulnerable patient groups (nosocomial infection).55,56 can also help protect infants by preventing transmission.

There is evidence that health workers are at risk of contracting influenza and that many health workers continue to work while infected.57 Influenza vaccines are shown to be as effective in HWs as in other adults of similar age. Data on whether vaccinating HWs protects patients is of mixed quality and does not universally indicate a protective outcome.58 However, there are strong signals from studies in long term care facilities that HW vaccination protects patients, especially with regard to mortality.59

ABOUT SEASONAL INFLUENZA VACCINES 9 WHO recommends that children aged two years to five years People living with chronic conditions receive influenza vaccines, which can be either live attenuated or inactivated. Evidence suggests that LAIVs may be more effective for this group.65 Children being vaccinated against influenza for the first time should receive two doses of vaccine.

Influenza vaccines can cause localized side effects in children that are usually mild. Safety concerns about influenza vaccines in children are extremely rare. In 2010, an inactivated TIV (Fluvax) was associated with increased risk of febrile seizures in under-five-year-olds.66 But further investigation found this to be an isolated occurrence and confirmed that no other TIVs carry a greater risk of febrile seizure.67

Influenza vaccine effectiveness in children varies by season and, as in adults, is influenced by the match between vaccine and People with chronic health conditions, such as asthma, chronic circulating strains of the virus. Evidence suggests that the overall heart or lung disease, HIV or diabetes, have a higher risk of vaccine efficacy in preventing laboratory-confirmed influenza infection, severe illness, hospitalization and death if they get in healthy children ranges from 67–74%.68,69 Wider variation in influenza. This risk varies with demographic characteristics vaccine efficacy (from 20–77%) has been reported in LMICs.70 and severity of the underlying condition but holds true for both children and adults.75 The elderly (65 years of age and older) Immunocompromised people (including, for example, chemotherapy and transplant patients) also have a higher risk of influenza infection.76

Chronic lung diseases are the conditions most often associated with a severe health outcome. A meta-analysis of 2009 A (H1N1) pandemic influenza cases found that individuals with chronic conditions (most often chronic lung disease) accounted for 31% of hospitalized cases, 52% of ICU admissions, and 62% of fatal cases.77 Among children in the USA, those with asthma are hospitalized two to four times more often than those without medical conditions.78

Overall, there is limited evidence available on the effectiveness The elderly have a greater risk of hospitalization and death if of influenza vaccination among patients with underlying health they contract influenza. Data suggest that influenza-related conditions.79 Nevertheless, influenza vaccination has been deaths in over-65-year-olds may be higher in LMICs than in HICs. associated with health benefits in patients with cardiovascular One study estimates these deaths at 545 per 100,000 in South or lung disease, including fewer outpatient visits, fewer Africa compared with 133 per 100,000 in the United States.71 hospitalizations, and fewer deaths; so, influenza vaccines are recommended for these patients.80,81 WHO recommends that anyone over the age of 65 receive inactivated TIVs. Similarly, influenza vaccination has been found to be beneficial for people living with HIV. For example, a meta-analysis of Influenza vaccination is considered to be safe for the elderly and influenza vaccine effectiveness found that vaccinated people effective in reducing illness and death. Vaccine efficacy may living with HIV were 66% less likely to contract influenza 72,73 decrease with increasing age. Efficacy is also lower in elderly compared to non-vaccinated people living with HIV.82 In some people with underlying medical conditions. cases, vaccine effectiveness may be influenced by higher viral HIV loads and anti-retroviral treatment. High-dose and adjuvanted influenza vaccines have been shown to prompt a stronger immune response in the elderly and be more effective in preventing influenza.74

10 SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS 5. SEASONAL INFLUENZA VACCINE COVERAGE

Vaccine coverage data are critical to understand vaccine uptake 5.1. Estimates of global coverage and population immunity. They enable health authorities to assess coverage gaps and to measure trends over time, both of WHO/UNICEF joint reporting form which are key components of a successful influenza prevention Global information on influenza vaccination and control programme. programmes comes from the WHO/UNICEF Joint Reporting Form on Immunization (JRF), a standard Monitoring vaccine coverage among vulnerable populations is questionnaire sent to all Member States each year particularly important. In 2003, the 56th World Health Assembly to collect information on immunization, vaccines, called on all countries to achieve 75% vaccination coverage and biologicals.86 It includes a section on seasonal among the elderly by 2010.83 Years later, many countries still influenza vaccination, with questions on policy, do not monitor or measure influenza vaccine coverage among vaccine type and distribution. the elderly, or any other vulnerable population. Without data, countries cannot know if they are achieving their vaccination targets (estimates suggest that vaccination rates remain well below recommended targets).84

In many cases, the lack of data is due to practical challenges in estimating vaccine coverage, particularly for high-risk groups in LMICs (see Box 6. Coverage challenges).

Box 6. Coverage challenges

Common challenges associated with estimating vaccine coverage for high-risk groups include: 85 • Denominator data. Coverage estimates for subgroups require reliable estimates of the group size (the A look at 2018 JRF data shows that around half the countries ‘denominator’). But such detailed demographic data that reported data have a national influenza immunization are unavailable in many LMICs: up to 88% of WHO policy, with policies most prevalent in the region of the Member States in the Eastern Mediterranean and Americas (AMR), the Eastern Mediterranean region (EMR) and African regions do not have reliable estimates of the European region (EUR) (see Figure 4).87 size of influenza high-risk groups. • Overestimates. The coverage estimates for high- risk groups in LMICs that do exist are often based on the proportion of vaccine doses that have been distributed or administered, rather than the proportion of the target population that was vaccinated. In many cases, these estimates also fail to account for unused or otherwise wasted doses, which results in an overestimation of vaccine coverage.

11 Figure 4. Proportion of countries with national influenza immunization policies, as reported through the 2018 JRF.*

COUNIES ...that have a policy 97 90 52% ...that have a policy or recommend risk groups 117 70 63%

EIONS ...with highest proportions of countries that have a policy EUR AMR EMR 85% 69% 65%

*This data does not include countries that did not provide data to the 2018 JRF. As such, the true proportion of countries with an influenza policy may be higher.

By comparison, in the 2014 JRF, 115 Member States (59%) Few recommendations for priority groups. Only 29 out reported having a national influenza immunization policy, with • of 187 countries that responded to the JRF reported AMR, EUR, and the Western Pacific Region (WPR) having the recommending influenza vaccination for all priority highest proportions of countries with national policies.88,89 The groups (children over 6 months of age, adults with chronic difference between the 2018 and 2014 data may be at least conditions, the elderly, travelers, health workers and pregnant partially explained by data quality and/or lack of reporting in women). 2018 rather than a drop in the number of countries with national influenza immunization policies. Limited progress in meeting coverage targets. Only 10 • countries provided coverage data for all priority groups, with Other key features of the 2018 JRF data include: just three countries seeming to meet the WHA target of 75% coverage among the elderly. A total of 41 countries reported • Limited coverage data. Few countries answered the 2018 coverage of pregnant women, but this varied significantly, JRF questions on how many vaccine doses were distributed, from 0–90%. how many were administered to target groups, and what coverage was achieved for target groups. Poor coverage data quality. In several cases, reported • coverage among some priority groups exceeded 100%, pointing to problems with data quality.

12 SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS Influenza vaccine distribution Seasonal influenza vaccine coverage In the absence of more robust data, global influenza vaccine in the tropics distribution can be used as a proxy measure for vaccine In 2015, WHO published a review of seasonal influenza vaccine coverage. According to one study in 2015, influenza vaccine use and effectiveness in LMICs in the tropics.95 The review, distribution (and presumably use) increased 87% from 2004– which covered more than 200 articles and four global databases, 2013; but only 12% from 2008–2013.90 The study found that all found that only 46% of LMICs in the tropics had a national over the world, seasonal influenza vaccination coverage was well policy for seasonal influenza vaccination. Furthermore, vaccine below recommended targets. coverage among all priority groups in most of these countries was low, less than 5 per 1,000 population. It also found that vaccine distribution varied significantly from region to region: • AMR had the highest levels of vaccine distribution. WHO GUIDANCE EUR distribution was mostly flat. WHO’s Methods for assessing influenza vaccination • coverage in target groups are designed to support • WPR had sharp growth in vaccine distribution. countries estimate vaccine coverage.96 Not all methods AFR, EMR and the South East Asia Region (SEAR) had described will work for all countries and multiple methods • limited distribution. may be used simultaneously to achieve accurate estimates. The following are all reasonable approaches to Influenza vaccine is an underutilized public health tool in LMICs estimating coverage in high-risk populations: for prevention and control of this disease. • Analysis of data from health care facilities or healthcare providers. 5.2. Estimates of regional coverage Analysis of data from national health insurance records. In some cases, vaccine coverage is collected and reported by • region. • Analysis of administrative data from well-documented national or private vaccination programmes targeting European Health Information Gateway specific groups. The European Health Information Gateway includes data Evaluation of national vaccination registries. on seasonal influenza vaccination policies and coverage for • countries in EUR. Data are presented as interactive graphs National surveys of individuals. and maps, segregated by priority group. Groups covered by • the data include the elderly, pregnant women, health workers, The WHO manual on How to implement seasonal children, people with chronic diseases and people living in long- influenza vaccination of health workers provides term care facilities.91 guidance on monitoring vaccine coverage among health workers, with a focus on data from health Pan American Health Organization facility registries, national vaccination programmes and (PAHO) analyses surveys.97 PAHO Data and Statistics provide summary analyses of influenza Similarly, the WHO manual on How to implement vaccine coverage for countries in AMR.92 This includes tables seasonal influenza vaccination of pregnant women of seasonal influenza vaccine coverage in individual countries, provides guidance on monitoring coverage among among children, the elderly, health workers, pregnant women and pregnant women.98 people with chronic diseases.93 It also includes visual snapshots of the region, presenting regional data on the burden of seasonal The PAHO Maternal and Neonatal Immunization Field influenza, vaccine production and distribution, and vaccine Guide includes a tool for establishing the denominator to coverage and effectiveness.94 calculate vaccine coverage among pregnant women (i.e. the number of pregnant women in a population).99

SEASONAL INFLUENZA VACCINE COVERAGE 13 6. OTHER PREVENTION AND CONTROL MEASURES

6.1. Antivirals Licensed influenza antivirals are widely available. Six influenza antivirals, including generics, are approved for use, though some Influenza antivirals are essential components in countries’ are only available or approved in a few countries. Treatments clinical management of influenza since they play an important also vary in how they work and how they are administered (see part in treating and reducing disease severity in people infected Table 1). For guidance on clinical management of influenza with influenza. Antivirals complement vaccination in both through antivirals please refer to the upcoming WHO clinical seasonal influenza programmes and pandemic preparedness guidance document. planning, and thus, serve as an additional tool for countries to protect vulnerable risk groups and health systems. Generally, antiviral treatments should be given within the first 48 hours of influenza symptoms to be most effective.100,101

Table 2. Influenza antiviral treatments.

Antiviral Name Mechanism of Action Mode of Administration

Oseltamiviri Neuraminidase inhibitor Oral

Zanamivir Neuraminidase inhibitor Inhalation

Peramivir Neuraminidase inhibitor Intravenous

Laninamivir Neuraminidase inhibitor Inhalation

Favipiravir Polymerase inhibitor Oral

Baloxavir marboxil Polymerase inhibitor Oral

Table sources: i. Hurt AC. Antiviral therapy for the next influenza pandemic. Trop Med Infect Dis. 2019;4(2):67. doi: http://doi.org/10.3390/tropicalmed4020067. ii. Ison MG. Antiviral treatments. Clinics in Chest Medicine. 2017; 38(1): 139–153. doi: https://doi.org/10.1016/j.ccm.2016.11.008 iii. CDC. What you should know about flu antiviral drugs. In: CDC/Influenza (Flu) [website]. Atlanta: Centers for Disease Control and Prevention; 2019 (https://www.cdc.gov/flu/treatment/whatyoushould.htm, accessed 2 January 2020). iv. Principi N, Camilloni B, Alunno A, Polinori I, Argentiero A, et al. Drugs for influenza treatment: Is there significant news? Front Med (Lausanne). 2019;6:109. doi: http://doi.org/10.3389/fmed.2019.00109. v. Ison MG. Clinical use of approved influenza antivirals: therapy and prophylaxis. Influenza Other Respir Viruses. 2013;7(Suppl. 1):7–13. doi: http://doi.org/10.111/irv.12046. vi. Japan Ministry of Health, Labour and Welfare. Report on the Deliberation Results: Favipiravir. March 4, 2014. (https://www.pmda.go.jp/files/000210319.pdf, accessed 28 February 2020).

How an antiviral is given can help or hinder its use for specific have already been withdrawn from use because of high levels target groups. For example, antivirals that have to be given of resistance. Antiviral resistance against oseltamivir and intravenously are of limited use in non-hospital settings. other neuraminidase inhibitors has also been reported.102,103 Concerns about rising levels of resistance means that Some antivirals are not suitable for specific groups: favipiravir, antivirals are generally only given to high-risk patients. These for example, cannot be administered to pregnant women due concerns have also prompted research into drug repurposing to the risk of birth defects or other serious complications and therapeutics with new mechanisms of action, such as during pregnancy. immunotherapies or immunomodulators; most remain in early stages of development.104,105,106 Across nearly all antiviral treatments, resistance is a rising concern. One class of influenza antivirals called adamantanes

14 6.2. Public Health Measures (PHMs) WHO GUIDANCE PHMs are public health measures that can be used by governments and the public to reduce transmission and limit WHO is developing guidance on antivirals for patients geographic spread of infectious diseases like influenza. They can with severe seasonal influenza in clinical settings. be used alongside pharmaceutical interventions like vaccines and antivirals; PHMs can also be used when vaccines and treatments are unavailable, for example during the early stages of a pandemic.107

WHO recommends using a range of PHMs, depending on the severity of the influenza outbreak (see Figure 5).108

Figure 5. Recommended PHMs for use during influenza outbreaks.

International Workplace No mass EAOINA travel closures gatherings EVEN restrictions

SEVEE EIEIC Crowd School PPE in ANEIC avoidance closures public

Respiratory Face masks Isolation of AN etiquette for the sick the sick OUEA Environmental Disinfection Travel Handwashing cleaning of surfaces advice

The social and economic consequence of using any extreme PHM, for example during an extraordinary outbreak of influenza, should be weighed carefully against the public health benefits WHO GUIDANCE they may provide. WHO has issued guidance on Non-pharmaceutical public In all cases, there are some measures that are not recommended health measures for mitigating the risk and impact because there is not enough evidence to suggest that they are of epidemic and pandemic influenza, summarizing effective against influenza. These include: the evidence on a range of PHMs and making recommendations on their use. border closures or screening at borders, • PAHO has a practical tool on PHMs, which gives contact tracing, governments a checklist of PHM options, explaining • why each is important, how it can be implemented and • environmental humidity modification, requirements for success. • use of UV light, and • quarantine of exposed individuals.109

OTHER PREVENTION AND CONTROL MEASURES 15 7. SEASONAL INFLUENZA VACCINES FOR PREPAREDNESS

Implementing a seasonal influenza vaccination programme can Increasing acceptance of vaccine have benefits beyond fewer illnesses and deaths. In particular, Seasonal influenza vaccination programmes can help ensure it can increase preparedness for pandemics and other disease vaccine acceptance during a pandemic. For example, studies of epidemics by helping to sustain manufacturing facilities, develop vaccine uptake during the 2009 pandemic suggest that people deployment capacities, increase vaccine acceptance, train health who had experience in being vaccinated against seasonal workers, familiarize regulatory systems, strengthen decision- influenza were more likely to get vaccinated against pandemic making processes, practice risk communication and community influenza.114 engagement and exercise response systems. Training and targeting health workers Sustaining manufacturing facilities Having a seasonal influenza vaccination policy—especially Increasing the demand for seasonal vaccine from LMICs can one that prioritizes health workers—lays the foundations help sustain vaccine production capacity that has been built for strengthening health workers skills. Seasonal influenza 110 since 2006, that can be leveraged during a pandemic. vaccination of health works can support systems for vaccine The WHO Global Action Plan for Influenza Vaccines (GAP) was a deployment to this high-risk group quickly in the event of other 115 catalyst for developing influenza vaccine manufacturing capacity disease outbreaks, such as Ebola. Implementing an annual across the globe, including in LMICs.111 By the end of the GAP influenza vaccination programme should include health worker in 2016, the potential influenza vaccine production capacity training and empowerment. Health workers responsible for had quadrupled from 1.5 billion doses to 6.4 billion doses, with annual seasonal vaccination should be trained how to administer substantial capacity improvements in LMICs.112 But without and track vaccines. Through annual seasonal influenza continued demand through seasonal influenza programmes, vaccination programmes, countries can regularly update these gains could be lost. their health worker registries and practice communication for vaccine advocacy. These systems and processes can support Developing delivery capacities rapid delivery and uptake during pandemics or other disease Seasonal influenza vaccination programmes help build the epidemics. regulatory, operational and legal capacities needed for a Strengthen decision-making pandemic response. In 2009, countries with seasonal influenza vaccination programmes in place were two times more likely In some cases, introducing a seasonal influenza vaccination to be able to meet the requirements to receive WHO donated programme can also drive the establishment of a National pandemic vaccines than those without. Reviews after the Immunization Technical Advisory Group (NITAG); or if one 116 pandemic showed that those countries that did not manage to already exists, can strengthen its technical expertise. A new deploy the vaccine lacked critical capacities such as regulatory or stronger NITAG can help governments with decision-making pathways for rapid licensing and vaccine deployment plans.113 on policy issues around influenza vaccination—seasonal or pandemic— that is informed by the evidence base.

16 Exercising systems regularly Finally, because seasonal influenza vaccination campaigns are repeated every year, countries with a seasonal influenza vaccination programme exercise their systems for procuring and deploying these vaccines regularly. This repeated practice strengthens a country’s preparedness to fulfil these functions during a pandemic.117

WHO GUIDANCE

The WHO Pandemic Influenza Preparedness (PIP) Framework encourages countries that are seeking new vaccine technologies to consider implementing a seasonal influenza programme as a way of sustaining manufacturing facilities.

The WHO Global Influenza Strategy (2019-2030) includes a specific objective to “support countries to develop and implement national seasonal immunization policies for health workers and other target groups, as recommended by SAGE.”

The WHO’s Checklist for pandemic influenza risk and impact management highlights the links between seasonal influenza vaccination programmes and pandemic preparedness, and lists a number of essential and desirable actions for countries that already have, are considering or do not have a programme in place. In all cases, the checklist includes establishing regulatory pathways to expedite the import and licensing of pandemic vaccine as an essential action point.

SEASONAL INFLUENZA VACCINES FOR PREPAREDNESS 17 8. INTRODUCING SEASONAL INFLUENZA VACCINES

A country interested in establishing a seasonal influenza Key questions for the Ministry of Health to consider include: vaccination programme can begin by determining whether introducing seasonal influenza vaccines is a public health • What are our priority target groups for seasonal influenza priority; and assessing its existing readiness to start. vaccination? In all cases, countries should consider the potential impact • Do we know what the costs, benefits, risks, and trade-offs of introducing seasonal influenza vaccines on the financing, associated with manufacturing, procuring, and distributing planning and operation of the broader immunization programme seasonal influenza vaccines are? and on the overall health system. Can our cold chain system support the introduction of a • seasonal influenza vaccine?

8.1. Is seasonal influenza vaccination Can our supply chains and health system distribute seasonal a public health priority? • influenza vaccines?

Each country should evaluate whether a seasonal influenza Does our health workforce have the capacity to handle the vaccination programme is a public health priority. Influenza • addition of a seasonal influenza vaccine? vaccine programmes have been shown to reduce illness, death and economic burden on a healthcare system. But they require Do we have the capacity to train health workers to manage financial, logistical and political commitments to be successful. • and administer the vaccine?

Key questions for the Ministry of Health to consider include: What information systems will we have to update to include • seasonal influenza vaccine? Does preventing seasonal influenza align with, and/or • contribute significantly to, the goals and priorities in our Incorporating seasonal influenza vaccination into existing EPI national health and development plans? schedules builds from existing capacities and systems.

Will preventing seasonal influenza help improve health equity • within our population? WHO GUIDANCE 8.2. How to Develop a Seasonal WHO’s Principles and considerations for adding a vaccine to a national immunization programme is designed to Influenza Vaccination Programme support countries make informed decisions about adding Before introducing a seasonal influenza vaccination programme, a vaccine to their national immunization programme. It countries should consider if they have the necessary capacities. provides comprehensive guidance on deciding whether The health system must, for example, be capable of properly or not to introduce a vaccine, planning and managing handling, storing and administering the vaccine. The health the vaccine introduction and monitoring and evaluating system and public’s acceptance and demand of vaccines is vaccine coverage and safety after it has been introduced. also important to consider as part of a country’s readiness. Introduction of seasonal influenza vaccination involves evidence-based decisions about the type of vaccine to use and when to deploy it, which can be facilitated by the SAGE recommendations.

18 REFERENCES

1 Global Health Estimates 2016: Deaths by Cause, Age, Sex, 13 Mcmorrow ML, Tempia S, Walaza S, Treurnicht FK, Ramkrishna by Country and by Region, 2000-2016. Geneva, World Health W. Prioritization of risk groups for influenza vaccination in Organization; 2018. resource limited settings - A case study from South Africa. Vaccine. 2019; 3(37): 25–33. doi: http://doi.org/10.1016/j. 2 Paules C, Subbarao K. Influenza. Lancet. 2017; 390: 697–708. vaccine.2018.11.048. doi: http://doi.org/10.1016/S0140-6736(17)30129-0. 14 Orenstein EW, Orenstein LAV, Diarra K, Djiteye M, Sidibé D, et 3 WHO surveillance case definitions for ILI and SARI. Geneva: al. Cost-effectiveness of maternal influenza immunization World Health Organization; 2014 (https://www.who.int/ in Bamako, Mali: a decision analysis. PLoS One. 2017; 12(2): influenza/surveillance_monitoring/ili_sari_surveillance_case_ e07171499. doi: http://doi.org/10.1371/journal.pone.0171499. definition/en/, accessed 27 August 2019). 15 WHO. Guidance on the economic evaluation of influenza 4 WHO. GISRS: Global Influenza Surveillance and Response vaccination. Geneva: World Health Organization; 2016. System. Geneva: World Health Organization; 2018 (https://www.who.int/influenza/gisrs_laboratory/updates/ 16 Bhan MK, Sinha B. Immunisation against influenza in GISRS_one_pager_2018_EN.pdf?ua=1, accessed 26 low-income and middle-income countries. The Lancet. February 2020). 2019; 7(7): PE827–E828. doi: http://doi.org/10.1016/S2214- 109X(19)30195-0. 5 WHO. Global epidemiological surveillance standards for influenza. Geneva: World Health Organization; 2014 17 Tisa V, Barberis I, Faccio V, et al. Quadrivalent influenza vaccine: (https://www.who.int/influenza/resources/documents/ a new opportunity to reduce the influenza burden. J Prev Med influenza_surveillance_manual, accessed 26 February 2020). Hyg. 2016; 57(1): E28–E33.

6 WHO. A Manual for Estimating Disease Burden Associated with 18 Belshe RB. The need for quadrivalent vaccine against seasonal Seasonal Influenza. Geneva: World Health Organization; 2015 influenza. Vaccine. 2010; 28(4): D45–D53. (https://apps.who.int/iris/handle/10665/178801, accessed 26 doi: http://doi.org/10.1016/j.vaccine.2010.08.028. February 2020). 19 Ambrose CS, Levin MJ. The rationale for quadrivalent influenza 7 Influenza (Seasonal) In: WHO/Newsroom [website]. Geneva: vaccines. Human Vaccines & Immunotherapeutics. 2012; 8(1): World Health Organization; 2018 (https://www.who.int/news- 81–88. doi: http://doi.org/10.4161/hv.8.1.17623. room/fact-sheets/detail/influenza-(seasonal), accessed 26 February 2020). 20 De Boer PT, Kelso JK, Halder N, Nguyen T-P-L, Moyes J, et al. The cost-effectiveness of trivalent and quadrivalent influenza 8 Cohen C, Cozza V, Fitzner J, et al. Advances in measuring vaccination in communities in South Africa, Vietnam and influenza burden of disease. Influenza Other Respir Viruses. Australia. Vaccine. 2018; 36(7): 997–1007. 2018; 12:3-9. doi: http://doi.org/10.1111/irv.12533. doi: http://doi.org/10.1016/j.vaccine.2017.12.073.

9 WHO. Vaccines against influenza: WHO position paper – 21 Grohskopf LA, Alyanak E, Broder KR, Fry AM, Jernigan November 2012. Weekly Epidemiological Record. 2012; DB. Prevention and control of seasonal influenza with 47(87):461–476 (https://www.who.int/wer/2012/wer8747. vaccines: Recommendations of the Advisory Committee on pdf?ua=1, accessed 30 December, 2019). Immunization Practices – United States, 2019-20 influenza season. MMWR Recomm Rep. 2019; 68(3); 1–21. 10 Coleman BL, Fadel SA, Fitzpatrick T, Thomas SM. Risk factors doi: http://doi.org/10.15585/mmwr.rr6803a1. for serious outcomes associated with influenza illness in high- versus low- and middle-income countries: Systematic literature 22 Vaccine types. In: Vaccines.gov [website]. Washington review and meta-analysis. Influenza Other Respir Viruses. 2018; DC: US Department of Health and Human Services; 2020 12(1): 22–29. doi: http://doi.org/10.1111/irv.12504. (https://www.vaccines.gov/basics/types, accessed 26 February 2020). 11 Peasah SK, Azziz-Baumgartner E, Breese J, Meltzer MI, Widdowson M-A. Influenza cost and cost-effectiveness studies 23 Table 7. In: WHO. Vaccines against influenza: WHO position globally – a review. Vaccine. 2013; 31(46): 5339–5348. paper – November 2012. Weekly Epidemiological Record. doi: http://doi.org/10.1016/j.vaccine.2013.09.013. 2012; 47(87):461–476 (https://www.who.int/wer/2012/ wer8747.pdf?ua=1, accessed 30 December, 2019). 12 Ting EEK, Sander B, Ungar WJ. Systematic review of the cost- effectiveness of influenza immunization programs. Vaccine. 24 Sridhar S, Brokstad KA, Cox RJ. Influenza vaccination 2017; 35(15): 1828–1843. doi: http://doi.org/10.1016/j. strategies: comparing inactivated and live attenuated influenza vaccine.2017.02.044. vaccines. Vaccines. 2015; 3(2): 373–389. doi: http://doi.org/10.3390/vaccines3020373.

19 25 Falkenhorst G, Harder T, Remschmidt C, Terhardt M, Zepp 37 Lambert LC, Fauci AS. Influenza vaccines for the future. N Engl F, et al. Background paper to the recommendation for the J Med. 2010; 363: 2036–2044. doi: http://doi.org/10.1056/ preferential use of live-attenuated influenza vaccine in children NEJMra1002842. aged 2–6 years in Germany. Bundesgesundheitsbl. 2013; 56: 1557 – 1564. doi: http://doi.org/10.1007/s00103-013-1844-9 38 Chapter 5: Vaccine storage and handling. In: CDC. Epidemiology and prevention of vaccine-preventable 26 WHO. Questions and answers: Recommended composition of diseases. Atlanta: Centers for Disease Control; 2015 influenza virus vaccines for use in the southern hemisphere (https://www.cdc.gov/vaccines/pubs/pinkbook/vac-storage. 2020 influenza season and development of candidate vaccine html, 27 February 2020). viruses for pandemic preparedness. Geneva: World Health Organization; 2019 (https://www.who.int/influenza/vaccines/ 39 WHO. Immunization Module 2: The vaccine cold chain. Geneva: virus/recommendations/201909_qanda_recommendation. World Health Organization; 2015 (https://www.who.int/ pdf?ua=1, accessed 26 February 2020). immunization/documents/IIP2015_Module2.pdf, accessed 30 August, 2019). 27 WHO recommendations on the composition of influenza virus vaccines. In: WHO/Influenza [website]. Geneva: World Health 40 WHO. Guidelines for establishing or improving primary Organization; 2020 (https://www.who.int/influenza/vaccines/ and intermediate vaccine stores. Geneva: World Health virus/recommendations, accessed 26 February 2020). Organization; 2002 (https://apps.who.int/iris/bitstream/ handle/10665/67807/WHO_V-B_02.34_eng.pdf?sequence=1, 28 Influenza vaccine in tropics and subtropics. In: WHO/ accessed 30 August 2019). Influenza [website]. Geneva: World Health Organization; 2020 (https://www.who.int/influenza/vaccines/tropics, accessed 26 41 WHO. MI4A Vaccine purchase data for countries. Geneva: February 2020). World Health Organization; 2018. (https://www.who.int/ immunization/programmes_systems/procurement/v3p/ 29 Influenza vaccine in tropics and subtropic. In: WHO/Influenza platform/module2/MI4A_2018_Vaccine_Purchase_Data_Cover_ [website]. Geneva: World Health Organization; 2020 Note_Countries.pdf, accessed 30 August, 2019). (https://www.who.int/influenza/vaccines/tropics, accessed 27 February 2020). 42 PAHO. Expanded program of immunization vaccine prices for year 2019. Washington DC: Pan-American Health Organization; 30 McLean KA, Goldin S, Nannei C, Sparrow E, Torelli G. The 2015 2019 (https://www.paho.org/hq/index.php?option=com_ global production capacity of seasonal and pandemic influenza docman&view=download&category_slug=revolving- vaccine. Vaccine. 2016; 35(45): 5410–5413. fund-2625&alias=25038-revolving-fund-vaccine-prices- doi: http://doi.org/10.1016/j.vaccine.2016.08.019. 038&Itemid=270&lang=en, accessed 30 August 2019).

31 Sanofi Pasteur. Influenza Vaccine Production Timeline for the 43 Hendriks J, Hutubessy RC, Grohmann G, Torelli G, Friede M, U.S. Paris: Sanofi Pasteur; 2017 (http://www.news.sanofi.us/ Kieny MP. Quadrivalent influenza vaccines in low and middle download/COM11508-1R%2BInfluenza%2BVaccine%2BUS% income countries: cost-effectiveness, affordability and 2BProduction%2BTimeline%2B23May2016.pdf, accessed 30 availability. Vaccine. 2018 Jun 27;36(28):3993-7. August, 2019). 44 WHO. Information sheet: observed rate of vaccine reactions 32 Rimmelzwaan G, Leroux-Roels I, Gilbert S, Thomson A. for influenza vaccine. Geneva: World Health Organization; 2012 Influenza vaccines: Where do we stand? Where do we go? (https://www.who.int/vaccine_safety/initiative/tools/Influenza_ A bumpy but steady road upwards. Vaccine. 2015; 33(49): Vaccine_rates_information_sheet.pdf?ua=1, accessed 27 7026–7028. doi: http://doi.org/10.1016/j.vaccine.2015.07.068. February 2020).

33 Erlewyn-Lajeunesse M, Brathwaite N, Lucas JSA, Warner JO. 45 Guillan-Barré Syndrome. In: CDC/Vaccine safety [website]. Recommendations for the administration of influenza vaccine Atlanta: Centers for Disease Control; 2020 (https://www.cdc. in children allergic to egg. BMJ. 2009; 339: b3680. gov/vaccinesafety/concerns/guillain-barre-syndrome.html, doi: http://doi.org/10.1136/bmj.b3680. accessed 27 February 2020).

34 Manini L, Trombetta CM, Lazzeri G, Pozzi T, Rossi S, et al. 46 Schmid P, Rauber D, Betsch C, Lidolt G, Denker M-L. Barriers Egg-independent influenza vaccines and vaccine candidates. of influenza vaccination intention and behavior: a systematic Vaccines. 2017; 5(3): 18. doi: http://doi.org/10.3390/ review of influenza vaccine hesitancy, 2005–2016. PLoS ONE. vaccines5030018. 2017; 12(1): e0170550. doi: http://doi.org/10.1371/journal. pone.0170550. 35 Perdue ML, Arnold F, Li S, Donabedian A, Cioce V, et al. The future of cell culture-based influenza vaccine production. 47 Antunes JL, Waldman EA, Borrell C, Paiva TM. Effectiveness of Expert Review of Vaccines. 2011; 10(8): 1183–1194. influenza vaccination and its impact on health inequalities. Int doi: http://doi.org/10.1586/erv.11.82. J Epidemiol. 2007; 36(6): 1319–26. doi: http://doi.org/10.1093/ ije/dym208. 36 How influenza (flu) vaccines are made. In: CDC/Influenza (Flu) [website]. Atlanta: Centers for Disease Control; 2020 48 Tosh PK, Jacobson RM, Poland GA. Influenza vaccines: (https://www.cdc.gov/flu/prevent/how-fluvaccine-made.htm, from surveillance through production to protection. Mayo accessed 27 February 2020). Clinic Proceedings. 2010; 85(3): 257–273. doi: http://doi. org/10.4065/mcp.2009.0615.

20 SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS 49 WHO. Safety of Immunization during Pregnancy: A Review of 61 Morales K, Menning L, McCarron M, Lambach P. The Faces the Evidence. Geneva: World Health Organization; 2014. of Influenza Vaccine Recommendation: A Literature Review of The Determinants and Barriers to Health Providers’ 50 Ortiz, J.R., J.A. Englund, and K.M. Neuzil. Influenza vaccine for Recommendation of Influenza Vaccine in PregnancyVaccine pregnant women in resource constrained countries: a review of 2020 (to be published shortly). the evidence to inform policy decisions. Vaccine. 2011; 29(27): 4439–52. doi: http://doi.org/10.1016/j.vaccine.2011.04.048. 62 Jenkin DC, Mahgoub H, Morales KF, Lambach P, Nguyen-Van- Tam JS. A Rapid Evidence Appraisal of influenza vaccination 51 Reuman, PD, Ayoub EM, Small PA. Effect of passive maternal in health workers: an important policy in an area of imperfect antibody on influenza illness in children: a prospective study evidence. Vaccine: X. 2019; 11:100036. of influenza A in mother-infant pairs. Pediatr Infect Dis J. 1987; 6(4): 398–403. doi: http://doi.org/10.1097/00006454- 63 Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V. 198704000-00011. Vaccines for preventing influenza in healthy children. Cochrane Database of Systematic Reviews. 2008; 2: CD004879. 52 McMillan M, Porritt K, Kralik D, Costi L, Marshall H. Influenza doi: http://doi.org/10.1002/14651858.CD004879.pub3. vaccination during pregnancy: a systematic review of fetal death, spontaneous abortion, and congenital malformation 64 Sakala IG, Honda-Okubo Y, Fung J, Petrovsky N. Influenza safety outcomes. Vaccine. 2015; 33(18): 2108–2117. immunization during pregnancy: benefits for mother and infant. doi: http://doi.org/10.1016/j.vaccine.2015.02.068. Vaccines & Immunotherapeutics. 2016; 12(12): 3065–3071. doi: http://doi.org/10.1080/21645515.2016.1215392. 53 Lindley MC, Kahn KE, Bardenheier BH, D’Angelo DV, Dawood FS, et al. Vital signs: burden and prevention of influenza and 65 Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and pertussis among pregnant women and infants – United States. effectiveness of influenza vaccines: a systematic review and MMWR. 2019; 68(40): 885–892. doi: http://doi.org/10.15585/ meta-analysis. The Lancet Infectious Diseases. 2012; 12(1): mmwr.mm6840e1. 36-44. doi: http://doi.org/10.1016/S1473-3099(11)70295-X.

54 Morales K, Menning L, McCarron M, Lambach P.The Faces 66 Global Advisory Committee on Vaccine Safety, 16–17 June of Influenza Vaccine Recommendation: A Literature Review 2010. WHO Weekly epidemiological record. 2010; 85: 285–292 of The Determinants and Barriers to Health Providers’ (https://www.who.int/vaccine_safety/committee/reports/ Recommendation of Influenza Vaccine in PregnancyVaccine wer8530.pdf, accessed 27 February 2020). 2020 (to be published shortly). 67 Lambach P. Safety aspects of influenza vaccine. Geneva: World 55 Jenkin DC, Mahgoub H, Morales KF, Lambach P, Nguyen-Van- Health Organization; 2011 (http://www.who.int/immunization/ Tam JS. A rapid evidence appraisal of influenza vaccination sage/meetings/2012/april/3_P.Lambach_120404_SAGE_ in health workers: an important policy in an area of imperfect presentation_influenza1.pdf, accessed 27 February 2020). evidence. Vaccine. 2019; X2. doi: http://doi.org/10.1016/j. jvacx.2019.100036. 68 Manzoli L, Schioppa F, Boccia A, Villari P. The efficacy of influenza vaccine for healthy children: a meta-analysis 56 Salgado CD, Farr BM, Hall KK, Hayden FG. Influenza in the evaluating potential sources of variation in efficacy estimates acute hospital setting. Lancet Infectious Diseases. 2002; 2: including study quality. Pediatr Infect Dis J. 2007; 26(2): 97–106. 145–155. doi: http://doi.org/10.1016/s1473-3099(02)00221-9. doi: http://doi.org/10.1097/01.inf.0000253053.01151.bd.

57 Jenkin DC, Mahgoub H, Morales KF, Lambach P, Nguyen-Van- 69 Fu C, He Q, Li Z, Xu J, Li Y, et al. Seasonal influenza Tam JS. A Rapid Evidence Appraisal of influenza vaccination vaccine effectiveness among children, 2010-2012. in health workers: an important policy in an area of imperfect Influenza Other Respir Viruses. 2013; 7(6): 1168–74. evidence. Vaccine: X. 2019; 11:100036. doi: http://doi.org/10.1111/irv.12157.

58 Jenkin DC, Mahgoub H, Morales KF, Lambach P, Nguyen-Van- 70 PAHO. Vaccines: The most effective intervention Tam JS. A Rapid Evidence Appraisal of influenza vaccination to prevent seasonal influenza and respond to in health workers: an important policy in an area of imperfect pandemics [Brochure]. Washington DC: Pan American evidence. Vaccine: X. 2019; 11:100036. Health Organization; 2019 (https://www.paho.org/ hq/index.php?option=com_docman&task=doc_ 59 Jenkin DC, Mahgoub H, Morales KF, Lambach P, Nguyen-Van- download&gid=49589&Itemid=270&lang=en, accessed 30 Tam JS. A Rapid Evidence Appraisal of influenza vaccination December, 2019). in health workers: an important policy in an area of imperfect evidence. Vaccine: X. 2019; 11:100036. 71 Cohen C, Simonsen L, Kang J-W, Miller M, McAnerney J, et al. Elevated influenza-related excess mortality in South African 60 Paterson P, Meurice F, Stanberry LR, Glismann S, Rosenthal elderly individuals, 1998-2005. Clinical Infectious Diseases. SL, Larson HJ. Vaccine hesitancy and healthcare providers. 2010; 51: 1362–1369. doi: http://doi.org/10.1086/657314. Vaccine. 2016 Dec 20;34(52):6700-6706. doi: http://doi.org/10.1016/j.vaccine.2016.10.042 72 McElhaney JE. Influenza Vaccine Responses in Older Adults. Ageing Res Rev. 2011; 10(3): 379–388. doi: http://doi.org/10.1016/j.arr.2010.10.008.

REFERENCES 21 73 Lambert ND, Ovsyannikova IG, Pankratz VS, Jacobson RM, 2015; 33(42): 5598–5605. doi: http://doi.org/10.1016/j. Poland GA. Understanding the immune response to seasonal vaccine.2015.08.082. influenza vaccination in older adults: a systems biology approach. Expert Rev Vaccines. 2012; 11(8): 985–994. 85 Siddhivinayak H. Seasonal influenza vaccine use in doi: http://doi.org/10.1586/erv.12.61. low and middle income countries in the tropics and subtropics: A systematic review. Geneva: World Health 74 Fluzone high-dose seasonal influenza vaccine. In: CDC/ Organization; 2015 (https://apps.who.int/iris/bitstream/ Influenza (Flu) [website]. Atlanta: Centers for Disease Control; handle/10665/188785/9789241565097_eng.pdf?sequence=1, 2020 (https://www.cdc.gov/flu/prevent/qa_fluzone.htm, accessed 29 August, 2019). accessed 27 February 2020). 86 WHO/UNICEF Joint Reporting Process. In: WHO/Immunization, 75 WHO SAGE Working Group. Background paper on influenza vaccines and biologicals [website]. Geneva: World Health vaccines and immunization. Geneva: World Health Organization; 2019 (https://www.who.int/immunization/ Organization; 2012 (https://www.who.int/immunization/ monitoring_surveillance/routine/reporting, accessed 27 sage/meetings/2012/april/1_Background_Paper_Mar26_v13_ February 2020). cleaned.pdf, accessed 30 December 2019). 87 World Health Organization. Joint Reporting Form data 2018. 76 Memoli MJ, Athota R, Reed S, Czajkowski L, Bristol T, Proudfoot Provided by WHO. K, Hagey R, Voell J, Fiorentino C, Ademposi A, Shoham S. The natural history of influenza infection in the severely 88 European Health Information Gateway: Seasonal influenza immunocompromised vs nonimmunocompromised hosts. vaccination policies and coverage [website]. Copenhagen: Clinical infectious diseases. 2014: 58(2):214-24. World Health Organization Regional Office for Europe; 2019 (https://gateway.euro.who.int/en/datasets/influenza, accessed 77 Van Kerkhove MD, Vandemaele KA, Shinde V, Jaramillo- 30 December, 2019). Gutierrez G, Koukounari A, et al. Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global 89 Ortiz JR, Perut M, Dumolard L, Wijesinghe PR, Jorgensen P, pooled analysis. PLoS Medicine. 2011; 8(7): e1001053. Ropero AM, Danovaro-Holliday MC, Heffelfinger JD, Tevi- doi: http://doi.org/10.1371/journal.pmed.1001053. Benissan C, Teleb NA, Lambach P. A global review of national influenza immunization policies: Analysis of the 2014 WHO/ 78 Neuzil KM, Wright PF, Mitchel Jr EF, Griffin MR. The burden UNICEF Joint Reporting Form on immunization. Vaccine. 2016 of influenza illness in children with asthma and other chronic Oct 26;34(45):5400-5. medical conditions. The Journal of Pediatrics. 2000; 137: 856–64. doi: http://doi.org/10.1067/mpd.2000.110445. 90 Palache A, Oriol-Mathieu V, Fino M, Xydia-Charmanta M, Influenza Vaccine Supply task force. Seasonal influenza 79 Michiels B, Govaerts F, Remmen R, Vermeire E, Coenen S. A vaccine dose distribution in 195 countries (2004-2013): little systematic review of the evidence on the effectiveness and progress in estimated global vaccination coverage. Vaccine. risks of inactivated influenza vaccines in different 2015; 33(42): 5598–5605. doi: http://doi.org/10.1016/j. target groups. Vaccine. 2011; 29(49): 9159–70. vaccine.2015.08.082. doi: http://doi.org/10.1016/j.vaccine.2011.08.008. 91 European Health Information Gateway: Seasonal influenza 80 Nichol KL, Baken L, Nelson A. Relation between influenza vaccination policies and coverage [website]. Copenhagen: vaccination and outpatient visits, hospitalization, and World Health Organization Regional Office for Europe; 2019 mortality in elderly persons with chronic lung disease. Annals (https://gateway.euro.who.int/en/datasets/influenza, accessed of Internal Medicine. 1999; 130: 397–403. doi: http://doi. 30 December, 2019). org/10.7326/0003-4819-130-5-199903020-00003. 92 Data and Statistics. In: PAHO/Immunization [website]. 81 Ciszewski A. Cardioprotective effect of influenza and Washington DC: Pan American Health Organization; 2020 pneumococcal vaccination in patients with cardiovascular (http://www.paho.org/Immunization/Data, accessed 27 diseases. Vaccine. 2018; 36(2): 202–206. February 2020). doi: http://doi.org/10.1016/j.vaccine.2017.11.078. 93 PAHO. Immunization in the Americas: 2019 Summary. 82 Anema A, Mills E, Montaner J, Brownstein JS, Cooper C. Efficacy Washington DC: Pan American Health Organization; of influenza vaccination in HIV‐positive patients: a systematic 2018 (https://www.paho.org/hq/index.php?option=com_ review and meta‐analysis. HIV medicine. 2008: 9(1):57-61. docman&view=download&category_slug=brochures- 1581&alias=50553-immunization-in-the-americas-2019- 83 Resolution WHA56.19. Prevention and control of influenza summary&Itemid=270&lang=en, accessed 30 December, 2019). pandemics and annual epidemics. In: Fifty-sixth World Health Assembly, Geneva, 28 May, 2003. Geneva: World Health 94 PAHO. Vaccines: The most effective intervention Organization; 2003 (http://apps.who.int/gb/archive/pdf_files/ to prevent seasonal influenza and respond to WHA56/ea56r19.pdf, accessed 29 August, 2019). pandemics [Brochure]. Washington DC: Pan American Health Organization; 2019 (https://www.paho.org/ 84 Palache A, Oriol-Mathieu V, Fino M, Xydia-Charmanta M, hq/index.php?option=com_docman&task=doc_ Influenza Vaccine Supply task force. Seasonal influenza download&gid=49589&Itemid=270&lang=en, accessed 30 vaccine dose distribution in 195 countries (2004-2013): little December, 2019) progress in estimated global vaccination coverage. Vaccine.

22 SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS 95 Siddhivinayak H. Seasonal influenza vaccine use in 107 World Health Organization Writing Group. Nonpharmaceutical low and middle income countries in the tropics and interventions for pandemic influenza, national and community subtropics: A systematic review. Geneva: World Health measures. Emerg Infect Dis. 2006; 12(1): 88–94. Organization; 2015 (https://apps.who.int/iris/bitstream/ doi: http://doi.org/10.3201/eid1201.051371. handle/10665/188785/9789241565097_eng.pdf?sequence=1, accessed 29 August, 2019). 108 WHO. Non-pharmaceutical public health measures for mitigating the risk and impact of epidemic and pandemic 96 EURO. Methods for assessing influenza vaccination coverage influenza. Geneva: World Health Organization; 2019 (https:// in target groups. Copenhagen: World Health Organization www.who.int/influenza/publications/public_health_measures/ Regional Office for Europe; 2016 (http://www.euro.who. publication, accessed 27 February 2020). int/en/health-topics/communicable-diseases/influenza/ publications/2016/methods-for-assessing-influenza- 109 WHO. Non-pharmaceutical public health measures for vaccination-coverage-in-target-groups-2016, accessed 27 mitigating the risk and impact of epidemic and pandemic February 2020). influenza. Geneva: World Health Organization; 2019 (https:// www.who.int/influenza/publications/public_health_measures/ 97 WHO. How to implement seasonal influenza vaccination publication, accessed 27 February 2020). of health workers. Geneva: World Health Organization; 2019 (https://www.who.int/immunization/documents/ 110 WHO. Global pandemic influenza action plan to increase ISBN_9789241515597, accessed 27 February 2020). vaccine supply. Geneva: World Health Organization; 2006 (https://www.who.int/csr/resources/publications/influenza/ 98 WHO. How to implement seasonal influenza vaccination of CDS_EPR_GIP_2006_1.pdf?ua=1, accessed 30 August 2019) pregnant women. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/handle/10665/250084, accessed 27 111 Report of the second WHO Consultation on the Global Action February 2020). Plan for Influenza Vaccines (GAP). Geneva: World Health Organization; 2011 (https://www.who.int/influenza_vaccines_ 99 PAHO. Maternal and Neonatal Immunization Field Guide for plan/resources/gap2consultationreport.pdf, accessed 27 Latin America and the Caribbean; pages 41–42. Washington February 2020). DC: Pan American Health Organization; 2017 (https://iris.paho. org/handle/10665.2/34150, accessed 27 February 2020). 112 WHO. The ten years of the Global Action Plan for Influenza Vaccines: Report to the Director-General from the GAP Advisory 100 Hurt AC. Antiviral therapy for the next influenza pandemic. Group. Geneva: World Health Organization; 2016 (https://www. Trop Med Infect Dis. 2019; 4(2): 67. doi: http://doi.org/10.3390/ who.int/influenza/GAP_AG_report_to_WHO_DG.pdf?ua=1, tropicalmed4020067. accessed 30 August 2019).

101 Ison MG. Antiviral treatments. Clinics in Chest Medicine. 2017; 113 Bresee JS, Lafond KE, McCarron M, Azziz-Baumgartner E, 38(1): 139–153. doi: http://doi.org/10.1016/j.ccm.2016.11.008. Chu S, et al. The partnership for influenza vaccine introduction (PIVI): Supporting influenza vaccine program development 102 Hurt AC. Antiviral therapy for the next influenza pandemic. in low and middle-income countries through public-private Trop Med Infect Dis. 2019; 4(2): 67. doi: http://doi.org/10.3390/ partnerships. Vaccine. 2019; 37(35): 5089–5095. tropicalmed4020067. doi: http://doi.org/10.1016/j.vaccine.2019.06.049.

103 WHO. Global monitoring of antiviral resistance in currently 114 Bish A, Yardley L, Nicoll A, Michie S. Factors associated with circulating human influenza viruses, November 2011. Weekly uptake of vaccination against pandemic influenza: a systematic Epidemiologic Record. 2011; 45(86): 497–508 (https://www. review. Vaccine 2011; 29(38): 6472–6484. doi: http://doi. who.int/wer/2011/wer8645.pdf?ua=1, accessed 27 February org/10.1016/j.vaccine.2011.06.107. 2020). 115 Bresee J, Kieny MP. Seasonal Influenza Vaccination: A 104 Pizzorno A, Padey B, Terrier O, Rosa-Calatrava M. Drug Tool to Advance Epidemic and Pandemic Preparedness In repurposing approaches for the treatment of influenza viral Low- and Middle-Income Countries. Health Affairs Blog. infection: reviving old drugs to fight against a long-lived 7 June 2019. https://www.healthaffairs.org/do/10.1377/ enemy. Front Immunol. 2019. doi: http://doi.org/10.3389/ hblog20190604.614921/full/ fimmu.2019.00531. 116 WHO. Principles and considerations for adding a vaccine 105 Koszalka P, Tilmanis D, Hurt AC. Influenza antivirals currently to a national immunization programme: from decision to in late-phase clinical trial. Influenza and Other Respir Viruses. implementation and monitoring. Geneva: World Health 2017; 11(3): 240–246. doi: http://doi.org/10.1111/irv.12446. Organization; 2014 (https://www.who.int/immunization/ programmes_systems/policies_strategies/vaccine_intro_ 106 Sparrow E, Fried M, Sheikh M, Torvaldsen S, Newall AT. Passive resources/nvi_guidelines, accessed 27 February 2020). immunization for influenza through antibody therapies, a review of the pipeline, challenges and potential applications. Vaccine. 117 Bresee JS, Lafond KE, McCarron M, Azziz-Baumgartner E, Chu 2016; 34(45): 5442–5448. doi: http://doi.org/10.1016/j. S, et al. The partnership for influenza vaccine introduction vaccine.2016.08.057. (PIVI): Supporting influenza vaccine program development in low and middle-income countries through public-private partnerships. Vaccine. 2019; 37(35): 5089–5095. doi: http://doi.org/10.1016/j.vaccine.2019.06.049.

REFERENCES 23 ANNEX 1. Example costs for different influenza vaccines

The table below provides examples of seasonal influenza vaccines and their cost per dose.

Table. Examples of seasonal influenza vaccine costs.

Vaccine Type Presentation Cost per Dose Prequalified (USD) by WHO? Southern Hemisphere Trivalent, $1.095 (via PAHO 20 dose vial No 2019 - Pediatric - Korea Origini seasonal vaccine Revolving Fund) Northern Hemisphere Trivalent, Pre-filled syringe $4.50 via PAHO No 2019-2020 - Adult - France Origini seasonal vaccine (1 dose) Revolving Fund) Southern Hemisphere Quadrivalent, $4.40 (via PAHO 10 dose vial No 2019 - Adult - Korea Origini seasonal vaccine Revolving Fund) Northern Hemisphere Quadrivalent, Pre-filled syringe $6.00 (via PAHO No 2019-2020 - Adult - France Origini seasonal vaccine (1 dose) Revolving Fund) Trivalent, seasonal, $1.19 (LMIC) - $4.50 Hualanii split virion, 1 dose vial Yes (UMIC) (EURO Region) inactivated vaccine Trivalent, seasonal, $7.67-$8.08 IL-Yangi 1 dose vial Yes inactivated vaccine (HIC, WPRO Region) Quadrivalent, 10 dose vial, 1-dose $13.832 (U.S. CDC) - Fluzone® Quadrivalentiii Yes seasonal vaccine vial, or syringes $18.314 (private sector)

Table sources: i PAHO. Expanded programme of immunization vaccine prices for year 2019. Washington DC: Pan American Health Organization; 2019 (https://www. paho.org/hq/index.php?option=com_docman&view=download&category_slug=vaccines-9979&alias=49243-vaccine-prices-2019&Itemid=270&lang=en, accessed 28 February 2020). ii WHO. MI4A Vaccine Purchase Data for Countries. Geneva: World Health Organization; 2018 (https://www.who.int/immunization/programmes_ systems/procurement/mi4a/platform/module2/MI4A_2018_Vaccine_Purchase_Data_Cover_Note_Countries.pdf, accessed 28 February 2020). iii CDC. Adult influenza vaccine price list. Atlanta: US Centers for Disease Control and Prevention; 2019 (https://www.cdc.gov/vaccines/programs/vfc/ awardees/vaccine-management/price-list/index.html#adflu, accessed 28 February 2020).

Estimates of the current cost per dose for pandemic influenza the US Centers for Disease Control & Prevention’s price lists vaccines are not available. The 2009 H1N1 influenza pandemic • for pediatric and adult seasonal influenza vaccines, and vaccine cost countries between US$2.50–20 per dose, with HICs paying between US$10–20 per dose, MICs paying approximately • WHO Market information for access to vaccines resource half that amount, and LICs paying roughly a quarter that gateway (including its most recent market report on vaccine amount.a WHO reported that after accounting for local funding purchase data). and financial support provided by the WHO Vaccine Deployment Initiative, the average cost per dose for vaccine deployment and Notes administration ranged from US$0.16 in SEARO to US$0.66 in AFRO.b a WHO. WHO supports fair access to influenza A (H1N1) vaccine: an interview with Marie-Paule Kieny. Bull World Health Organ. 2009; 87(9): For more detailed information on influenza vaccine types and 645–732 (https://www.who.int/bulletin/volumes/87/9/09-030909, pricing, see: accessed 28 February 2020). b WHO. Report of the WHO pandemic influenza A (H1N1) vaccine WHO’s database of prequalified vaccines, • deployment initiative. Geneva: World Health Organization; 2012 (https://www.who.int/influenza_vaccines_plan/resources/h1n1_ the Expanded Program of Immunization’s 2019 vaccine price deployment_report.pdf, accessed 28 February 2020). • list for AMR,

24 SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS 25 Working together for better global tools & stronger country capacities

Promote research & innovation Expand seasonal prevention to address public health needs & control policies and programmes to protect the vulnerable Strengthen global influenza surveillance, monitoring & Strengthen pandemic preparedness data utilization & response for influenza to make the world safer

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www.who.int/influenza/en/26 SEASONAL INFLUENZA VACCINES: AN OVERVIEW FOR DECISION-MAKERS