Industry and Government Perspective in Influenza Control

Abstract

We have had recent reminders of the threats posed by naturally occurring and bioengineered pandemic respiratory infections. It is estimated that if a pandemic infection were to arise anywhere in the world, such an infection would become widespread within 3 months and would have its maximum effect within 6 months. At present, the fastest that a vaccine effective against a new combination of antigens can be developed, purified, and produced is 9–12 months, not counting time for mass production.

The current rate at which the production of influenza vaccines can be accelerated is limited by the fact that production is carried out in eggs. Therefore, there is urgent need for cell-based vaccine technologies. These are under way in several centers, yet attainment of a safe product remains several years away. Furthermore, there is need for public and private investment in manufacturing surge capacity and/or dedicated National Institutes of Health facilities to enable accelerated production. We must support efforts to shorten development time by developing and approving subunit antigens and immunogens that anticipate the most virulent viral mutations.

Surveillance sites and their electronic interconnections must be expanded. Another component still lacking is funding for laboratories with high throughput screening and strong informatics capabilities to enable the fingerprinting and cataloguing of all known specimens of influenza and other pathogenic organisms for rapid identification of emerging or bioengineered pathogens. In all these efforts, we look to the federal government and to the biomedical research community in both public and private sectors.

Most assuredly, the question is not “if” but “when” a new strain of highly infective influenza will emerge to produce havoc worldwide. The “Spanish flu” of 1918 claimed the lives of more than half a million Americans, and of over 20 million individuals worldwide. A pandemic influenza is the product of genetic mutation, re-assortment, and transmission from animals to man of an influenza virus strain both sufficiently virulent and sufficiently dissimilar from recent varieties that herd immunity cannot prevent transmission to a majority of individuals. While influenza usually has its greatest impact on the elderly and chronically ill populations, the 1918 type A H1N1 strain was highly lethal in young adults.

As a nation, we have had recent reminders of the threats posed by naturally occurring pandemic respiratory infections: additional outbreaks of so-called pandemic influenza in 1957 (“Asian”) and 1968 (“Hong Kong”), the SARS (severe acute respiratory syndrome) outbreak in 2002, and the Asian avian flu in 2003–2004. Our vulnerability has been increased by the specter of bioterrorism: both the threat of smallpox and the actual release of a highly micronized version of anthrax, which killed 5 persons in 2001. We look to the federal government and the biomedical research community in both public and private sectors for guidance and support in response to these threats.

Federal Role

Both the United States Department of Health and Human Services (DHHS) and the newly formed Department of Homeland Security (DHS) have primary responsibility for the national response to pandemic illness. The DHHS has responsibility for public health policy, for the support of scientific research and development, for surveillance through the Centers for Disease Control and Prevention (CDC), and for collaboration with international health departments and the World Health Organization (WHO) to create an international strategy. The DHS has the lead in the event of emergency response, as in a national disaster such as a bioterrorist attack. These departments work closely with each other and with correlative departments, such as the Department of Defense, which maintains surveillance centers in several remote areas.

“Policy” as defined by the dictionary is a “definite course of action, adopted and pursued by a government,” with descriptors such as “prudent and wise.” The 3 principal components of sound public health policy are surveillance, response, and national infrastructure. Thus, one outcome of national policy is the development of a plan for response to pandemic influenza or a similar devastating infection with the following primary objectives: to limit the burden of disease, to minimize social disruption, and to reduce economic loss. Within DHHS, the National Vaccine Program Office has the primary responsibility to develop the Pandemic Influenza Plan.^*

Surveillance involves the capability at both global and regional levels to increase the likelihood of early detection and effective tracking of the incidence and spread of disease. There are currently 112 laboratories in 83 countries that participate in the WHO's network, with major centers in Atlanta, London, Melbourne, and Tokyo, and additional sites maintained by the U.S. Department of Defense. Nevertheless, as evinced by the recent experience with SARS, gaps exist—especially in regions lacking adequate public health infrastructure. Surveillance includes monitoring of disease outbreaks in animals, especially fowl; maintaining a sentinel physicians' network operated by the CDC; developing systems to detect signals by monitoring patterns of hospitalizations, emergency room visits, and prescriptions; and transferring technology via training of personnel, distribution of diagnostic reagents, and communication in the form of health alerts.

It is estimated that if a pandemic infection were to arise anywhere in the world, given transcontinental travel, such an infection would become widespread within 3 months and would have its maximum effect within approximately 6 months. During interpandemic years, there is extensive collaboration among the National Institutes of Health (NIH), CDC, Food and Drug Administration (FDA), and private sectors to select the strain for each year's influenza vaccine and to establish the guidelines for its administration. Such collaboration would need to be intensified in the event of a pandemic. At present, even in the most favorable circumstances, the fastest that a vaccine effective against a new combination of antigens can be developed, purified, and produced is approximately 9 to 12 months, not counting the time required for accelerated mass production. There is no margin for error.

Response requires local, state, and national preparedness plans. We must have clear definitions of roles and responsibilities, must plan interim therapies (including antiviral agents and antibiotics), and, if necessary, must prioritize vaccine recipients. Further, we must develop guidelines for mass vaccination and transmission control (including quarantine and travel advisories) and take inventory of hospital facilities in regard to their available and surge capacities. Each locality should maintain an inventory of persons at high risk for example, the homebound elderly. Although much has been learned from the planning for smallpox and the recent experience with SARS and anthrax, much still needs to be done. HealthCanada ¹ (the Canadian Health Department's Web site) and multiple articles in the lay media provide valuable information regarding the rapid identification and containment of SARS, including dis-cussion of quarantine and isolation procedures.

Infrastructure refers to the state and national resources that can be brought to bear in support of a national response. One critical component is improvement in the rates of interpandemic vaccination, which have fallen well below goals. Annually, interpandemic influenza in the United States claims over 20,000 lives, causes 114,000 hospitalizations, and costs $1–$3 billion in direct medical costs. Nonetheless, national averages show that only 60% of those eligible are immunized. Improvement is critical, and we must strengthen efforts in inner cities, community health centers, and nursing homes. The application of electronic systems to identify and track the people in whom vaccination is recommended has raised vaccination rates to over 90% even in the remote areas served by the Indian Heath Service. Research directed toward the development of more sensitive and specific diagnostic agents, newer vaccines, and antiviral agents must be supported. The current rate at which the production of influenza vaccines can be accelerated is limited by the fact that production is carried out in eggs. Therefore, there is an urgent need for cell-based vaccine technologies. These are under development in several centers, yet commercial production of a safe product remains several years away. There is a need to strengthen our public health communication networks to improve information transfer across the nation in cooperation with the news media.

Our hopes are that efforts toward national readiness will progress at the most rapid possible pace, so that when our nation is challenged by the next serious respiratory pandemic, federal response will be optimal.

Role of the Private Sector

There are currently 3 suppliers of influenza vaccine for the American market in interpandemic years: 2 manufacturers of injectable vaccine and 1 of a newly approved intranasal product for certain populations. Guidelines for eligibility are updated as needed by the Advisory Committee for Immunization Practices and are published yearly by the CDC. There has been a steady attrition of vaccine manufacturers, largely due to the economics of vaccine production. Major capital investment is required to manufacture large amounts of any biologic product such as influenza vaccine, in accordance with the FDA's Good Manufacturing Practices. Companies cite high development risk, together with liability concerns, as impediments to further vaccine research and development. While monovalent vaccine (current vaccine is trivalent) would likely suffice for prompt response to a pandemic, there are complicating factors: the possible need for a booster dose, the likely recommendation of universal vaccination, and worldwide need, such that demand would rapidly exceed supply in the event of pandemic infection. Consequently, there is a need for public and private investment in surge capacity and/ or dedicated NIH facilities to enable accelerated production. Further, we must support efforts to shorten development time by developing and approving subunit antigens and immunogens that anticipate the most virulent viral mutations. As noted above, the development and registration of a vaccine that can be produced by means of cell-based technology is critical.

Despite reassuring data about the safety of the influenza vaccine and the recommendation of interpandemic immunization of additional populations by the Advisory Committee for Immunization Practices and by the American Academy of Pediatrics, the industry has relied largely upon federal, state, and local pub-lic programs to improve immunization rates. Most recently, there are intriguing data regarding the protective effect of influenza immunization against cardiovascular disease. ^2,3 The safety of the vaccine is not well appreciated by the public, and neither is the cooperation among the various federal agencies and vaccine manufacturers in the timely preparation of each year's antigens. This cooperation must be supported and strengthened if we are to realize full preparedness for an emergency.

Role of Bioterrorism Preparedness

Within the DHS, the Office of Emergency Preparedness, FEMA (Federal Emergency Management Agency), and the National Biodefense Analysis and Countermeasures Center contribute during an emergency. Data regarding the genetic bases for influenza virulence and infectivity exist in the public domain. A bioengineered influenza can be imagined, which gives us even more reason to be prepared. In the event of the release of a bioengineered influenza, how rapidly would the manipulation be detected? A necessary component still lacking is funding for several laboratories with high throughput screening and strong informatics capabilities to enable the fingerprinting and cataloguing of all known specimens of influenza and other pathogenic organisms for rapid identification of emerging or bioengineered pathogens. ⁴ Have reagent antigens—directed against the more virulent subtypes —been developed and prepared? If not, whose responsibility should this be?

One fortunate byproduct of the threat posed by bioterrorism has been the infusion of federal monies to rebuild state and local public health infrastructures, and smallpox planning clearly will provide a framework for response to any pandemic illness. Further resources have been allocated to the new DHS to include support for exercises such as TopOff2, which simulated simultaneous release of aerosolized plague in 2 United States cities. Funding for biodefense research has reached unprecedented levels, now exceeding $1.75 billion in the 2003 NIH budget. Bioshield, as proposed in the President's 2004 budget, includes monies directed toward effective vaccines against anthrax, botulinum toxin, Ebola virus, and plague. Many state and local public health consortia (in the greater Houston community, ⁵ for example) have devised disaster preparedness plans.

Clearly, every reasonable effort must be undertaken to provide Americans with protection against the inevitable appearance of the next pandemic influenza strain, the possible emergence of other severe communicable pathogens, and the unlikely possibility of a bioterrorist event. Progress has been substantial; however, we cannot rest until our nation's preparedness is optimal.