Contamination problems in their British manufacturing facilityat Speke, Liverpool, recently forced the Chiron Corporationof San Francisco, one of only two companies licensed to provideinactivated influenza vaccine in the United States, to withdrawtheir vaccine (Fluvirin) from the market. Currently, it appearsthat about 54 million doses of inactivated vaccine (Fluzone)will be available from the remaining manufacturer, Aventis,with another 1.1 million doses of intranasal live influenzavaccine (FluMist) available from MedImmune for use in healthypeople 5 to 49 years of age. This represents about half theamount of vaccine expected for the 2004 vaccination campaign— enough to vaccinate approximately one third of the personsto whom the vaccine is usually targeted. Unsettling reportsof price gouging by suppliers are already beginning to circulatein the public media.
Glitches can crop up in the manufacturing of any pharmaceuticalproduct, and public health officials have long been aware ofthe vulnerability of the vaccine supply chain, which often relieson only one or two manufacturers for critical products. Influenzavaccine is especially vulnerable to interruptions in supply,because of the unique features of influenza-vaccine production.Unlike any other vaccine, influenza vaccine must be reformulatedto keep pace with antigenic changes in the hemagglutinin andneuraminidase proteins of influenzaviruses — essentiallynecessitating the manufacture of a brand new product from scratchevery year. The process is a long one, beginning with the identificationof new antigenic variants in the autumn of the previous yearand the selection of the strains for inclusion in the vaccine,and proceeding to the generation of appropriate reference reagents,the production and purification of the vaccine antigens, andpackaging and distribution, all within a period of six to eightmonths (see Figure).1 In addition, the vaccine is produced inembryonated hens' eggs and requires the sometimes laboriousadaptation of an appropriate seed virus for high-yield growthin this substrate in order to allow efficient production. Problemsare compounded when there is a simultaneous change in more thanone of the three included influenza strains.
Figure. Outline of the Annual Process of Development, Manufacturing, and Distribution of Influenza Vaccine.
Efforts are under way to determine whether additional suppliesof vaccine might be obtained from a variety of sources, includingCanada, but planning must proceed under the assumption thatthe amount of available vaccine will be limited. Therefore,the Centers for Disease Control and Prevention has prudentlyrecommended that the vaccine be targeted to those persons whoare most likely to have complications of influenza, includingsevere illness, hospitalization, or death (see Table). In addition,it is important to continue efforts to vaccinate health careworkers who provide direct, hands-on care to patients —a critical strategy for limiting the nosocomial spread of influenza.Although it will be extremely difficult to prioritize amongthe subgroups listed in the recommendations, the risk of influenza-relatedhospitalization increases linearly with age after 50 years,2and the rate of hospitalization among women in the first twotrimesters of pregnancy is somewhat lower than that among personsolder than 65 years. It should be noted that only the Aventisvaccine was licensed for use in young children, so that theloss of the Chiron vaccine may not have much effect on the effortto vaccinate this group.
The available vaccine should be used as efficiently as possible.Live vaccine (FluMist) is licensed for intranasal use in healthyadults and could be used in health care workers in order tosave the doses of inactivated vaccine for high-risk patients.In one recent study,3 the serum antibody responses of healthyyoung adults to the administration of a half-dose of vaccinewere very close to those after a full dose. This is a strategythat could be considered for use in healthy adults, but theavailable data are restricted to a single year. In addition,no data in high-risk populations are available, and there areno data on efficacy. Given the urgent need for more vaccine,additional studies of vaccine doses that are less than full-strengthshould be explored. Antiviral agents, such as the adamantanesamantadine and rimantadine and the newer neuraminidase inhibitorszanamivir and oseltamivir, are also available for both preventionand treatment of influenza,4 though supplies of these drugsare also limited.
What is likely to be the effect of reduced vaccination coverageon the morbidity and mortality related to influenza in the UnitedStates this year? Our current use of influenza vaccine is designedprimarily to reduce morbidity and mortality and probably haslittle effect on the transmission of influenza or the overallnumber of cases. Since the vaccine is clearly effective at reducingthe rates of influenza-associated hospitalization and death,reductions in vaccine coverage could be anticipated to resultin corresponding increases in the rates of these events. However,this observation is made in the context of the poor job we doof immunizing high-risk patients even when there is no apparentshortage of influenza vaccine. On the basis of the most recentNational Health Interview Survey, only 43 million doses of vaccinewould be required in 2004 to immunize the high-priority groupsat the same rates reported for the 2002–2003 season.5
The magnitude of the effect will also depend on the severityof this year's influenza season. Influenza epidemics are notoriouslydifficult to predict, but experience has shown that the worstseasons are typically those in which an antigenically driftedinfluenza A virus of the so-called H3 hemagglutinin subtypepredominates.2 Last year's epidemic, caused mainly by virusesresembling A/Fujian/411/2002 (H3N2), was an example of thisphenomenon. To date, no important new H3 virus has been detectedthrough surveillance, so if we are lucky, the impact of thevaccine shortage may be mitigated by a relatively mild influenzaseason.
Regardless of how we fare with this year's influenza epidemic,it is clear that we need to substantially expand our optionsfor dealing with the threat posed by influenza. The continueddevelopment of influenza vaccines grown in mammalian cell culturerather than embryonated hens' eggs will increase the flexibilityof the manufacturing process. Use of protein expression systems,such as recombinant baculovirus, for production of the influenzahemagglutinin and neuraminidase as vaccine antigens may shortenthe time required between the identification of new strainsand the production of the new vaccine. It might even be possiblesome day to use conserved viral proteins to make vaccines thatdo not need to be updated every year. In the meantime, however,we should take sensible steps to encourage more manufacturersto make influenza vaccines and to facilitate the licensure andmarketing of more such vaccines in the United States, as wellas in other countries. At a time when vast resources are beingfunneled into the development of vaccines against agents thatmight hypothetically be used by terrorists, we must find waysto protect our citizens against a virus that predictably —each and every year — causes major morbidity and mortality.
Dr. Treanor reports having received consulting fees from PowderJect.
Source Information
From the Infectious Diseases Unit, University of Rochester Medical Center, Rochester, N.Y.
This article was published at www.nejm.org on October 18, 2004.
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