Questions & Answers on Influenza

101 Influenza on & Answers Questions 101 Questions & Answers

Prof. Dr. A.D.M.E. (Ab) Osterhaus is David De Pooter is working at Link Inc on professor of virology at Erasmus Medical since 2003, the Antwerp (Belgium) based Centre Rotterdam, and professor of communication consultancy agency, Environmental Virology at the Utrecht specialised in strategic communication University. Fascinated by the ingenious and social marketing. Link Inc is working ways viruses circumvent the immune with the European Scientific working Influenza system of their hosts to multiply and Group on Influenza (ESWI) since 1998 and spread, Osterhaus started his quest at the is taking care of the positioning of the interface of virology and immunology. He group, the strategy and the implementa Ab Osterhaus quickly translated new insights in this tion of the strategy by developing complex field to applications in animal and targeted communication tools. In this human vaccinology. In addition, he started capacity, David De Pooter is a professional David De Pooter his work on virus discovery, not only writer on medical topics and a communi focussing on the identification of a series cation manager of ESWI. As such he has of animal viruses, but also of new human established a fruitful and long standing viruses. collaboration with Prof Ab Osterhaus. (www.linkinc.be)

101 Questions & Answers on Influenza 101 101 Questions & Answers on Influenza

Ab Osterhaus David De Pooter

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Table of content

Foreword 11 Preface 13

I All you need to know about influenza

1 What is a virus? 16 2 What are the differences between viruses, bacteria and parasites? 18 3 How are viruses classified? 20 4 How do viruses replicate? 21 5 What do viruses look like? 22 6 What do influenza viruses look like? 23 7 Which organisms can be infected with viruses? 24 8 Which scientific disciplines study viruses? 25 9 What are the existing types, subtypes and clades of influenza viruses? 26 10 Which animals are the natural hosts of influenza A viruses? 27 11 What other species can be infected with influenza A viruses? 28

II All about influenza viruses and the disease influenza

12 Where does the word ‘influenza’ come from? 32 13 What are the different forms of human influenza? 33 14 How do influenza viruses change? 35 15 How and where do influenza viruses enter the human body? 37 16 How does the body combat influenza? 39 17 What are possible complications of seasonal influenza? 41 18 Who belongs to the special risk groups for influenza? 42 6 All you need to know about influenza

III How influenza viruses spread

19 How are influenza viruses transmitted from human to human? 44 20 How are influenza viruses transmitted from animals to humans? 45 21 What are the most important factors that determine influenza virus transmission to humans? 46

IV How to recognize influenza

22 What is the difference between influenza and a common cold? 48 23 What is the difference between clinical and lab-confirmed diagnosis? 49 24 When is a lab-confirmed diagnosis appropriate? 50

V All about seasonal influenza

25 What is seasonal influenza? 52 26 How many people get ill or even die from influenza each year? 53 27 What is the social and societal impact of seasonal influenza? 54 28 What is the economic impact of seasonal influenza? 55 29 How to prevent seasonal influenza? 56 30 How to treat seasonal influenza? 57 table of content 7

VI All about avian influenza

31 What is avian influenza? 60 32 What is the difference between low pathogenic avian influenza (LPAI) and highly pathogenic avian influenza (HPAI)? 61 33 How dangerous is HPAI-H5N1 virus infection for animals? 62 34 How dangerous is avian influenza for humans? 63 35 How does avian influenza spread among animals? 65 36 Can birds be vaccinated to stop the spread of avian influenza? 66 37 What else can be done to stop the spread of avian influenza? 68 38 How can I personally prevent infection with the HPAI-H5N1 virus? 69 39 Is it safe to eat poultry and poultry products? 71

VII All about pandemic influenza

40 What is pandemic influenza? 74 41 What are the pandemics which have occurred in the past century? 76 42 What is the origin of influenza pandemics? 78 43 Will there be other influenza pandemics in the future? 79 44 What is the expected impact of future pandemics? 80 45 What are the basic elements of pandemic planning? 81 46 Who is responsible for influenza pandemic preparedness plans? 83 47 Are we prepared for the current pandemic? 84 48 Will the ‘Mexican flu’ virus cause the first influenza pandemic of thest 21 century? 88 8 All you need to know about influenza

VIII All about influenza vaccines

49 What are the medicinal intervention options for influenza? 91 50 What is the difference between vaccines, antiviral drugs and antibiotics? 93 51 Are over-the-counter products effective against influenza? 94 52 How do influenza vaccines work? 95 53 What types of seasonal influenza vaccines exist? 97 54 How are viruses chosen for the vaccine each year? 98 55 How are vaccines produced in chicken eggs? 99 56 How are vaccines produced in cultured cells? 100 57 How effective are influenza vaccines? 101 58 Is influenza vaccination cost-effective? 102 59 Who should be vaccinated annually? 103 60 Should seasonal flu vaccination be repeated every year? 104 61 When should the vaccine be given? 105 62 Should healthy people be vaccinated? 106 63 Should children be vaccinated? 107 64 Should healthcare workers be vaccinated? 108 65 Does influenza vaccination also protect against other diseases like the common cold? 110 66 Does vaccination cause side effects? 111 67 Can you get influenza from the vaccine? 112 68 How many people are vaccinated annually? 113 69 Where can I get the seasonal influenza vaccine? 115 70 What is the role of family doctors in influenza vaccination? 116 71 What is the role of pharmacists in influenza vaccination? 117 72 What are the drivers for influenza vaccination? 118 73 What are the barriers for influenza vaccination? 120 74 Does the seasonal influenza vaccine protect against pandemic influenza? 121 75 What is a pandemic influenza vaccine? 122 76 What is an adjuvant? 123 table of content 9

77 What is pre-pandemic influenza vaccination? 124 78 Can we be vaccinated against pandemic influenza now? 125 79 Will there be enough pandemic vaccine? 127 80 Who should be vaccinated first during a pandemic? 128 81 What are pneumococcal vaccines and should they be stockpiled for pandemic influenza? 130 82 What are the most common misconceptions about flu and flu vaccines? 131

IX All about antiviral drugs

83 What are antiviral drugs against influenza? 134 84 When should antiviral drugs against influenza be used? 136 85 How effective are antiviral drugs against seasonal, avian, and pandemic flu? 137 86 Should we stockpile antiviral drugs against pandemic influenza? 139 87 Should antibiotics be used against influenza? 140 88 Should antibiotics be stockpiled for pandemic influenza? 141

X How to prepare for an influenza pandemic

89 What is an influenza pandemic preparedness plan? 144 90 What are pandemic alert phases? 145 91 What is the role of international health organizations in pandemic preparedness? 147 92 What is the role of your government in pandemic preparedness? 149 93 What is the role of healthcare workers during an influenza pandemic? 151 94 What is the role of pharmaceutical companies before and during an influenza pandemic? 152 95 What can you do personally to prepare for an influenza pandemic? 153 96 Will schools and workplaces be closed during an influenza pandemic? 154 10 All you need to know about influenza

XI Who monitors influenza spread and why?

97 What is the role of the World Health Organization in influenza surveillance? 158 98 What other international organizations play a role in influenza surveillance? 160 99 What about animal influenza surveillance? 161

XII What’s more?

10 0 What aspects of epidemic and pandemic preparedness need further research? 164 101 Where can I find the most essential flu info on the Web? 166

Biography 167 Acknowledgements 168 11

Foreword Flu, flu epidemics and why primary care matters more than ever

Not that long ago, epidemics were considered a the president of the World Organization of Fam- public health problem of the past in developed ily Doctors, Wonca, I congratulate ESWI with this societies; it was a nostalgic past for that matter, excellent publication, and I would like to take the full of reminiscences of practitioners and health opportunity to summarize the role and position of officers who sometimes imposed, from their limited primary care and family doctors, in the orchestra- understanding of the patho-physiology of infection of societies’ response to flu epidemics. Five tious diseases, draconic measures on individuals core components define this: and populations.  Prevention as an integral part of treatment and care. Vaccination – in particular of those at highest Since the emergence of HIV/AIDS, and in particu- risk – requires careful liaison with flu monitoring, to lar since the recent SARS and bird flu epidemics, select the best vaccine strains and the most ap- a different perspective has developed: individual propriate timing of vaccination. But also once an healthcare, in which patients take the initiative to epidemic has broken out, prevention is the best contact a medical practitioner when they fall ill, is treatment, with isolation and hygiene measures. an insufficient platform to orchestrate a valuable This asks for a strong primary care – public health response to epidemics. Effective responding will interaction. only be possible when individual healthcare is an  Governance of the healthcare system. The com- integral part of an organization to secure preven- munity is the preferred place to treat those who tive and pro-active measures. have contracted flu, unless vital support warrants hospitalization. This makes it possible to keep This book brings together the expertise of the those with an acute infection away from the most European Scientific Working group on Influenza vulnerable. And in case (suspected) cases have to (ESWI), and its international leaders in the field be seen in hospitals – where by definition vulnera- of infectious diseases and primary care/general ble patients tend to be concentrated – pre-emptive practice. In 101 Questions and Answers it pres- precautions must be taken. This asks for a strong ents valuable background information on flu and interaction of primary care and hospital care. its potential of causing pandemics. Providing this  Leadership is required to explain and maintain user-friendly information is in itself part of the preventive arrangements towards individuals and orchestrated response, and the timing of its pub- the community at large. The two most unwelcome lication could not have come at a better time. As public responses – panic and undue phlegmatic – 12 All you need to know about influenza

threaten preventive measures, and family doctors In our preparations, the information presented in the local community should make all reasonable in this book is timely presented. I trust it will give efforts to raise awareness and understanding of family doctors and other primary care professionals their patients. This asks for a well-established inter- around the world the support they need, to serve action with the local community. their patients and populations.  Inter-sectorial actions – are vital in identifying and containing epidemics. Agriculture and the Chris van Weel travel industry are obvious examples, but each Professor of family medicine community is different and detailed knowledge of Radboud University Nijmegen Medical Centre, a community’s infrastructure can support shaping The Netherlands and fine tuning of measures. This asks for knowl- President World Organization of Family Doctors, edge of the social determinants of health in the Wonca community.  Access to and equity in the provision of care are the key to fulfilling this role. Patients with (worries of) suffering from flu, should be able to find timely health care – but without undue risk for themselves or others. And even at the height of a flu epidemic, a substantial number of patients will need care for other than flu-related illness. This is particularly true for patients with chronic diseases. Keeping the healthcare system functioning for its overall objectives, and guaranteeing access to those in greatest need, is the most fundamental contribution of primary care and family doctors. It asks for a strong team in the community. 13

Preface

This book was commissioned by the European Sci- Nothing is more enjoyable than concrete cases entific Working group on Influenza (ESWI), a multi- from daily practice. That is exactly why this book is disciplinary group of key opinion leaders who aim accompanied by an audio CD. In ten short tracks, to combat epidemic and pandemic influenza. The Prof Ab Osterhaus speaks about his long standing group was founded in 1993 and focuses on com- experience as a ‘virus hunter’, policy adviser and munication to achieve its goals. This book is part of influenza expert. If an article in the book is marked that strategy. with , this implies that the audio track with that 101 Questions and Answers on Influenza is a number links up with the content of that article. major work of reference for anyone with an interest in `flu’. Its multilayered structure makes it easily Enjoy reading! accessible for both the interested lay person and healthcare providers who are confronted with influenza patients in their daily practice. In addition, The authors the Q&A concept allows the reader to quickly `zap’ through the information on flu as a moving target. Whenever unfamiliar medical or scientific terms appear, cross-references allow the reader to quickly acquire the necessary information.

All you need to know about influenza 15

I All you need to know about influenza 16 101 questions & answers on influenza 1 In 1882, the Russian researcher Dmitri Ivanovsky showed for What is a virus? the first time that tobacco mosaic disease infectivity could successfully be passed through a bacterial filter. In 1899, the Dutch microbiologist Martinus Beijerinck was the first to use the word ‘virus’ to describe the infectious agent causing this disease as an agent smaller than a bacterium. It wasn’t before 1933, when the first electron microscopes were used, that viruses could actually be made visible. Indeed, viruses are particularly small: they range in size from about 20 to 400 nanometres in diameter (1 nanometre = one millionth of a millimetre). The diameter of an influenza virus, for instance, ranges between 80 and 100 nanometres. This means that if the surface of a pinhead were a soccer pitch, an influenza track   virus would be about the size of a ping pong ball. Since viruses lack the machinery to reproduce autono- mously, they are formally not to be considered living organisms. In fact, they are little more than a complex of DNA or RNA molecules surrounded by protein molecules. This complex sometimes is enveloped in a lipid membrane in which again proteins are present. A virus requires a living cell to replicate, or better to have itself reproduced. Therefore,

Tobacco Mosaic Virus — magnification: x34,000 All you need to know about influenza 17

outside of a living cell, a virus is no more than a dormant particle; whereas within an appropriate host cell, it becomes an active entity capable of redirecting the cell’s metabolic machinery for the production of new virus particles.

Dmitri Ivanovsky (1864-1920) 18 101 questions & answers on influenza 2 Viruses, bacteria, and parasites are commonly called germs or What are the microbes, although the latter term would better be reserved for self-replicating organisms. Germs are everywhere in our differences environment and are found in the air, water, soil, food, plants, animals, and on just about every surface. The human body is no between viruses, exception, as germs are present on its surface, but also within bacteria and it. These germs range in size from viruses which are sub-microscopic, to single-cell organisms like bacteria and finally para- parasites? sites. Parasites, for their part, range from microscopic creatures (like malaria parasites) ranging from mites to worms that can grow to several feet in length. Bacteria are complete one-cellular organisms that contain DNA and RNA and are visible with a microscope. They’re shaped like track  short rods, spheres or spirals. Bacteria are self-sufficient: they generally don’t need a host cell to reproduce and they multiply by dividing themselves. Among the earliest forms of life on earth, bacteria have evolved to thrive in a variety of environments. Some can withstand searing heat or frigid cold, and others can survive radiation levels that would be lethal to humans. Several bacteria, however, prefer the mild environment of a human or animal body. Not all bacteria are harmful. In fact, the vast majority is not. Many bacteria that live in the bodies of humans and animals are actually beneficial. For instance, Lactobacillus acidophilus — a harmless bacterium that resides in human intestines — helps digest food, destroys or competes with some disease-causing organisms and provides nutrients to the body. A good equili Lactobacillus Acidophilus, a harmless brium within the bacterial flora of the intestinal tract is therefore bacterium that helps digest food considered of utmost importance. Pathogenic bacteria, however, may cause disease in several ways. They may invade and colo- nize tissues and organs and in some cases they produce toxins — powerful chemicals that damage specific cells in the tissue they’ve invaded and beyond. The organism that causes gonor- All you need to know about influenza 19

rhoea (gonococcus) is an example of a bacterial invader. Others include certain strains of the bacterium Escherichia coli — better known as E. coli — which may cause severe gastrointestinal illness and are most often contracted through contaminated food. Bacteria may also cause secondary complications in tissues that have already been damaged by a virus infection, like pneumonia secondary to a primary respiratory virus infection. Viruses, in their simplest form, consist of a DNA or a RNA molecule surrounded by protein molecules. Their main mis- Plasmodium, a protozoan parasite causing sion is to replicate in order to perpetuate themselves. However, malaria in humans. Mosquitoes are the unlike bacteria, viruses aren’t self-sufficient — they need a vector transmitting the deadly parasite, suitable host cell in which to reproduce. When a virus invades which then causes the disease. a host, it enters its cells, taking over to a lesser or greater extent the metabolic machinery and instructing these host cells to make what it needs for viral reproduction. Host cells may eventually be destroyed during this process, although certain viruses may persist in host cells without causing any damage to the cell or organism. Polio, measles, AIDS, influenza and SARS are examples of viral diseases. Parasites are complete organisms that contain DNA and RNA. They live together with a host organism from which they benefit, while the host organism suffers negative effects. They may be transmitted between different hosts, possibly including humans. Several parasites have emerged as significant causes of disease. These organisms live and reproduce within the tissues and organs of infected human and animal hosts, and are often excreted with the faeces. Parasites are of different types and range in size from tiny, single-celled, microscopic organisms (protozoa) to larger, multi-cellular worms (helminths) that can be seen without a microscope. Parasites do not always live inside their hosts: for instance fleas and lice are so-called ectoparasites as they live on the exterior of their hosts. 20 101 questions & answers on influenza 3 A universal system for classifying viruses and a unified tax- How are viruses onomy were established by the International Committee on Taxonomy of Viruses (ICTV) in 1966. The system is regularly classified? updated on the basis of new scientific data and insights and makes use of a series of ranked taxons that was originally introduced by the Swedish Father of Taxonomy, Carolus Linnaeus (1707-1778), for the classification of all living organisms. Hence, influenza viruses are classified as RNA viruses belonging to: Family: Orthomyxoviridae Genus: Influenza virus A, B and C Species: Influenza A, B and C viruses Within the group of influenza A viruses, which is also called the influenza A virus type, different subtypes such as H3N2, H5N1… have been identified (see Q9). The most recent (2005) Eighth Report of the ICTV lists more than 5,400 viruses in 1938 species, 287 genera, and 73 families. All you need to know about influenza 21 4 On the one hand, viruses are extremely primitive since they How do viruses have only very limited genetic information that does not allow them to exist independently from living cells. On the replicate? other hand, they are extremely efficient and well equipped to exploit the metabolic machinery of their host cells for their own replication: once they infect a cell by either getting inside or by bringing their genetic material inside, they hijack the cell’s natural production systems to produce the components needed for the construction of new viruses. In general, there is no benefit to the cell or the organism, and in many cases this process harms the cell by hindering its own production of components or structures that it needs to function properly. Not to mention that it may lead to the track  death of the cell either by mere exhaustion or, once enough copies of the virus have been made, by bursting out of the cell, killing it outright in the process. 22 101 questions & answers on influenza 5 Virus particles (called virions) always consist of two main What do viruses components: 1 Nucleic acids — the RNA or DNA molecules that harbour look like? all the genetic information necessary for replication and persistence of the virus and which is unique to each individual virus, 2 Protein — that surrounds and protects the nucleic acid and is structured to form the so-called capsid or nucleocapsid together with the nucleic acid. Most viruses have a number of different proteins, although in the simplest form only one protein is sufficient.

track 

Ebola virus belonging to the Filoviridae family

In some viruses, this basic structure is enveloped in a lipid membrane or envelope that also contains proteins. These viruses are called enveloped viruses as opposed to those without an envelope, which are called naked viruses. Viruses come in many different forms and sizes and many of them have fascinating appearances based on regular multi-facetted geometrical figures that are energetically the most efficient way to package the respective components. They may also look like elongated or looped structures and may have all kinds of different additional features such as spikes. Many viruses are multi-sided and while some are Human immunodeficiency virus (HIV), oval, others may be rectangular with spherical envelopes. causing AIDS in humans All you need to know about influenza 23 6 Influenza viruses belong to the RNA viruses and the family What do of Orthomyxoviridae. Their shape is usually spherical with a diameter of 80-120 nm (nanometres). There are some 500 influenza viruses distinct spike-like surface projections protruding from the envelope, each projecting 10 to 14 nm from the surface. look like? There are 3 distinct types of influenza viruses: types A, B and C. They are distinguished on the basis of lack of cross- reactivity in certain laboratory assays. The genome consists of 8 (type A and B viruses) or 7 (type C virus) segments of RNA joined together with the nucleoprotein, thus forming the nucleocapsid.

Cross-section of an influenza virus 24 101 questions & answers on influenza 7 Viruses can, in principle, be found in all living cells, including Which organisms those of multicellular animals and plants, but also in unicel- lular organisms such as protozoa and bacteria. Although can be infected many viruses may cause disease in their host organisms, certainly not all do and some only under specific conditions with viruses? or circumstances. After all, the primary aim of a virus is not to negatively affect or even kill its host. As a matter of fact, a rule of thumb is that after a first introduction period in which it initially needs to ‘enter’ the host, the longer a virus man- ages to adapt to its host, the less pathogenic it eventually will become due to a process of mutual adaptation. Human herpes viruses, for instance, have co-evolved with humans and their other primate ancestors for probably millions of years, and co-exist with their host in almost perfect harmony, as long as their immune system is functioning adequately. The Ebola virus, by contrast, is poorly adapted to humans, since its kills the vast majority of infected humans within days. Generally speaking, one could say that the better a virus and its host are adapted to one another, the less likely the virus is to cause disease.

E.coli bacterium attacked by viruses. Many yellow viruses are seen, each with a swollen head and a tail. Magnification: x15,250. All you need to know about influenza 25 8 Virology is the discipline that studies viruses and their Which scientific effects on living creatures. It is a relatively young discipline, which originated from microbiology. Microbiology itself disciplines study emerged at the end of the 19th century, when the first bacteria were identified as infectious agents that cause viruses? major diseases in humans, animals and plants. From the second half of the 20th century onward, virology started to become a full-fledged discipline, with virologists devot- ing their scientific interests and studies solely to the study of viruses and their effects on their hosts. Obviously, there are now many other disciplines that study certain aspects of viruses, and their direct and indirect interactions with living creatures. Pathology, electron microscopy, molecular track  biology, immunology and epidemiology are among the best examples.

Virology researcher at work, adding turkey blood cells to samples of influenza viruses of unknown strains. 26 101 questions & answers on influenza 9 There are three types of influenza viruses: A, B, and C. They What are the are distinguished on the basis of lack of cross-reactivity in certain laboratory assays. Influenza type A viruses are existing types, divided into subtypes and named on the basis of two proteins on the surface of the virus: haemagglutinin (HA or H) subtypes and neuraminidase (NA or N). For example, an ‘H7N2 virus’ and clades of designates an influenza A subtype that has H7 and N2 as its surface proteins. Similarly an ‘H5N1’ virus has the H5 influenza viruses? and N1 proteins. To date, 16 H subtypes and 9 N subtypes have been identified in influenza A viruses. Many combinations of H and N proteins are possible, the majority of which has been identified in waterfowl. Strains within subtypes of influenza viruses are formally described according to their type (A, B, or C), host species, location of first isolation (city or country), strain number (if any), year of first isolation, and antigenic subtype (H and N designation); shorthand methods of identification are limited to the H/N description. For example: influenza virus A/eq/Prague/56(H7N7) is a type A influenza virus, from a horse, isolated in Czechoslovakia in 1956 that has H7 and N7 as its surface proteins. All you need to know about influenza 27 10 Wild birds are. In principle, all subtypes of influenza A vi- Which animals ruses can be found in them. Typically, little or no disease is caused by infection of wild birds with these avian influenza are the natural viruses, which are therefore called low pathogenic avian influenza (LPAI) viruses (see Q32). However, when LPAI hosts of influenza viruses of the H5 or H7 subtypes are transmitted to domes- A viruses? tic poultry, such as turkeys and chickens, they may acquire mutations in their HA, by which they change into so-called highly pathogenic avian influenza (HPAI) viruses. These HPAI viruses then cause very severe disease outbreaks in domestic poultry, of which up to one hundred percent may die. Such viruses can also cause serious disease and death when transmitted to wild birds, although some avian species have track  recently been shown to be less susceptible.

Wild birds are the natural hosts of influenza A viruses. 28 101 questions & answers on influenza 11 In certain domestic mammalian species, influenza A virus infec- What other tions cause a major burden of disease.

species can be Pigs can be infected by avian and human influenza A viruses as well as by true porcine influenza A viruses that have been infected with circulating in pigs: over the years, several swine flu viruses have influenza A emerged. Currently, the main circulating influenza A viruses in pigs are of the H1N1, H1N2, H3N1 and H3N2 subtypes. Here it viruses? is interesting to note that the swine influenza viruses circulating in America are different from those circulating in Europe and Asia. This is due to the rather limited volumes of pigs transport- ed between the continents. As pigs are susceptible to infection with both avian and mammalian/human influenza A viruses, track  their intermediary role readily seems to allow for the exchange of genome segments (reassortment, see Q14) between viruses of both origins. This process may result in a completely new virus with pandemic potential (see Q40). The recent outbreak of ‘Mexican flu’ indeed indicates that pigs may play an important role as ‘mixing vessels’, since this new influenza A H1N1 virus is a reassortant between different swine viruses, which eventually are all of avian origin.

Equine influenza is currently caused by influenza A viruses of the H3N8 subtype and less frequently of the H7N7 subtype. These viruses, originating from the avian world, have adapted to horse to horse transmission and have thus become real horse viruses. They affect horses, donkeys, mules, and other members of the Equidae family. Equine influenza is widespread and only Iceland, New Zealand, and Australia are considered to be free of the virus. All you need to know about influenza 29

Dogs may become ill with a specific type A influenza virus referred to as a ‘canine influenza virus’. An influenza A virus of the H3N8 subtype that originated from an equine (horse) influenza virus has now developed into a virus that can spread from dog to dog. It causes severe and even fatal disease in dogs in the USA. Domestic dogs may be infected naturally with the highly pathogenic avian influenza HPAI- H5N1 virus (see Q31) by eating infected wild birds or by eating raw poultry. While the infection in cats is fatal in many cases, the course of the infection generally seems to be milder in dogs although fatal cases have also been reported.

Cats can be infected with human influenza A viruses without showing clinical signs. Both domestic cats and large felids such as tigers and leopards are also susceptible to infection with the HPAI-H5N1 virus (see Q31), often with a fatal outcome. The HPAI-H5N1 virus causes systemic infection in the cats, implying that the infection spreads throughout the body, with the lungs and liver being among the most severely affected organs. The virus has been shown to spread from cat to cat, which may at least in part be related to the excretion pattern of the virus and the social behaviour of the animals. It is likely that cats are infected in endemic areas by catching and eating infected wild birds or by eating raw poultry. In fact, to date, more cats have died from the HPAI- H5N1 virus infection than humans. Since cats infected with the HPAI-H5N1 virus excrete the virus from their throat and with their faeces, cats may pose a risk of spreading the virus to other animal species, including domestic poultry and humans in endemic areas. 30 All you need to know about influenza

Several wild carnivores such as foxes, stone martens and mink are also susceptible to infection with the HPAI-H5N1 virus. These predatory mammals have feeding habits similar to those of feral cats and dogs and most likely acquire the infection by eating the raw meat of infected birds. All about influenza viruses and … 31

II All about influenza viruses and the disease influenza 32 101 questions & answers on influenza 12 The word ‘influenza’ derives from Medieval Latin, where Where does the ‘influencia’ meant a liquid or flow emanating from the stars, and this fluid was believed to control human affairs. When word ‘influenza’ ‘influencia’ became ‘influentia’ in Italian, its meaning narrowed to any epidemic or sickness attributed to the come from? stars, so diseases were referred to as ‘influentias’. In 1658, an observer wrote: ‘suddenly a Distemper arose, as if sent by some blast from the stars, which laid hold on very many together: that in some towns, in the space of a week, above a thousand people fell sick together.’ Evolution in medical thought led to its modification to ‘influenza di freddo’, meaning ‘influence of the cold’, referring to the disease’s link with the winter season. By the 18th century, the word ‘influenza’ had become the prevalent terminology in the English- speaking world as well.

In the Middle Ages, influenza was a disease attributed to the stars. All about influenza viruses and … 33 13 Seasonal influenza or ‘winter flu’ outbreaks occur annually What are the in humans in the moderate climate zones, and are currently caused by one of the two subtypes of influenza A viruses, different forms of H1N1 or H3N2, or by an influenza B virus. These viruses have managed to circulate among people for many years by human influenza? constantly escaping from the immunity that builds up in the population while they are spreading. The mechanism involved in this escape is called antigenic drift (see Q14). Seasonal influenza may be a serious illness, especially in people at an increased risk of developing complications following influenza (see Q16). Fortunately, effective vaccines and antivirals (see Q49) against seasonal influenza are available. Avian influenza, or bird flu, refers to sporadic cases of influenza in humans that are caused by avian influenza viruses that naturally infect birds. Waterfowl, such as ducks and geese, are the natural reservoir of avian influenza viruses and in these birds most of these viruses are low pathogenic avian influenza (LPAI) viruses (see Q32) that are present in their gastrointestinal tract, causing little if any signs of disease. These viruses are excreted with their faeces into the environment, from where they may infect other animals, including domestic poultry such as chickens and turkeys. LPAI viruses of the H5 and H7 subtypes may develop by mutation in these domestic poultry into highly pathogenic avian influenza (HPAI) viruses that can cause severe disease and up to 100% mortality. Although avian influenza viruses are in principle avian or bird viruses, they occasionally cross the species barrier to infect several species of mammals includ- An estimated 5 to 15 % of the population ing humans. Such sporadic avian influenza virus infections in becomes infected with seasonal influenza humans are usually limited to one or a few individuals and each year. do not spread further in the human population. However, if 34 101 questions & answers on influenza

these sporadic avian influenza virus infections were to start to spread efficiently from human to human, an influenza pandemic could be imminent. Pandemic influenza refers to the emergence of a major new subtype of influenza A virus against which the entire human population has little or no immunity (see Q16), thus allowing the virus to spread worldwide rapidly. This is also the reason why infection with a pandemic virus is likely to cause a high burden of severe disease and death in the human population (see Q44). Influenza pandemics have probably occurred every 30 to 40 years in history and have been X-rays of human lungs, infected with H5N1 caused by avian viruses that had not only acquired the abil- avian influenza virus. ity to cause serious disease in humans, but also to spread efficiently among them after a process of re-assortment or sequential mutation (see Q14). After an influenza pandemic, the pandemic virus then reappears annually as one of the seasonal influenza viruses that, through a process of constant mutation, manage to escape from the immunity that continually builds up in the human population. Although gastrointestinal symptoms may be part of the clinical presentation of influenza, the term stomach flu is a misnomer. It is often erroneously used for an infectious gastrointestinal disease that is characterized by vomiting, diar- rhoea and stomach ache, is highly contagious, and is caused by viruses of other families such as noroviruses.

Hospital during the 1918-1919 Great Flu Pandemic. All about influenza viruses and … 35 14 Influenza viruses in humans change constantly which allows How do influenza them to sustain themselves in the human population. Anti- genic drift allows seasonal influenza epidemics to take place viruses change? every year, while antigenic shift, caused by re-assortment or sequential adaptive mutation, results in worldwide outbreaks of influenza in humans (pandemics) from time to time. Antigenic drift is caused by small changes in the virus that happen continually over time. After all, the replication of viral RNA is an error-prone process and any new viral RNA genome copies will contain one or more mutations. Depending on the nature of the mutation, the new virus may or may not ‘survive’, and if it ‘survives’ may or may not be recognized by the host’s pre-existing immune defences that track  were educated by previous influenza virus infections. This process works as follows: a person infected with a particular influenza virus strain develops antibodies against that virus. As newer virus strains appear, the antibodies against the older strains no longer recognize the newer virus, and re- infection is possible. This, together with the fact that several seasonal influenza viruses circulate at the same time — currently two influenza A virus subtypes and one influenza B virus — is why people can get seasonal flu more than once. Each year, the three virus strains in the influenza vaccine are updated to keep up with the changes in the circulating influenza viruses (see Q54). Therefore, people who want to be protected from the flu need to get their flu shot every year. Another type of change — and of even greater public health concern — is called antigenic shift. Antigenic shift is an abrupt, major change in the circulating influenza A virus subtype, carrying a new haemagglutinin and/or new haemagglutinin and neuraminidase proteins. This may happen 36 101 questions & answers on influenza

when an avian and a mammalian (human) influenza A virus simultaneously infect one mammalian host — e.g. a pig or a human — and their genome segments are shuffled like a deck of cards, resulting in a virus with a new combination of genome segments, with the H (and N) segments being of avian origin. When the associated new H (and N) surface proteins have not been in the human population before, there are no antibodies against them in the population, which could allow the virus to spread rapidly. Consequently, a new influenza A virus is introduced in the human population, often with devastating consequences such as a pandemic outbreak of influenza. Another way in which an antigenic shift may arise is through a process of sequential adaptive mutation of a virus that repeatedly crosses the species barrier from birds to mammals. This may lead to the gradual adaptation of the virus to the mammalian species, allowing it eventually to spread efficiently from mammal to mammal. This may happen directly in humans, or in another mammalian species such as the pig or cat, from which it may then be transferred to humans and become a real human virus. All about influenza viruses and … 37 15 Influenza viruses usually enter the body by attaching to cells How and where of the respiratory tract or tissues around the eye (conjunc-ti- vae). The virus subsequently enters the cell and in so doing do influenza releases its genetic information (RNA) and some essential proteins into the cell. This contains a complete blueprint for viruses enter the production of new viruses by the cell’s machinery. Thus, the human body? virus is replicated by the cell and numerous copies of the virus are produced. Since small mistakes take place during this copying process, small mutations or changes may occur in the new generation of viruses. The newly produced virus particles are released from the membrane of the cell, which itself eventually dies in most cases. The released viruses will subsequently infect neighbouring or other cells of the respiratory tract. If this process continues without limit, soon all of the susceptible cells of the respiratory tract disappear and the patient dies. However, the body’s immune response rapidly responds to the onslaught by the invader. The infected cells themselves produce several protective molecules that hinder or even stop replication of the virus. In response to the ongoing invasion, killer cells are attracted from the blood stream that will recognize the infected cells as ‘foreign’ and kill them or produce mediators that will stop replication of the virus. This results in inflammation of the tissue of the respiratory tract and starts within hours after the invasion takes place. Soon thereafter, cells that specifically recognize the virus and kill the cells are activated, while other cells start to produce specific antibodies that neutralize the virus as it is released (see Q16). The death of many cells of the respiratory tract and the associated inflammation results in the first symptoms that may already start within 24 to 48 hours after the first virus enters the respiratory tract. 38 101 questions & answers on influenza

While human influenza viruses tend to preferentially attach to and infect cells of the upper respiratory tract, avian influenza viruses such as the HPAI-H5N1 virus (see Q31) tend to preferentially target cells deep in the human lungs. This may at least in part explain why the HPAI-H5N1 virus has not thus far infected more than several hundred people and why human-to-human transmission has been limited. The H protein, with which avian viruses attach to cells of the respiratory tract, and the N protein on the virus membrane, would probably need to mutate to allow the virus to efficiently transmit from human to human and become a human pandemic virus. All about influenza viruses and … 39 16 When a foreign pathogen such as an influenza virus invades How does the the body, several protective mechanisms combat it. The infected cells start to produce special molecules to hinder or body combat even stop replication of the virus. In response to the ongoing invasion, the body’s immune system is activated to com- influenza? bat the invader. The immune system consists of a complex network of closely interacting cells that can kill abnormal cells and produce a large variety of mediators. Collectively, this network of cells and their mediators recognizes and destroys the invading pathogen. This immune system can be divided into two compartments: the innate and adaptive immune systems. The innate immune response can be considered to be the track  first line of defence. This response does not require prior exposure to the infectious agent. Several cell types, among which the natural killer (NK) cells are particularly important, respond to the invasion by recognizing the intruder or its products as foreign or by recognizing abnormally altered cells, and by subsequently killing the cells or secreting complex mixtures of mediators such as lymphokines and cytokines that further activate other cells of both the innate and adaptive immune responses. The adaptive immune response kicks in later, when enough time has elapsed to allow specific recognition of the invading virus by specialized cells, and the subsequent Natural killer cell secreting a mix of action of this response is specifically targeted towards the mediators to destroy attacking viruses. specific virus. This targeted action is more effective and targeted than the innate response. Adaptive immunity may be divided into two main components: J Humoral immunity: B lymphocytes are the effector cells of this type of immunity. They are specialized white blood cells that develop upon specific stimulation by foreign entities 40 101 questions & answers on influenza

such as an invading virus into plasma cells that produce specific molecules called antibodies directed towards specific parts of the virus called antigens. This recognition of antigens by antibodies ensures a highly specific interaction that is also stored in an ‘immunological memory’ (see below). The most effective antiviral antibodies that are thus generated are usually directed against viral surface components and are therefore most effective in inactivating or neutra lizing the virus. J Cellular immunity: T lymphocytes are the effector cells of this type of immunity. They are also specialized white blood cells that, upon stimulation by an invading virus or a cell infected with a virus, and after recognizing those elements as foreign, are activated to carry out their specific functions. There are, in fact, two main subtypes of these T lymphocytes with different functions: T helper (Th) lymphocytes and cytotoxic T lymphocytes (CTL). Th cells help B lymphocytes and CTL in their specific functions: B cells or plasma cells are helped to produce specific antibodies, while the CTL specifically recognize virus infected cells and destroy them. In addition, upon the specific recognition, they also produce a plethora of mediators such as lymphokines and cytokines. Viral vaccines trigger the adaptive immune system by pre- senting the virus against which one wants to induce protection as the entire virus or parts thereof which are either in an attenuated or ‘crippled’ form or an inactivated or ‘killed’ form. When vaccinated, the human body produces anti bodies and specific T cells against the vaccine and therefore also against the virus for which the vaccine is supposed to elicit protection. The body will fight off the infection upon possible later exposure to the actual virus. All about influenza viruses and … 41 17 Symptoms of seasonal influenza usually include a combina- What are tion of the following manifestations of the infection: acute and high fever, coughing, sneezing, muscle aches, runny possible nose, congestion, and extreme tiredness. These symptoms, although often very uncomfortable, are generally not dan- complications gerous or life threatening. However, influenza may also lead of seasonal to more serious complications. High-risk individuals, such the elderly over the age of 60 years, are particularly suscep- influenza? tible to complications such as: J Viral pneumonia J Bacterial pneumonia J Dehydration J Sinus problems and ear infections (primarily in children) J Worsening of pre-existing conditions such as cardiac disease, asthma or diabetes.

In children, influenza frequently leads to complications such as ear infection. 42 101 questions & answers on influenza 18 High-risk individuals who are particularly susceptible to Who belongs serious complications of influenza include: J The elderly. Although it is difficult to give an exact age, to the special the immune system starts to perform less well in people over 50 to 55 years of age and immunity decreases in a non- risk groups for linear way with increasing age. This malfunction becomes influenza? most pronounced in the elderly who are frail. Since the immune system is the key player in the combat against influenza and its complications, this so-called immune senes- cence leads to a higher susceptibility to severe influenza and its complications. Consequently, most flu deaths are seen among the elderly. Annual influenza vaccination as of the age of 50 years is recommended in some countries, includ- track  ing the US. In many European countries, people over 60 or 65 years of age are considered to belong to the high-risk groups. J Individuals over six months of age suffering from chronic heart or lung disease. J Individuals over six months of age having required regular medical follow-up or hospitalization during the preceding year because of a chronic metabolic disease (such as diabetes), kidney disease, blood disorder, or weakened immune system (including people with HIV/AIDS). J In several countries, pregnant women are also considered to among the high-risk individuals.

The above categories of people are at increased risk of In many European countries, people death from influenza or of a severe complication. It is pre- over 60 years of age are considered to cisely for this reason that the World Health Organization be at high risk of developing serious (WHO) strongly recommends that the high-risk groups be complications of influenza. vaccinated against the seasonal flu annually. how influenza virusus spread 43

III How influenza viruses spread 44 101 questions & answers on influenza 19 Seasonal and pandemic influenza are highly contagious dis- How are eases and are spread primarily by coughing and sneezing. When they sneeze, people release tiny droplets of fluid into influenza viruses the air. Those tiny droplets can fly up to 1 metre and infect persons nearby by reaching susceptible cells of the respira- transmitted from tory tract. The virus can also be spread indirectly when a human to human? person touches objects such as door knobs, tap handles or phones that are contaminated with the influenza virus through sneezing or touch. The influenza virus may remain infectious on surfaces for up to three months in cool temperatures, and in water at 0 °C for more than 30 days or in water at 22 °C for up to 4 days. People who are infected with an influenza virus can pass track  along the virus even before the symptoms kick in, and may remain infectious for about five days after they start sneezing. Young children can be infectious even longer and seven days is no exception. how influenza virusus spread 45 20 Many different animals, including birds such as ducks, How are geese, gulls and domestic poultry, and mammals such as pigs, whales, horses, dogs and seals, can be infected with influenza viruses influenza viruses (see Q11). Remarkably, however, certain subtypes of influenza are solely or predominantly found transmitted in certain animal species. Birds, of course, are hosts to all from animals to known subtypes of influenza A virus, but also in birds a pref- erence of certain influenza viruses for certain species does humans? exist. Occasionally, an influenza A virus normally seen in one species crosses the species barrier and causes illness in another species. In humans, this may for instance happen after close contact with birds infected with avian influenza viruses. Notoriously, sporadic infections with highly pathogenic avian influenza (HPAI) H5N1 viruses (see Q31) transmitted from birds to humans in Asia and in Europe have caused at least hundreds of serious infections reported in the past few years, the majority of which were associated with a fatal outcome. Significant human to human transmission of this virus was not observed. Obviously, the main concern is that this could happen and a pandemic outbreak of influenza would thus emerge. It cannot be predicted whether an HPAI-H5N1 virus will indeed be at the basis of a future pandemic. Other influenza A virus subtypes such as the H1, H2, H7, and H9 subtypes are also likely candidates. They may spill over directly from birds, but also from other mammals previously infected by birds, such as pigs, horses, dogs or cats. The adaptation to transmission among humans or other mammals may either happen by acquiring sequential mutations, or by Avian flu viruses may spill over directly a re-assortment event (see Q14). from animals to humans through close contact with infected birds. 46 101 questions & answers on influenza 21 Whether an influenza A virus will be transmitted from birds What are the most to humans primarily depends on two factors: the nature of the exposure to infected birds or their products and the important factors susceptibility to infection with the influenza virus concerned. Initially, it was speculated that humans are relatively unsus- that determine ceptible to direct infection with avian influenza viruses. How- influenza virus ever, in the past decade it has become clear that humans, like other mammals, may be susceptible to direct infection transmission to with several avian influenza A viruses. These infections may directly spill over from birds or via an intermediate mam- humans? malian host. Although to date several hundreds of people have been hospitalized with an HPAI-H5N1 virus infection that in most cases spilled over directly from domestic birds, this number is relatively low given the enormous number of poultry that have been infected in Europe, Asia and Africa to date. Apparently, one only becomes infected after close contact with infected birds. Slaughtering and de-feathering as well as consumption of insufficiently heated or raw meat or blood are important risk factors (see Q38). Swimming in contaminated water is also a risk factor. how to recognize influenza 47

IV How to recognize influenza 48 101 questions & answers on influenza 22 Although they share many symptoms, influenza is not the What is the same as a cold. A common cold is caused by a different virus, often a rhinovirus (belonging to the family of Picornaviri- difference dae), and its symptoms tend to be milder than those of the between flu. Colds are also less likely to cause serious complications. influenza and a common cold? Symptoms Cold Flu Fever Rare Usual; high (37.8°C to 38.9°C occasionally higher, especially in young children); lasts 3 to 4 days Headache Rare Common General Muscle Slight Usual; often severe A stuffy nose is typical of a common Aches, Pains cold, not influenza. Fatigue, Weakness Sometimes Usual; can last up to 2 to 3 weeks Extreme Rare Usual; at the begin- Exhaustion ning of the illness Stuffy Nose Common Sometimes Sneezing Usual Sometimes Sore Throat Common Sometimes Chest Discomfort, Mild to mod- Common; can Cough erate; hack- become severe ing cough how to recognize influenza 49 23 During influenza outbreaks, a doctor can diagnose a case of What is the influenza based on typical symptoms of fever, chills, head- aches, cough and body aches. To complement this clinical difference judgement and prove that the disease is indeed caused by an influenza virus, laboratory investigation is needed. between Virus isolation and subsequent identification and typing are clinical and predominantly carried out by more specialized reference laboratories. Currently, molecular diagnostic tests are used lab-confirmed to rapidly and accurately come to the final diagnosis of influenza A or B. Further identification and typing of the virus diagnosis? involved can be carried out using specific antisera raised in ferrets in so-called serological assays and by further molecular analysis by a specialized laboratory. Rapid diagnostic tests have recently become available and can be used to detect influenza viruses within 30 minutes. These tests do indeed detect influenza, but in most cases do not differenti- ate between the influenza virus types (A or B) involved. The sensitivity and specificity of any test to identify influenza in patients may vary depending on the laboratory involved, the type of test used, and the type of specimen tested. 50 101 questions & answers on influenza 24 Laboratory-confirmed diagnosis of influenza may be indicat- When is a lab- ed to demonstrate the first introduction of seasonal influenza (see Q25) in a certain area, as this may lead to the imple- confirmed mentation of different treatment strategies for respiratory diseases there. In situations in which high-risk people (see diagnosis Q18) may become exposed to seasonal influenza, like in appropriate? nursing homes or hospital wards with immunocompromised patients, diagnosing seasonal influenza may be crucial when choosing the appropriate preventive and therapeutic intervention strategies. It also may reduce the inappropriate use of antibiotics, which eventually leads to the development of resistant bacteria. Because influenza shares many of the symptoms of the common cold and other diseases, getting the diagnosis right is not always easy on clinical grounds. During influenza outbreaks, well-trained general practitioners can identify up to 70% of all influenza illnesses on clinical grounds alone, since the majority of persons seeking medical advice for upper respiratory tract infections are likely to be infected with influenza. To be absolutely sure, confirma- tion by a diagnostic lab test is necessary. All about seasonal influenza 51

V All about seasonal influenza 52 101 questions & answers on influenza 25 Seasonal influenza, often called ‘the flu’, is an infectious dis- What is seasonal ease of the respiratory tract caused by an influenza virus and spread efficiently from person to person. The viruses that influenza? may be involved belong to different influenza A subtypes (currently influenza A H1N1 and H3N2) or influenza B viruses (see Q9). Outbreaks of seasonal flu follow largely predict- able seasonal patterns and occur annually. In the temperate climate zones, they occur predominantly in the winter months and may emerge from late autumn to early spring. A seasonal influenza epidemic in the temperate climate zones usually lasts from six to ten weeks with an average of 2-10% of the population developing clinical influenza. In tropical zones, seasonal patterns may be less pronounced, with more than one peak of infection. All about seasonal influenza 53 26 Although many people think of the flu as a mild annoyance How many that we have to deal with each winter, it can actually be a dangerous disease. During annual influenza epidemics in people get ill or temperate climate zones, an estimated 5-15% of the population become infected and an average of 2-10% of the popu- even die from lation develop clinical influenza. The WHO estimates that influenza each these annual epidemics result in between 3 and 5 million cases of severe illness and between 250,000 and 500,000 year? deaths every year around the world. Most influenza deaths in industrialized countries occur among the elderly over 65 years of age. As a matter of fact, in developed countries, seasonal influenza annually claims more lives than traffic accidents.

Seasonal influenza annually claims more lives than traffic accidents. 54 101 questions & answers on influenza 27 Besides the suffering of individual patients caused by sea- What is the sonal influenza, which also has an impact on society as a whole, several other negative effects on society and its func- social and tioning may take place. Adults missing working days due to influenza represent a considerable proportion of the burden societal impact of influenza. In addition, children and elderly patients may of seasonal need additional care, which may also impact on family and/ or friends. Owing to the rapid onset of influenza symptoms, influenza? there is little time for patients to plan for days or weeks out of action from work, school or other day-to-day activities. This may result in suboptimal functioning or even disruption of usual services, like those provided by hospitals, other healthcare facilities, banks, stores, government offices and post offices. All about seasonal influenza 55 28 Seasonal influenza places a heavy demand on healthcare What is the resources and the economy each year, as a direct result of increased primary care consultations, hospitalizations, economic impact clinical complications and patient treatment. In addition to direct medical costs, the most significant cost of influenza to of seasonal society is the indirect cost of lost productivity and absentee- influenza? ism. In Europe, influenza accounts for approximately 10% of sickness absence from work. Adapting data on health economics to all EU Member States is not easy since local practice patterns in the treatment and management of influenza differ from country to country. Data from individual countries, however, speak volumes. In England and Wales, for example, influenza accounts for over 400,000 general practitioner consultations annually. In England, 11,000 elderly respiratory hospital admissions during epidemics of influenza cost the UK health service over £22 million every winter. It is estimated that in excess of 6 million working days are lost in the UK due to seasonal influenza every year.

In Europe, influenza accounts for about 10% of sickness absence from work. 56 101 questions & answers on influenza 29 The most cost-effective way to prevent influenza is vaccina- How to prevent tion. People who are at a high risk of infection with influenza and are more likely to get complications when infected (see seasonal Q18) are strongly advised to get vaccinated against seasonal influenza every year. The effectiveness of vaccination influenza? is less in people with an impaired immune system, including the elderly who are frail. In healthy adults, influenza vaccination works very well (see Q57). If they would rather not be off with influenza for a week, healthy adults would also clearly benefit from a yearly flu shot. Antiviral drugs can be used to prevent infection with influenza virus and influenza. General practitioners may pre- scribe these drugs when a person in a high-risk group has had a recent exposure to someone with influenza, in order to prevent the infection or mitigate its course. Typically, these drugs may be used during epidemics of influenza to protect still unvaccinated people in nursing homes, or the elderly who are frail and who are vaccinated but may be expected to benefit insufficiently from vaccination. The influenza virus is usually passed on through the air by coughing or by contact, such as when shaking hands or kissing. For this reason, practicing good hygiene can help to avoid becoming infected with the influenza virus or spreading it to others: J Cover your nose and mouth when you cough or sneeze. J Wash your hands often with soap and water, especially after you cough or sneeze. Alcohol-based hand cleaners are Vaccination is the best and safest effective. way to prevent influenza. J Try to avoid close contact with apparently sick people. J If you have the flu, stay home from work or school and limit contacts with others. J Avoid touching your eyes, nose or mouth. Influenza virus may spread this way. All about seasonal influenza 57 30 For most people, influenza is ‘just’ an upper respiratory tract How to treat infection that lasts several days. The main treatment is then to rest adequately, avoid extreme activities and drink plenty. seasonal Normal activities may resume 24 to 48 hours after body temperature returns to normal, but in most people it takes many influenza? additional days to recover completely. Antibiotics, such as penicillin, are designed to kill or inhibit bacteria and do not combat viruses. Therefore, antibiotics have no role in treating influenza in otherwise healthy individuals, although they are used to treat certain complications of influenza caused by bacterial infection (see Q87). Antiviral drugs for influenza are an important adjunct to influenza vaccination for the prevention and treatment of influenza, but they are not a substitute for vaccination. For many years now, antiviral drugs that act by preventing influenza virus replication have been available. They differ in terms of their mechanism of action, side effects, routes of administration, target age groups, dosages and costs. When taken before infection or during early stages of the disease (within 48 hours of onset of the illness), antivirals may help prevent infection, and if infection has already been established, their early administration may reduce the severity of the disease, the risk of developing complications and the duration of symptoms by one to two days. In cases of severe influenza, admission to hospital, intensive care, antibiotic therapy to prevent or limit secondary bacterial infection and symptomatic treatment such as breathing support may be required. In children who are suspected of having influenza, and who have high fevers, the use of aspirin to reduce fever should be practiced only with great care. (To learn more about vaccines, antivirals and antibiotics, also see Q47 and Q49.)

All about avian influenza 59

VI All about avian influenza 60 101 questions & answers on influenza 31 Avian influenza, or ‘bird flu’, is a disease caused by an avian What is avian influenza A virus that normally infects only birds. In fact, all subtypes of the influenza A virus have their origin in wild influenza? birds, which means that influenza is a disease which cannot be eradicated. Waterfowl, such as ducks and geese, are natural reservoirs and many of such wild birds carry low pathogenic avian influenza (LPAI) viruses in their gastrointestinal tract. These birds develop no or minor clinical signs upon infection with these viruses. In domestic poultry, LPAI viruses of the H5 and H7 subtypes may develop into highly pathogenic avian influenza (HPAI) viruses by mutation of their H proteins. Such HPAI viruses cause massive disease outbreaks in domestic poultry with mortality rates of up to track   100%. Avian influenza viruses are viruses of birds that may from time to time cross species barriers to infect mammals, including humans. All about avian influenza 61 32 Pathogenicity is a measure of the extent to which a virus What is the causes disease. Avian influenza is caused by either LPAI or HPAI viruses. LPAI viruses cause very mild disease signs, difference between such as ruffled feathers and reduced egg production, or no signs at all. The highly pathogenic forms are far more low pathogenic dramatic, spreading very rapidly through poultry flocks, with avian influenza mortality that can approach 100%, often within 2-3 days. Only viruses of the H5 and H7 subtypes (see Q9) may mu- (LPAI) and highly tate from LPAI into HPAI viruses. LPAI viruses are introduced into poultry flocks through contacts with wild birds. In poul- pathogenic avian try, LPAI viruses can develop mutations in their HA surface influenza (HPAI)? glycoprotein, by which they become HPAI viruses that cause huge outbreaks of fatal disease in domestic poultry.

track  

In poultry flocks, mortality caused by highly pathogenic avian influenza can approach 100%. 62 101 questions & answers on influenza 33 HPAI-H5N1 viruses cause fatal infections in domestic poul- How dangerous try and also in certain species of wild birds. In these highly susceptible birds, replication of the virus is not localized is HPAI-H5N1 in certain restricted tissues or organ systems but usually disseminates all over the body. These birds spread the virus infection for infection with their excreta and their infected bodily fluids animals? into their environment and thus also to other birds. Preda- tors such as cats and dogs may become infected by eating infected birds or bird carcasses. Certain wild bird species have been shown to be less susceptible to infection with HPAI-H5N1 viruses and subsequent development of serious disease. These include pigeons and certain wild duck species such as the mallard. The latter can be infected and track  subsequently spreads the virus for a number of days from its upper respiratory tract but not with its faeces. Although the amount of virus that is thus excreted is relatively limited and is predominantly found in the surface water, it still is an efficient way of virus spreading as the animals stay alive and in good condition. In addition to birds, an ever-increasing list of mammalian species has been shown to be naturally or experimentally in- fectable with the HPAI-H5N1 virus. These include carnivores such as large felids, domestic cats, civet cats, dogs, and ferrets, but also omnivorous species such as pigs, monkeys and humans. In October 2004, for example, 147 of 441 tigers in a breeding centre in Thailand died or had to be euthanized as a result of infection after being fed infected chicken carcasses. Although cat-to-cat transmission has been docu- mented in both tigers and domestic cats, to date there is no evidence that the virus is efficiently transmitted among any of the above-mentioned mammals, allowing it to become a real mammalian virus. All about avian influenza 63 34 Of the many subtypes of avian influenza A viruses, only four How dangerous are known to cause human infections today: H5N1, H7N3, H7N7, and H9N2. In general, human infection with these is avian influenza viruses has resulted in mild symptoms and few cases of severe illness, with two notable exceptions. The first is for humans? the HPAI-H5N1 virus that has caused serious infections in hundreds of people in Asia, Europe and Africa with a case fatality rate of more than 60%. The other is the HPAI-H7N7 virus that caused a fatal infection in 2003 in a Dutch veteri- narian, who unlike most of the other exposed people, was not treated preventively with an antiviral drug. The other 88 people who developed clinical symptoms associated with H7N7 infection during this outbreak survived the infec- track  tion. The widespread persistence of H5N1 in poultry populations poses two main risks for human health. The first is the risk of direct infection when the virus passes from poultry to humans. Of the avian influenza viruses that are known to have crossed the species barrier to infect humans, H5N1 has caused the largest number of cases of severe disease and death in humans (Unlike normal seasonal influenza, that causes relatively mild respiratory symptoms in most people, the disease caused by HPAI-H5N1 virus infection is usually highly aggressive, with fast deterioration of condition. Pneu- monia and multi-organ failure are common. Many of the fatal human cases have occurred in previously healthy children and young adults. Due to the limited number of autopsies carried out on fatal cases thus far, the pathogenesis of this infection in humans has largely been deduced from reported clinical symptoms and the results of limited laboratory investigations carried out on body fluids sampled before death of the patients. 64 101 questions & answers on influenza

The second risk, of even greater concern, is that the virus will eventually change into a form that is highly infectious for humans and spreads easily from person to person. Such a change could mark the start of a pandemic influenza virus outbreak. Some experts in the field would argue that the HPAI-H5N1 virus has been around in humans for more than a decade now, and that it has had ample opportunity to become a pandemic virus. As it has still not happened, it would be highly unlikely to occur at all. In contrast, it could also be argued that the virus has probably not infected more than1000 to 2000 people, which is not a sufficiently high number to allow it to develop into a pandemic virus by sequential mutation or re-assortment (see Q14). Paradoxi- cally, it may be speculated that if the HPAI-H5N1 virus became less aggressive and less lethal, it would actually have a greater chance of becoming a pandemic virus since it could start spreading more efficiently among people. All about avian influenza 65 35 Domestic poultry may become infected with avian influenza How does avian viruses (LPAI and HPAI) in several ways. It may happen through direct contact with infected waterfowl or other infected poul- influenza spread try or through contact with contaminated materials such as dirt on cages containing contaminated faeces or other excreta among animals? or feed contaminated with excreta. LPAI viruses are predominantly spread with the faeces of usually healthy infected birds, whereas HPAI viruses may be excreted with all the excreta of severely affected birds or from the respiratory tract of mallards and other less susceptible wild birds. The LPAI viruses of the H5 and the H7 subtypes can accumulate mutations in the HA to become HPAI viruses in poultry. Several mammalian species can also be infected with LPAI or track   HPAI viruses. These include several carnivores but also omni- vores such as pigs, monkeys and humans. In Germany, a highly Avian influenza is primarily spread pathogenic avian influenza was detected in a domestic cat by migratory waterfowl found dead on the northern island of Rügen in 2006. By that time, over 100 birds had died on the island from infection with an HPAI-H5N1 virus. The cat most likely contracted influenza by eating raw meat from these infected birds. To date, more domestic cats have died from H5N1 than humans. However, there is no evidence that this virus is efficiently transmitted among any mammals, which probably would allow it to become a real mammalian virus. Next to being spread by migratory fowl, avian influenza viruses are also spread by trade involving birds and their products. This may happen for instance through trade in live exotic birds, chicks, eggs, (frozen) meat, bones, feathers and used cages. Such products and practices may indeed bring avian influenza into a country: infected chicken parts used in feed or fertilizer, second-hand cages used to house infected birds, or meat that is used on a farm or in a home where other birds are kept. 66 101 questions & answers on influenza 36 Yes, they can. Vaccination with high quality vaccines reduces Can birds be the risk of birds becoming infected with HPAI viruses, and helps to decrease the risk of spreading. Vaccination is now vaccinated common practice for the protection of collections of endan- gered bird species in zoos. Yet, veterinary practices usually to stop the prefer to control influenza epidemics in livestock by imple- spread of avian menting extermination strategies, which imply destroying sick, exposed and possibly exposed domestic poultry. influenza? One of the main reasons for reluctance to vaccinate domestic poultry, apart from trade related issues, is that vaccination could mask the introduction and presence of HPAI viruses in vaccinated poultry. In a vaccinated flock, low levels of virus replication may still take place in individual vaccinated birds and spread of the virus from animal to animal may still continue, albeit to a very limited extent. Since vaccinated and subsequently infected birds are not likely to All about avian influenza 67

show any signs of disease, such ‘silent epidemics’ would be hard to spot, and might still be at the basis of new outbreaks among unvaccinated flocks. These problems may be avoid- ed by introducing unvaccinated and well-marked birds in the vaccinated flocks that would immediately show the introduction or presence of the virus by developing disease signs and dying. A second tool to identify ‘silent infections’ in vaccinated flocks is the use of specific assays carried out on blood (serum) samples from vaccinated birds. Infected birds can be identified with such an antibody test that can then distinguish between infected birds and those that have not been infected after vaccination. In any case, when vaccinating poultry, surveillance is crucial. If low quality vaccines are used without adequate monitoring, they can have a boo- merang effect and even contribute to the spread of the virus rather than controlling it. It is important to note that in countries or areas where all the domestic poultry were vaccinated systematically against the HPAI-H5N1 virus for a certain period, such as in Vietnam and Hong Kong, no human cases were observed during that period 68 101 questions & answers on influenza 37 An important strategy to prevent the introduction and What else can be spread of avian influenza is the implementation of bans on the importation of poultry, other birds and their products. done to stop the At least as important are strict controls and strong enforce- ment to curb illegal trade. Illegal wildlife smuggling can spread of avian cause a disaster. In October 2004, for instance, Belgian influenza? custom officials prevented an animal and public health disaster when they stopped a Thai man travelling from Bang- kok to Brussels. He was found to be illegally carrying two live mountain hawk eagles in his hand luggage. The birds were immediately put into quarantine at the airport. They later tested positive for the HPAI-H5N1 virus and had to be euthanized. This case illustrates that international air travel track  and smuggling represent major threats for introducing and disseminating HPAI viruses worldwide. An outdoor ban on domestic poultry during the wild bird migration season is a measure that is implemented in some countries with high densities of free range poultry, to prevent the HPAI-H5N1 virus from spilling over from wild birds. During such a ban, poultry must be kept and fed indoors or under a roof to avoid direct and indirect contacts with migratory fowl and their excrements. All about avian influenza 69 38 The risk of humans catching an HPAI-H5N1 virus infection How can I is low. In spite of the extensive spread of the virus through Eurasia and Africa, which has resulted in many millions of personally infected and culled poultry, a relatively limited number of people have become infected upon contact with infected prevent infection poultry or their products (see Q34). The chances of becom- with the HPAI- ing infected with the HPAI-H5N1 virus in endemic areas are largely associated with risky behaviour. Therefore, people H5N1 virus? who are travelling in areas where the HPAI-H5N1 virus is present in wild birds or domestic poultry need to take special precautions to reduce the chance of exposure. J Avoid direct or indirect contact with birds or their excrements. track  70 101 questions & answers on influenza

J Avoid farms and other places where birds are kept in large numbers. J Avoid live bird markets and contact with poultry excrements and feathers. J Avoid consumption of raw poultry meat and blood. J Avoid raw eggs and foods made with raw eggs (e.g. may- onnaise, ice cream). J Practice strict hygiene: wash your hands frequently and use alcohol-based hand cleaners. Alcohol-based hand cleaning is usually more effective in inactivating bacteria and viruses than hand washing alone. All about avian influenza 71 39 Yes, if sufficiently heated. With proper handling and cook- Is it safe to eat ing, avian influenza presents no food safety hazard. Influenza viruses are sensitive to heat and therefore temperatures poultry and used normally for cooking (>70 °C for several minutes in all parts of the food) will inactivate the virus. Be sure that all poultry products? parts of the poultry are fully cooked and that eggs, too, are properly cooked. Beware of cross-contamination. Juices from raw poultry and poultry products should never be allowed, during food preparation, to come into contact or mix with items to be consumed raw. When handling raw poultry or raw poultry products, persons involved in food preparation should wash their hands thoroughly and frequently and clean and disinfect surfaces in contact with the poultry products. The extensive use of soap or detergents and hot water are sufficient for this purpose.

All about pandemic influenza 73

VII All about pandemic influenza 74 101 questions & answers on influenza 40 Influenza viruses are changing continuously and new strains What is pandemic emerge from time to time. If a new influenza virus subtype, that is very different from all previous viruses, emerges and influenza? causes disease in the human population, people will have little or no specific immunity to it, and consequently this virus may spread quickly and become a worldwide threat. Antigenic drift (see Q14) is caused by small changes in the virus surface proteins that happen continually over time and allow the virus to escape from antibodies that were generated in the population upon infection with previous seasonal influenza viruses. Each year, the virus strains represented in the seasonal influenza vaccine are updated to keep up with changes in the circulating influenza viruses track  (see Q54). Another type of change – of even greater public health concern – is called antigenic shift (see Q14). Antigenic shift is an abrupt, major change in the circulating influenza A virus subtype. This may happen when an avian and a mammalian (human) influenza A virus simultaneously infect one mammalian host – e.g. a pig or a human being – and their genome segments are shuffled like a deck of cards. This results in a virus with a new combination of genome segments. If the surface proteins (H and N) are now of avian origin and have not been ‘seen’ by the human population before, there will be little or no antibodies against such a hybrid human-avian virus in the human population. Consequently, the resulting new influenza A virus may start spreading in the human population, with devastating consequences: a pandemic outbreak of influenza. Another way in which an antigenic shift may arise is through a process of sequential adaptive mutation of a virus that repeatedly crosses the species barrier from birds to mammals. This may lead to the gradual All about pandemic influenza 75

adaptation of the avian virus to the mammalian species, allowing it to spread efficiently from mammal to mammal. This may happen directly in humans, or in another mammalian species such as the pig or the cat, from which it is then transmitted to humans (see Q20). Unlike seasonal influenza, a new pandemic virus can show up any time when the above-mentioned events take place. However, the most favourable conditions for its spread in moderate climate zones are, like for seasonal influenza, present during the winter months. The resulting wave of illness and associated mortality can then spread rapidly across the globe, affecting many millions of people.

The WHO criteria for a pandemic are:  v  x The virus is new for humans and limited or no immunity is present in the human population  v  x The new virus has already infected humans.   x The virus is highly transmissible from human to human.

 v Conditions met by the HPAI-H5N1 virus  x Conditions met by the new H1N1 Mexican flu virus

The World Health Organization has defined different alert phases on the way to an influenza pandemic (see Q90). 76 101 questions & answers on influenza 41 Three influenza pandemics crippled the world during the What are the twentieth century. Of all pandemics, the one that began in 1918 is generally regarded as the most deadly single infec- pandemics which tious disease event in history. Known as the ‘Spanish flu’, the disease killed at least 40 million people worldwide, an have occurred in estimated five times greater loss of life than that caused the past century? by war activities during the whole First World War. The ‘Spanish flu’ swept across the world in multiple waves in 1918 and 1919. More than half of the people killed were 18 to 40 years old and most of them were healthy before this pandemic struck. It has been speculated that their rapid immune response became their downfall: in the process of fighting the disease, their immune system is thought to have track  severely damaged their lungs, resulting in their acute death. However, the way in which pandemic influenza viruses cause severe disease is not yet fully understood. Recent studies have shown that the severity of infections with pandemic influenza viruses as well as avian influenza viruses that are highly pathogenic to humans is largely determined by a complex series of viral and host factors. Some of the viral factors are related to interference with the action of the innate immune system (see Q16). The ‘Spanish flu’ virus (H1N1) had appeared in the US and France before it emerged in Spain. But the WWI allies came to call it the ‘Spanish flu’, primarily because the pandemic received greater media attention after it was introduced into Spain in November 1918. Spain was not involved in the war and had not imposed wartime censorship. The next pandemic influenza virus, the ‘Asian flu’ virus (H2N2) emerged in Asia about 40 years later in 1957. Although the proportion of people infected was high, the illness was relatively mild compared to what was seen during All about pandemic influenza 77

the ‘Spanish flu’, resulting in a lower overall disease burden and fewer deaths. The first wave of the ‘Asian flu’ pandemic was concentrated in school children and the second in the elderly. It is estimated that the ‘Asian flu’ caused between 1 and 4 million deaths worldwide. The most recent pandemic virus of the last century, the ‘Hong Kong flu’ virus (H3N2), probably also originated in Asia in 1968. Whilst it is considered by many experts to have been the mildest of the three pandemic influenza viruses, it killed over eight hundred thousand people in the first six weeks of its destructive course. Besides the direct and early destructive effects caused in the lungs and other respiratory tissues by infection with a pandemic virus, the role and importance of secondary bacterial pneumonias in overall mortality in the respective pandemics has not been fully elucidated. There are several similarities between the 2009 ‘Mexican Influenza poster, displayed in American flu’ and the 1918 ‘Spanish flu’: theatres during the Great Flu Pandemic 1 both have been caused by an influenza A virus of the in 1918. H1N1 subtype 2 both have probably emerged in North America 3 both have probably emerged from avian influenza A viruses that emerged from a domestic pig reservoir 4 both caused relatively mild disease during the first months of their emergence 5 both caused the highest attack rate in relatively young individuals and not in the elderly

A clear difference is that the new H1N1 virus starts to circulate whilst another virus of the same H1N1 subtype is still circulating as a seasonal influenza virus. 78 101 questions & answers on influenza 42 Molecular analyses, including some highly sophisticated stud- What is the origin ies using preserved tissue samples from victims of the ‘Spanish flu’, have provided valuable insights into the origin of the viruses of influenza that caused the pandemics of the last century. The viruses responsible for the 1957 ‘Asian flu’ and 1968 ‘Hong Kong flu’ pan- pandemics? demics were both genetic hybrid (re-assorted) viruses between the previously circulating seasonal human influenza A virus and an avian influenza A virus. In the process of re-assortment, the ‘Hong Kong flu’ virus acquired a new haemagglutinin protein distinct from the avian virus (i.e. the virus became a new virus subtype). Because the human population at that time had not previously been exposed to a similar virus subtype, it was highly susceptible to severe infection compared to the usual seasonal influenza viruses created by continuous mutation of their surface proteins under pressure of the antibodies in the population (i.e. antigenic drift). The 1957 ‘Asian flu’ virus had inherited both a new haemagglutinin and a new neuraminidase surface protein from an avian ancestor virus. It has been speculated that the greater virulence of the ‘Asian flu’ compared with the ‘Hong Kong flu’ virus was related to the introduction of two new surface proteins. There are indications that the ‘Spanish flu’ arose directly through adaptation of an avian influenza virus to humans by a process of sequential adaptive mutation that allowed it to efficiently spread from human to human (see Q14). Whether the process of genetic mixing (re-assortment) was also involved is not entirely clear. The recently emerged ‘Mexican flu’ virus, which is the first pandemic influenza virus of the 21st century, probably came from a swine reservoir in Mexico and is a genetic mix of a North American influenza A swine flu virus and a Eurasian influenza A swine flu virus. It is not clear whether this re-assort- Avian and human flu viruses combining. ment occurred in a pig or in another animal species. All about pandemic influenza 79 43 Yes, there is no reason to believe that there will be no Will there be other influenza pandemics in the future. In fact, the question should not be if, but rather when the next pandemic other influenza will strike. And that question is hard to answer. May be next year, may be in 10 years. As a matter of fact, all of the ingre pandemics dients for generation of a new influenza virus with pandemic in the future? potential are there, particularly in Asia: almost year-round circulation of seasonal influenza viruses and a dense population of people, pigs and domestic poultry in contact with wild birds. In addition, new and more intensive agricultural production systems result in more frequent and intense contacts between people, domestic poultry and wild birds.

track 

The ever increasing number of travellers may contribute to the rapid spread of a new pandemic influenza virus. 80 101 questions & answers on influenza

Currently, humans catch the often fatal H5N1 bird influenza virus infection from infected birds. It may re-assort with a seasonal influenza virus or gradually mutate into a form that spreads easily from human to human. Yet, a new pandemic virus could also arise elsewhere and from an influenza A virus subtype different from H5N1. H9 avian influenza viruses have recently shown their deadly potential in humans in Asia. In addition, the increased world population since the last pandemic, an ever-increasing number of travellers, and large human populations without adequate healthcare are among a complex mix of factors that may favour the emergence of a new pandemic. Unfortunately, it is impossible to predict where and when future pandemics will strike, which virus will be at their basis and how severe their impact on the global society will be. Therefore, early warning systems (see Q97) and pandemic preparedness plans (see Q45) are of critical importance. The recent emergence of the new influenza A virus of the H1N1 subtype from Mexico, a reassortant between different viruses from pigs, had become the greatest pandemic threat since the last influenza pandemic in 1968 (see Q41). Since the ‘Mexican flu’ virus was declared pandemic as of 11 june 2009, pandemic preparations are being updated at the level of national governments, and WHO is coordinating these efforts at the global level. All about pandemic influenza 81 44 Given the uncertainties about the nature of the virus that What is the causes a pandemic, the impact of any influenza pandemic is hard to predict. Mathematical models may give us insight expected into the possible spread and impact of influenza pandemics in different scenarios. And the outcome may be quite impact of future disturbing: a simulation in 383 million people in fifteen EU pandemics? countries plus Switzerland showed that one-third of the Eu- ropean population or more could become ill during the first months. Work absenteeism might reach 15% in the worst week (and even more in case of school closures). In fact, there may be a difference of up to 4-5 weeks in the timing of the peak of the pandemic between the first and the last afflicted country in the EU, and almost the same vari- track  ation between regions within the same country. The average peak of 1,700 daily cases per 100,000 people throughout the EU could be as high as 1,900 for a large country and 2,500 in a local district. The actual number of victims of an influenza pandemic would depend on the severity of the infection and how fast it spreads from one population to another. But even if the impact of the ongoing ‘Mexican flu’ pandemic is still uncer- tain, the World Health Organization (WHO) had estimated that in a best case scenario, 2 to 7 million people would die globally. In developed countries alone, mathematical models project a demand for 134-233 million outpatient visits and 1.5-5.2 million hospital admissions. Obviously, much can be done to slow the spread and mitigate the impact of a pandemic. Such measures should be laid down in a so-called national pandemic preparedness plan that every country should have in place. 82 101 questions & answers on influenza

There are several scenarios that could be envisaged for the further development of the currently ongoing spread of the new influenza A virus of the H1N1 subtype and its pandemic potential. In the first months of its emergence in North America the disease signs and symptoms have been reported to be relatively mild with relatively low mortality. Consequently, one of the following three scenarios is most likely to occur: The ongoing epidemic 1 could stop spreading. Given the spread that has taken place by June 2009, this scenario does not seem very likely. 2 could continue to spread, initially possibly most intensely at the Southern hemisphere, to eventually cause a relatively mild pandemic. This would be a scenario similar to that of the `Asian flu’ or the `Hong Kong flu’. 3 could - upon mutation or re-assortment of the virus - cause a serious pandemic that may be reminiscent of the `Spanish flu’.

Any intermediate scenario is also possible. All about pandemic influenza 83 45 A well-balanced influenza pandemic preparedness plan cov- What are the ers many aspects. In fact, the WHO has urged all its member states to develop their own influenza pandemic preparedness basic elements plans, adapted to their own local needs and healthcare systems. Although several predominantly industrialized countries have in- of pandemic deed developed national influenza pandemic preparedness plans planning? in different stages of completion, most countries would currently be completely unprepared if a pandemic were to strike now. The first distinction to be made is between non-medical and medical intervention strategies. Non-medical intervention strategies may include: J Social distancing measures to reduce contact between adults in the community and workplace. For example, cancel- track  lation of large public gatherings and alteration of workplace environments and schedules. J Another social distancing measure would be school closures to protect school children and to slow the spread of the pandemic virus. J Isolation of all persons with confirmed or probable influenza. Since hospital isolation facilities would soon be overwhelmed, isolation may have to occur in the home setting. J Voluntary home quarantine of household members with confirmed or probable influenza cases. Medical intervention strategies include: J Surveillance, to monitor the emergence and spread of a pandemic influenza virus and to initiate and adapt implementation of the subsequent steps of the pandemic preparedness plan. J Antiviral therapy. Stockpiling doses of antiviral drugs for at least 20% of a country’s population is generally recommended by WHO to treat priority groups and to bridge the time it takes to develop and distribute a pandemic influenza vaccine. An important issue concerning the effectiveness of the use of 84 101 questions & answers on influenza

antiviral stockpiles is the threat that the virus may develop resistance to the compound. Therefore, a strategy of stockpiling more than one antiviral compound, based on different working mechanisms, should be favoured. J Vaccination. Vaccines that protect humans against the circulating HPAI-H5N1 viruses are currently becoming available and are being licensed (see Q77). Most of these vaccines combine the principle of inducing a specific immune response by the inactivated virus or its components with that of a powerful and safe adjuvant that increases this immune response in a non- specific way (see Q76). Some of these vaccines, which have now been shown to provide broad protection against different clades of HPAI-H5N1 viruses, could be stockpiled in prepara- Cancellation of large public gatherings is a tion for the possibility that indeed an HPAI-H5N1 virus is at the possible social distancing measure to slow basis of the next influenza pandemic. In addition, vaccination the spread of a pandemic influenza virus. of groups of people that are crucial for implementation of the pandemic preparedness plan could be considered. Adjuvanted vaccines are designed to build up a person’s immune system against a pandemic influenza virus. Since pandemic viruses need not originate from an HPAI-H5N1 virus, strategies to rapidly generate and produce vaccines against pandemic viruses originating from other influenza A virus subtypes have also been developed, and will hopefully prove to be quite effective in combating the ‘Mexican flu’ virus.

Because a pandemic virus may not be expected to spread in a linear way, the result of the intervention strategy is not a linear function of effort. Therefore, combining multiple non-overlap- ping interventions will have a higher impact than the sum of the individual impacts. What is more, such layered interventions, like combining surveillance with antiviral treatment and vaccination, will be the most effective and failsafe. All about pandemic influenza 85 46 National governments are responsible for the development Who is and implementation of influenza pandemic preparedness plans. The reason is evident: they are in the best position to responsible develop tailor-made plans that totally fit the local situation with respect to the organization of the public health system, for influenza consultative structures and decision-making processes. pandemic International organizations like the WHO play an important role as well as they provide national governments with preparedness recommendations and guidelines (see Q91). Commercial companies and institutions (like hospitals plans? and schools) would also benefit from establishing their own tailor-made pandemic preparedness plans. Such business continuity plans would help to mitigate the potential effects track  of a pandemic on companies, customers, and employees. 86 101 questions & answers on influenza 47 No, we are not. Even the best prepared countries still have Are we prepared major issues to solve, especially when it comes to surveillance, antiviral stockpiling and access to pandemic vaccines. for the current Pandemic preparedness should be achieved at the global, regional and national levels. The WHO is responsible for pandemic? coordinating preparedness measures at the global level and it issues recommendations about the stockpiling of antivirals and the use of vaccines during the pre-pandemic and pandemic stages. European authorities, such as the Euro- pean Centre for Disease Prevention and Control (ECDC), are in charge of advising national authorities on implementing a pandemic response in the EU. Major cross-border gaps in Europe, however, remain: surveys have shown huge dispari- track  ties in coverage for seasonal influenza vaccines in high-risk populations across the EU, which may have major implications for pandemic planning in the low coverage countries (see Q68). It actually ranges from 2 percent in Lithuania to 82 percent in the Netherlands, with only the latter surpass- ing the WHO’s recommended target of 75 percent. Moreo- ver, only 12 of the member states have a national contingen- cy plan for maintaining essential services. National health authorities are responsible for the infrastructural measures to cope with emergency situations within individual countries. However, the level of pandemic preparedness also heavily depends on a country’s ability to conduct adequate influenza surveillance and have timely access to antiviral agents and pandemic vaccines. This could be a problem for countries that do not have a vaccine manufacturing plant on their soil and for developing countries that cannot afford to buy expensive vaccines. Here again, the WHO plays an important role. In close consultation with its member states, the organization aims to install mechanisms to ensure All about pandemic influenza 87

fair and equitable distribution of antivirals and pandemic influenza vaccines at affordable prices. After all, the general moral feeling that there should be an equitable distribution of scarce medicines will not be enough in a critical emergency situation.

Timely access to antiviral agents and pandemic vaccines could be a problem for developing countries that cannot afford to buy expensive medication. 88 101 questions & answers on influenza 48 From spring 2009, a new influenza A virus of the H1N1 sub- Will the type started to circulate among humans in Mexico. Tens of thousands were infected before the virus spread to Texas ‘Mexican flu’ and California, where it was first identified as a virus that probably had originated from different pig influenza viruses virus cause the by reassortment (see graph). The virus has not been identi- first influenza fied in pigs and it is not clear whether the reassortment (see Q14) had really taken place in these animals. Since April, pandemic of the the virus spread efficiently among people in the USA and st Canada. By the middle of June it was identified in more than 21 century? 80 countries in the world, due to transportation via air traffic. In most countries little or no sustained human transmission (see Q19) took place initially, probably because effec- track  tive measures to prevent its spreading were taken. These included intensive surveillance activities among travelers from Mexico and other areas where sustained transmission did take place initially, and antiviral treatment (see Q84) of infected individuals and their contacts. The clinical manifestations of the ‘Mexican flu’ were relatively mild by the end of May and reminiscent of what is normally seen in seasonal influenza (see Q25), although gastro-intestinal symptoms were more frequently observed. The case fatality rate of the ‘Mexican flu’ proved to be relatively low, although the initial figures from Mexico were hard to interpret. Furthermore it became clear that the burden of disease and mortality were highest in relatively young people, between 5 and 25 years of age. The transmissibility of the new virus proved at least comparable with that of the seasonal influenza viruses. On the basis of the transmissibility and the spread of the virus in humans, WHO declared that the world was in pandemic phase 5 (see Q90) by the end of April 2009. On 11 June, WHO decided to raise the level of All about pandemic influenza 89

1998 PB2, PA: Triple reassortant

1968 1998 PB1: A/California/4/2009 N-America PB2 PB1 PA 1918 HA HA, NP, NS: Classical swine NP NA MA NS 1979 Eurasian swine PB2, PA: Eurasia

The origin of the ‘Mexican flu virus’ as pandemic alert to phase 6. This in contrast to the phase 3 deduced from sequence analysis of the that was declared for the HPAI-H5N1 virus. respective genome segments of the virus. How the ‘Mexican flu’ will eventually manifest itself from All the eight genome segments originate the summer of 2009 onward is hard to predict. from avian influenza A viruses and were 1 The virus could spontaneously disappear and eventu- introduced into pigs directly from birds or ally stop causing any further disease in humans. Given the through a human intermediate host. The characteristics of the virus that is apparently not yet fully colour codes correspond with those of the adapted to the human species, this scenario does not seem parent viruses. Where and in which species to be very likely. the final reassortment has taken place has 2 A more likely scenario is that the virus competes with the not fully been elucidated and remains a regular seasonal influenza viruses at the start of the winter matter of discussion. season in the Southern hemisphere, ultimately replacing one of them. In that scenario, the virus returns to the Northern hemisphere at the beginning of the winter season there, if not earlier. With only minor further changes in the virus, this would eventually lead to a relatively mild influenza. 3 A more devastating scenario would include a ‘Mexican flu’ virus that gradually mutates or reassorts to a much more 90 101 questions & answers on influenza

pathogenic and possibly also more transmissible virus. A pandemic similar to the ‘Spanish flu’ (see Q41) could be the result. In this light, it is interesting to note that there are several similarities between the ‘Mexican flu’ threat and the start of the ‘Spanish flu’. Both were caused by an H1N1 virus that originally came from birds, but probably was transmitted to humans via pigs in America. Both caused relatively mild disease and little mortality in the first months of their appearance. The main burden of disease and mortality were found in relatively young people and not in the elderly. A clear difference between both events is that the introduction of the ‘Spanish flu’ happened in the absence of an already circulating seasonal H1N1 virus. 4 Intermediate scenarios are possible.

At the beginning of the summer of 2009, it is impossible to predict which scenario is most likely to occur. However, the mere fact that scenario 3 might actually happen, the implementation of the appropriate pandemic preparedness plan measures (see Q45 and Q89) is called for. Since the situation at the beginning of the summer of 2009 is reminiscent of that of 1918, it would indeed be prudent to prepare for the worst.

All about influenza vaccines 91

VIII All about influenza vaccines 92 101 questions & answers on influenza 49 Medicinal interventions for influenza consist of two major ap- What are the proaches: the use of vaccines and antiviral drugs. J Vaccines. The most cost-effective way to combat influenza is medicinal vaccination. Vaccines induce a specific immune response in the body by exposing it to an inactivated or weakened virus, or its intervention relevant components. Influenza vaccines work best in healthy options for individuals with a properly-functioning immune system. However, in individuals with a suboptimal immune system, such as the eld- influenza? erly and the immune-compromised, the current vaccines against seasonal influenza may not offer sufficient protection. These individuals may need extra protection against seasonal influenza. The use of antiviral drugs can offer a welcome adjunct to vaccination. track  J Antivirals. Antiviral drugs used for influenza are drugs that directly interfere with the replication of influenza viruses in the body and consequently their activity is limited to the period that they are administered. By contrast, current influenza vaccines are designed to protect against certain virus strains only, but are effective within one to two weeks of their administration and for a prolonged period. There are two classes of antiviral compounds against influenza viruses: adamantanes (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir). The first class is effective against influenza A viruses only, resis tant viruses develop fast and their use causes considerable side events. The second class is effective against influenza A and B viruses, resistant viruses do not develop fast while cross-resistance (resistance against more than one drug) has not been observed. The use of neuraminidase inhibitors causes little side events. Antivirals are primarily used to treat flu infection, but could also be used in a prevention strategy. J Other medicinal interventions like the use of pneumococcal vaccines and antibiotics are not effective against influenza, but they are against certain complications (see Q81 and Q87). All about influenza vaccines 93 50 Influenza vaccines prevent or mitigate infections. They are What is the designed to induce a protective immune response in the body against the viruses represented in the vaccine. When difference vaccinated, the immune system of the body produces a specific response, consisting of specific T cells and specific anti- between bodies that fight off the infection when exposure to the virus vaccines, antiviral occurs at a later stage. More importantly, vaccination also leads to the induction of a specific immunological memory drugs and against the viruses represented in the vaccine. Upon contact with the virus at a later stage, the immune system is able to antibiotics? mount a specific response much more rapidly than the non- primed immune system. Antivirals are drugs that can treat people who have already been infected by a virus. They also can be used to prevent or limit infection when given before or shortly after exposure, before illness occurs. A key difference is that the antiviral drug is effective only when administered within a certain time frame before or after exposure and is effective during the time that the drug is being administered. By contrast, a vaccine is given long before exposure to the virus and can provide protection over a long period of time. Antibiotics are medicines that interfere with the reproduction of bacteria and are, therefore, only useful for treating bacterial infections. Viral diseases, like influenza, can therefore not be treated with antibiotics. What is worse, inappropriate use of antibiotics contributes to the development of antibiotic resistance, a growing health concern. Secondary bacterial infections that may occur in tissues that have been damaged by influenza virus infection may well be treated with antibiotics (see Q87). 94 101 questions & answers on influenza 51 Over-the-counter medications are available without a Are over-the- doctor’s prescription. They are usually so-called household medicines containing vitamins and analgesics or pain counter products relievers, which in some cases may prevent a certain degree of symptomatic discomfort like fever and pain and may be effective against commonly found at the pharmacy. These medications, how- influenza? ever, do not target the virus or its replication, their potential to stop the development of symptoms is limited and they do not prevent the development of complications. All about influenza vaccines 95 52 When a person is exposed to an influenza virus, the innate How do influenza and subsequently the adaptive or specific immune response kicks in and provides defence against the invading vaccines work? virus (see Q16). Depending on the nature of the virus and the effectiveness of the immune response, the infected individual suffers from more or less severe consequences of the influenza virus infection: in the process of developing specific immunity, the body produces a specific response, consisting of specific T cells and specific antibodies that fight off the infection. Once the immune system has been exposed to an invading virus, it stores this information in the form of educated memory cells, resulting in an immunological memory that upon re-exposure to the same or closely related virus reacts much faster to produce the specific T cells and antibodies than the non-primed immune system.

Antibodies (red) attacking viruses (yellow) are part of the human immune system. Influenza vaccines mimic a protective response with viruses in an inactivated or weakened form. 96 101 questions & answers on influenza

Influenza vaccines against seasonal influenza take advan- tage of this adaptive immune system by exposing the body before the seasonal influenza epidemic starts, through vaccination with viruses in an inactivated or weakened form or their relevant components. Thus, instead of suffering the natural virus infection and risking its consequences, vaccines induce immune and memory responses similar to those of the natural virus infections. This results in immunity towards the influenza viruses that are expected to circulate in the following seasons. A problem with influenza, however, is that immunity to one type or subtype of influenza does not provide protection to other influenza virus types or subtypes (so called cross-protection). Even cross-protection against viruses of the same subtype, which have undergone antigenic drift (see Q14), becomes more and more limited as drift progresses over time. This is why seasonal influenza vaccines contain a mix of influenza virus types and subtypes and the composition has to be reviewed by the WHO strain selection mechanism twice every year for the northern and southern hemisphere winter epidemics. All about influenza vaccines 97 53 There are in principle two types of seasonal influenza vac- What types cines. The first is the traditional flu shot which is an inactivated vaccine that does not contain live virus. It is given of seasonal by injection, usually in the upper arm muscle. Inactivated vaccines are available in three forms: whole-virus, split-virus, influenza vaccines and subunit-virus vaccines. Whole-virus vaccines are classi- exist? cally produced by injecting influenza virus into chicken eggs and harvesting the fluids surrounding the chick embryo 2-3 days later. The virus is subsequently purified and inactivated or ‘killed’. Split-virus vaccines are essentially made in the same way, but the virus is treated with a detergent and therefore these preparations contain essentially all viral structural proteins and disrupted portions of the viral membrane. Subunit vaccines are also essentially made in the same way, but at the end of the procedure the surface proteins (H and to a lesser extent N) are purified from the virus preparation. Split-virus and subunit vaccines are the most widely used influenza vaccines since they combine a high level of effectiveness with little or no side effects. A newer vaccine is administered via a nasal spray. It is directed against the same strains of virus as the classical seasonal influenza vaccine. It is also produced in chicken eggs, but differs in that it contains attenuated or weakened live influenza viruses instead of killed viruses. The vaccine is therefore referred to as Live-Attenuated Influenza Vaccine (LAIV). Attenuated vaccine viruses do not cause influenza, but like the inactivated vaccines, do stimulate the immune system to produce a specific immune response and immune memory. Currently, the LAIV is only available in the US. 98 101 questions & answers on influenza 54 Each year, the seasonal influenza viruses change slightly (an- How are viruses tigenic drift, see Q14), which leads to a less perfect match between the vaccine viruses and the circulating viruses chosen for the rendering the vaccine used in previous years less effective. Therefore, each year, a new vaccine must be prepared that vaccine each will be effective against the influenza virus strains that are year? expected to circulate in the next season. On the other hand, the vaccine takes about six months to manufacture, so the formula for the vaccine is developed on the basis of viruses that have circulated in the previous season. Hence, there is always a slight chance that the match will be imperfect, resulting in a less protective effect of the vaccine. Three different strains of the influenza virus are currently chosen to be included in the vaccine: two influenza A viruses (subtypes H1N1 and H3N2) and one influenza B virus. To make that selection, researchers in the WHO’s Global Influenza Surveillance Network (see Q97) study the influenza viruses that are circulating in humans. Based on information collected by the network, the WHO recommends a vaccine that targets these circulating viruses bi-annually — for the northern and the southern hemispheres. The WHO Col- laborating Centres then release suitable prototype viruses or primary seed viruses to the vaccine manufacturers. These viruses carry the H and N proteins of viruses that were originally isolated from humans suffering from influenza. All about influenza vaccines 99 55 Influenza vaccine manufacturers use the primary seed virus How are vaccines strains to produce vaccines that match the strains of the respective virus subtypes that are likely to circulate during produced in the next influenza season. First, the virus strains are sepa- rately propagated in embryonated chicken eggs to produce chicken eggs? large amounts of the viruses, called the working seed virus stock. This secondary seed virus serves as a source for the production of virus batches on a large, industrial scale. In this process, millions of eggs with 10 to 11 day-old embryos are automatically inoculated with a small amount of secon dary seed virus. After an incubation period of three days at a temperature of 32 to 36°C, the liquid that surrounds the embryos (allantoic fluid) and contains huge amounts of the virus particles is extracted from the eggs. The viruses are then purified and inactivated so that they can no longer replicate. In the last step, the different virus preparations are mixed and filled into syringes. Obviously, live vaccine (LAIV) viruses are not inactivated, since they are weakened or attenuated viruses that still need to replicate in the vaccinated person.

Manual inoculation of chicken eggs in the years 1950. 100 101 questions & answers on influenza 56 An alternative way of producing influenza virus for vaccine How are vaccines production is based on the use of cell cultures in a bio- logical fermentation process. Mammalian cells are usually produced in used for this purpose. The cells are infected with the virus and the virus is left to multiply for several days. During the cultured cells? course of this process, most of the cells die. The virus is then separated from the cell residue, purified and inactivated via a chemical process. This production method is still not used for large-scale production, although some cell culture based influenza vaccines have now been licensed. It may be expected that cell culture based influenza vaccines will be used extensively in the near future. The major advantages over egg-based vaccines are that the procedure is more flexible and independent of embryonated chicken eggs. Cell culture based systems could more easily be scaled up in times of a pandemic, although obviously also for this type of production system adequate planning is of key importance: the up-front costs for operational readiness of production plants with huge fermenters are definitely not negligible.

Fully automated cell culture system. All about influenza vaccines 101 57 Vaccination is an effective way to prevent influenza. Vaccina- How effective tion against seasonal influenza reduces the number of cases of influenza in healthy adults by up to 80%. In addition, it will are influenza reduce the severity of the disease in those who still get influenza. Influenza vaccination may be slightly less effective vaccines? in very young children, but few studies have addressed this question so far. In the elderly, influenza vaccination is less effective due and proportional to the ageing of their immune system. It is important to realize that vaccination also prevents serious complications and deaths associated with influenza. Furthermore, the number of vaccinations a person has received in previous seasons also plays a role in the effec- track  tiveness of seasonal vaccination: regular annual vaccination improves the protection.

Seasonal flu vaccines reduce the numbers of influenza in healthy adults up to 80 %. 102 101 questions & answers on influenza 58 A vaccination cost-effectiveness analysis is a method to Is influenza assess the health gains relative to the costs of vaccination. It is an important criterion for deciding how to allocate vaccination cost- resources, since it compares the costs and health effects of vaccination to assess whether it is worthwhile from an eco- effective? nomic perspective. In the case of influenza, cost-effectiveness studies compare the costs of vaccination programmes with the burden on healthcare facilities and their staff, the costs of medicines for treatment and, in the case of working adults, lost work time due to illness. Such economic evaluations have been carried out in many countries and for different age groups. Most of them have indicated that vaccination of senior citizens is cost-effective and often even cost-saving. The same goes for healthy working adults, for whom at least 4 to 5 days loss of work is the usual outcome of influenza. For companies, those lost working days may be a financial burden. Therefore, the number of companies which offer a free annual influenza vaccination to their working staff has been increasing steadily.

Economic evaluations indicate that vaccination of senior citizens is cost effective and often even cost-saving. All about influenza vaccines 103 59 Anyone anywhere can catch influenza and the influenza vac- Who should cine can be administered to any person aged 6 months or older to reduce the chance of getting influenza, or to reduce be vaccinated the severity and consequences of the disease. Yet, national and international health authorities worldwide recommend annually? that the influenza vaccine be given to protect people who are most likely to have serious health problems if they get influenza. These include: J Elderly people: depending on the country, people above 50, 55, 60, 65, and 70 years of age are included. J Adults and children over six months of age who have a chronic heart or lung disease. J Adults and children over six months of age having required regular medical follow-up or hospitalization during the preceding year because of a chronic metabolic disease (such as diabetes), kidney disease, blood disorder, or weakened immune system (including people with HIV/AIDS). J Pregnant women are often also considered to be a high risk group. J Vaccination of young healthy children is officially recommended and implemented in various countries, including the US, Canada and Finland.

Vaccination is also strongly recommended for people who may transmit influenza to those at high risk. Decreasing the transmission of influenza from caregivers and household contacts will reduce influenza-related deaths among those at high risk 104 101 questions & answers on influenza 60 People may get influenza many times throughout their lives. Should seasonal The reason is that there are different types and subtypes of influenza viruses that, in turn, are subject to continuous flu vaccination be changes or antigenic drift (see Q14). This allows viruses to break through the immunity that is continually being built up repeated every in the human population by infection and to a lesser extent year? by vaccination. Each year, a new vaccine must be prepared that will be effective against the expected type of influenza virus (see Q54). A second reason for the continuing susceptibility in spite of vaccination is that the level of protection produced by the host in response to the vaccine declines over time, and is usually too low to still provide protection one year after vaccination (see Q16). track  All about influenza vaccines 105 61 In the northern hemisphere, the best time to be vaccinated When should the is from mid-October to mid-November. Because the flu season can run until May, you can still get an influenza vac- vaccine be given? cination in December or later, but earlier is more beneficial in preventing the flu. However, for elderly people it may be beneficial not to be vaccinated too early, since due to suboptimal responses, protection may disappear before the end of the season when influenza viruses can still be around. In the southern hemisphere, the best time to be vaccinated is from mid-March to May. 106 101 questions & answers on influenza 62 Although healthy adults do not belong to the at-risk groups, Should healthy they may choose to be vaccinated. In fact, everyone who does not wish to be ill with influenza in the winter season, people be will benefit from a yearly flu shot. In addition, it has been shown in many countries that there is an economic benefit vaccinated? of vaccinating healthy working adults. On average, influenza patients are absent from work at least 4 to 5 days. That is why many companies offer free vaccination to all their employees. Knowing that yearly 2.5-10% of all personnel may get ill with the flu, the costs for such a vaccination campaign may be an interesting investment. Healthy adults who take care of patients who are at risk of developing complications when they get influenza (see Q18), should also take an annual flu shot. As a matter of fact, vaccinated persons are less likely to transmit influenza virus to other people. In other words, healthy adults can protect the ones they care for by protecting themselves. All about influenza vaccines 107 63 Children can certainly benefit from influenza vaccination. In- Should children fluenza is usually considered an illness that primarily affects the elderly. In fact, this is only partly true since the burden be vaccinated? of seasonal influenza is greatest in children under 3 years of age and 40% of these children develop ear infections (acute

otitis media) as a complication of influenza. However, overall mortality in children is low compared to that in the elderly. Children are also the main spreaders of the virus, in both school and household settings. In other words, children do bring joy to the elderly… but also bring them influenza viruses. As a consequence, vaccination of children has many advantages: it limits transmission of influenza, reducing the track  overall burden of seasonal influenza (see Q27) as well as school absenteeism. The influenza vaccine can be used in children over the age of six months. The LAIV is currently licensed in the US only for use in persons from 2 to 49 years. To give a good response, the first year that they are vaccinated, children under nine years of age need two doses of the vaccine given at least one month apart. Children over nine years of age and younger children who have had a flu shot previously only need one single injection each year. 108 101 questions & answers on influenza 64 Yes, they should be vaccinated against seasonal influenza Should annually. Although healthy adults do not belong to the at-risk population, there are good reasons for healthcare healthcare providers to get immunised against influenza, especially when they have regular contacts with patients and high-risk workers be patients. vaccinated? First of all, an obvious rule of thumb is that healthcare workers should not pose a risk to their own patients: healthy adults who take care of patients at risk of developing complications when they get influenza (see Q18), should also get their annual flu shot. Secondly, healthcare workers should be able to provide care for their patients when they need it, particularly during the influenza season. Now, we know that the immunisation of healthy adults substantially reduces absenteeism from work. In ordinary workplaces such as factories and offices, this provides a purely economic benefit. In addition, for healthcare workers, immunisation provides the opportunity to keep taking care of their patients when they are needed the most. Thirdly, it is important to protect those who protect others against health hazards. Just as adult airline passen- gers are instructed when the cabin pressure falls to put on their automatic drop-down oxygen mask first — before fit- ting any to children — the same logic applies to healthcare workers dealing with influenza. Yet, the rate of vaccination among healthcare workers is low across the globe (see graph at Q68). Although many countries recognize the need for their healthcare workers to be vaccinated, the fact remains that application of this principle in general remains low. Even in Europe — with some of the world’s most pervasive healthcare systems — vaccination rates among healthcare workers is generally less than All about influenza vaccines 109

25%. Should vaccination be made mandatory for instance for those who work with the elderly who are frail? This is currently a major discussion point among medical ethicists.

Coverage of healthcare workers is lower than other target groups 100%

90%

80%

71% 70% 75% 68% 70% 66% 63%

60% 56% 53% 53% 51% 50% 50%

39%

2006/7 Vaccination Coverage Rate (%) 2006/7 Vaccination 40% 37% 37% 37% 35% 34% 30% 30% 28% 25% 25% 24% 24% 24% 25% 22% 22% 22% 20% 20% 16% 17% 17% 17% 13% 14%

10%

0% Spain UK France Italy Ireland Portugal Germany Finland Austria Czech Rep. Poland

246/186/98 384/176/130 400/204/134 348/166/84 241/130/141 384/185/74 481/287/170 299/332/162 419/159/205 326/249/106 297/277/78

>_65 years <65 years at risk Healthcare Workers

adapted from: Blank et al, accepted, Journal of Infection, 2009 110 101 questions & answers on influenza 65 No, it does not. The influenza vaccination provides good Does influenza protection against influenza virus infection, but it does not provide any protection against other viruses that cause vaccination also common cold or other respiratory illnesses. As a matter of fact, there are over 100 different viruses that cause com- protect against mon colds. Rhinoviruses are the most important causing at other diseases least half of all common colds. These viruses belong to a completely different virus family, the Picornaviridae, whereas like the common influenza viruses belong to the Orthomyxoviridae family (see cold? Q22). All about influenza vaccines 111 66 Influenza vaccines are among the safest vaccines in the Does vaccination world. The most common side effects of influenza vaccination include local soreness, redness, or swelling at the site of cause side the injection. These reactions are generally mild, temporary and occur in 15%–20% of the recipients. Less than 1% of effects? vaccine recipients develop more general symptoms such as fever, chills, and muscle aches. These symptoms may persist for one to two days and do not indicate that the recipient is getting influenza from the vaccination, which is a common misconception (see Q67 and Q82). The most common side effects of intranasal influenza vaccination (see Q52) are mild and include getting a runny nose or nasal congestion, headache and a sore throat. More serious adverse reactions to either of the vaccines are very rare. Such reactions could result from a very rare allergy to a vaccine component, such as egg proteins in vaccines produced in embryonated chicken eggs. 112 101 questions & answers on influenza 67 No, neither the flu shot nor the nasal spray vaccine can Can you get cause influenza. The flu shot contains only killed viruses or its components and therefore cannot cause influenza. The influenza from nasal spray vaccine cannot cause influenza either. It does contain live viruses that replicate in the nose and throat to the vaccine? produce protective immunity. But since the viruses are weakened or attenuated, they do not cause real disease and can for instance not replicate effectively in the lungs. Getting the flu after vaccination? It’s a misconception and this is why. Protective immunity develops within one to two weeks after vaccination. Some people may still get influenza shortly after vaccination, but the disease they develop is the result of being exposed to the virus before the vaccine has properly induced immunity (which takes one to two weeks). Also, to many people, influenza is any illness with fever and cold symptoms. If they get any respiratory illness, which are quite common during the vaccination period, they blame it on the influenza shot or think they got the flu despite being adequately vaccinated. Influenza vaccine only protects against the circulating seasonal influenza viruses, not against all viruses. All about influenza vaccines 113 68 Vaccine use varies widely between countries, even within the How many EU. Among the major determining factors are the success of national awareness campaigns, whether or not the vaccine is people are reimbursed by national health insurance and the attitude of healthcare workers towards vaccinating their patients. vaccinated The accompanying graph shows influenza vaccine use in annually? 32 countries in the year 2005. A more urgent matter than vaccine use in a country’s entire population, however, is the question of vaccine use in the high-risk groups (see Q18) and among healthcare workers. After all, the elderly and the chronically ill are at a high risk of severe complications when they get influenza, and healthcare workers should get their annual flu shot to protect themselves and their patients (see Q64). For that reason, the European Union has endorsed the WHO’s objectives of increasing vaccine coverage in high-risk

Influenza vaccination in Europe 2005

Malta 637 Germany 255 Belgium 238 Spain 233 UK 227 Netherlands 201 Latvia 185 France 183 Iceland 181 Switzerland 168 Ireland 162 Italy 160 Finland 153 Greece 150 Russian Fed. 148 Austria 140 Croatia 139 Portugal 139 Sweden 138 Hungary 136 Slovenia 129 Denmark 127 Norway 123 Slovak. Rep. 113 Romania 8 4 Poland 76 Czech Rep. 65 Lithuania 56 Bulgaria 51 Estonia 40 Turkey 34 Serbia & Mon 30 Ukraine 26 Moldova 21 Albania 2 Uzbekistan 2 Georgia 1 Kyrgyz Rep. 1

0 50 100 150 200 250 300 Doses of influenza vaccine distributed / 1000 population 114 101 questions & answers on influenza

Vaccination coverage rates differ widely across key target groups and countries

100%

90%

80%

71% 70% 68% 70% 66%

63%

60% 56%

53% 53% 51%

50% 2006/7 Vaccination Coverage Rate (%) 2006/7 Vaccination

39% 40% 37% 37% 37% 35% 34%

30% 28% 30% 25% 25% 25% 24% 24% 24% 22% 22% 22% 20%

20% 17% 17% 17% 16% 14% 13%

10%

Austria Czech Rep. Finland France Germany Ireland Italy Poland Portugal Spain UK

419/159/205 326/247/106 299/332/162 400/204/134 481/287/170 241/130/141 348/166/84 297/277/78 384/185/74 246/186/98 384/176/130

>_65 years <65 years at risk Healthcare Workers

adapted from: Blank et al, accepted, groups to 75% by 2010. The second graph, however, dem- Journal of Infection, 2009 onstrates the gap between the objectives and the actual immunisation rates. Coverage amongst healthcare workers in particular is extremely low. All about influenza vaccines 115 69 The best place to receive your flu shot is at the doctor’s of- Where can I get fice. Your doctor knows your medical history and will know why you need to have a flu shot or if there is any reason why the seasonal you should not get it. Flu shots may also be available at pharmacies, hospitals and occupational health instances. In influenza vaccine? the US, influenza vaccines are available at a wider range of venues, including drive-through clinics and shopping malls. High-risk patients should automatically receive an invita- tion to get the annual flu shot. If this is not the case, and if you think you are at risk, talk to your family doctor and ask whether it would be advisable to get vaccinated against influenza.

In the US, influenza vaccines are available at a wide range of venues. 116 101 questions & answers on influenza 70 As a patient’s first point of contact and medical adviser, What is the role healthcare workers play a crucial part in the fight against influenza. As a matter of fact, when asked why they take the of family doctors annual influenza vaccine, a majority (over 60%) of high-risk patients answers: ‘Because my doctor or nurse recommends in influenza it’. Indeed, family doctors are in a unique position to in- vaccination? form their patients about the benefits and effectiveness of seasonal influenza vaccination and the risks of not receiving a flu shot. However, even a clear understanding of the risk of influenza may not always lead to vaccination of the patient. The possible costs associated with immunization, the fear of needles, supposed side effects and a whole series of misconceptions (see Q82) are also major reasons for not seeking vaccination. In those cases, it is a family doctor’s duty to offer the appropriate advice. General practitioners and other primary healthcare workers also contribute to the fight against influenza by setting a good example. They should take the flu shot themselves not only for their own protection, but also to prevent transmission of influenza to their patients (see Q64).

Patients are most likely to take the annual flu vaccine if their family doctor actively promotes vaccination. All about influenza vaccines 117 71 Many professional groups have a role to play in the fight What is the role against the impact of influenza. Pharmacists play an increasingly important role in raising awareness with the general of pharmacists public about influenza and the ways to prevent and cure the disease. Indeed, as key primary healthcare providers, phar- in influenza macies are often also a first port of call for influenza suffer- vaccination? ers. Since no appointment is needed, pharmacists are easily accessible for all patients. Hence, pharmacies are a natural place to reach those at high risk of hospitalization and death from the disease. People with diabetes and asthma regularly see their pharmacists to refill their prescriptions. Pharma- cists are well placed to encourage them to visit their general practitioner in case they have not taken the vaccine yet. In some EU countries, pharmacists have recently been given the authority to administer the vaccine themselves, which immediately led to a rise in vaccine use, especially among the elderly and other high-risk groups. 118 101 questions & answers on influenza 72 The level of vaccination coverage is the result of the in- What are terplay of many factors: the commitment, motivation and organization of healthcare workers, policy decisions at the the drivers level of the healthcare system and the awareness of patients themselves. Nonetheless, the role of the healthcare worker for influenza is crucial. It was recently shown that when a doctor or nurse vaccination? recommended vaccination to positively predisposed patients, 87% of patients got vaccinated. Moreover, even when patients had a negative attitude towards vaccination, 70% of them still got vaccinated if their healthcare provider recommended it. In contrast, when patients had a positive attitude but their physician did not recommend vaccination, only 8% got vaccinated. A proactive healthcare worker, therefore, has a huge impact on the likelihood of a patient to become vaccinated. The second most important driver for influenza vaccination is reimbursement. There is an obvious correlation between lack of funding and dramatically lower vaccination rates. A third way to improve vaccine use is the implementation of wide and effective public communication and education campaigns on influenza and influenza vaccines. After all, patients will then also ask to be vaccinated. All about influenza vaccines 119

Three key drivers would improve vaccination coverage

1 2 3

Pro-active More education/ Adequate funding behaviour communication on the disease of vaccine/ 100% of HCW and vaccine vaccine 90% administration

80%

70% 65 61 60%

50%

Percentage of respondents (%) of respondents Percentage 40% 31 29 30 28 30% 25 23 22 21 20%

10%

0% If Doctor/nurse More information on More information on More information on If it were cheaper/ recommended it vaccine efficacy the disease vaccine tolerance reimbursed/free

Sample size all countries: 3825 Elderly Under 65s w/chronic illness Sample size all countries: 2349

adapted from: Blank et al, accepted, Journal of Infection, 2009 120 101 questions & answers on influenza 73 Myths and misconceptions (see Q82) about influenza and What are influenza vaccination are major barriers to better protection of healthy and high-risk persons. Some common examples the barriers are:

for influenza ‘The flu is just a common cold!’ vaccination? ‘I had the flu last year, so I cannot get it this year.’

‘You can get the flu from a flu shot.’

‘Flu shots offer little protection anyway.’

Healthcare providers and public health authorities (both on a national and local level) play a key role in informing and educating their patients and the public about the true dan- gers of influenza and the benefits of vaccination. A second important barrier is the lack of organised programmes offering easy access to vaccines. Offering vaccination in non-traditional venues could be a solution. The majority of all patients are vaccinated at doctor’s offices, but other important venues could be walk-in clinics, work sites and even pharmacies. The third most important barrier is ‘forgetting to take the vaccine’. Healthcare providers could therefore use patient reminders and other strategies to increase patient demand for vaccination. Individual persons, however, should recognize their own responsibility. Anyone can ask their doctor to be vaccinated against influenza. All about influenza vaccines 121 74 No, current seasonal influenza vaccination only provides Does the good protection against viruses closely related to the vaccine strains. An influenza virus that causes a pandemic, how- seasonal ever, will be a new influenza A virus that is not represented in the seasonal influenza vaccine. Therefore, it should not influenza vaccine be expected that the seasonal influenza vaccine will provide protect against protection against a newly emerging pandemic influenza virus. pandemic The current pandemic ‘Mexican flu’ virus happens to be of the same subtype (H1N1) as one of the seasonal influenza A influenza? viruses. Yet little or no cross-protection seems to be induced by the seasonal influenza vaccines. 122 101 questions & answers on influenza 75 To prepare the world for the next influenza pandemic, the What is a WHO has advised national governments to develop pandemic preparedness plans (see Q45). The production, dis- pandemic tribution and administration of a pandemic influenza vaccine play a major role in such plans. Pandemic influenza vac- influenza vaccine? cines would reduce spreading of the virus and the burden of disease in the population, like the risk of serious illness or death, very much like regular flu shots offer protection against seasonal influenza. However, the production of an influenza vaccine that matches the pandemic virus strain cannot begin until after the pandemic influenza virus has been identified. Since it may take up to six months to produce and market the first doses of such a vaccine, the pandemic influ- track  enza vaccine is unlikely to arrive in time. In addition, global vaccine production capacity is limited to about 700 million doses. Knowing that two shots with a higher than regular antigen dose will be needed to elicit sufficient immune response against a newly emerging virus strain, it would not be realistic to just rely on the availability of a pandemic vaccine when it happens. However, recently, attempts to develop new generations of vaccines that provide protection against possible pandemic viruses, have shown promising results. These vaccines, which were supplemented with an adjuvant, allow a decrease of the dose size and act against a broader range of influenza A viruses within a certain subtype. Possibilities to store candidate pandemic vaccines or to even start vaccinating groups of people that will be crucial for the implementation of pandemic preparedness plans (see Q80), are now being evaluated. All about influenza vaccines 123 76 Adjuvants are substances that can be added to human vac- What is an cines. They stimulate the immune system and increase the response to a vaccine, without having a specific antigenic adjuvant? effect themselves. The advantages, certainly in a pandemic situation, are obvious: they improve the immune response (see Q16) whilst the dose size (the amount of virus material or antigen in the vaccine) can be decreased. The latter is an excellent way to increase global vaccine manufacturing capacity. Compared to the normal antigen dose of 15 µg in seasonal influenza vaccines, an adjuvanted vaccine would only need to contain as little as 4 µg of antigen or less, in a two dose regimen, to be effective. To date, several adjuvants have met regulatory standards for safety. These include aluminium salts (which have been used safely in seasonal vaccines in the past) and complex oil in water emulsions. Active research and development programmes are ongoing to develop more new generations of adjuvants that are safe and antigen-sparing and broaden the immune response against influenza when incorporated in seasonal, avian and (pre-)pandemic vaccines.

Antigen + adjuvant

Immune response

Antigen only

Adjuvants enhance the protection provided by vaccines Time 124 101 questions & answers on influenza 77 Pre-pandemic influenza vaccination takes place before a pan- What is demic (see Q40) has actually started. Vaccines for this purpose are produced in advance of the start of a pandemic as part of pre-pandemic national and international pandemic preparedness strategies. The principle of pre-pandemic influenza vaccination is based on influenza the idea that one may anticipate which subtype of influenza A vaccination? virus will be at the basis of the next pandemic. This virus will be used to develop seed viruses for vaccines in the pre-pandemic period that induce specific immunity or immune memory in people against the chosen influenza virus. When indeed an influenza pandemic of the same subtype emerges, the induced immunity may either be sufficient or be eventually boosted with the true pandemic vaccine. Priming and boosting an individual’s immune system in a pre-pandemic vaccination strategy would allow for more rapid protection than with a pandemic vaccine alone. Such a ‘pandemic vaccination only’ strategy would probably come too late when a pandemic emerges. The first vaccines for pre-pandemic use have been licensed since 2008 and most are based on the use of adjuvants. As it was generally anticipated that the currently circulating HPAI- H5N1 virus has high pandemic potential, several H5N1 virus based vaccines for pre-pandemic use or for stockpiling for immediate use when the threat increases, had been tested in animals and humans. Based on the technologies used, other influenza A virus subtypes could be incorporated in future pre- pandemic vaccination strategies as well, implying the development of multivalent pre-pandemic vaccines. Obviously the current pandemic threat posed by the new influenza A virus of the H1N1 subtype has prompted the development of vaccines against this rapidly spreading virus. It is expected that the first doses of pandemic vaccines against the ‘Mexican flu’ H1N1 virus will be available by October or Novem- ber 2009. All about influenza vaccines 125 78 No, not at this moment. At least, not with a vaccine that Can we be offers optimal protection against the ‘Mexican flu’ virus. After all, the virus is new to humans and a vaccine to pro- vaccinated tect against it cannot be produced within half a year. Before the pandemic started, it was difficult, if not impossible, to against pandemic predict which virus subtype or strain would cause it. It could influenza now? well be argued that also viruses of the H2, H5, H7 and H9 subtypes should not be considered as unexpected candidates. WHO has declared pandemic alert phase 6 for this ongoing ‘Mexican flu’ epidemic in June of 2009 (see Q90). In contrast, the also still ongoing HPAI-H5N1 virus epidemic has only reached phase 3, since although it is highly pathogenic for humans, this virus is not yet transmissible track  from human to human. Of the more than 430 reported hospitalized individuals more than 60% have died. If this virus were to be the source of a future pandemic, its case fatality rate could even exceed that of the ‘Spanish flu’ (see Q41). Vaccines that protect humans against the highly pathogenic and often lethal H5N1 subtype have currently been licensed. They are designed to induce an H5N1-specific immunity in people that within one week could be boosted by a real pandemic H5N1 vaccine to protective levels of immunity. The emergence of the ‘Mexican flu virus’ illustrates again that predictions and expectations about the emergence of pandemic influenza viruses may prove wrong. Therefore vaccine manufacturers have now largely switched towards the development and production of a ‘Mexican flu’ vaccine rather than an HPAI-H5N1 based pandemic influenza vaccine. Finally it should be realized that any vaccination may come at the price of inducing side effects. Although such side effects will probably be minor, they will need to be 126 101 questions & answers on influenza

weighed against the benefits of vaccination. Strategies that allow separate stockpiling of viral material (antigen) preferably of more than one subtype (e.g. H1N1 and H5N1), in addition to an adjuvant, will probably lead to the most flexible approach. Possibilities that allow early vaccination of groups of people who will be crucial in the implementation of pandemic preparedness plans (see Q80) are also now being evaluated. All about influenza vaccines 127 79 There will not be enough vaccine to immunize the entire Will there be world population against the ‘Mexican flu’ pandemic. It probably will take up to 6 months before the first doses of enough pandemic a pandemic vaccine will be available. Secondly, the global seasonal influenza vaccine production capacity is currently vaccine? about 700 million doses worldwide per year. For induction of a protective response, two doses of the pandemic vaccine should be given at least a number of weeks apart. This could mean that only a fraction of the world’s population can be vaccinated in time once a pandemic vaccine becomes available. Can we do better? Yes, we can. For example, by improv- ing the production systems. Instead of relying on chicken track  embryo-based vaccine production methods, cell culture technology can be used. This will significantly increase the production flexibility. Furthermore, the use of adjuvants will allow for dose sparing and the production of vaccines that act against a broader range of influenza A viruses (see Q76). Collectively, these improvements may eventually lead to an increase of influenza vaccine production capacity.

The global influenza vaccine production capacity is limited to 700 million doses per year. 128 101 questions & answers on influenza 80 Since it would be impossible to vaccinate the entire world Who should population against a pandemic influenza virus when the pandemic emerges, it is necessary to determine which groups be vaccinated must be immunized with priority. After all, effective alloca- tion of vaccines will play a critical role in slowing down the first during a spread of the influenza pandemic and reducing its effects pandemic? on health and society. In Europe, the envisaged prioritiza- tion differs from country to country. The American Advisory Committee on Immunization Practices (ACIP) has issued recommendations that could serve as an example. Groups are listed in order of importance:

1 Healthcare workers J Healthcare workers with direct patient contact and critical healthcare support staff J Vaccine and antiviral manufacturing personnel

2 Highest-risk groups J Patients 65 and older with at least one high-risk condition J Patients 6 months to 64 years with at least two high-risk conditions J Patients hospitalized in the past year because of pneumonia, influenza or another high-risk condition

3 Household contacts and pregnancy J Household contacts with children under 6 months J Household contacts with severely immune-compromised individuals J Pregnant women

4 Pandemic responders J Key government leaders and critical pandemic public health responders All about influenza vaccines 129

5 Other high-risk groups J Patients 65 and older with no high-risk condition J Patients 6 months to 64 years with one high-risk condition J Children 6 to 23 months

6 Critical infrastructure groups J Other public health emergency responders, public safety workers, utility workers, critical transportation workers and telecommunications workers J Other key government healthcare decision-makers J Individuals providing mortuary services J Healthy patients 2 to 64 years without any high-risk conditions.

It should be noted that it is difficult to predict the impact of a future pandemic on different groups of individuals and high-risk populations, which has also differed between the respective influenza pandemics of the last century. 130 101 questions & answers on influenza 81 During previous pandemics (see Q41), secondary bacte- What are rial pneumonia has been an important cause of illness and death. Among those who acquired secondary bacterial pneumococcal pneumonia during pandemics, 20-40% died. The big difference between previous pandemics and a future pandemic vaccines and should may be that pneumococcal vaccines are available. Adminis- they be stockpiled tering pneumococcal vaccines before or at the start of the next pandemic, however, may be complicated for several for pandemic reasons: the future contribution of pneumococci versus other bacteria as well as the effectiveness of pneumococcal influenza? vaccines in such situations are not clear. Furthermore, like the supply of the pandemic influenza vaccine, the pneumococcal vaccine supply will be insufficient at the start of a pandemic due to excessive demand, and personnel to carry out the vaccination may not be present due to illness. There- fore, ensuring that all persons with pneumococcal vaccine indications have been vaccinated before a pandemic occurs may be the best way to prevent a major impact of pneumococcal disease during a pandemic.

During a pandemic, bacterial pneumonia may be an important cause of illness and death. All about influenza vaccines 131 82 Misconception #1: Influenza is not a serious disease What are the Fact: Influenza is a highly contagious and potentially life- threatening disease. Even young and healthy people may take most common two weeks or more to fully recover from the illness. Influenza causes 3 to 5 million cases of severe illness and between misconceptions 250,000 and 500,000 deaths every year around the world. about flu and flu Misconception #2: Influenza vaccination can cause influenza vaccines? Fact: None of the Influenza vaccines used in the EU contain any live viruses and therefore cannot cause the disease. Fur- thermore, the live attenuated influenza vaccines that are used in the US do not contain viruses that can cause significant disease symptoms.

Misconception #3: The influenza vaccine causes serious side effects Fact: Influenza vaccines are among the safest vaccines used today. Serious side effects are extremely rare, with the most common mild side effects of vaccination being local redness and swelling. Allergic reactions may occur in people with a severe egg allergy but these are very rare and such people should not receive the influenza vaccine.

Misconception #4: Healthy people do not need to get vaccinated Fact: Anyone can contract influenza and being fit and healthy does not protect against infection. In high-risk individuals, infection can lead to severe complications and even death. If healthy people do not want to get influenza for individual reasons, they may also be vaccinated. In fact, influenza vaccines work best in healthy immune-competent individuals. Healthcare workers and those taking care of 132 101 questions & answers on influenza

high-risk individuals should be vaccinated against influenza annually (see Q64).

Misconception #5: The influenza vaccine is not effective Fact: In healthy persons under 65 years of age, seasonal influenza vaccination protects up to 80% against influenza and the remaining cases are usually mild. Furthermore, studies have convincingly demonstrated that vaccination reduces the cases of serious complications such as pneumonia as well as total deaths occurring during an influenza season in those aged 65 years and over.

Misconception #6: It is not necessary to get vaccinated against influenza every year Fact: The circulating influenza viruses change from year to year. A new vaccine is therefore made each year to protect against the expected strains. The match between vaccine and circulating strains is therefore very good in most cases. In addition, immunity provided by influenza vaccines be- gins to fade within about six months and even sooner in the elderly. All about antiviral drugs 133

IX All about antiviral drugs 134 101 questions & answers on influenza 83 Antivirals are drugs that act directly against viruses, like an- What are antiviral tibiotics do against bacteria. Flu antiviral drugs are prescription drugs (pills, liquid, or inhaler) that actively combat the drugs against influenza virus and decrease its ability to replicate. There are two types of antiviral drugs currently licensed influenza? for influenza, which have different mechanisms of action: 1 M2 inhibitors or adamantanes, which include amantadine (brand names Symadine® and Symmetrel®) and rimantadine (brand name Flumadine®). Amantadine and rimantadine were the first generation of influenza antiviral drugs to combat influenza A viruses. They inhibit the function of the M2 protein of the virus and therefore block the virus in its pro cess of entering the host cell. The use of these agents, how- track  ever, is limited, due to the rapid development of resistance of the virus, the relative toxicity of the drug (amantadine) and the lack of activity against influenza B viruses, which do not have this protein. Flumadine® and Symmetrel® are available as tablets and as a syrup for oral administration. Flumadine®, however, is not available in Europe. The use of these antiviral medicines should be started as early as possible, but certainly within 48 hours of the first symptoms, and continued for 7 days. Amantadine is removed from the body by the kidneys, rimantadine by the liver. This difference may have an impact on which medicine is used to treat people who have diseases affecting the kidneys or liver. 2 Neuraminidase inhibitors, which include oseltamivir (Tamiflu®) and zanamivir (Relenza®). They block the function of the viral neuraminidase protein, which is crucial for the release of newly produced virus from the infected cell, and thus prevent the virus from spreading throughout the respiratory tract. Neuraminidase inhibitors are active against both influenza A and B viruses, cause few side effects and All about antiviral drugs 135

viruses develop little resistance against them. However, it has been shown that the majority of one of the recently circulating seasonal influenza A viruses (H1N1) had become resistant to oseltamivir even when the drug was barely used. This started in Europe in the 2007-2008 season in which the resistant virus rapidly replaced the sensitive H1N1 virus in many places. Since February 2009, 98 percent of all the H1N1 viruses identified in the US were resistant to oseltamivir. The virus, however, remained sensitive to zanamivir, amantadine and rimantadine. Oseltamivir is marketed under the trade name Tamiflu®. It Antiviral drugs actively combat the comes as a capsule and a suspension (liquid) to take orally. influenza virus by either inhibiting the When oseltamivir is used to treat flu symptoms, it is usually function of the M2 protein, or by blocking taken twice daily (morning and evening) for 5 days. When the neuraminidase protein. oseltamivir is used to prevent the flu, it is usually taken once a day for at least 10 days, or for up to 6 weeks during a community flu outbreak. Zanamivir was the first neuraminidase inhibitor commer- cially developed. It is currently marketed under the trade name Relenza®. This antiviral drug is a powder that is inhaled twice a day for 5 days from a breath-activated device called a Diskhaler. For preventive use to reduce the risk of getting influenza, Relenza® is inhaled once daily for 10 to 28 days. Relenza® is not recommended for patients with severe asthma or a lung condition called chronic obstructive pulmonary disease (COPD). 136 101 questions & answers on influenza 84 Although the best way to combat influenza is vaccination, When should antiviral drugs against influenza can be used as an adjunct to vaccines. They can be used prophylactically in high-risk antiviral drugs individuals when vaccination comes too late or may not be expected to be fully effective (see Q54). When used pro- against influenza phylactically, antiviral drugs are about 70 to 90% effective. be used? Antiviral drugs against influenza are predominantly used for the treatment of influenza. Treatment with influenza antiviral drugs should be started as soon as possible when the first symptoms of the disease are recognized and definitely within 48 hours. It has been shown that the sooner the drugs are used, the more effective they are. When used this way, antiviral drugs can reduce flu symptoms, shorten the time of track  illness by one to two days and reduce the number of complications. Antiviral drugs against influenza are not over-the-counter drugs and must be prescribed by a doctor. Antiviral drugs against influenza are highly specific and are thus not effective against other virus infections, such as common colds. All about antiviral drugs 137 85 H1N1 (the virus strain that was first introduced into the hu- How effective are man population during the Great Pandemic in 1918-1919) and H3N2 (introduced into the human population during the antiviral drugs Hong Kong flu pandemic in 1968) are the influenza A virus subtypes that together with influenza B viruses are currently against seasonal, circulating in humans as seasonal influenza viruses. Both avian, and types of antiviral drugs — M2 inhibitors and neuraminidase inhibitors — are active against these and all other influenza pandemic flu? A virus strains, rendering them an effective tool against all seasonal and avian virus strains. The use of M2 inhibitors, however, is limited to influenza A viruses, and due to the high mutation rate of the M2 protein, rapidly results in the development of resistance. This severely limits the utility of 138 101 questions & answers on influenza

these drugs during an influenza pandemic, although it may be considered to stockpile also M2 inhibitors to be used as part of a combination therapy strategy. M2 inhibitors offer no protection against influenza B viruses, that lack the M2 protein and generally cause slightly milder forms of influenza. Neuraminidase inhibitors — oseltamivir and zanamivir — are considered a key weapon against an influenza pandemic. Its broad antiviral activity against influenza A and B viruses and the ease of its oral administration have rendered oseltamivir in particular an attractive agent for the treatment of influenza and, in many countries, the drug of choice to stockpile in preparation for a future influenza pandemic. However, the recent development of resistance in one of the major seasonal influenza A viruses (H1N1) suggests that a future pandemic influenza virus could also evade the effects of this antiviral drug. Since February 2009, 98 percent of all flu samples from the H1N1 strain in the US were resistant to oseltamivir. The virus, however, remained sensitive to zana mivir, amantadine and rimantadine. The use of zanamivir or a combination of drugs is now considered the most effective way to treat this H1N1 infection. This also implies that antiviral stockpiling strategies in influenza pandemic preparedness plans should best be based on combinations of antiviral drugs. At the start of the ‘Mexican flu’ pandemic, the virus proved to be sensitive to both types of neuraminidase inhibitors. Monitoring of resistance development should be considered a major priority in pandemic influenza surveillance. All about antiviral drugs 139 86 By stockpiling combinations of antiviral drugs in preparation Should we for an influenza pandemic, governments can treat exposed individuals and patients when the pandemic starts, and stockpile antiviral in doing so help contain the pandemic or slow its spread. Stockpiling is necessary since it will be impossible to order drugs against or produce the drugs in sufficient amounts when the pan- pandemic demic strikes. It may take up to six months before the first doses of pandemic vaccine become available and can be influenza? distributed. During that time, antivirals can provide protection against the disease and, equally important, will help to slow the spread of the pandemic virus. For this reason, the World Health Organization (WHO) has urged national governments to stockpile antiviral drugs in advance of an influenza pandemic for at least 20% of the population as one component of their pandemic preparedness plans. The WHO itself has created a global antiviral stockpile of several million treatments, donated by industry. This is primarily meant to be used at places where a new influenza A virus subtype starts to spread from human to human and a pandemic threat emerges. This strategy might even lead to the abrogation of a starting pandemic. Antiviral therapy, using stockpiles that have been established by many national authorities, has proven to be a major and successful intervention strategy in the combat against the ‘Mexican flu’ virus. 140 101 questions & answers on influenza 87 Antibiotics cannot be used to treat an influenza virus infec- Should antibiotics tion. Antibiotics kill or inhibit bacteria and should only be used to treat bacterial infections. Viral infections, like influ- be used against enza, require a different treatment. Still, antibiotics can be useful during the flu season. Why influenza? exactly? In fact, influenza virus infection causes destruction of cells of the respiratory tract, resulting in a great deal of debris that needs to be removed and replaced by new vital cells. This is a very active process that starts immediately after the initial influenza virus infection. The damaged tissue with the debris may however serve as a feeding ground for pre-existing bacteria or bacteria that infect the patient after they became infected with an influenza virus. Bacteria that are notorious for causing ‘secondary bacterial pneumonia’ are pneumococci, although several other bacteria may play a role. The importance of vaccination against pneumococci in preparation for influenza epidemics and pandemics is discussed in the answer to Q81. Obviously, complications of influenza caused by bacteria, especially when they occur in high-risk individuals such as the frail and elderly, should be treated with antibiotics. All about antiviral drugs 141 88 During a pandemic, many people who have suffered from Should antibiotics the respiratory influenza virus infection may subsequently develop bacterial pneumonia (see Q81). These patients be stockpiled would indeed benefit from antibiotic treatment. As is true for the use of all necessary medication during a pandemic for pandemic influenza outbreak, due to the huge and rapidly increas- influenza? ing demand that builds up during a short period of time, stockpiling of antibiotics would be advisable in addition to stockpiling of antivirals and vaccines for pre-pandemic or early pandemic use.

how to prepare for an influenza pandemic 143

X How to prepare for an influenza pandemic 144 101 questions & answers on influenza 89 Detailed planning is essential to ensure a coordinated re- What is an sponse to an influenza pandemic, both at the national and international levels. Should schools be closed to prevent influenza influenza from spreading? What about hospital capacity in case of a severe pandemic? How can we track the pandemic pandemic virus as it spreads? How and to whom will the stockpile of preparedness antiviral drugs be distributed? Who will be vaccinated first and with which vaccine? How to deal with disruption of plan? social and economic life? These are but a few of the questions that must be answered or at least be anticipated in a pandemic preparedness plan. The final goal of all pandemic preparedness plans should be to minimize the disease burden, the number of deaths and societal disruption. track   National governments are responsible for the planning and management of a pandemic in their country. In 1999, the WHO launched its first advice to member states to develop influenza pandemic preparedness plans, clarifying the specific roles and responsibilities of the WHO and those of national authorities in preparing for the management of such a disaster. It provided guidelines to assist governments in national and regional planning. It recommended that all countries should: J Establish an effective management process and an agreed chain of command. J Decide on a vaccination and treatment strategy, laying out the extent of vaccinations possible in the event of a pandemic and bearing in mind their likely shortage. J Develop stockpiles for antiviral treatment. J Plan an overall communication strategy for a pandemic response, including the supply of information to physicians and the public about the outbreak. how to prepare for an influenza pandemic 145 90 The World Health Organization (WHO) has developed an What are alert system to help inform the world about the development of the different stages towards a pandemic. The alert pandemic alert system is comprised of six phases. The current situation with the HPAI-H5N1 virus in ani- phases? mals and humans places the world in pandemic alert phase 3. This means that H5N1 is currently causing disease (and deaths) in humans, but is not yet spreading efficiently from human to human. The situation with the new ‘Mexican flu’ H1N1 virus places the world in pandemic alert phase 6. This means that there are large clusters of infection with extensive and sustained human-to-human spread in the general population at different continents.

Interpandemic period Phase 1: No new influenza virus subtypes have been detected in humans. An influenza virus subtype that has caused human infection may be present in animals. If present in animals, the risk of human infection or disease is considered to be low. Phase 2: No new influenza virus subtypes have been detected in humans. However, a circulating animal influenza virus subtype poses a substantial risk of human disease.

Pandemic alert period Phase 3: Human infection(s) with a new subtype, but no human-to-human spread, or at most rare instances of spread to a close contact. Phase 4: Small cluster(s) with limited human-to-human transmission but spread is highly localized, suggesting that the virus is not well adapted to humans. 146 101 questions & answers on influenza

Phase 5: Larger cluster(s) but human-to-human spread still localized, suggesting that the virus is becoming increasingly better adapted to humans but may not yet be fully transmissible (substantial pandemic risk).

Pandemic Period Phase 6: Pandemic: increased and sustained transmission in general population.

Recently it has been recognized that a very crucial event in the emergence of a pandemic virus is the transition from phase 3 to phase 4, which may go much faster than previously supposed. This is an important insight, since, at this transitional stage, major intervention strategies can still be initiated and implemented successfully in countries with a well-developed pandemic preparedness plan. This proved to be the case with the emergence of the ‘Mexican flu’ pandemic in 2009. It took three days between phase 4 and 5, and six weeks between phase 5 and 6. how to prepare for an influenza pandemic 147 91 There are three major UN organisations that deal with influ- What is the role enza in animals and humans: the World Health Organization (WHO), the ‘Organisation Internationale des Epizooties’ of international (OIE) or World Organization for Animal Health, and the Food and Agriculture Organization (FAO). The WHO keeps a close health watch on influenza viruses in humans and the spread and organizations evolution of influenza viruses in animals that may spread to humans. For this purpose it has built an international surveil- in pandemic lance network, in which influenza centres in most of the 193 member states participate (see Q97). The WHO involves preparedness? and collaborates with many scientists and scientific organisations worldwide and in doing so collects and shares data on animal and human influenza viruses with the scientific track  community around the globe. In addition, it coordinates measures at a global level and issues recommendations to the member states about all important developments in the field and measures that should be taken in response to a pandemic threat. Since the level of pandemic preparedness in a particular country heavily depends on its ability to have timely access to antiviral drugs and pandemic vaccines, non-vaccine producing countries and many developing countries will be specifically vulnerable. In close consultation with its member states, the WHO aims to install mechanisms to ensure fair and equitable distribution of tools for intervention strategies in all countries, such as access to antiviral stockpiles and pandemic influenza vaccines at affordable prices. The OIE is the ‘animal equivalent’ of the WHO and con- centrates its activities largely on influenza viruses that have an impact on animals and the trade in animals and animal products. Obviously there are many areas where both organizations have a common interest in sharing information and activities. 148 101 questions & answers on influenza

In the area of influenza, the FAO predominantly focuses on issues related to influenza virus infections that may be transmitted through infected food animals and their products for human consumption. In recent years, also fuelled by the unprecedented spread of the HPAI-H5N1 virus throughout Eurasia and recently also in Africa, the collaboration between the three organisations has intensified considerably. This has resulted in several joint meetings, missions and research activities. At the European level, the European Centre for Disease Prevention and Control (ECDC) carries out a range of activities to provide a solid scientific base for influenza control in Europe and to improve preparedness for a pandemic at the local level, at the level of the regions within Europe, the European Union and the EU member states. It carries out evaluations on the degree of pandemic preparedness in the EU member states. how to prepare for an influenza pandemic 149 92 First of all, national governments are responsible for de- What is the veloping, testing, implementing and updating national pandemic preparedness plans. Secondly, financial support role of your and stimulation of scientific research (see Q100) spanning all disciplines that contribute to better epidemic and pan- government demic preparedness is a key role of national governments as in pandemic well. And thirdly, by establishing public-private partnerships with vaccine manufacturers, national governments can help preparedness? solve what is called the ‘pandemic paradox’. In many countries, the vaccine for seasonal flu fails to reach many elderly and other high-risk people, resulting in many unnecessary deaths each year. A paradox lies in the fact that, if coun-

track  150 101 questions & answers on influenza

tries are not using seasonal influenza vaccination to the full extent, the industry’s capacity to produce seasonal influenza vaccines is currently too limited to accommodate the production of a pandemic influenza vaccine when it would be needed. Once the World Health Organization declares the transition of alert phase 4 to 5 and 6 (see Q90) or the start of a pandemic, governments will want the pandemic vaccine to be available in sufficient numbers of doses. The current industrial influenza vaccine production capacity lies at around 700 million doses of seasonal influenza vaccine. This too limited capacity will lead to a public health crisis during an influenza pandemic. Increased use of seasonal influenza vaccines with a coverage of up to 30% of the overall population would not only be medically justified and cost-effective in most countries, it would also leave the world better prepared for the production of a pandemic vaccine early in the pandemic alert phases. Public-private partnerships will be of great help in solving the pandemic vaccine supply issue. Since the government is responsible for the overall implementation of the integral pandemic preparedness plan, it should also ensure appropriate and co-ordinated communication at all the relevant levels. Communication is a key element in the whole pandemic preparedness strategy. how to prepare for an influenza pandemic 151 93 Healthcare workers — such as general practitioners, nurses What is the role and paramedics — will play an essential role during an influenza pandemic. Healthcare workers will: of healthcare J provide care and treatment (including antiviral treatment according to the recommended priority list) to patients with workers during pandemic influenza, an influenza J vaccinate their patients with the pandemic vaccine as soon as it becomes available, according to a pre-defined pandemic? recommended immunization priority list, J educate the public about the risks associated with pandemic influenza, J maintain other essential health services.

Healthcare providers will also play an important role in surveillance, and might be the first to identify and report cases of pandemic influenza to public health authorities. 152 101 questions & answers on influenza 94 Pharmaceutical companies play a crucial role in pandemic What is the role preparedness planning and during an influenza pandemic. Antiviral drugs manufacturers will have to produce and de- of pharmaceutical liver additional doses of antiviral drugs to cover the period between the start of a pandemic and the launch of a vac- companies before cine that matches the pandemic influenza strain. Vaccine and during manufacturers will have to develop and produce sufficient doses of a pandemic influenza vaccine in the shortest time an influenza possible. However, we now already know that there will not be enough vaccine to immunize the entire world population pandemic? (see Q79), since global production capacity for seasonal influenza vaccines is currently too limited. The key challenges for industry are therefore the development of adjuvant technology and the gradual increase of global production capacity to help solve this pandemic supply issue. Finally, pharmaceutical companies that produce antibiotics and pneumococcal vaccines will also face supply capacity problems. It is important to realize that all these activities require close collaboration between the private and the public sec- tor and public-private partnerships are therefore crucial. how to prepare for an influenza pandemic 153 95 In principle, the options for personal preparation for the What can you next pandemic are limited and to a large extent you have to rely on the measures taken by your government. do personally There are however a number of measures and precautions that can be taken at the personal level to reduce the risk to prepare for during a pandemic. an influenza J Stay informed about the measures being advocated, taken and implemented by your national and local authorities. This pandemic? may relate to issues of risk assessment, social distancing and distribution of antiviral drugs and pandemic vaccines (see Q45). J Stop the spread of the pandemic virus towards yourself and your environment. J Comply with recommendations issued by your national and local authorities. J Wash your hands frequently and extensively with soap and warm water and preferably use alcohol-based disinfec tants. J Do not touch your mouth, nose, or eyes without washing your hands first. J Cover your nose and mouth with a tissue when you cough and sneeze and safely dispose of it. J Do not share contaminated items such as cigarettes, lip- stick, beverages, etc. J Stay at home when you develop the first signs of influenza and limit contacts to the absolute minimum. 154 101 questions & answers on influenza 96 We know that it may take up to six months before all the Will schools and necessary medical and non-medical intervention strategies to combat an influenza pandemic will be deployed to workplaces be the full extent. Social distancing is an important part of the non-medical intervention measures that can be taken to closed during slow down the spread of the pandemic virus. Children and an influenza adolescents attending school, where they regularly gather before going back again to their family settings, are known pandemic? to be efficient spreaders of seasonal influenza viruses. Also, in the spreading of a pandemic influenza virus, they may be expected to play an important role. Therefore, it has been discussed extensively whether closure of schools will be an effective way to not only protect children and adolescents against pandemic influenza before effective treatment or vaccination is available, but also to slow the spread of the pandemic virus. This is but one of the possible community- based interventions. Other measures to be considered are: J Other social distancing measures to reduce contact between adults in the community and at the workplace. For example, cancellation of large public gatherings and alteration of workplace environments and schedules. The main challenge in case of a pandemic is to preserve a healthy workplace to the greatest extent possible without disrupting essential services. J Isolation and treatment of persons with confirmed or probable influenza. Isolation may occur in the home or healthcare setting. J Voluntary home quarantine of household members with confirmed or probable influenza cases.

Non-medical interventions like school closures and workplace closings, however, have their own costs in terms of how to prepare for an influenza pandemic 155

creating new challenges: closing schools for 12 weeks would, apart from disrupting the overall educational process, create huge childcare problems. Closing workplaces could lead to major shortages in production processes and services. In view of such public concerns, effective strategic planning is required in order to achieve an optimal ratio between benefit and harm. Plans need to be tailored to the scale and severity of the pandemic and it will now become clear to what extent the previous planning in ‘peace time’ has contributed to our preparedness for the ‘Mexican flu’ pandemic.

who monitors influenza spread and why? 157

XI Who monitors influenza spread and why? 158 101 questions & answers on influenza 97 Keeping a close watch on the evolution of seasonal and What is the avian influenza viruses is essential when it comes to reducing the burden of human influenza worldwide. National and role of the international networks have been established worldwide to monitor the evolution of influenza viruses and to exchange World Health information on this evolution and influenza activity. The Organization World Health Organization (WHO) plays a leading role in influenza surveillance. By far the best surveillance system for in influenza any infectious disease in humans is the global surveillance network for seasonal influenza. This Global Influenza Sur- surveillance? veillance Network comprises 5 WHO Collaborating Centres (London, Tokyo, Atlanta and Melbourne, as well as Mem- phis for animal viruses) and currently 122 institutions in 94 countries, which are recognized as WHO National Influenza Centres (NICs). These NICs collect specimens and influenza-related epidemiological data in their country and ship who monitors influenza spread and why? 159

newly isolated strains to the WHO Collaborating Centres for further analysis and characterization. The NICs themselves receive clinical samples and information in their country or area through a network of general practitioners and hospitals. Such a sentinel network usually represents 1-5% of physicians working in that country or region. The recent implementation of mathematical modelling of the data as they emerge and the associated antigenic cartography, has added an important and novel dimension to the functioning of the network. It contributes to the identification of novel vaccine virus strains, and also provides novel insights into the way in which these viruses spread geographically over time. In spite of the major achievements of this network, it should be realized that there are still major gaps in its global geographical coverage. As this surveillance network currently plays a role in following the spread of avian influenza viruses in humans and in the characterization of these viruses, it will also function as an early warning system for an emerging pandemic influenza virus. This makes the issue of geographical coverage even more important, since in several areas WHO’s global surveillance network where this could reasonably be expected to happen, surveil- for seasonal influenza comprises 122 lance coverage is far from satisfactory. institutions in 94 countries. 160 101 questions & answers on influenza 98 An additional player in human influenza surveillance in Europe What other is the European Influenza Surveillance Scheme (EISS), which collects and exchanges information on influenza activity from international 26 EU member states, plus Norway, Serbia, Switzerland and Ukraine. Data is reported to the EISS by approximately 13,500 organizations sentinel physicians covering a total population of about 484 play a role million inhabitants. This information is published as a weekly surveillance report during the influenza seasons and is used to in influenza help determine influenza vaccine content for the following year, provides relevant information about influenza to health profes- surveillance? sionals and the general public, and contributes to European influenza pandemic preparedness activities. The EISS surveillance network plays an important role in the early identification and ongoing monitoring of a pandemic influenza virus as well as the annual epidemics in Europe and is an adjunct to the activities of the NICs in Europe which also participate in this network. In the US, in addition to functioning as one of the international WHO collaborating centres, the Center for Disease Control and Prevention (CDC) collects similar information about influenza virus activity in the US. This information is also published as a weekly report. From January 2007, the CDC has re- quested that all states report all cases of human infection with novel influenza A viruses. A rapid increase in the number of human infections with novel influenza A viruses may signal the beginning of an influenza pandemic. Monitoring for such infections will aid early implementation of public health responses. Other countries such as Canada, Australia and Japan have similar surveillance structures in place, which in addition to their WHO reference tasks in the framework of the WHO Global Influenza Surveillance Network, provide valuable local information that can also be used for national purposes. who monitors influenza spread and why? 161 99 Influenza surveillance should not be limited to surveillance What about in humans, but should also include surveillance in birds and other animals, as they play an important role in the animal influenza emergence of pandemic influenza viruses. In several geographical areas such as North America, Eurasia and Africa, surveillance? combined activities between virologists, ornithologists and data managers have been started in the past decade to map the spread of avian influenza A viruses in waterfowl and the threat they may pose to other wildlife, domestic poultry, other domestic animals and eventually mankind. The value of these activities besides mapping of the spread and the associated risk is that they generate a large and continuously updated repository of avian influenza A viruses. This may track  allow the continuous development of an updated repository of seed viruses for eventual pandemic vaccine production, which will save precious time in developing a vaccine when the next pandemic emerges. The specific roles of international organizations such as the WHO, OIE and FAO are highlighted in Q91.

Monitoring migratory birds is an essential part of influenza surveillance.

All about viruses 163

XII What’s more? 164 101 questions & answers on influenza 100 To date we know a great deal about measures that should What aspects be taken in the framework of an influenza pandemic pre paredness plan as advocated by the WHO. Several industri- of epidemic alized countries have indeed created the necessary commit- tees and working groups that have looked into the practical and pandemic implications for establishment of early warning systems and preparedness implementation of non-medical and medical intervention strategies. An important part of all plans is rehearsal of their need further implementation by all stakeholders, which is happening in some countries. The ECDC provides state-of-the-art reviews research? of the situation in EU countries with regard to influenza pandemic preparedness and is committed to following this process during the ongoing ‘Mexican flu’ pandemic and in the future. Furthermore, we cannot assess the actual risk of the currently circulating avian influenza viruses that from time to time cross the species barrier to humans. We can however be sure that if indeed the HPAI-H5N1 virus is involved in a future pandemic virus, it could well become a major catastrophe with an unprecedented high fatality rate. Therefore, a better understanding of the determinants governing the pathogenesis — and even more importantly the transmissibility — of influenza A viruses for humans at the molecular level, should currently be among the highest research priorities.

In spite of all these efforts, preparedness in Europe is far from satisfactory now and there are doubts whether this situation will allow the implementation of the adequate intervention strategies during the ongoing ‘Mexican flu’ pandemic. All about viruses 165 101 World Health Organization, influenza homepage: Where can I www.who.int/csr/disease/influenza/en/

find the most European Centre for Disease Prevention and Control, influenza homepage: essential flu info www.ecdc.europa.eu/en/Health_Topics/influenza/ on the Web? US Centers for Disease Control and Prevention: www.cdc.gov/flu/

European Influenza Surveillance Scheme: www.eiss.org

European Scientific Working group on Influenza: www.eswi.org

Online knowledge centre on influenza: www.flucentre.org

International Federation of Pharmaceutical Manufacturers & Associations: www.ifpma.org/influenza

Computer game: the Great Flu www.thegreatflu.com 166

Biography

Prof. Dr. A.D.M.E. (Ab) Osterhaus is professor of David De Pooter is working at Link Inc since 2003, virology at Erasmus MC Rotterdam, and professor the Antwerp (Belgium) based communication of Environmental Virology at Utrecht University. consultancy agency , specialised in strategic com- Fascinated by the ingenious ways viruses circum- munication and social marketing. Link Inc is work- vent the immune system of their hosts to multiply ing with the European Scientific working Group and spread, Osterhaus started his quest at the on Influenza (ESWI) since 1998 and is taking care interface of virology and immunology. He quickly of the positioning of the group, the strategy and translated new insights in this complex field to the implementation of the strategy by developing applications in animal and human vaccinology. In targeted communication tools. In this capacity, addition, he started his work on virus discovery, not David De Pooter is a professional writer on medical only focussing on the identification of a series of topics and a communication manager of ESWI. As animal viruses, but also of new human viruses. such he has established a fruitful and long standing Osterhaus is now considered an international collaboration with Prof Ab Osterhaus. authority in virology, and a leader in the field of (www.linkinc.be) respiratory and zoonotic virus infections as well as in virus discovery. Several recent breakthroughs illustrate his internationally recognized achievements: his group identified for the first time the H5N1 influenza virus in humans in Hong Kong (1997), discovered and characterized the human metapneumovirus (hMPV), which causes serious disease in young children, the elderly and the immunocompromised (2001), and proved that a newly discovered coronavirus was the primary cause of SARS (2003). Whilst pursuing his scientific activities, he currently also is the chairman of the European Scientific Working group on Influenza (ESWI) and acts as a key expert in various other national and international organizations (including WHO and the EU). 167

Acknowledgements

Illustration question 68: courtesy of MIV Study Group Illustrations questions 6, 55 and 56: courtesy of Solvay Biologicals Illustrations questions 55 and 79: courtesy of GSK Biologicals Illustrations questions 64, 68, 72 and 73: courtesy of Prof. Dr Thomas Szucs Illustrations questions 48, 76 and 100: courtesy of Erasmus MC, Rotterdam Illustrations questions 11, 13, 43, 61, 75 and 82: courtesy of Zeppo.be Illustration question 80: courtesy of Koen Broos All other illustrations: copyright Van Parys Media

1 What virus research has done for us

2 How the world coped 6 How to prepare for an influenza

with SARS pandemic

3 H7N7 influenza 7 Investing in pandemic outbreak in 10 Viral preparedness plans: a The Netherlands stories matter of priority 4 Will there ever be from the 8 How H5N1 experience of a universal conquered Asia, Africa Prof. Ab Osterhaus flu vaccine? and Europe

5 Why AIDS is still 9 Are we prepared for

among us a global outbreak of the

Mexican flu?

10 Vaccines: weapons of mass protection 101 Influenza on & Answers Questions 101 Questions & Answers