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2: Pandemic Influenza Priority Medicines for Europe and the World "A Public Health Approach to Innovation"
Preparing for Pandemic Influenza: A Research Agenda for the European Union During the Interpandemic Period
This chapter has been compiled by David S. Fedson, M.D. in collaboration with the Global Influenza Programme 11 October 2004
6.2: Pandemic Influenza
Table of Contents
Executive Summary.............................................................................................................................3 Background..........................................................................................................................................6 Burden of Disease ...............................................................................................................................8 The Influenza Virus.................................................................................................................8 Interpandemic Influenza: The Burden of Disease....................................................................8 Avian Influenza: Increasing the Risk for a Pandemic...............................................................9 Pandemic Influenza and its Potential Impact on Europe and the World..................................10 Prevention and Control of Influenza.................................................................................................10 The Current Control Strategy and its Effectiveness................................................................10 Influenza Vaccination........................................................................................................10 Antiviral Agents ................................................................................................................11 Use of Vaccines and Antivirals During a Pandemic..........................................................12 Non-Medical Interventions ...............................................................................................13 Current Implementation of the Control Strategy.....................................................................13 The Interpandemic Use of Influenza Vaccine in Europe and the Rest of the World .......13 The Interpandemic Use of Antivirals in Europe and the Rest of the World......................18 Affordability of the Interventions.......................................................................................18 Constraints to Better Control............................................................................................................19 Interpandemic Period............................................................................................................19 Pandemic Period...................................................................................................................20 Limitations of the Vaccination Strategy.............................................................................20 Limitations of the Antiviral Strategy...................................................................................21 Lessons Learned from Research into Pharmaceutical Interventions.............................................22 Vaccination Strategies...........................................................................................................22 Reverse Genetics..................................................................................................................25 Existing Research Resource Flows.......................................................................................26 Pipeline of Products...........................................................................................................................27 Pipeline for Influenza Vaccines .............................................................................................27 Pipeline for Antiviral Agents ..................................................................................................29 The Safety and Efficacy of Products in the Pipeline...............................................................29 Research into New Pharmaceutical Interventions...........................................................................31 Vaccines with Broad Spectrum and Long Lasting Immunity ..................................................31 Newer Antiviral Agents .........................................................................................................33 Other Pharmaceuticals..........................................................................................................33 Institutions and Human Resources .......................................................................................34 Gaps and Opportunities for Pharmaceutical Research...................................................................34 Research to Be Carried Out in 5 Years..................................................................................35 Vaccines............................................................................................................................35 Antiviral Agents.................................................................................................................35 Non-Pharmaceutical Research.........................................................................................36 Translational Research.....................................................................................................37 Research to be Carried Out in the Longer Term....................................................................38 Research in Need of Increased Support................................................................................39 The Comparative Advantage of the EU .................................................................................40 References..........................................................................................................................................41
6.2: Pandemic Influenza Executive Summary
The threat of a new influenza pandemic, its potential impact on health and the social and economic life of nations are clearly recognized by World Health Organization and the European Union. The key strategies to prepare for a pandemic have been adopted by the Member States of both organizations. Although all agree that vaccines and antiviral agents will be the only reliable interventions for reducing the morbidity and mortality of a pandemic, current vaccines and antivirals and have several disadvantages and supplies of both will be severely limited. Annual outbreaks of influenza are due to minor changes in the virus that enable it to evade the immunity humans have developed following previous infection or vaccination. For this reason, the vaccine needs to be reformulated each year and vaccination must be repeated. Occasionally, one or more genes will be replaced by the genes of another (often avian) influenza virus. When this occurs, most people will have little or no immunity to this new virus. If it can be efficiently transmitted from one person to the next, a new pandemic will emerge. Outbreaks of influenza in animals, especially when they occur simultaneously with annual outbreaks in humans, increase the chance that genes from the two viruses will reassort and produce a new pandemic virus. During the past few years, the world has experienced several outbreaks of avian influenza that have resulted in human infections. These events remind us that the arrival of the next pandemic is just a matter of time. The impact of the next pandemic will depend on the infectivity and virulence of the pandemic virus. Mortality estimates for the next pandemic have ranged from 2-7 million deaths, and for a 1918-like pandemic could reach 175 to 350 million. Even with the most conservative estimates, millions of people will become seriously ill or die. Compared with the relatively small number of cases of SARS and their focused social and economic impact, one can expect the worldwide impact of the next influenza pandemic to be far greater. The main strategy for controlling seasonal epidemics of influenza is yearly vaccination of high-risk individuals. Although vaccination is considered costeffective in developed countries, vaccine uptake remains low in many of these countries. In developing countries, basic information on the burden of disease does not exist, making it difficult for policymakers to justify programmes for influenza prevention and control. Low vaccine uptake is mirrored by the world’s vaccine production capacity. Approximately 300 million doses of the current inactivated trivalent influenza vaccine are produced each year, two-thirds of them by companies located in the European Union. These European companies provide virtually all of the doses of influenza vaccine used in countries that do not have influenza vaccine companies. Antiviral agents reduce severity and duration of influenza but due to high prices they are little used. As a result, the current supply and production capacity for these agents is severely limited. These shortcomings in vaccine and antiviral supply will become evident when the next pandemic emerges. It will take several months before full-scale pandemic vaccine production can begin. Because countries with influenza vaccine companies can be expected to delay or prohibit the export of pandemic vaccines until their domestic needs have been met, countries without vaccine production facilities will 6.23
6.2: Pandemic Influenza
be unable to obtain supplies of pandemic vaccines. Unlike vaccines, antiviral agents could be stockpiled in advance, but stockpiles will be limited because of their high cost and uncertainty regarding the effectiveness of these agents. Interventions other than vaccines and antivirals might delay transmission of a pandemic virus, but would unlikely interrupt its global transmission. In order to overcome limitations in the supply of pandemic vaccines, several options have been explored. The results show that compared with current trivalent inactivated vaccines, monovalent pandemic vaccines formulated with a low antigen dosage and including a commonly available adjuvant could increase the number of doses of pandemic vaccine that could be produced by 12- to 24-fold. These findings offer the best hope for producing an adequate supply of pandemic vaccines for Member States of the European Union and for other countries throughout the world. Reverse genetics provides a rapid and safe alternative to traditional genetic reassortment for preparing seed strains for pandemic vaccine production. However, the use of reverse genetics is constrained by issues regarding intellectual property rights and public concern about the use of ‘genetically modified organisms’. In order to take full advantage of this important technology, these issues must be resolved as soon as possible. In order to guarantee rapid licensing of pandemic vaccines, the European Medicines Evaluation Agency (EMEA) has issued guidelines for vaccine manufacturers on how to prepare a pandemic vaccine dossier. The dossier is based on a ‘mock-up’ vaccine that could contain the highly pathogenic avian H5N1 influenza strain currently causing widespread disease in Asia. Although a reverse genetics-engineered vaccine seed strain has been offered free-of-charge to all manufacturers, the companies have little or no incentive to invest in costly clinical trials of a vaccine they will never market. In the United States, the NIH is currently providing public funding for such clinical trials. Although the vaccine formulations the NIH will test will not allow for greatly expanded production of pandemic vaccines to meet global demand (they will not be low-dose, adjuvanted preparations), Europeans should recognize that public funding will be necessary if clinical trials of pandemic vaccines are to be undertaken in Europe. The recent introduction of an intra-nasally administered live-attenuated influenza vaccine in the US (but not yet in Europe) is promising, but this vaccine is unlikely to have much impact on the influenza vaccine market in Europe for several years. A more long-term research strategy should include studies of vaccines targeting one of several highly conserved virus antigens that induce broad spectrum and longlasting protection. The EU currently provides modest support for the developing human influenza vaccines: €2.1 million for FLUPAN and €1.76 million for NOVAFLU. The US government has committed a far larger amount (at least $50-100 million, if not more) to this research. However, even in the US investment in pandemic vaccine development is modest compared with investments in developing vaccines for other diseases. In the field of antivirals, there is little commercial investment in research. Public funding to support research on current or new antiviral agents is largely limited to the US.
priorities for pharmaceutical research on influenza vaccines and antiviral agents should focus on short. Intellectual property rights and regulatory issues related to the use of reverse genetics to prepare seed strains for pandemic vaccine production need to be resolved. Successful implementation of this agenda will allow the European Union to fulfil its obligations to all Europeans and meet its responsibilities to people in other countries throughout the world. For antiviral agents. Long-term research should focus on developing broad spectrum vaccines that provide long lasting protection. In addition. adjuvanted ‘pandemic-like’ vaccines. pharmaceutical research should go hand-in-hand with translational research that will provide the basis for implementing programs for using newer vaccines and antivirals. Short-term research (within the next five years) should focus on evaluating the immunogenicity and safety of low-dose. The benefits of expanded use of existing vaccines (including live attenuated influenza vaccines) and expanding vaccine manufacturing capacity should be further explored. 6. there is an urgent need for research on newer antiviral agents.6. some of which might target new virus antigens. Research is also needed on the possible impact of commonly available medications such as statins on the clinical course of influenza-related illness. their effects on reducing serious complications of influenza should be further explored.2: Pandemic Influenza In the European Union. More important. The ability of Europeans to respond to the next influenza pandemic will in considerable measure depend on the willingness of the European Union to provide public support for a research agenda on pandemic vaccines and antiviral agents in interpandemic years. Support for research on the basic immunology of the response to vaccination. Moreover.25 . the molecular pathophysiology of influenza virus infection and the role of biological response mediators in host defense should go hand-in-hand with research on influenza vaccines and antiviral agents. Studies on the effectiveness of a lower dose and shorter duration of treatment with anti-neuraminidase agents could increase their availability during a pandemic. the development of new antiviral agents that overcome the disadvantages of current agents is urgently needed.and long-term research.
especially in developing countries. and (iv) accelerate national and international action on pandemic preparedness. virologists. for 6.2: Pandemic Influenza Background Despite a considerable increase in our knowledge of influenza viruses.” They recognized the need to improve vaccine formulations.2. (ii) improve knowledge of the health and economic burden of influenza. Many of these deaths could be prevented by increasing the use of existing vaccines. and economic costs they invariably cause. the recent worldwide increase in the size of at-risk populations. They are listed according to four main objectives: (i) strengthen surveillance.2) The Global Agenda responds to the challenges posed by poor understanding of the impact of influenza. (iii) increase influenza vaccine usage. Member States acknowledged that influenza affects millions of people worldwide and causes fatal complications in up to 1 million people each year.26 .3) In this resolution. including the private sector. vaccines.1 The World Health Organization (WHO) has historically focused its influenza activities on virological surveillance to support annual vaccine strain selection. It gained strong political backing in May 2003 when the World Health Assembly (WHA) adopted a resolution on the “Prevention and Control of Influenza Pandemics and Annual Epidemics”. major breakthroughs in the prevention and control of annual epidemics and influenza pandemic preparedness have not been made.(See Appendix 6. especially in view of the recurrence of such pandemics and the high mortality. increase manufacturing capacity for vaccines. Each priority activity is further defined in a series of recommended activities for researchers. the long time frame needed to manufacture influenza vaccines. The last pandemic occurred more than 35 years ago and the recent years' outbreaks of avian influenza in poultry in Asian countries have heightened global concern that a new human pandemic could follow.2. and strengthen disease surveillance as part of national and global pandemic preparedness. WHO convened a consultation of influenza experts. In May 2002.6. in order to develop and produce an influenza vaccine formulation capable of conferring long-lasting and broad protection against all influenza virus strains. and the development of resistance to first-line antibacterial drugs. WHO expanded its focus to address new challenges. particularly in high-risk groups. Member States expressed concern about “the general lack of national and global preparedness for a future influenza pandemic. and the need for surveillance activities to be more closely related to control. The consensus that was achieved led to the publication of the first Global Agenda on Influenza Surveillance and Control 2. social disruption. which may now be exacerbated by rapid international travel. This is especially worrying as an influenza pandemic becomes more and more likely. ensure more equitable access to antiviral drugs. particularly concerning their suitability for use in developing countries. governments. persisting inadequate vaccine coverage in most countries. The Global Agenda has been widely accepted by scientists all over the world. 3 (See Appendix 6.” WHO was asked ”to search jointly with other international and national partners. Recently. The WHA resolution called for Member States ”to support research and development on improved influenza vaccines. antiviral agents and other control measures. and maps out a strategic plan for doing so. and WHO. industry. epidemiologists and public health officials. It encourages collaboration among all those in the public and private sectors who can contribute to better influenza surveillance and control. The Global Agenda identifies 17 priority activities judged necessary to reduce the burden of epidemics and prepare the world for the next pandemic. Among the priorities are research on pandemic viruses.
in the process of early recognition of the identity and origins of pandemic strain. 6. " Since these reports were published. there has been limited progress in developing new interventions to prevent or delay a pandemic and that are accessible by the majority of the world’s population. influenza vaccines and antiviral drugs. therefore.6. Members of the public will not excuse authorities. In the event of a pandemic millions of people could die. Measures should. such as Ebola and Lassa fever and more recently SARS. noting that "research leading to the development of new vaccine technology should remain a priority and be linked to routine and fast-track licensing procedures for influenza vaccines. Current and emerging anti-viral drug resistance developments in influenza need to be addressed through coordinated research at the European level.”4 In March 2004 the European Commission published a working document on “Community Influenza Pandemic Preparedness and Response Planning”. be considered with a view to ensuring equity of access. who will be held responsible for not having put in place up-to-date preparedness. be further limited by measures imposed by Member State authorities to provide maximum protection to their own population.2: Pandemic Influenza solutions to reduce the present global shortage of. in critical situations. This can be remedied only through greater investment by the public sector.” The event that marks the beginning of European planning for the next influenza pandemic was the EU-sponsored conference “Pandemic Preparedness in the Community” that was held in Brussels on 27 November 2001. Vaccine availability is not secured. Availability of vaccines or antivirals to populations most at risk may. Antiviral stocks do not exist and will not be under the current market forces. as was the case in the past with similar threats.7 Nonetheless." The Commission emphasized that research performed during the interpandemic period would be vital for preparing an effective pandemic response. both for epidemic and global pandemic situations. the role of international scientific cooperation is key. The Commission will therefore continue to develop its collaborative research networks to integrate partners in third countries.5 (See Appendix 6. and inequitable access to. Manufacturers’ reserve capacity is not likely to be enough to support a sudden increase in demand. This need was strongly emphasised in the report of a recent WHO Consultation on “Priority Public Health Interventions Before and During a Pandemic” that was held in March 2004.6 The research components for various Community actions had already been identified in the Community’s 5th and 6th Framework Programmes.8 This report can and should be used as an inspiration to all the readers of this document.2. In addition. Furthermore. Two projects for developing new influenza vaccines are currently being funded and a call was recently issued for proposals for post genomic research in the field of influenza vaccines.27 . In its preliminary conclusions.1) The document noted that "current vaccine production capacity is not deemed to be sufficient to meet the demands of the Community in the event of a pandemic. EU Member States are not prepared. considerable progress has been made in formulating plans for pandemic preparedness within the European Union and outsite. in April 2004 the European Agency for the Evaluation of Medicinal Products (EMEA) published guidelines for developing and registering pandemic influenza vaccines through a procedure that will be based on ‘mock-up’ dossiers for candidate pandemic vaccines submitted by individual vaccine companies. economies will be affected and services (medical. the conference noted: “The next pandemic is imminent. civil) could collapse.
Most deaths associated with influenza in industrialized countries occur among people over 65 years of age. matrix protein (M1). Epidemics of varying degrees of severity occur each winter. and each year 5 to 20% will develop symptomatic illness 9. The mortality impact of these outbreaks has been especially severe in children. especially for older people. a recent report from Hong Kong for the period 1998-2001 documented rates of excess influenza-related hospital admissions for pneumonia. chronic obstructive pulmonary disease and heart failure that were comparable to those reported in developed countries. three polymerases (PB1. infection rates are higher in children than in any other age group. hospital admissions for influenza-related conditions have caused major problems for health service delivery each winter. these annual epidemics are thought to result in between three and five million cases of severe illness and up to 1.the hemagglutinin (HA) and neuraminidase (NA) antigens. lead to the antigenic shifts that uniquely characterize new pandemics.21 22 23 24Recently. Although most cases of influenza are self-limited.000 deaths worldwide. nucleoprotein (NP).14 There have been few studies of the health and economic burden of influenza in tropical and developing countries. in England and Wales. H2 and H3) and NA (N1 and N2) antigens. In England and Wales. Point mutations in the HA and less frequently NA antigens lead to the antigenic drift characteristic of interpandemic yearly epidemics. attention has been drawn to influenza-associated complications such as febrile seizures and acute influenza-associated encephalopathy.17 Several studies from European countries have documented the impact of childhood influenza on ambulatory care visits 18 19 20and hospitalizations. The type A viruses that cause epidemics in man are classified according to their HA (H1. additional medical care and economic loss. Although difficult to assess.10 and this experience is duplicated in other countries. an estimated 6200 to almost 30.12 an experience common to other countries where influenza morality has been studied. an ion channel protein (M2) and two non-structural proteins (NS1 and NS2). and children are the principle disseminators of influenza throughout communities. estimates put the economic costs of annual influenza epidemics at several billion dollars per year.15 In the developing countries of Madagascar and the Democratic Republic of Congo. However. PB2 and PA).13 In the United States. they are responsible for an enormous amount of work absenteeism. Sudden substitutions of whole genes from one subtype to another.6.9 The influenza virus genome consists of eight RNA segments that code for 10 proteins: two envelope glycoproteins . In developed countries. by mixing human and animal influenza viruses in animal hosts. Influenza is a major cause of acute otitis media 16 and in children < 2 years of age hospitalization rates approach those seen in elderly adults.28 . rates similar to those experienced in developed countries during the 1918 pandemic. recent outbreaks have been extensive and case-fatality rates have been 3-4%. a condition that is either fatal or causes serious neurological sequelae in more that half of cases. for example. of which type A is the most pathogenic for humans.25 Influenza 6.000.000 people died of influenza-related illnesses during each of the epidemics between 1975 and 1989. Interpandemic Influenza: The Burden of Disease Influenza affects people of all ages in all parts of the world.11 Moreover.2: Pandemic Influenza Burden of Disease The Influenza Virus Influenza viruses are negative-stranded RNA viruses.
a previously healthy veterinarian. in 1997. As a result. and this time 24 (68%) of the 34 people who were infected died. if any.29 Europeans have also had recent experience with avian influenza. One of these persons could serve as the “mixing vessel” for the emergence of a novel influenza virus subtype possessing the genetic phenotype that permits efficient person-to-person transmission. an H7N7 avian virus infected seals on Cape Cod in New England.30 This is not the only documented instance of the transmission of an avian influenza virus to mammals. and the effects of influenza on pregnant women and perinatal outcomes.26 In most European countries there are no estimates of excess influenzaassociated mortality nor are there measures of influenza’s impact on the economic life of communities and nations. However. Again.2: Pandemic Influenza is also an important cause of respiratory illness and hospitalization for acute cardiopulmonary conditions in pregnant women. is that of an avian virus mutating at a critical site to allow for a stronger binding of the virus to cells in the human respiratory tract and therefore speeding up viral replication and facilitating a more efficient man-to-man transmission The World Health Organization and infectious disease experts throughout the world are concerned that events such as the recent avian influenza outbreaks in Asia could lead to a new human influenza pandemic.31 The persistence of highly pathogenic avian influenza viruses in poultry flocks in Asian countries provides continuing opportunities for the direct infection of humans. more than 400 poultry workers and their family members developed conjunctivitis and influenza-like illness and one person. In early 2003 a highly pathogenic avian influenza H7N7 outbreak affected commercial poultry farms in The Netherlands and infection was transmitted to humans.6.29 . although adverse effects on perinatal outcomes have not been noted. and different from the “mixing vessel” mechanism.28 Avian influenza has persisted in poultry flocks in several of the counties affected. In the early 1980s. Little. six of whom died 27. specific complications such as acute encephalopathy. the essential requirement for a new pandemic virus32. but compared with other countries. As more humans become infected. Human cases of H5N1 influenza reappeared in 1999 and again in early 2003. Accurate assessment of the health and economic impact of influenza in different populations will enable policy-makers to set priorities and justify budgets for programs for influenza prevention and control. died. an unprecedented outbreak of avian H5N1 influenza swept through poultry flocks in many countries in East and Southeast Asia. Another possible and alarming scenario.1 33 6. human cases of H5N1 infection occurred. avian H5N1 influenza appeared in the poultry markets of Hong Kong and infection spread to 18 people. the likelihood increases that humans might be concurrently infected with human and avian influenza strains. and in August 2004 three additional fatal cases of human H5N1 influenza were reported from Vietnam. Avian Influenza: Increasing the Risk for a Pandemic Avian influenza viruses do not normally infect species other than birds and pigs. Several studies have documented aspects of the burden of influenza in European children. interhuman spread was recorded. and within two months 25% had died. In late 2003 and early 2004. less is known about rates of hospitalization.
The case-fatality rate was far worse than what was seen in 1918. Recent experience with SARS has shown that an emerging disease that causes a small number of cases in a region can rapidly spread to distant countries and create anxiety in the community. a respected influenza expert cautioned against what he called ‘influenza extrapolitis’.210 .2: Pandemic Influenza Pandemic Influenza and its Potential Impact on Europe and the World The influenza pandemic of 1918 was one of the most significant disease outbreaks in all of recorded history.2 million hospital admissions.34 Within a two-year period.37 Many regard these estimates as very conservative and believe that the burden of pandemic disease will be more severe. Medical facilities can be easily overwhelmed. In high income countries that account for 15% of the world’s population. Atlanta.4 million deaths worldwide. far more than died in World War I.6. In addition to their consequences for health. especially in developing countries.Asian influenza in 1957-59 and Hong Kong influenza in 1968 .9 The trivalent inactivated vaccines currently available are immunogenic and safe. the assumption that the next pandemic will be as severe as the one in 1918. “the only thing more difficult than planning for an emergency is having to explain why you didn't". 6. that is.5–5. influenza outbreaks can have a huge impact on the social and economic life.39 Prevention and Control of Influenza The Current Control Strategy and its Effectiveness Influenza Vaccination Influenza vaccines are the mainstay of influenza prevention and control. but nonetheless caused widespread social disruption and substantial excess mortality. USA project that today a pandemic could result in 2 to 7.34 No one can know with certainty how severe the next pandemic will be. No country will be spared. 68% of the human cases of avian H5N1 influenza seen in Vietnam and Thailand died. If the next pandemic is as severe as the one in 1918. the situation could be much worse. in making plans for responding to the next pandemic.were much milder.36 Epidemiological models from the Centers for Disease Control and Prevention. it killed an estimated 50-100 million people worldwide. Compared with the SARS experience. If a pandemic virus with this degree of virulence were to acquire the transmission characteristics of a usual pandemic influenza virus.38 These people would die not in 100 years but in 1 or 2. a severe influenza pandemic can be expected to be far worse. In early 2004. epidemiological models project a demand for 134–233 million outpatient visits and 1. and anxiety can quickly disrupt community life. remembering that. Given the more than 3-fold increase in the world’s population since 1918. it would be prudent to anticipate the ‘worst case scenario’. Thus. Widespread illness may result in significant shortages of personnel who provide essential community services and public fear may put immense political pressure on decision makers. This is more than the number of people killed in all wars and by the most murderous governments throughout the 20th Century.35 Two later pandemics . the health consequences for human populations everywhere could be catastrophic. Several years ago. a reappearance of a 1918-like pandemic could also kill as many as 175 to 350 million people.
with the goal of attaining vaccination coverage in the elderly population of at least 50% by 2006 and 75% by 2010. four antivirals have proven efficacy in treatment and prophylaxis of influenza A infections: two M2 inhibitors (amantadine and rimantadine) and two neuraminidase inhibitors (zanamivir and oseltamivir). There are few data on their efficacy in high-risk individuals. and establish appropriate strategies for doing so. McCullers. WHO recommends the use of influenza vaccine in nationally defined risk groups. children and pregnant women. serological responses to the hemagglutinin (HA) antigen of the influenza virus correlate well with clinical protection. the protective efficacy of vaccination is up to about 70% against disease and even more so against adult hospitalizations and death.50 People at risk include residents of institutions for the elderly or the disabled. Early treatment with M2 inhibitors reduces the duration of symptoms and the time to recovery by one to two days.48 and vaccination during pregnancy has the potential to benefit not only mothers themselves but also their newborn infants.6. it shortens the course of clinical illness.211 . Zanamivir is administered by inhaler and its use has been limited. are sensitive to the anti-neuraminidase agents oseltamivir and zanamivir.53 Antivirals reduce virus shedding and thus infectivity of treated infected persons.47 Pregnant women are at increased risk of hospitalization for influenza-related illness.2: Pandemic Influenza Following vaccination. Moreover. the avian H5N1 viruses isolated in Asia have not been inhibited by these agents. The WHA resolution on influenza in 2003 recommended that Member States undertake the following:3 • where national influenza vaccination policies exist: increase vaccination coverage of all high-risk groups. including the elderly and persons with underlying chronic disease. • Antiviral Agents Currently. All influenza type A and B viruses.9 The therapeutic efficacy of all of these agents was established in clinical trials conducted in adults and children who received treatment within two days of the onset of the symptoms. Provided there is a close match between the vaccine virus and the virus causing disease. 16 June 2004]. pulmonary. and when given within the first 48 hours of the onset of symptoms.49 There are relatively few European studies on the effectiveness of influenza vaccination preventing influenza-associated hospitalizations and death in adults.41 42 and these antibodies protect against both influenza itself43 and secondary bacterial pneumonia [J. limiting their use.45 Vaccination of children is also clinically effective46 and high levels of coverage among schoolchildren induce herd immunity and prevent deaths in older adults. 6. persons (> 6 months of age) with chronic cardiovascular. When M2 inhibitors are used in treatment. antiviral resistance develops rapidly. metabolic or renal disease. where no national influenza vaccination policies exist: assess the health and economic impact of annual influenza epidemics as a basis for developing and implementing influenza prevention policies within the context of other national health priorities. influenza vaccination has also been shown to be cost-effective in European countries. Oseltamivir has been more widely used. including the avian viruses. persons who are immunocompromised and individuals who are above a nationally defined age limit irrespective of their medical risk status (most countries define the age limit as ≥ 65 years).40 Vaccination also stimulates an increase in anti-neuraminidase antibodies. personal communication.44 In addition to being clinically effective.
Use of Vaccines and Antivirals During a Pandemic Influenza vaccines and antiviral agents are the two essential components of a comprehensive pandemic response. However.2: Pandemic Influenza reduces antibiotic use and reduces rates of pneumonia and hospital admissions. Possible target groups for pandemic vaccination include the following:53 (See Appendix 6. which requires a prohibitively large stockpile. the size of the target groups and the specific goals to be achieved. early treatment represents a more efficient use of resources than prophylaxis. Considerations for establishing priority groups for vaccination will be different for each country. Given this. Other components include adequate supplies of antibiotics and other resources for providing hospital and outpatient care to populations affected by the pandemic.4) • • • Essential service providers including health care workers (to maintain essential services) Groups at high risk of death and severe complications (to prevent or reduce death and hospital admissions) Persons without risk factors or complications (to prevent or reduce morbidity).9. 6.8 Vaccination should still be the primary method of prophylaxis.6. Options for the use of antiviral agents will depend on their availability.2.212 .51 Thus far. antiviral resistance has not become an important clinical problem with oseltamivir. Most countries will have limited or inadequate resources to manage a pandemic. 52 There are no European data on the effectiveness of neuraminidase inhibitors in preventing influenza-associated hospitalizations and death in adults. Decisions as to who should be included in priority groups will depend on the primary goals of the vaccination programs. children and pregnant women. prophylaxis is more likely that treatment to prevent serious complications from influenza because it prevents influenza virus infection itself. ranging from 2–6 weeks depending on whether one or two doses of vaccine is recommended Prophylaxis of individuals following exposure to pandemic influenza (approximately one week per course) Treatment of ill persons for whom treatment can be initiated within the first 48 hours of illness Treatment of exposed persons for whom influenza vaccination is contraindicated In general. national authorities must address the question of which citizens should be given priority for receiving the limited supplies of pandemic vaccines and antiviral agents. not only because of differences in vaccine availability and resources but also because of differences in population structure and the organization of essential services. The main options include:53 • • • • • • Long term prophylaxis (prevention) of defined populations for the duration of a wave of pandemic activity (minimum of 4 weeks) Prophylaxis during outbreaks in closed institutions (usually lasting about 2 weeks) Protection of individuals for the period between vaccination and the development of protection.
even though some of them might have limited effectiveness. cost. opportunities for preventing the spread of the pandemic virus to these regions will probably remain open even after the pandemic has begun. and the susceptibility of the virus to antiviral agents. antiviral agents will be in very short supply and vaccines will not be available for many months.8 A wide range of non-medical interventions – from personal hygiene and wearing masks to quarantine and screening travellers – could potentially limit the transmission of the pandemic virus. In all instances. 6.6. However. implementing these measures may require changing public health laws at both national and international levels. This strategy of ‘buying time' was discussed during the WHO Consultation on”Priority Public Health Interventions Before and During an Influenza Pandemic” that was held in March 2004. simple measures such as hand washing. In addition to their effectiveness. its virulence. During this phase. Thus non-medical interventions may be important 'additional control measures'. prior guidance on the most appropriate interventions will be particularly important. Because the window of opportunity will close quickly. Although many of these interventions were tested during the response to the SARS outbreak. their use under the very different conditions of an influenza pandemic has not been systematically evaluated. the duration of virus shedding. planning for pandemic vaccine supply requires an ongoing understanding of the global epidemiology of influenza vaccination54.213 . the general public will probably be strongly motivated to adopt personal preventive behaviours. During this period other nonmedical interventions could delay the national and international spread of the pandemic.2: Pandemic Influenza Non-Medical Interventions In the early stages of a pandemic. Mathematical modelling suggests that early detection of the first chains of human-to-human transmission might provide a unique opportunity to prevent or at least delay further virus transmission. its attack rate in different age groups. Knowing that a pandemic has emerged. It is unlikely that any single measure would have a meaningful impact on its own. Once efficient and sustained human-to-human transmission is established in a region. Some behaviours such as avoiding travel to affected areas will probably be followed regardless of official recommendations. ease of implementation and likelihood of acceptance by the public. More than 30 non-medical public health interventions for controlling a pandemic have been suggested. Their effectiveness will depend on the transmissibility of the virus. containment of the virus will become virtually impossible and opportunities for averting the pandemic or appreciably slowing its spread will end. but by themselves they will not be able to stop or control a pandemic. Thus. Current Implementation of the Control Strategy The Interpandemic Use of Influenza Vaccine in Europe and the Rest of the World Supplies of influenza vaccine for the next pandemic will be critically dependent on the levels of vaccine use during the interpandemic period. as all regions of the world are unlikely to be affected simultaneously during the first wave of infection. Travel-related measures such as exit screening of persons departing from affected areas might limit or delay international spread. the use of masks and voluntary quarantine for symptomatic persons could help reduce transmission. the choice of non-medical interventions will be driven by their availability.
the use of influenza vaccine was largely limited to four countries in South America (Argentina.S. the U.2: Pandemic Influenza An overview of the global production and distribution of influenza vaccines during the interpandemic period has been provided by the Influenza Vaccine Supply (IVS) International Task Force. Compared with 1994. the level of vaccine distribution ten years later had more than doubled. 20% in Canada and the US. when approximately 135 million doses of influenza vaccine were distributed worldwide. vaccine distribution increased from 69 million doses to 85 million doses. 230 million doses of influenza vaccine were distributed worldwide. vaccine distribution increased 18% in Western Europe. vaccine distribution increased to 292 million doses.. 162 million (70%) of which were distributed in Canada. In 2004. Chile and Uruguay). Brazil. For the rest of the world. For these other countries. 25% in Australasia and 134% in Japan. 6. During this four-year period. Australasia and Japan. Western Europe.6. several countries in Central Europe (especially Hungary and Poland).1). The IVS Task Force is sponsored by the International Federation of Pharmaceutical Manufacturers Associations (IFPMA). of which 207 million (71%) were used in these same countries. Its report for the period 2000-2003 was recently submitted to WHO (see Table 6. a 23% increase.2.214 . Russia and South Korea. In 2000.
230 72.291 104.693 78.. In addition. Berna Biotech. Medimmune produced ~4-5 million doses of CAIV-T and distributed ~830.004 65. GSK Biological. the Russian Federation and Romania.733 41. The Netherlands 6.562 *Individual reports on the numbers of doses of influenza vaccine distributed each year were submitted by all IVS Task Force companies: Aventis Pasteur. Central 27.238 134 1.. data were gathered from non-IVS Task Force companies located in Hungary.491 646 13. but only ~250. The Association of Japanese Biologicals Manufacturers reported data on behalf of four Japanese vaccine companies.916 3.163 1.345 114.087 20.094 67.530 230.943 9.1: Global Distribution of Influenza Vaccine.864 Southeast Asia 253 Eastern Mediterranean 1.874 99.389 10. liveattenuated trivalent influenza vaccine distributed by Medimmune. Solvay Pharmaceuticals B.700 122.593 11. Shire Biologicals.000 doses. †The data for the United States in 2003 do not include doses of cold-adapted.V.2: Pandemic Influenza Table 6. Aventis Pasteur MSD.012 103. Inc.348 84. The data were reported for calendar years according to WHO Regions.424 4.230 270. and Wyeth Vaccines.900 68. For some regions.368 Europe Americas 123. CSL Limited. additional information was obtained on vaccine distribution in countries within the regions. Five of these countries are EU Member States .891 Western Europe 76. 2000-2003 WHO Region Total Doses Distributed (000s)* ______________________________________________ 2000 2001 2002 2003 93.600 82. Almost all of the world’s influenza vaccine is produced in nine countries.913† 29.201 1.043 2. Germany.364 82 1.802 668 17.000 doses were actually sold. Medimmune. Italy.705 25.979* 2.523 Central & Eastern 26.100 United States Mexico.795 4. The Task Force was unable to obtain information on doses produced and distributed in other counties. Chiron/Powderject. Ltd.000 24.725 95 1.6.189 Australia Japan New Zealand Other countries 26.864 31.215 .415 12.812 31.2.824 Europe 102.130 27.France.540 Africa GLOBAL TOTAL 291.253 715 16.440 627 39.565 & South America Western Pacific 61. In 2003.444 29.632 17.298 256.928 3.578 Canada 11.357 29.
but it obtains its bulk virus from a vaccine company located in Australia. In 2003.2. Canada. Recently. However. yet they produced ~95% of the world’s influenza vaccine. the Macroepidemiology of Influenza Vaccination (MIV) Study Group was established to provide this information. Countries within the European Union showed varying levels of vaccine use. Romania and Russia were used domestically.216 . and a few countries in South America used more vaccine that did some European countries. companies located in five EU countries produced 190 million doses of influenza vaccine. Japan. Information has been gathered from 40 countries and the results for 2002 are shown in Figure 6. However. Almost none of the doses produced in Canada. 6. The EU companies produced 85% of the 93 million doses used in countries outside Western Europe. with those in Western Europe generally having higher levels than the new Member States of Central and Eastern Europe. The IVS Task Force survey has provided an accurate summary of influenza vaccine production and the distribution of vaccine to different regions of the world. these nine countries had only 12% of the world’s population. and the US. The data are reported as rates of vaccine distribution per 1000 total population. The other four countries are Australia. 65% of the world’s supply. a Swiss company markets influenza vaccine. Russia and Hungary had higher levels of vaccine use that did several Western European countries.8 million doses produced in Hungary. The Republic of Korea ranked third.6. the survey cannot provide country-specific information on vaccine distribution for more than a few countries. Canada. Individual investigators in each country now submit data on the total number of doses of vaccine distributed each year. (In Europe. unpublished observations). primarily because its largest province (Ontario) has a universal influenza vaccination program. Australasia and Japan. and all of the 13. in part because a vigorous vaccination program was undertaken in the wake of the SARS outbreak in early 2003. Japan and the US were exported to other countries.1 (MIV Study Group. The largest user of influenza vaccine was Canada.2: Pandemic Influenza and the UK. the US.) In 2003.
6. Estonia and Malta.55 Nonetheless.1: Rates of Influenza Vaccine Distribution in 40 Countries in 20021 Number of doses distributed per 1000 total population All EU Member States and almost all other developed and rapidly developing countries have national recommendations to vaccinate elderly people and others with high-risk medical conditions. ten-fold variations in vaccine use are still seen within the EU. No data were obtained for Cyprus.2: Pandemic Influenza Figure 6. Factors that contribute to these variations include different levels of understanding of the health and economic consequences of 1 Member States of the European Union are shown in solid bars.217 .2. 6. non-EU countries are shown in the hatched bars.
In addition. In the event of a pandemic. the value of influenza vaccination is still regarded as very high. Most countries in the EU and virtually all non vaccine-producing countries in the rest of the world are critically dependent on supplies of interpandemic influenza vaccines produced in only five EU countries. the total cost of vaccinating an individual in three Western European countries was €15-30. The time needed to increase production capacity in the current facility is at least 9-12 months. approximately 7 million oseltamivir ‘treatments’ (one treatment is a five-day course for an individual patient) were distributed by the manufacturer (Brown P. a number of underlying cultural factors are important. even though annual revaccination is required. 6. personal communication.218 . The total number of ‘treatments’ was similar to the population of the country where oseltamivir is produced.6. In Western Europe. but recent supply constraints and expanding markets have been accompanied by increased prices. Approximately half of the treatments were used in Japan. particularly oseltamivir. and the views of small groups of policy makers. The Interpandemic Use of Antivirals in Europe and the Rest of the World There is very little epidemiological information available on the use of antiviral agents worldwide. the EU and global production capacity for this agent is extremely limited. The M2 inhibitors have several disadvantages. In 2000. the export of oseltamivir might be prohibited. This dependence will directly affect the availability of supplies of pandemic vaccines for the other 20 EU Member States and for all other countries that do not have influenza vaccine companies of their own. However. The data provided by the IVS Task Force and the MIV Study Group document a reality of enormous logistical and political importance for the Member States of the European Union. and consequently supplies will be available only in countries that have stockpiled oseltamivir (at great expense) in advance. although it is considering building one or more additional production sites in other countries. 17 June 2004). Cost-effectiveness analyses for three Western European countries show that vaccinating elderly persons is highly costeffective and in some instances may even be cost saving. as are new and less expensive antiviral agents. Only one company located in Switzerland produces oseltamivir. 18 August 2004]. the presence or absence of public programs for vaccine delivery and vaccination reimbursement. have received more attention and are the only agents that would be effective against the avian H5N1 viruses. Greater and more diversified manufacturing capacity for antineuraminidase agents is needed. In 2003. Roche Pharmaceuticals. There are no publicly available data on the distribution of oseltamavir in EU countries or in the rest of the world.2: Pandemic Influenza influenza.45 There is little public knowledge about vaccine prices and the costs of vaccination programs in the newer Member States of the EU and in the rest of the world. personal communication. the current (2004) retail price to health care providers is € 5-16 per dose [Bertrand Verwee. Affordability of the Interventions Several years ago. In most developing countries the cost of the vaccine probably puts influenza vaccination outside the range of affordability for public vaccination programs. if not longer. have not been heavily marketed and have fallen out of favour. The anti-neuraminidase agents.45 Despite recent price increases. influenza vaccines were sold in developed countries at relatively low prices.
distribution and administration would add greatly to the total cost per person. In the event of a pandemic.219 . • No currently available influenza vaccines confer protection against all strains of the three influenza virus subtypes that cause human disease. and a 4-week course of chemoprophylaxis cost € 130215. The current costs of antiviral agents represent a major obstacle to their supply and will severely limit their use in the control of pandemic influenza. Because each subtype exhibits frequent antigenic drift.45 Chemoprophylaxis was 30-50 times more expensive than vaccination. At present. In addition. • Some countries in the European Union have made considerable progress in increasing influenza vaccination coverage. mainly in the industrialized world. Little is known about their current prices in all EU countries. influenza vaccines are considered affordable. Vaccination coverage rates in developing countries are minimal. Surveillance and control activities in these countries receive little support. despite strong evidence that health care workers contribute to outbreaks in institutions caring for the elderly and are highly susceptible to infection themselves. Antiviral agents are considerably more expensive than influenza vaccines. vaccination rates among health care workers in direct contact with the elderly high-risk group are low. the increase in vaccine use documented for many rapidly developing countries indicates that for large segments of the populations in these countries. and health and economic burden of influenza in developing countries.6. particularly when operational targets have been set. anti-neuraminidase agents could be stockpiled in bulk and formulated for use when a pandemic threat is declared. Health officials in these countries have little available evidence for concluding that influenza is a significant health problem and that policies for its control should be adopted. but it is unknown to what level prices would drop. only 10–20% of people in high-risk groups in these countries are vaccinated.8.53 • There is an urgent need for better understanding of the occurrence. knowledge about the benefits of influenza vaccination has not been translated into effective vaccination programs in most Member States. However. epidemiology. However. Constraints to Better Control Interpandemic Period Despite the effectiveness of global influenza surveillance. in 2000 the cost of a five-day course of anti-neuraminidase treatment ranged from € 30-40 in three Western European countries. Greater use of antivirals would eventually have the effect of reducing their price. Nonetheless. the vaccine formulation must 6. the basic cost of the bulk drug for a five-day treatment course would be at least € 7 and the cost of its formulation. Recent WHO-sponsored consultations have identified several areas of concern. Despite numerous studies demonstrating the safety and effectiveness of vaccines. and as a result the WHO surveillance network has important geographical gaps. national and international responses to influenza suffer from several weaknesses that could have severe consequences for public health in the event of a pandemic. only ~50 countries.2: Pandemic Influenza Nonetheless. have policies for influenza vaccination. although properly timed treatment of symptomatic patients was reasonably costeffective.
citing national emergencies. If a pandemic vaccine is formulated to contain 15 µg HA. In addition. Research on novel vaccines. One new EU-based company is scheduled to enter the market within the next 2-3 years and it plans to market 40-50 million doses of cell culture-produced inactivated influenza vaccine each year. Further. well under the total EU population of 450 million. Because they will be immunologically naïve. several potential limitations in the supply of pandemic vaccines immediately become apparent. However. This change requires re-licensing of the vaccine and repeat vaccination. only 375 million people could be vaccinated with a ‘same strength’ monovalent vaccine. 6. All of these companies currently produce their vaccines in embryonated eggs. Given that five EU-based companies produced 190 million doses of trivalent vaccine in 2003 (Table 6. it is possible that up to 750 million doses of same-strength (15 µg HA) monovalent pandemic vaccine could be produced within the EU.6. but the incremental increase year-on-year will not be large. Countries outside the EU that have traditionally been supplied with interpandemic vaccines by EU-based companies might not be able to obtain any supplies of pandemic vaccines.54 This means that in the 25 EU countries. vaccine delivery methods and production technologies is needed to overcome the limitations of current influenza vaccines. it usually takes five or more years to build and obtain regulatory approval for a new vaccine production facility. the production capacities of vaccine companies will increase in parallel. Greater efforts are needed to implement current recommendations for influenza vaccination in order to reach coverage levels specified by the World Health Assembly in its resolution on influenza. None of the other EU-based companies is expected to have an appreciable capacity to produce cell culture vaccines within the next five years. they will require two doses of vaccine to be fully protected54. Thus stockpiling influenza vaccine is not an option. the overall capacity of EU-based companies for pandemic vaccine production within the next five years is unlikely to exceed the equivalent of ~250 million doses of trivalent vaccine each year. 100 million people in the 20 EU countries without vaccine companies will have to wait several months or more for supplies of pandemic vaccines.2: Pandemic Influenza be adjusted each year.2. Because the pandemic vaccine will almost certainly contain only the pandemic vaccine virus (it will be a monovalent vaccine).56 If the interpandemic use of vaccine increases in the next few years. Moreover.33. to ensure that there is enough vaccine to vaccinate their own populations. in many if not most countries.1) and that an additional 40-50 million doses will soon be added. influenza vaccine continues to be moderately expensive for people who live in developed countries and its price is out of reach for most of those who live in developing countries. most if not all people will not have been previously infected with a virus like the pandemic virus. government leaders in the five countries that have vaccine companies could be tempted to ‘nationalize’ their vaccine production facilities.54 Pandemic vaccine production will be totally dependent on the capacities of the existing vaccine companies in the EU and the rest of the world. Pandemic Period Limitations of the Vaccination Strategy If a new pandemic virus emerges within the next few years..220 . when a pandemic virus appears. public health authorities will want to vaccinate everyone in their populations.
they could be stockpiled. as are new and different antiviral agents. Important differences between the M2 inhibitors and the neuraminidase inhibitors will require careful definition of their respective roles in pandemic control. 6. supplies of antiviral agents will be available only to countries that have stockpiled them (at great expense) in advance. However. In the event of a pandemic. and a global distribution system for what will inevitably be limited supplies does not exist. Antivirals will have to be used in special situations.2: Pandemic Influenza Limitations of the Antiviral Strategy One or more antiviral agents currently in use will likely be effective in the prophylaxis and treatment of illness caused by a new pandemic virus. Manufacturers require regular estimates of demand on which to base production plans. There is currently no global estimate of the future demand for antiviral agents. and the current market-based system has limited or no surge capacity to respond to a sudden increase in demand. for most countries the cost of stockpiling will be a significant burden. Greater and more diversified manufacturing capacity for antineuraminidase agents is needed.53 Countries will be able to meet their pandemic requirements only if they make plans for obtaining supplies of antivirals in advance. All countries will need to consider the complementary use of vaccines and antiviral agents in planning for various phases of pandemic control.221 . Vaccination will remain the primary means of prevention once vaccines become available.6. Because these agents are relatively stable over time. the issue of liability for adverse reactions to antiviral treatment has not been addressed. However. supplies of these agents will quickly be exhausted in the first few weeks of the pandemic. Moreover.
leads to the development of protective levels of antibodies when measured after another 3 weeks.2. alum-adjuvanted vaccine strategy is central to the thinking of all EU vaccine companies. For example. that the production facilities would be available. The clinical efficacy of these strategies could not be tested in man. Both adjuvanted and non-adjuvanted vaccines have been produced using both whole virus and subunit virus preparations. but later studies have used a simple alum adjuvant of the kind widely available and used by all vaccine companies that produce childhood vaccines. H5 and H9 ‘pandemic-like’ viruses have been tested.875 µg (i. but an ‘antigen sparing’ strategy has critical implications for the amounts of vaccine that could be produced at any given time during the course of a pandemic vaccination program.2: Pandemic Influenza Lessons Learned from Research into Pharmaceutical Interventions Vaccination Strategies Within the past few years. but could be evaluated using appropriate animal models. How low the HA content of a pandemic vaccine can be set is uncertain. if the world’s vaccine companies were told to produce a monovalent alum-adjuvanted whole virus pandemic vaccine with an HA content of 1. 62 A single injection of one these low-dose vaccines primes the immune system and a second dose. The vaccines have been formulated with HA concentrations as low as 1.61. almost one-third the world’s population. The strategy is based on using a lower dose of HA antigen and including an adjuvant. this amount of vaccine would probably exceed the vaccine delivery capacities of all of the world's health care systems. several groups of European investigators have carefully explored a promising strategy for developing ‘pandemic-like’ vaccines that (1) induce protective levels of antibodies when two doses are given to immunologically naïve subjects.e. This would be enough to vaccinate 2. they would be able to produce 4. Most European and WHO experts consider it to be the most promising approach for guaranteeing adequate supplies of pandemic vaccines for all EU Member States and for all other countries that will depend on EU companies for supplies of pandemic vaccines. Nevertheless. and that the immunogenic properties of the pandemic virus would be similar to those of the H2. they could theoretically produce approximately 36 times more vaccine than normal.5 x 8. These estimates are hypothetical and they assume that the pandemic virus would have similar growth/yield characteristics as current vaccine strains. The low-dose. and (2) could be produced in abundant supply by vaccine companies using their existing facilities 54. The initial studies were conducted using a proprietary MF59 adjuvant 57 58 59 60. If normally they would produce 130 million doses in a 6-month period. 6. 8-fold less than normal strength). One should also consider the option of using a single low-dose priming strategy without a second dose.68 billion doses of pandemic vaccine (130 x 3 x 188.8.131.52 .875 µg per dose.. 62 Vaccines against H2. usually given 3 weeks later. H5 and H9 viruses already tested.2). A one-dose strategy might be sufficient to reduce the frequency of severe illness and death when the pandemic virus hits an unprotected population.34 billion people (2 doses). see pandemic supply model in Figure 6.
∆ = 45 million doses per week and = 360 million doses per week.223 . Germany. Source: N Hehme et al.2: Pandemic Influenza Figure 6. GSK.2: Pandemic Vaccine Supply Model for Global Production million D 5000 4000 3000 2000 1000 0 1 0 0 0 0 2 0 0 0 0 3 10 30 45 360 4 50 150 225 1800 5 90 270 405 3240 * months 2 doses for 2.2. (8x) ** **doses / month ○ = ten million doses per week. 6. ● = 30 million doses per week.3 billion people 6 130 390 585 4680 7 170 510 765 6120 8 210 630 945 7560 * Trivalent Monovalent Whole virus Adjuv.6.
According to the NIH strategy. Its goal should be to determine the lowest amount of HA antigen that can be included in an adjuvanted vaccine that will be acceptably immunogenic when given in a two-dose schedule to a population. The US government hopes to increase domestic capacity for producing influenza vaccines by accelerating the introduction of cell culture vaccine production and expanding the supply of embryonated eggs. First.224 . the National Institutes of Health (NIH) in the US awarded contracts to Aventis Pasteur (US) and Chiron Vaccines (UK) to produce pilot lots of monovalent H5N1 'pandemic-like' vaccines. For the US to be able to offer two doses of standard-dose pandemic vaccine to each person (assume 300 million x 2 = 600 million vaccinations).6.2: Pandemic Influenza Box 1: The US Approach to Developing a Pandemic Vaccine: Lessons for the EU In June 2004. 6. it would be more beneficial for pandemic vaccine development to focus on ensuring that the largest possible supply of pandemic vaccine can be made available as quickly as possible. From a global perspective. vaccine development should focus on vaccines that are acceptably immunogenic for populations and that can be produced in existing production facilities. Most European vaccine experts already accept this strategy. A short-term development strategy should be based on existing egg-based production capacity. 50 million doses of domestically produced trivalent inactivated vaccine would be equivalent to 150 million doses of standard-dose (15 µg HA) monovalent pandemic vaccine and 50 million doses of high-dose (45 µg HA) vaccine.in order to comply with FDA requirements for currently licensed influenza vaccines. domestic production of trivalent vaccine would have to increase four-fold (and for a high-dose pandemic vaccine up to 12-fold) to reach the equivalent of 600 million doses of trivalent vaccine per year. This alternative strategy would respond to the needs of people in vaccine producing countries and would provide millions of doses of pandemic vaccine for people in other countries.15 µg and 45 µg of HA antigen (standard and high-dose. respectively) . They will be tested in the NIH Vaccine Trial and Evaluation Units. but these effort are almost certain to be of limited success within the next five years. and (2) the assumption that a new pandemic virus will not emerge for five or more years. public funding is driving the development of pandemic vaccines in the US. The current NIH strategy for developing an H5N1 ’pandemic-like' vaccine appears to be based on (1) the goal of determining the optimal dose of HA antigen for an individual rather than an acceptably immunogenic dose for a population. These vaccines will be formulated at two dosage strengths . Current evidence suggests that Europeans have yet to appreciate that public funding will be essential for pandemic vaccine development in Europe. Public funding will support the full costs of this project. Second. To expect such an expansion of domestic vaccine production capacity within the next five years is not realistic. The US currently has a domestic influenza vaccine production capacity of approximately 50 million doses of trivalent vaccine per year. Europeans can learn two lessons from the current US approach to developing pandemic vaccines.
6. the polybasic amino acids associated with H5N1 virulence are removed from the HA cleavage site.1. no commercially viable human H5N1 vaccine could be produced.225 . WHO has been instrumental in developing guidelines for safety testing of these reassortants and has provided advice on risk assessment for vaccine manufacturers intending to use them63 . vaccine reference strains have been prepared using the technique of genetic reassortment. this technology cannot be used with highly pathogenic avian viruses because the resulting reassortants are highly pathogenic for embryonated eggs and may be capable of human infection. The methods for preparing RG-engineered viruses are straightforward. Within the past two years. Since the early 1970s. With this technique. This will ensure that the time between the isolation of a new pandemic virus and the beginning of full-scale vaccine production is minimized. 33. Genetic reassortants have been essential to the success of influenza vaccine production for more than 30 years. 33 In the first eight years following the 1997 outbreak of H5N1 avian influenza in Hong Kong. the resultant RG-engineered reference strains can be used as seed strains for egg-based vaccine production. Importantly. 32. Following subsequent cloning. Reverse genetics has been used to prepare reference strains using human isolates of H5N1 viruses obtained during the 2003 and 2004 outbreaks of avian influenza. Plasmids containing the genes for the avian virus HA and NA antigens are then cloned and transfected into Vero cells along with plasmids containing the six A/PR8 genes.1. reference strains suitable for producing human 'pandemic' influenza vaccines have been prepared in several laboratories using the techniques of reverse genetics (RG). 9. the results are predictable and the process can take as little as 10-20 days. propagated in embryonated eggs and tested for stability and pathogenicity. a progeny genetic reassortant virus is isolated that has two genes coding for the surface (HA and NA) antigens of the epidemic virus and six genes derived from the A/PR8 virus that are associated with high growth. purified. The progeny virus is rescued from cell culture.2: Pandemic Influenza Reverse Genetics There is a possibility that the next influenza pandemic could be caused by a highly pathogenic avian virus. The reassortants do not always grow efficiently in egg-based production systems.6. Moreover. It is important that virologists working in WHO-affiliated laboratories and in vaccine companies gain more experience with reverse genetics-engineered influenza viruses. The time needed to isolate a genetic reassortant suitable for commercial vaccine production can take many weeks. These reasons explain why no commercially viable seed strain for human H5N1 vaccine production has yet been prepared using genetic reassortment. 58 Using this technique. embryonated eggs are coinfected with an influenza virus considered most likely to cause epidemic disease and a high-growth strain of influenza A/PR8 virus. but they have disadvantages. when used with avian viruses.
765. The 3-year NOVAFLU project (€ 1.2: Pandemic Influenza Existing Research Resource Flows Two projects for influenza vaccine development have been funded by the EU. The 4-year FLUPAN project (€ 2. Inactivated and live-attenuated egg-based and non-egg based vaccines (e. research and surveillance. standardisation of animal models and strategies for multi-centre clinical vaccine evaluation in man. the National Institute of Allergy and Infectious Disease (NIAID) at the NIH supports activities for developing and testing effective countermeasures against pandemic influenza that range from basic and applied research to partnerships with industry.g. DNA and recombinant protein vaccines) are also being evaluated..100. 6.S. Its goal is to develop more effective strategies for vaccination against interpandemic and pandemic influenza.226 . The investigators have also produced libraries of reagents for the production and standardization of several avian and swine virus vaccines and explored the use of genetically modified mammalian cells that express influenza virus proteins for future use in diagnostic tests.6. Studies should focus on the development of a system that allows for rapid design of safe and efficient vaccines and scale-up of production and should address the development of improved adjuvants. NIAID also supports the production and clinical evaluation of different types of pandemic influenza vaccines to assess their safety and age-related immunogenicity. In the U. Current NIAID projects include developing a library of reference viruses and producing and distributing reagents for vaccine standardization.000) was begun in January 2001. considering several novel vaccine candidates and evaluating animal model systems of influenza virus infection to establish better laboratory correlates of clinical protection. The EU is also funding the VIRGIL project to monitor and evaluate the evolution of resistance to antiviral agents in Europe. Its goal has been to develop better methods to rapidly detect the emergence a pandemic virus in animals and its spread in man. exploring alternative approaches for vaccine production in cell culture systems. The investigators are developing better strategies for vaccine strain selection.000) was begun in autumn 2002.. and to more rapidly produce a safe and effective vaccine. The major focus of the research has been to use reverse genetics to produce reference strains of vaccine viruses (mostly avian viruses) to produce pilot lots of vaccines in cell culture systems and to evaluate the immunogenicity and safety of these vaccines in Phase I/II clinical trials. The EU Framework programme is currently open (until the 16th of November 2004) again for new research proposals exploring post-genomic approaches to a pandemic vaccine.
S. Pipeline of Products Pipeline for Influenza Vaccines The most important new influenza vaccine product introduced in recent years.2: Pandemic Influenza Recent NIAID activities include: • • • • • Evaluation of a recombinant mono-component (HA only) H5 vaccine in Phase I/II clinical trials (1997 H5 strain) Grant award to Aventis Pasteur to produce an inactivated cell culture-based H7 influenza vaccine Evaluation of a Phase I inactivated subunit H9N2 vaccine (serology in process) Award of contracts to Aventis Pasteur and Chiron to pilot lots of an inactivated 2004 H5N1 vaccine (both companies are licensed in the U. Currently the world's largest source of non-governmental funding for all vaccine-related research is the Bill and Melinda Gates Foundation in the US. Major reasons for this failure were the vaccine’s very high price. has been Medimmune’s intranasal cold-adapted live-attenuated influenza vaccine (LAIV. Medimmune’s LAIV is not yet being used in EU countries. However. and the preclinical and clinical evaluation of new drugs.6. the company will market its LAIV product at a lower price.64 The LAIV product was launched in the US in 2003-2004. Recent accomplishments include the production and clinical evaluation of the first trivalent baculovirus-expressed influenza vaccine in a phase II clinical trail and phase I/II clinical trials to enhance the effectiveness of inactivated influenza vaccines for the elderly. Clinical trials have shown very promising clinical efficacy in children and younger adults against infection with homotypic and heterotypic influenza viruses. alternate delivery systems and dose range. but sales were far lower than had been planned for or anticipated.) Award a contract to Chiron (Sienna. A fully liquid non-frozen preparation will also be forthcoming. FluMist). Activities range from basic research to identify new drug targets. Italy) to evaluate an MF59 adjuvanted inactivated H9N2 influenza vaccine Support for the development and testing of improved inactivated influenza vaccines and new production technologies include the development of cell culturebased vaccine technologies.4 billion Bioshield program. In future years. There is little knowledge of funding levels for influenza research that is supported by individual EU governments and by non-governmental organizations. the limited age group (5 to 49 years) for which it was licensed. The resources currently committed to this NIAID research program (excluding extramural funding) are in the range of US$ 50-100 million. NIAID also supports the development of new antiviral drugs against influenza. in vitro and in vivo antiviral screening programs. The foundation has yet to fund research devoted to influenza prevention and control. but will probably be introduced within the next few years. it is unlikely that it will command a 6.227 . and the inconvenience of handling a product that must be stored frozen. Additional safety data will lead to recommendations for using it in children less than 5 years of age. Additional funding might become available under the $ 5. broadly cross-protective influenza vaccines and the improvement of inactivated vaccines by assessing the role of adjuvants.
It will take many years. All European vaccine companies are seriously considering investments in cell culture vaccine production systems.2. before cell cultureproduced vaccines command a substantial share of the European or global influenza vaccine market.228 . It is widely believed that one advantage of cell culture production will be to free manufacturers from their dependence on supplies of embryonated eggs.64. and applications for registration are pending in at least two countries. uncertainties regarding intellectual property rights for the reverse genetics-engineered H5N1 reference strains and lack of public funds to support the clinical trials. 45 and 135 µg for each HA) are said to be more encouraging.65 In addition. In the US. however. two doses of a monovalent H5 HA-containing vaccine were poorly immunogenic at relatively high doses (90 µg HA). An overview of some of the products in company pipelines is shown in Table 6. However.6. Whether this anticipated ‘surge capacity’ will materialize remains an open question. progress has been limited due to biosafety requirements. but recent unpublished Phase II (b) dose-ranging studies of two doses of a trivalent HA vaccine (15. Questions that still must be addressed are the immunogenicity of only one dose. the effect that the absence of an NA antigen will have on its acceptability for registration and the cost of its production relative to egg-derived vaccines.66 Clinical trials have shown that this vaccine is safe and immunogenic. Vaccines produced in embryonated eggs are likely to be the mainstay of influenza prevention for at least the rest of this decade. Two European vaccine companies are collaborating on the development of a virosomal influenza vaccine. 6. and several have built facilities that are already licensed or will be licensed within the next few years. As mentioned earlier.67 In an early clinical trial. several vaccine companies have been making preparations for producing clinical lots of H5N1 and other 'pandemic-like' vaccines. if not longer. it is believed that cell culture systems will allow companies to rapidly increase vaccine production when confronted with a sudden increase in demand. there can be little doubt that companies with a commercial need to increase their vaccine production capacity will do so by building cell culture facilities.2: Pandemic Influenza substantial share of the European influenza vaccine market for many years to come. the possible need for an adjuvant. a new influenza vaccine is being developed by a biotechnology company using a recombinant baculovirus-expressed HA antigen that is prepared in insect cell culture .2. as will occur with a pandemic. Nonetheless.
68 Experimental studies showed complete protection of experimentally infected mice when treated 7 days before infection. 6. H7.6. H9 or H2 vaccines) Stage Phase 1 finished Long term Phase 2 Phase 1 research Phase 3 fall this year Phase 1 research Phase 2 finished Antivirals: animal testing Approved in NL Commercial agreement with Aventis Approved in NL Under approval in NL and CH Under approval in NL and CH Phase 1 Phase 1 research See text Planning stage Zymetx Shire Baxter Crucell Solvay BernaBiotech GSK Biota / Sankyo EU vaccine manufacturers Pipeline for Antiviral Agents Little is know about pharmaceutical company pipelines for new antiviral agents. and Phase I studies in man showed that this agent’s active metabolite could be detected in urine up to 6 days after the inhalation of one dose. concerns about safety are always present. Nonetheless. The commercial dimensions of this company’s development program are unknown.2: Overview of Pipeline Products2 Company Aventis Chiron Protein Science Sort of product/ development Alternative delivery system (intradermal) Cell culture Cell culture MF59 adjuvanted subunit egg grown H5N3 vaccine FluBlok . Interest in their development may have waned as a result of the commercial difficulties experienced by companies that have already introduced antineuraminidase agents. The Safety and Efficacy of Products in the Pipeline Currently available influenza vaccines have a well-established record of safety.229 .recombinant HA Rec H5 HA vaccine Recombinant Neuraminidase (Additive) ViraZYme: technology to be used for diagnostics and antiviral development Cell culture Cell culture Cell culture Cell culture Virosomal influenza vaccine (with Berna) Virosomal influenza vaccine (with Solvay) Subunit vaccine Low dose subunit/whole virus alum adjuvanted H2N2 and H9N2 vaccines Long acting neuraminidase inhibitors Pandemic ‘mock-up’ vaccines for EU licensing (ie H5. one pharmaceutical company in Japan recently reported results of a Phase I study of a long-acting neuraminidase inhibitor administered by inhalation. The swine influenza vaccine used in the US in 1976 was associated with an increase in the occurrence 2 Table contains information published on internet.2: Pandemic Influenza Table 6. However. this and/or other similar antiviral agents could have widespread applicability for the control of pandemic influenza.2. The contents have not been checked with the companies and may be incomplete. One company has essentially withdrawn from the market and another has discontinued its development program. Given its simplicity of administration and its long-lasting activity.
The acute and long-term safety of vaccines still under development is not known. There have been extensive safety studies of Medimmune’s LAIV and no serious adverse events have yet been noted.70 Also. there is no information on their safety. and the vaccine has not been reintroduced into the market.2. although vaccines used since then have been essentially free of this association. clinical data from the core pandemic dossier can be extrapolated to the true pandemic vaccine and it can be quickly registered.2.230 . These vaccines must include viral antigen(s) to which humans are immunologically naïve. With few if any influenza antiviral agents in the pipelines of pharmaceutical companies. 6. Because there will be no time to conduct clinical trials of a true pandemic vaccine. In Europe. Concerns have been raised about the safety of workers involved in vaccine production.69 More recently. As with all other vaccines. an intranasally administered inactivated vaccine produced by a European company was quickly withdrawn from the market because it was associated with Bell’s palsy.6) The document addresses the quality requirements.5 and 6.6.7 (See appendices 6.2: Pandemic Influenza of Guillain–Barre syndrome. A risk assessment sponsored by WHO provides reassurance on this issue63. the EMEA has published its Note for Guidance on dossier structure and content for pandemic influenza vaccines marketing authorization applications. an inactivated vaccine produced by a Canadian company was associated with cases of an ocular complication that was traced to a correctible change in the vaccine’s manufacturing process. immunogenicity and safety data should be obtained for 'mock-up vaccines' that are developed and tested during the interpandemic period. the non-clinical safety and immunological requirements and the clinical requirement for ‘mock-up’ pandemic vaccines. rare and delayed complications of vaccination cannot be known without careful postmarketing surveillance and evaluation of suspected adverse events.71 The adverse effect was attributed to the adjuvant used in the vaccine. One relates to the safety of using a reverse genetics-engineered vaccine strain in commercial vaccine production facilities. Assuming the true pandemic vaccine is similar to and is produced in the same way as the ‘mock-up’ vaccines.
The goal of this meeting was to identify critical scientific issues and gaps in knowledge that must be addressed in order to accelerate the development of new influenza vaccines that induce broad spectrum and long-lasting immunity. They must also be reformulated and re-administered each year. duration and cross-reactivity of anti-HA antibodies and these antibodies correlate with protection against disease.6. the current yearly vaccination strategy could be revised to one that would be easier to implement in developing countries.2: Pandemic Influenza Research into New Pharmaceutical Interventions Vaccines with Broad Spectrum and Long Lasting Immunity In February 2004. Given the importance of these two antibodies. This would make the manufacturing process more flexible and less time constrained. improvements in existing inactivated vaccines could be important. they do induce a certain degree of heterotypic immunity to infection with variants related to the vaccine virus. 6. WHO held a meeting on the “Development of Influenza Vaccines with Broad Spectrum and Long-lasting Immune Responses”72. A broadly protective vaccine that is affordable in developing countries could be important in light of the avian influenza outbreak in Asia and concern that a virus from this avian reservoir might acquire the capacity for human-to-human transmission and result in a pandemic. and antibody to the invariant M2 protein may also have an important role in protection. Increased levels of antibody to the NA antigen also reduce the intensity of infection and limit its transmission to others. It would not need to be updated each year because it would offer equal protection against infection with antigenically drifted virus strains not perfectly matched (by HA and NA) with current inactivated influenza vaccines. Currently available inactivated influenza vaccines cannot be used to protect children less than 6 months of age and are less than optimally protective in older adults. and possibly others) induce CTL responses. However. In addition to anti-HA and NA antibodies. Vaccines containing these invariant antigens could induce long-lasting immunity and provide in advance significant protection against a yet-to-emerge pandemic virus. By inducing better antibody responses to these two antigens. an improved inactivated vaccine could contribute to better heterotypic immunity and provide longer-lasting protection against infection caused by antigenic variants within a subtype. Vaccine Type A broad spectrum influenza vaccine would offer protection against infections caused by divergent influenza virus types and subtypes and would also protect against infection caused by an antigenically new virus characteristic of a pandemic. NP. Increasing the dose of HA correlates with an increasing magnitude. cytotoxic lymphocytes (CTL) also help to reduce the intensity and duration of viral shedding. Several invariant antigens (M1. If the vaccine were also able to induce long-lasting immunity.231 .
In mice. Several potential new conjugated vaccines prepared with the ectodomain of the influenza M2 protein have induced homotypic and heterotypic immunity to infection by antigenic variants within a subtype and by different influenza A subtypes73. as was shown in the clinical trials of live-attenuated influenza vaccine. heterotypic protection against infections by influenza A viruses of different subtypes. and defining the need for adjuvants to improve antibody responses. more than five years) would be undertaken. Children benefit from LAIV but evidence for the superiority of LAIV over inactivated vaccines in adults is mixed.232 . the type of immune response required and the target population for vaccination. Mucosal vaccine delivery could facilitate vaccine use. M1) induce broad. In mice. Preclinical studies of this ‘universal’ influenza A vaccine in experimental animal models of infection have been promising. This route stimulates both mucosal and systemic immune responses. Despite a recent setback. Regulatory Issues Several difficult regulatory issues will have to be addressed before a new vaccine that promises to induce cross-protective and long-lasting immunity can be licensed. achieving a proper balance between IgA and IgG antibodies.72 Influenza virus infections can induce both broad spectrum and long-lasting immunity against reinfection with an influenza virus within a subtype. LAIV have induced potent protection against both homotypic and antigenically drifted viruses. ISCOMS can induce TH1 and TH2 responses and have induced long-lasting immunity and increased immune responses in both young and elderly subjects. several obstacles stand in the way. It is unlikely that a clinical trial to demonstrate true long-lasting protection (e. including the need to develop an optimal delivery system. Regulatory authorities must be convinced that laboratory correlates of immunity provide reliable evidence of protection. regulatory officials will probably have to accept evidence of heterotypic protection over fewer years. If regarded as a replacement vaccine. Virosomal vaccines containing IL–2 or CpG as an adjuvant have induced enhanced immune responses in clinical trials. while DNA vaccines against conserved internal proteins (NP.2: Pandemic Influenza Delivery Options and Adjuvants Many of the disadvantages of current inactivated influenza vaccines could be overcome by mucosal delivery. Consequently. ferrets and humans. licensure will likely 6. especially in developing countries.. overcoming concern about inducing immune tolerance.72 Intranasal administration of influenza virus seems promising because administration of antigens to the mucosa is required for optimal IgA antibody responses. However.g. the potential value of mucosal vaccination is sufficient reason to continue research on this approach to vaccine delivery.74 DNA vaccines that induce antibody responses to surface antigens have been shown in animal models to induce homologous protection. More important will be the decision on whether to regard a new cross-protective vaccine as a replacement for or as a supplement to the current inactivated influenza vaccines. cationic liposomes containing antigens are highly immunogenic without added adjuvants.6.72 The choice of adjuvant depends on the proposed antigen. Several adjuvants are available for improving immune responses to vaccines. This suggests that live-attenuated influenza vaccines (LAIV) could induce similar protection and that this would be due to immunity to viral components other than the hemagglutinin 75.
high-risk individuals. If a new vaccine is to be regarded as a supplemental vaccine. Newer Antiviral Agents One new approach to the treatment of influenza focuses on short interfering RNAs (siRNAs). TNF-alpha and interferon beta). 77 Protection is not mediated by interferon. A placebo-controlled trial could be conducted in healthy younger adults in whom serious consequences of infection in the placebo group would not be expected. (None of the evidence for the effectiveness of current inactivated vaccines in preventing hospitalisation and death has come from placebo-controlled trials conducted in community-dwelling older adults. Yet such understanding could help us develop new ways of reducing the morbidity and mortality caused by interpandemic and pandemic influenza. siRNAs specific for highly conserved regions of the nucleoproein (NP) of acidic polymerase molecules inhibit virus replication in the lungs and protect against lethal challenge. 79 The NS1 protein could be evaluated as a target for newer antiviral agents. Such a trial would be large. In experimental influenza infection in mice.g.2: Pandemic Influenza depend on a Phase III clinical efficacy trial. Currently there is no consensus on how a candidate vaccine that promises broad spectrum and long-lasting protection is to be evaluated. High serum concentrations of the chemokines interferon induced protein-10 (IP-10) and monokine induced by interferon gamma (MIG) have also been reported in patients with H5N1 disease. Avian H5N1 influenza viruses are potent inducers of proinflammatory cytokines (e. Importantly. Another possible approach to antiviral treatment and prophylaxis involves the NS1 protein. the clinical trial would have to be structured to demonstrate noninferiority of the new vaccine compared with the inactivated vaccine.6. If laboratory correlates of protection were convincing. siRNA protects against lethal challenge with highly pathogenic H5 and H7 avian influenza A viruses. A placebo-controlled clinical trial in high-risk individuals might be possible if the trial were conducted in a developing country where there is little chance the inactivated vaccine could be introduced. 6.44 If evidence of efficacy were to be required in older. a clinical trial designed to demonstrate a significant degree of incremental improvement over the current inactivated vaccine alone would also be large and costly. Recent studies suggest that the biological basis for severe influenza in humans is associated with virus-induced cyotokine dysregulation81.78. but sooner or later this question will have to be addressed.76. such a vaccine might be licensed and incremental and (more important) long-lasting protection demonstrated in longterm observational studies. H5N1 influenza is lethal because the NS1 protein makes the virus resistant to the antiviral effects of interferons and tumor necrosis factor alpha. Other Pharmaceuticals Few laboratory and clinical investigators are currently studying the molecular pathophysiology of influenza virus infection and the role of the innate immune system in the response to infection 80. Such a trial would not be able to determine whether the new vaccine would prevent hospitalization and death. costly and difficult to justify. RNA interference has been shown to suppress influenza virus replication in vitro. A placebo-controlled trial in older adults could not be justified because infections would have to occur in the placebo group to demonstrate the efficacy of the new vaccine. and they could be severe or fatal..233 .
2: Pandemic Influenza In addition to these laboratory findings. Slowing the spread of a pandemic will depend on the available infrastructure for surveillance and early warning and possibilities for the quick determination of the causative agent. positively or negatively. nonmedical interventions may be are the only interventions affordable in most countries. most of the European research on pandemic influenza vaccines has been conducted by a few groups of dedicated investigators using funds obtained from either commercial sources or national governments.6. Much attention has been given recently to the positive effects of high intensity statin treatment for coronary heart disease. However. new advances in the understanding of cardiovascular treatments could have important implications for the prophylaxis and therapy of interpandemic and pandemic influenza. this chapter has focused on medical interventions only. A sharp distinction cannot be drawn between the two. Reducing the burden of pandemic influenza will not be possible by medical interventions alone. it is essential that both short. The research agenda outlined below is divided into studies that should be carried out over the next five years and studies that should be carried out over a longer period.44 Given these findings. These effects seem to be due to their anti-inflammatory effects rather than their effects on low-density cholesterol lipoproteins. if they are to be successful. However. Institutions and Human Resources In the last seven years. In the early weeks after a pandemic virus emerges. in the event of a pandemic. the clinical course of pandemic virus infection. epidemiologists recognize that influenza is associated with an increased risk of hospitalizations for cardiovascular and cerebrovascular diseases. The three most important priorities in this research agenda are outlined in bold. recurrent myocardial infarction and stroke following influenza vaccination. Gaps and Opportunities for Pharmaceutical Research The primary objectives of supporting new pharmaceutical research in the field of influenza is to reduce the burden of yearly epidemics.234 . to be better prepared to limit the health and socioeconomic burden of the next pandemic and to ensure equal access to vaccines and antiviral agents used in prevention and control. they will have to have adequate and stable funding for their research. In these circumstances. 6. The success of these interventions will also depend greater on understanding of the burden of disease and the health and economic benefits of these interventions. There are adequate numbers of European investigators and institutions to continue work on improving existing influenza vaccines and developing new vaccines and antiviral agents. it will be essential to know whether commonly used treatments could affect. Whether prophylaxis and/or treatment with statins or other commonly available therapeutic agents that affect the innate immune system could modify the clinical course of human influenza is unknown. These objectives cannot be met by pharmaceutical research alone. antiviral agents will be largely unavailable and vaccine supplies will be delayed. The budgets for these projects have been limited. Observational studies have documented reductions in hospitalization for congestive heart failure. Although there are many research opportunities in this area.and longterm research be conducted simultaneously. Most of the world’s influenza vaccine is produced in the European Union and a regulatory framework for pandemic vaccine development has been created by the EMEA. Because we do not know when the next pandemic will occur.
Determine whether use antiviral treatment reduces the occurrence of serious consequences of influenza. such as infants. Evaluate new methods of vaccination. H7N7. Evaluate the role of maternal vaccination and the transplacental transfer of neutralizing antibody in protecting newborn infants against influenza. • 6.235 ..2: Pandemic Influenza Research to Be Carried Out in 5 Years Vaccines The research agenda for vaccine development is based on the identified gaps in current knowledge. H9N2 and H2N2.6. Explore the use of different adjuvants and other new approaches (e. and egg-derived/ cell culture derived) and different vaccination schedules (one/two doses. Determine the minimally effective dosages and side effects of antiviral agents when used in selected high-risk populations. To ensure the most economical use of limited vaccine supplies. and elderly persons with underlying disease. different dose ranges) using vaccines directed against different hemagglutinin (HA) subtypes considered to have pandemic potential. Evaluate the safety and effectiveness of using reverse genetics to prepare reference strains of these ‘pandemic-like’ viruses that can be used as seed strains by vaccine companies in Europe and elsewhere to produce pilot lots of ‘pandemic-like’ vaccines. • Evaluate different types of monovalent inactivated influenza vaccines (whole virus/split and subunit. • • • • Determine the minimally effective dose and duration for antiviral therapy using anti-neuraminidase and other antiviral agents. Develop long-acting anti-neuraminidase agents that can be easily administered and are much less expensive to produce. • • • • • Antiviral Agents The research agenda for antiviral agents is based on identified gaps in knowledge as identified earlier. Evaluate the comparative effectiveness of the M2 inhibitors and neuraminadase inhibitors and the importance of antiviral resistance when they are used in treatment and prophylaxis. pregnant women. such as hospital admission for pneumonia and other influenza-related complications. especially H5N1. the evaluation of a low-dose priming strategy should be emphasized. immunocompromised persons. including mucosal and "needle free" vaccine delivery methods. that might offer improved immunogenicity and be more suitable for mass vaccination programs. adjuvanted/nonadjuvanted.g. as outlined earlier. higher doses of HA antigen) to improving the antibody response to inactivated influenza vaccines among elderly persons and those with immunocompromise. Continue to prepare libraries of reagents specific for a range of potential ‘pandemic-like’ viruses that can be used to test a future pandemic virus ahead of the time when specific reagents directed against the pandemic virus become available.
236 . Explore the effects of commonly available pharmaceutical agents that are known to affect biological response mediators on the response to influenza virus infection both in vitro and in vivo. the molecular pathophysiology of influenza virus infection and the role of the innate immune system in the host response to infection.2: Pandemic Influenza • • Further explore the mechanisms of antiviral resistance to both classes of antiviral agents and assess the biological consequences of resistance for transmissibility and virulence.6. Evaluate the molecular response to influenza virus infection in cell culture systems and the role of cytokines and other biological response mediators in determining the outcome of infection. • • 6. Develop new and improved antiviral agents directed at the M2 and NA antigens and explore possibilities for developing other classes of antiviral agents directed at other targets such as the NS1 and HA antigens Non-Pharmaceutical Research The research agenda for non-pharmaceutical research is based on identified gaps in basic knowledge of the immune response to vaccination. • Continue to explore how different components of the innate and adaptive immune systems confer protection against influenza following vaccination. ferrets and primates. giving special attention to factors that determine heterotypic and heterosubtypic protection and the contributions of CTL –based immunity. Evaluate also these responses in experimental infections in mice.
However. If one company attempts to open negotiations with only one patent holder. However. Moreover. if presented with a pandemic threat. The status of European patents is not publicly known. The technical support of the World Intellectual Property Organization and the WIPO Arbitration and Mediation Center could be especially helpful 83. However. all three of which are located in the United States. 6. Even if they were. The patent holders have agreed that RG can be used to prepare reference strains for research purposes. because IP issues are governed by national patent laws. if RG-engineered seed strains are to be used for commercial vaccine production. litigation by the other patent holders could follow. the US patent rights would apply only to the US. Even if there were no problems with RG-IP. efforts must be undertaken immediately to solve the intellectual property issues related to reverse genetics. achieving a solution to the problem of intellectual property for reverse genetics represents an important criterion for judging the world’s ability to achieve ‘good governance’ for global public health. This would allow companies to determine whether using RG-engineered seed strains would offer advantages for vaccine production when compared with genetic reassortants. Companies would have time to respond to regulatory requirements to upgrade their production facilities. The US Department of Health and Human Services recently conducted a patent search of its own and has formulated its future policy options. Unless the public sector provides a framework for RG-IP negotiations during interpandemic years. A few companies have probably already undertaken their own RG patent analyses. but most vaccine companies would be uncertain about the precise ownership of the IP rights for the RG-engineered seed strains they would be called upon to use. If we were now facing a true H5N1 pandemic threat. there is one essential difference between the two techniques: reverse genetics is associated with patents. but they are not publicly known. Intellectual Property and Influenza Vaccination Reverse genetics (RG) is a promising technique for the rapid and safe production of influenza vaccine seed strains. Moreover.82. Since some European countries regard RG-engineered viruses as ‘genetically modified organisms’. The intellectual property (IP) rights for RG are held by at least two academic institutions and one pharmaceutical company. The recent award of NIH contracts to Aventis Pasteur and Chiron to prepare pilot lots of H5N1 vaccine for clinical testing highlights several problems related to intellectual property rights for reverse genetics. 84 Translational Research The research agenda for translational research is based on gaps identified in current knowledge. companies will not be prepared to produce pandemic vaccines using RGengineered reference strains. Royalty payments could be negotiated with the RG patent holders. since patent rights in Europe and Japan are independent of those in the US. companies with no previous experience using RG-engineered viruses might have difficulty obtaining regulatory approval for the using them in their production facilities. an H5N1 pandemic vaccine would be needed. Whatever process is chosen. avoiding litigation. A strong argument can be made for resolving RG-IP ownership before the next pandemic threat appears 54. but no one should expect them to disclose their findings. Royalty payments for using RG would be determined by governments and would not be negotiated between patent holders and patent users. several obstacles still stand in the way. Experts in intellectual property describe the influenza RG-IP issue as a classic example of market failure. it will be difficult for a vaccine company to enter into negotiations on royalty payments for pandemic vaccine production. The practical advantages of reverse genetics over genetic reassortment are well known. An international solution is not readily apparent.2: Pandemic Influenza Box 2: Reverse Genetics. but WHO can address the technical but not the IP issues related to RG. Political and technical support might be sought not only from EU Member States but also from other institutions such as the Organization for Economic Cooperation and Development (almost all countries with vaccine companies are OECD Member States). patent holders expect to be paid royalties. there would be time for European vaccine companies to resolve uncertainties over GMO issues with national regulatory authorities and with the public.237 . In the absence of knowing who owns the intellectual property for RG.6. the governments of countries with vaccine companies would probably exercise compulsory use licenses. The need for an international solution has been acknowledged by WHO8. Because of its importance to the European and global supply of pandemic vaccine. any negotiating framework that is established must be international in scope.
Undertake studies of influenza virus infection in experimental animals to determine whether treatment with commonly available medications that affect the innate immune system alter clinical illness and/or virus shedding. Special attention should be given to the elderly. Conduct burden of disease studies in several EU Member States to determine the impact of interpandemic influenza on influenza-related hospitalizations and death. not just those associated with underlying cardiovascular or cerebrovascular diseases. • • • • • • Research to be Carried Out in the Longer Term The long-term research agenda for vaccines. young children and pregnant women. 6.. In addition. analyse the databases of large prospective randomized controlled trials of cardiovascular therapies to determine whether subjects in the treatment groups experience reductions or increases in influenza-related events that are independent of the effects of influenza vaccination. Undertake case-control studies during the next influenza season (or during past influenza seasons where appropriate administrative databases exist) to determine whether common treatments for cardiovascular and cerebrovascular diseases are associated with reductions or increases in all influenza-related hospitalizations and deaths. including assessments of potential correlates of immunity other than serum anti-HA antibody and of the value of each type of vaccine for induction of heterotypic immunity in the different age groups85. These obstacles include the status of intellectual property rights.g.238 . Conduct clinical studies comparing the efficacy of LAIV and IIV vaccines in children and adults. Special attention should be given to the effects of treatment on the development of secondary bacterial pneumonia. following an internationally designed WHO protocol for such studies.2: Pandemic Influenza • Remove obstacles to the use of reverse genetics to prepare seed strains for producing ‘pandemic-like’ vaccines and accelerate the introduction of this technology into the production of interpandemic vaccines. Undertake in vitro cell culture studies to determine whether specific treatments before or shortly after infection with influenza viruses affect the subsequent production of proinflammatory cytokines and other biological response mediators. including vaccines directed at the ectodomain of the M2 protein and other conserved influenza proteins. antiviral agents and pharmaceutical research is based on identified gaps in current knowledge.6. Explore the legal and political issues regarding liability for adverse events associated with pandemic vaccination. biosafety) for using these viruses in vaccine production facilities and the acceptability of using these ‘genetically modified organisms’ by regulatory authorities and the public. Conduct yearly observational studies (case-control studies) in several EU Member States on the effectiveness of influenza vaccination in reducing the occurrence of influenza-related complications and death. regulatory requirements (e. • non- • Continue to explore the potential for developing and clinically testing influenza vaccines that provide heterotypic (broad spectrum) and long-lasting protection.
Replacing the current vaccine with a long lasting vaccine would dramatically decrease profits for the current manufacturers. implementing this research strategy will require financial support from public sources. • Currently one antiviral agent is superior to other antivirals regarding its effectiveness and limited development of antiviral resistance. several factors might serve as positive incentives to drive the research agenda: • • With an increasing interest in vaccinating children. • Research in Need of Increased Support Most of the elements of the pharmaceutical and translational research agenda outlined above are not included in or likely to be included in pharmaceutical research traditionally carried out by companies. • Even if a potential pandemic vaccine could be of use in the interpandemic period (for example. the circulating A/Fujian strain could not be included in the Northern Hemisphere’s trivalent vaccine because a high-growth genetic reassortant seed strain that could be used for vaccine production was unavailable. However. 6. vaccinating poultry workers in Southeast Asia with an H5N1 vaccine). it would probably not be affordable in countries at greatest risk. • There may be limited interest on the part of other pharmaceutical companies to explore the possible impact of existing products or new antiviral agents because the profits expected from their sale during the interpandemic period may be limited. In 2003. an A/Fujian-containing seed strain was produced using reverse genetics. This experience should serve as a stimulus to solve intellectual property rights issues for reverse genetics during the interpandemic period. reducing production costs and increasing profit margins.6. Several factors are responsible for this: • No one knows when the next pandemic will occur. This technique might increase a company’s capacity to produce vaccine. However. Continue to evaluate the short and long-term occurrence of adverse events following influenza vaccination and antiviral treatment. There is increasing interest in using reverse genetics during the interpandemic period.239 . • The current inactivated interpandemic vaccine needs to be re-administered every year. this company has little incentive to look for alternative (cheaper) ways to make its product affordable to larger populations. since there is only one manufacturer and potentially a very great demand. The current pipeline for new vaccine and antiviral agents is limited because there are few incentives for companies to develop a wider variety of new products. Therefore. These vaccines have shown efficacy in pre-clinical studies and are an attractive alternative to the current vaccines because large-scale production of DNA vaccines would be easy. the development of influenza vaccines that are more easily administered could be commercially attractive. It is not commercially attractive for a company to invest in the development of a product that may never be sold or a technique that is of limited use during the interpandemic period. However. fast and inexpensive.2: Pandemic Influenza • Reassess efficacy and safety of DNA-based influenza vaccines using adjuvants and new delivery systems.
The research will require a level of public funding beyond that which can be expected from individual EU Member States. The Comparative Advantage of the EU Most of the world’s largest influenza vaccine companies are located in the EU and there is a global dependence on the influenza vaccines produced in the EU.6. In particular. and Should result in findings that will benefit to all Member States within the European Union Currently. Responds to European legislation. and egg-derived/ cell culture derived) and different vaccination schedules (one/two doses. a low-dose priming strategy should be investigated. most of the public support for developing pandemic vaccines and antiviral agents is being provided by the US government. the European Union will fulfil its responsibilities for maintaining the health and economic wellbeing of all Europeans and contribute to the health and wellbeing of people in other countries throughout the world. H9N2 and H2N2. • • Public funding provided by the European Union to support this research agenda will ensure that Member States are better able to conduct programs for the prevention and control of interpandemic and pandemic influenza. By supporting this research. especially H5N1. including vaccines directed at the ectodomain of the M2 protein and other conserved influenza proteins. Such support will bring added value to the EU because it: • • • Specifically addresses gaps in knowledge within Europe. H7N7. 6. Develop new and improved antiviral agents directed at the M2 and NA antigens and explore possibilities for developing other classes of antiviral agents directed at other targets such as the NS1 and HA antigens. three should be given highest priority: • Evaluate different types of monovalent inactivated influenza vaccines (whole virus/split and subunit. to ensure the most economic use of a limited vaccine supply.240 . There may be additional (political) arguments for obtaining public support for this research agenda in order to ensure that European citizens also benefit from the progress being made.2: Pandemic Influenza All of the research gaps that have been identified meet the requirements for public support by the European Union. Among the many topics outlined in the research agenda above. adjuvanted/nonadjuvanted. different dose ranges) using vaccines directed against different hemagglutinin (HA) subtypes considered to have pandemic potential. Continue to explore the potential for developing influenza vaccines that provide heterotypic (broad spectrum) and long-lasting protection. This constitutes a compelling argument for EU support for the research agenda described in this proposal.
241 .2: Pandemic Influenza References 6.6.
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