| | Lessons Learned: Role of Influenza Vaccine Production, Distribution, Supply, and Demand—What It Means for the ProviderAbstract The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC) has been increasing the size of the population for whom influenza vaccine is recommended to reduce the substantial and persistent annual health burden of influenza. Realization of current and future public health influenza immunization goals requires assuring vaccine supply will be adequate to meet demand. This has posed distinct challenges for the many stakeholders in the influenza vaccine program—government agencies, federal, state, and local policymakers, vaccine manufacturers and distributors, and the medical community—each of whom must make critical decisions in a constantly shifting environment. Factors such as the yearly changes in influenza virus strains, the complicated vaccine production and distribution process, revisions in vaccination recommendations, and changing demographics can all affect the delicate balance between supply and demand. While vaccine shortages and delays have been well-publicized concerns in the recent past, there has been a marked increase in supply in the past several years, with substantial growth in supply expected in the future. The primary issue today is to strengthen the demand for the influenza vaccine, which would in turn help ensure the continued availability of the vaccine to reduce disease burden. A number of strategies are discussed, including increased efforts to publicize and fully implement current CDC recommendations and to offer influenza vaccine beyond the typical vaccination season of October and November, because in the great majority of years, vaccination into January and beyond will still provide health benefits. Influenza causes the greatest vaccine-preventable burden of disease in the United States, accounting for an estimated annual average of 36,000 deaths and 226,000 hospitalizations.1, 2 To decrease this burden, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) gradually has increased the size of the population recommended for annual vaccination, which now covers about 73% of the US population, or 218 million people.3 This includes persons at high risk for complications from influenza and the individuals who might transmit the virus to them, such as their household contacts and healthcare workers. Starting no later than the 2009-2010 influenza season, vaccination recommendations will be extended to include all children 5 to 18 years of age,4 which will add approximately 30 million children (∼10% of the US population) to the group who should be vaccinated annually. In addition, the ACIP encourages anyone who wants to avoid influenza to obtain the vaccine. Thus, almost the entire US population is either recommended to be vaccinated annually or is covered by a permissive recommendation. Influenza vaccine is different from all other vaccines because it is administered annually to persons for whom it is recommended. More doses of influenza vaccine are used annually than of any other vaccine.5 Nevertheless, the burdens of providing influenza vaccine have left many providers frustrated. The purpose of this article is to explain the reasons why there may be problems in vaccine supply in a given season and to outline potential steps providers can take to help their patients avoid the burdens of influenza while at the same time enhancing production and distribution capacity to meet present and future demands. In the United States, the major stakeholders in the influenza immunization program include government agencies, state, federal, and local policymakers, vaccine manufacturers, distributors, and clinicians, including community immunizers as well as those who provide influenza vaccine at the workplace.6 These participants must make decisions regarding the vaccine composition, the assessment of vaccine potency and purity, the amount of vaccine to produce, how many doses to order, how to distribute, how to finance, when to administer the vaccine and to whom, and how to reach patients. Numerous factors come into play, many of them subject to change. For example, influenza viruses undergo frequent mutations. Thus, the vaccine must be reformulated each year to include new strains experts think are likely to circulate the following season. In any given year, availability of vaccine may be affected by low production yields, higher-than-expected demand, and changes in vaccine recommendations. Longer-term factors (e.g., demographic), such as the increase in the elderly population, a group at high risk for influenza-related complications, may also influence future supply and demand. There have been several influenza supply disruptions since the 2001-2002 season.7, 8 Disruptions have occurred, for example, when manufacturers have exited the marketplace or when manufacturers' products became available after the traditional influenza vaccination season, which the CDC had previously defined as October through November (now considered to be October into January and beyond).3, 9, 10 A highly publicized shortage occurred in 2004-2005, when contamination forced the vaccine manufacturer Chiron to suspend production of its anticipated 46 million influenza doses at its facility in Liverpool, England. At the time, Chiron was 1 of only 3 companies providing the influenza vaccine to the US market, and these lost doses represented about half of the anticipated US vaccine supply for 2004-2005. Although federal agencies moved quickly to prioritize who should receive the vaccine, concern eventually focused on the country's inability to administer all doses of even this limited supply.11, 12 With the subsequent entry of additional manufacturers into the marketplace, which now includes sanofi pasteur, Novartis, GlaxoSmithKline, MedImmune, and CSL Biotherapies, the vaccine production capacity appears to be less vulnerable. It is estimated that a record 130 million doses were produced for the 2007-2008 influenza season,13 and in the future, a steady and plentiful supply of vaccine is expected. Thus, the overriding issue today involves complying with ACIP recommendations to prevent the influenza burden each season. This requires increasing consumer demand and providing incentives to providers to ensure sufficient supply. For example, annual coverage for persons ≥65 years, 1 of the priority groups for vaccination, is typically <70%, when national targets call for ≥90%.14 This article discusses the current system of vaccine production, distribution, and financing in the context of supply and demand. It also highlights new developments and approaches that may help achieve immunization goals to the benefit of all influenza vaccine stakeholders. Production of the influenza vaccine  Although a larger manufacturing base will help to avert vaccine supply shortages, some degree of uncertainty is inevitable, given the inherent complexities of the influenza vaccine production process. Unlike manufactured drugs, biologics are natural products and therefore are less predictable.15 The lack of predictability begins with influenza viruses themselves. One or more of 3 strains of influenza viruses are responsible for seasonal influenza epidemics–2 strains of type A influenza (A/H1N1 and A/H3N2) and influenza type B. These viruses undergo antigenic changes (antigenic drift), resulting in new strains that may not be recognized by the body's immune system.16 To keep up with these changes and remain effective, the influenza vaccine is reevaluated each year and reformulated when new variants appear to be emerging. Even if there is no reformulation, vaccine must be produced anew each year because it is not until March that the strains to be included in the following season's vaccine are decided upon. Thus, the previous year's vaccine expires and must be discarded before the next influenza vaccination season. Vaccine production takes about 8 or 9 months, but is actually an ongoing process if one considers the importance of year-round global influenza surveillance.17 Based on global surveillance data collected by World Health Organization (WHO) Collaborating Centers, including the CDC, the US Food and Drug Administration (FDA) selects 3 influenza strains (type B, A/H1N1, and A/H3N2) thought to be the likely cause of influenza epidemics in the upcoming season. The efficacy of the vaccine depends in part upon a close match between the vaccine strains and circulating strains. However, even when the vaccine is not optimally matched to the predominant viruses, it usually still affords some protection, inasmuch as antibodies made in response to the vaccine can protect against related strains (cross-protection).18 In January, the CDC provides influenza “reference” viruses to the FDA, which distributes them, in turn, to the manufacturers.17 It should be noted that at this early point in the production process, well in advance of the upcoming influenza season, manufacturers must consider issues of both supply and demand. For example, they must estimate demand, taking into account “prebookings” from government, large public/private purchasers, and small private purchasers, as well as the previous year's demand.15, 17 They must consider the “yield,” or growth potential, of each strain, because this dictates the amount of vaccine that can be produced, while also estimating the number of doses that will be produced by other manufacturers. The vaccine production cycle extends through August, when completed lots become available.17 During this process, the FDA tests vaccines multiple times for purity and efficacy. Indeed, the testing and approval process accounts for a substantial proportion of production time. For both injectable and nasal vaccines, the 3 strains are produced separately in embryonic eggs. The monovalent concentrates are harvested and combined into the trivalent form, which is then used to fill vaccine delivery devices (vials, syringes, nasal sprayers).17 Injectable vaccines undergo additional steps after harvesting including inactivation and disruption of the lipid envelope of the virus resulting in split or subvirion products.19 Live attenuated vaccines for intranasal administration are produced by reassortment of cold-adapted, temperature-sensitive parent virus strains with wild viruses to produce a virus containing the 6 internal genes of the parent attenuated strain and the hemagglutinin and neuraminidase of the wild virus.20 Vaccines are packaged for distribution and kept at appropriate temperatures to guarantee potency. Each lot must be approved separately for release by the FDA before shipment. Thus, no matter how efficiently vaccine is produced, it will generally be distributed in stages over time. Distribution Private practices, public clinics, and other small and large (e.g., pharmacy chains and supermarkets) immunization providers may order vaccine either directly from the manufacturers, or from a distributor. Orders are taken by manufacturers and distributors as early as January of the prior season. Distribution normally begins in September and continues for as long as vaccine supplies are available. The timing of vaccine production as well as distribution issues generally results in vaccine supply reaching providers throughout the fall months. During the last 3 influenza seasons, about 70% of the vaccine supply was delivered by October.21 In previous seasons, when total supply was lower, early demand usually outpaced early supply. Given the recent increases in supply, this will hopefully no longer be the case. However, a substantial number of doses will continue to be delivered after the current peak in vaccination (Figure 1).21, 22 Extending vaccination efforts into January and beyond will harmonize supply-demand discordance and provide protection for more at-risk individuals. The existence of multiple vaccine producers coupled with numerous distribution channels also affects the timing of vaccine delivery, thereby creating real or perceived shortages and delays. Thus, there may be temporary shortages at the local level, even when the national supply is adequate. It is also possible that providers in the same local area who ordered from different manufacturers or distributors may receive their vaccine supply at different times. Indeed, these disparities in vaccine delivery at the local level, particularly early in the vaccination season, continue to be a substantial source of confusion and concern among physicians. Growing the demand to ensure the supply Public (federal, state, and local) and private (health plans, insurers, providers) stakeholders have an important role to play in increasing the demand for the influenza vaccine to reach the >80% of the US population (which includes the 30 million children recommended to be vaccinated no later than the 2009-2010 season) who should be vaccinated annually. Driving the demand up would not only ensure that individuals and populations who would benefit from the vaccine actually receive it, but would also help to mitigate some of the risks, thereby encouraging the continued participation of manufacturers, distributors, and providers in the system.7 The willingness of manufacturers and distributors to participate in the program depends, to a large degree, on demand for the vaccine and adequate returns from sales.10, 15 The financing of immunizations is 1 component of assuring vaccine availability. In the case of children, the government shares the burden for immunization coverage with the private insurance industry and private payers/parents.23 Two sources of federal funds are the Section 317 program, administered by the CDC, and the Vaccines for Children program. Since 1993, Medicare has reimbursed the costs of the influenza (and pneumococcal) vaccine for those aged ≥65 years without applying a copay or deductible.23 For other adults, the government has only a modest role, and influenza vaccines are purchased and administered in the private sector. Gaps and fragmentation of insurance coverage are areas of concern. Limited insurance coverage not only increases the stress placed on the public sector but also increases the burden on private providers. These financial barriers for patients and providers may lead to missed opportunities for immunization, depressing demand and ultimately supply.24 Addressing financing issues is only part of the solution, however. Influenza vaccination rates have remained suboptimal even in vulnerable populations (e.g., Medicare beneficiaries ≥65 years old) that have coverage. According to 1 study, Medicare recipients cited lack of knowledge of the need for immunization and the belief that the vaccine itself might cause disease as reasons for avoiding influenza vaccine.25 Demand may also wane when the influenza season is perceived to be of “mild” severity, while demand may increase in seasons where influenza is perceived to be severe or occurs early.7 This applies to healthcare workers as well. The CDC recommends that all healthcare providers obtain yearly vaccinations. By so doing, healthcare providers set an example for their patients, while protecting not only their own health but also that of their patients. Efforts should also be directed at following the CDC's recommendations to make use of the entire vaccination season (October into January and beyond) and take advantage of all opportunities to vaccinate patients, which would further bolster demand and ensure supply.3 Typically, demand is high in the fall and then subsides. The reason influenza vaccine ideally is administered in the fall is to protect against potential early influenza seasons. However, influenza activity peaked in February for 45% of the seasons during the period 1976-2006.3 In only 16% of the seasons did influenza disease peak before January, and in some seasons disease activity peaked as late as April or May. Thus, in the great majority of years, influenza vaccination into January and beyond is beneficial. The CDC has urged that healthcare providers make the influenza vaccine available throughout the entire vaccination season.3 This should increase demand beyond the traditional fall immunization time frame, and ensure that vaccines do not remain unused when they can still confer benefit. To take advantage of every opportunity, healthcare workers are advised to offer the vaccine during routine healthcare visits or during hospitalization. Although physician offices and clinics will likely remain the primary sites of vaccination, the CDC also supports immunizing patients in nontraditional settings, including the workplace, retail stores, and senior citizen centers.3 What this means for the provider Healthcare providers are in a unique position to strengthen demand by educating their patients about the serious consequences of influenza and the benefits of immunization, and by making the vaccine available from October into January and beyond. Providers can play a key role in encouraging and facilitating patients' receipt of routine annual influenza immunizations. In following this approach, providers will not only be providing an important service to their patients but also will be minimizing potential risks to themselves.26 Healthcare providers must decide how much vaccine to order, when to administer, and to whom. At the same time, they must incur the costs (which have increased) of purchasing the vaccine, and of storage, insurance against loss, and administration. In estimating how many doses to order, physicians have traditionally reviewed their records from previous years to purchase a supply sufficient to cover their at-risk patients. They have been reluctant to purchase more vaccine than they can use, out of concern that they would be left with unused (and unreturnable) doses and the financial loss that this entails.7 When supplies run out, physicians often refer their patients to other locations.27 However, patients may not always avail themselves of these opportunities, thus remaining exposed to infection and its complications. A factor that should enter into providers' calculations (Figure 2) in the present context is the CDC's recommendation that vaccination take place throughout the entire influenza vaccination season, beginning in October and continuing into January and beyond. Taking advantage of the full season will give providers added flexibility, enabling them to better deal with the vagaries of the vaccine market. Thus, if vaccine doses are delayed or distributed over a longer period, providers will have more opportunities to use their entire supply over the course of a longer vaccination season. Providers should continue to administer the vaccine early, to immunize as many persons as possible before influenza activity begins. Physicians should avail themselves of all opportunities to vaccinate in December, January, and later. Those working in other healthcare settings, such as public clinics, can schedule vaccine clinics throughout the season. In addition to providing a benefit to patients in the great majority of years, this approach will minimize the chances of financial loss. Providers should also be aware that the Centers for Medicare and Medicaid Services raised vaccine-administration payments beginning in the 2005-2006 season. Future developments New strategies and technologies that affect the influenza vaccine production system at various points are being explored. These may ultimately be beneficial in terms of reducing production time and ensuring a steady supply. As discussed, influenza vaccine preparation takes about 8 to 9 months; vaccine testing and approval at the FDA is an essential part of the process. The FDA is considering ways to accelerate the vaccine review and approval process as part of an effort to expedite the production process.27 Numerous alternatives to egg-based vaccine manufacturing technology are also being developed.28, 29 Although egg-based technology has been used since the 1950s, and has produced billions of safe, efficacious influenza vaccine doses, other newer technologies may prove to be beneficial in shortening the manufacturing process and perhaps easing delivery constraints by allowing the vaccine to be available sooner.30 Just how beneficial remains to be determined. Two technologies in development are cell culture10, 17 and reverse genetics.30 In contrast to traditional manufacturing methods, cell culture offers the possibility of faster startup of vaccine production, although this may represent time savings of only a few weeks, perhaps even days, at the beginning of the process.17 Reverse genetic technology is used to prepare reference virus strains and is applicable to either egg-based or cell culture production.17 This approach allows scientists to alter the virus in an effort to produce a vaccine that better matches the new strain of influenza and increases production yield.30 It is worth noting that these new technologies may prove to be more expensive and consequently may increase vaccine costs. Summary Influenza vaccination is the best defense against the morbidity and mortality associated with influenza, and meeting public health immunization goals is a top priority. To ensure that all those who would benefit actually receive the vaccine requires achieving a balance between supply and demand in the vaccine marketplace. In the past, the focus has been on the supply side, as persistent supply shortages and distribution delays dominated the news. Today there is ample supply, and those involved in the overall influenza vaccine system, including government agencies, federal, state, and local policymakers, vaccine manufacturers and distributors, and healthcare providers, have a role to play in making sure that demand is sufficient to make optimal use of the available supply to decrease the substantial health burden of influenza. It will also help to guarantee the continued availability of the influenza vaccine in the future and minimize the residual risks associated with vaccine production and distribution. Author disclosures The authors who contributed to this article have disclosed the following industry relationships: Walter A. Orenstein, MD, has received grant support for clinical trials and research from Merck & Co., Novartis, and Sanofi Pasteur, Inc.; and serves on 2 data safety monitoring boards for clinical vaccine trials, Encorium (formerly Dynport) for bioterrorism threats and GlaxoSmithKline for pneumococcal vaccine. William Schaffner, MD, serves as a consultant to GlaxoSmithKline, MedImmune, Merck & Co., Novartis, Sanofi Pasteur, Inc, and Wyeth Pharmaceuticals; and is a member of a data safety evaluation committee for experimental vaccines for Merck & Co. References 1. 1Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179–186. MEDLINE 2. 2Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004;292:1333–1340. 3. 3Centers for Disease Control and Prevention (CDC). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep. 2007;56(RR06):1–54. 4. 4Centers for Disease Control and Prevention (CDC). CDC's advisory committee recommends influenza vaccination for children 6 months through 18 years of age [press release]. http://www.cdc.gov/media/pressrel/2008/r080227.htm. 5. 5Mason D. A vaccine supply update for the US marketPresented at the National Vaccine Advisory Committee Meeting; Washington, DC: June 3, 2003 [PowerPoint slide presentation]. www.hhs.gov/nvpo/meetings/jun2003/mason-s.ppt. 6. 6Orenstein WA, Douglas RG, Rodewald LE, Hinman AR. Immunizations in the United States: success, structure, and stress. Health Aff (Millwood). 2005;24:599–610. MEDLINE 7. 7Layton C, Robinson T, Honeycutt A. Influenza Vaccine Demand: The Chicken and the Egg, Issue Brief, 2005. http://aspe.hhs.gov/pic/fullreports/06/8476-4.doc. 8. 8Rodewald LE, Orenstein WA, Mason DD, Cochi SL. Vaccine supply problems: a perspective of the Centers for Disease Control and Prevention. Clin Infect Dis. 2006;42(suppl 3):S104–S110. 9. 9Centers for Disease Control and Prevention (CDC). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2002;51(RR03):1–31. MEDLINE 10. 10Danzon PM, Pereira NS, Tejwani SS. Vaccine supply: a cross-national perspective. Health Aff (Millwood). 2005;24:706–717. MEDLINE 11. 11Gerberding JL. US influenza supply and preparations for the future (Testimony before the Committee on Government Reform, US House of Representatives). http://www.hhs.gov/asl/testify/t050210b.html. 12. 12Fishbein DB, Fontanesi J, Kopald D, et al. Why do not patients receive influenza vaccine in December and January?. Vaccine. 2006;24:798–802. 13. 13Fiore A. Influenza activity in the United States, February 2007. http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-Oct07/93-flu.pdf. 14. 14US Department of Health and Human Services. Healthy People 2010 influenza immunization goals. http://www.healthypeople.gov/document/html/objectives/14-29.htm. 15. 15Coleman M, Sangrujee N, Zhou F, Chu S. Factors affecting US manufacturers' decision to produce vaccines. Health Aff (Millwood). 2005;24:635–642. MEDLINE 16. 16Betts RF. Influenza virus. In: Mandell GL, Bennett JE, Dolin R editor. Mandell, Douglass, and Bennett's Principles and Practice of Infectious Diseases. 4th ed.. New York: Churchill Livingstone; 1994;p. 1546–1567. 17. 17Layton C, Lenfestey N. Influenza Vaccine Manufacturing, Issue Brief, October 2005. http://aspe.hhs.gov/pic/fullreports/06/8476-2.doc. 18. 18Bridges CB, Thompson WW, Meltzer MI, et al. Effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial. JAMA. 2000;284:1655–1663. MEDLINE 19. 19Bridges CB, Katz JM, Levandowski RA, Cox NJ. Inactivated influenza vaccines. In: Plotkin SA, Orenstein WA, Offit PA editor. Vaccines. 5th ed.. Philadelphia: Elsevier; 2008;p. 259–290. 20. 20Belshe RB, Walker R, Stoddard J, et al. Influenza vaccine-live. In: Plotkin SA, Orenstein WA, Offit PA editor. Vaccines. 5th ed.. Philadelphia: Elsevier; 2008;p. 291–309. 21. 21Wallace GS. Vaccine supply update & programmatic implications. http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-feb08/23-vac-supply.pdf. 22. 22Jones TF, Ingram LA, Craig AS, Schaffner W. Determinants of influenza vaccination, 2003-2004: shortages, fallacies and disparities. Clin Infect Dis. 2004;39:1824–1828. 23. 23Hinman AR, Orenstein WA, Rodewald L. Financing immunizations in the United States. Clin Infect Dis. 2004;38:1440–1446. 24. 24Institute of Medicine. Financing Vaccines in the 21st Century: Assuring Access and Availability. Washington, DC: The National Academies Press; 2003;http://www.iom.edu/?id=14451&redirect=0. 25. 25Adler GS. Influenza vaccination and self-reported reasons for not receiving influenza vaccination among Medicare beneficiaries aged ≥65 years: United States, 1991-2002. MMWR Morb Mortal Wkly Rep. 2004;53:1012–1015. 26. 26Poland GA, Tosh P, Jacobson RM. Requiring influenza vaccination for health care workers: seven truths we must accept. Vaccine. 2005;23:2251–2255. 27. 27National Influenza Vaccine Summit. Minutes of meeting; January 24-25, 2006; Atlanta, GA. http://www.ama-assn.org/ama1/pub/upload/mm/36/summit_minutes.pdf. 28. 28Belshe RB. Translational research on vaccines: influenza as an example. Clin Pharmacol Ther. 2007;82:745–749. 29. 29Cox MM. Progress on baculovirus-derived influenza vaccines. Curr Opin Mol Ther. 2008;10:56–61. 30. 30Abramson JS, Neuzil KM, Tamblyn SE. Annual universal influenza vaccination: ready or not?. Clin Infect Dis. 2006;42:132–135. a Emory Vaccine Center, Atlanta, Georgia, USA b Departments of Preventive Medicine and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA  Requests for reprints should be addressed to Walter A. Orenstein, MD, Emory Vaccine Center, 1462 Clifton Road NE, Suite 446, Atlanta, Georgia 30322.
Statement of author disclosure: Please see the Author Disclosures section at the end of this article. PII: S0002-9343(08)00467-1 doi:10.1016/j.amjmed.2008.05.004 © 2008 Elsevier Inc. All rights reserved. | |
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