6.2: Pandemic Influenza
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper
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
Table of Contents1.Executive Summary
2.Background
3.Burden of Disease
3.1.The Influenza Virus
3.2.Interpandemic Influenza: The Burden of Disease
3.3.Avian Influenza: Increasing the Risk for a Pandemic
3.4.Pandemic Influenza and its Potential Impact on Europe and the World
4.Prevention and Control of Influenza
4.1.The Current Control Strategy and its Effectiveness
4.1.1.Influenza Vaccination
4.1.2.Antiviral Agents
4.1.3.Use of Vaccines and Antivirals During a Pandemic
4.1.4.Non-Medical Interventions
4.2.Current Implementation of the Control Strategy
4.2.1.The Interpandemic Use of Influenza Vaccine in Europe and the Rest of the World
4.2.2.The Interpandemic Use of Antivirals in Europe and the Rest of the World
4.2.3.Affordability of the Interventions
5.Constraints to a Better Control
5.1.Interpandemic Period
5.2.Pandemic Period
5.2.1.Limitations of the Vaccination Strategy
5.2.2.Limitations of the Antiviral Strategy
6.Lessons Learned from Research into Pharmaceutical Interventions
6.1.Vaccination Strategies
6.2.Reverse Genetics
6.3.Existing Research Resource Flows
7.Pipeline of Products
7.1.Pipeline for Influenza Vaccines
7.2.Pipeline for Antiviral Agents
7.3.About Safety and Efficacy of Products in the Pipeline
8.Research into New Pharmaceutical Interventions
8.1.Vaccines with Broad Spectrum and Long Lasting Immunity
8.2.Newer Antiviral Agents
8.3.Other Pharmaceuticals
8.4.Institutions and Human Resources
9.Gaps and Opportunities for Pharmaceutical Research
9.1.Research to Be Carried Out in 5 Years
9.1.1.Vaccines
9.1.2.Antiviral Agents
9.1.3.Non-Pharmaceutical Research
9.1.4.Translational Research
9.2.Research to be Carried Out in the Longer Term
9.3.Research in Need for Increased Support
9.4.The Comparative Advantage of the EU
10.References
Appendix
6.2-1
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 cost-effective 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 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 long-lasting 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.
In the European Union, priorities for pharmaceutical research on influenza vaccines and antiviral agents should focus on short- and long-term research. Moreover, 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, adjuvanted ‘pandemic-like’ vaccines. 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. The benefits of expanded use of existing vaccines (including live attenuated influenza vaccines) and expanding vaccine manufacturing capacity should be further explored.
For antiviral agents, their effects on reducing serious complications of influenza should be further explored. Studies on the effectiveness of a lower dose and shorter duration of treatment with anti-neuraminidase agents could increase their availability during a pandemic. More important, there is an urgent need for research on newer antiviral agents, 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.
Long-term research should focus on developing broad spectrum vaccines that provide long lasting protection. In addition, the development of new antiviral agents that overcome the disadvantages of current agents is urgently needed. Support for research on the basic immunology of the response to vaccination, 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.
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. 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.
- Background
Despite a considerable increase in our knowledge of influenza viruses, major breakthroughs in the prevention and control of annual epidemics and influenza pandemic preparedness have not been made. This is especially worrying as an influenza pandemic becomes more and more likely. 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.[1]
The World Health Organization (WHO) has historically focused its influenza activities on virological surveillance to support annual vaccine strain selection. Recently, WHO expanded its focus to address new challenges. In May 2002, WHO convened a consultation of influenza experts, virologists, epidemiologists and public health officials. The consensus that was achieved led to the publication of the first Global Agenda on Influenza Surveillance and Control [2].(See Appendix6.2.2)The Global Agenda responds to the challenges posed by poor understanding of the impact of influenza, especially in developing countries, the long time frame needed to manufacture influenza vaccines, persisting inadequate vaccine coverage in most countries, and the need for surveillance activities to be more closely related to control. It encourages collaboration among all those in the public and private sectors who can contribute to better influenza surveillance and control, and maps out a strategic plan for doing so. The Global Agenda identifies 17 priority activities judged necessary to reduce the burden of epidemics and prepare the world for the next pandemic. They are listed according to four main objectives: (i) strengthen surveillance; (ii) improve knowledge of the health and economic burden of influenza; (iii) increase influenza vaccine usage, and (iv) accelerate national and international action on pandemic preparedness. Each priority activity is further defined in a series of recommended activities for researchers, industry, governments, and WHO. Among the priorities are research on pandemic viruses, vaccines, antiviral agents and other control measures.
The Global Agenda has been widely accepted by scientists all over the world. 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”. [3](See Appendix 6.2.3) In this resolution, Member States acknowledged that influenza affects millions of people worldwide and causes fatal complications in up to 1 million people each year. Many of these deaths could be prevented by increasing the use of existing vaccines, particularly in high-risk groups. Member States expressed concern about “the general lack of national and global preparedness for a future influenza pandemic, especially in view of the recurrence of such pandemics and the high mortality, social disruption, and economic costs they invariably cause, which may now be exacerbated by rapid international travel, the recent worldwide increase in the size of at-risk populations, and the development of resistance to first-line antibacterial drugs.” They recognized the need to improve vaccine formulations, increase manufacturing capacity for vaccines, ensure more equitable access to antiviral drugs, and strengthen disease surveillance as part of national and global pandemic preparedness. The WHA resolution called for Member States ”to support research and development on improved influenza vaccines, particularly concerning their suitability for use in developing countries, in order to develop and produce an influenza vaccine formulation capable of conferring long-lasting and broad protection against all influenza virus strains.” WHO was asked ”to search jointly with other international and national partners, including the private sector, for solutions to reduce the present global shortage of, and inequitable access to, influenza vaccines and antiviral drugs, both for epidemic and global pandemic situations.”
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. In its preliminary conclusions, the conference noted:
“The next pandemic is imminent. EU Member States are not prepared. Vaccine availability is not secured. Antiviral stocks do not exist and will not be under the current market forces. In the event of a pandemic millions of people could die, economies will be affected and services (medical, civil) could collapse. Members of the public will not excuse authorities, who will be held responsible for not having put in place up-to-date preparedness.”[4]
In March 2004 the European Commission published a working document on “Community Influenza Pandemic Preparedness and Response Planning”.[5] (See Appendix 6.2.1) 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. Manufacturers’ reserve capacity is not likely to be enough to support a sudden increase in demand. Availability of vaccines or antivirals to populations most at risk may, in critical situations, be further limited by measures imposed by MemberState authorities to provide maximum protection to their own population. Measures should, therefore, be considered with a view to ensuring equity of access." The Commission emphasized that research performed during the inter-pandemic period would be vital for preparing an effective pandemic response, 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. Furthermore, in the process of early recognition of the identity and origins of pandemic strain, 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, as was the case in the past with similar threats, such as Ebola and Lassa fever and more recently SARS. "
Since these reports were published, considerable progress has been made in formulating plans for pandemic preparedness within the European Union and outsite.[6] The research components for various Community actions had already been identified in the Community’s 5th and 6th Framework Programmes. 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. In addition, 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.[7]
Nonetheless, 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. This can be remedied only through greater investment by the public sector. 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.[8] This report can and should be used as an inspiration to all the readers of this document.