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Use of Vaccines and Antiviral Drugs in the Next Influenza Pandemic

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Use of Vaccines and Antiviral Drugs in the Next Influenza Pandemic H. Grant Stiver MD, FRCPC Use of vaccines and antiviral drugs in the next influenza pandemic While waiting for the development of an effective vaccine during the early stages of a pandemic, physicians will be able to rely on the antiviral drugs of oseltamivir and zanamivir. ABSTRACT: In the event of an influ- tadine, may be less efficacious, as andemic influenza has been enza pandemic, vaccination will be resistance is now common among associated with both moder- the main way to prevent spread of influenza strains, including H3N2, ate and severe morbidity and the virus. Current techniques for H1N1, and H5N1 subtypes. A clinical 1 Pmortality. The develop- developing a vaccine against a novel diagnosis of influenza in a pandem- ment of a pandemic requires the in - virus use genetic engineering to ic situation is likely to be accurate in troduction of a novel influenza strain allow rapid adaptation to hens’ eggs, the vast majority of patients with that the population of the world has no the medium in which vaccine virus is influenza-like illness. To be effec- immunity to, and for that strain to mass-produced. The effectiveness tive, the drugs must be administered be spread throughout the world until of immunization depends on how within 48 hours of the onset of disease incidence reaches a certain closely the vaccine matches the pan- influenza-like illness. The earlier the threshold level of immunity in the demic strain, and how immunogenic intervention, the better the reduc- population and abates. In addition to it is in humans. In the initial stages tion of illness. Canadian and British public health containment strategies of a pandemic it is unlikely that an Columbia pandemic plans require (e.g., closing schools, restricting trav- effective vaccine will be immediate- using antivirals in this way. Supply of el), there are strategies to mitigate the ly available. The only remaining op- antivirals will likely be limited, so spread of influenza and its clinical con- tion for treatment and prophylaxis medical personnel, essential service sequences: will be the influenza antiviral drugs. personnel, and high-risk patients • Immunization. Currently, these include the neu- will get priority, at least for the • Treatment and prevention with raminidase inhibitors oseltamivir oseltamivir that is stockpiled by pub- antiviral drugs. and zanamivir. Another drug, aman- lic health agencies. • Clinical management. Practitioners should be prepared to optimize the use of vaccines and antiviral agents, and to employ effec- tive clinical management of patients in the event of a pandemic. Dr Stiver is a professor in the Department of Medicine, Division of Infectious Dis- eases at the University of British Columbia and at Vancouver General Hospital, Van- couver Coastal Health Authority. VOL. 49 NO. 5, JUNE 2007 BC MEDICAL JOURNAL 249 Use of vaccines and antiviral drugs in the next influenza pandemic Immunization the severity of illness and results in ceptible to influenza viruses). These Inactivated intramuscular injectable significantly reduced hospitaliza- animals were protected from the vaccine and live attenuated intranasal tion and mortality (by up to highly virulent avian strain of H5N1 10 vaccine (FluMist—not yet licensed in 70%), possibly because it stimu- (A/Vietnam/1203/04) and a different 2 Canada), can be used to prevent influ- lates a cell-mediated partial protec- clinical Hong Kong strain of H5N1 11 enza, both with comparable efficacy tion. Immunization of infants and (A/Hong Kong/156/97) after vaccina- 3 and side effects. The current influenza small children is recommended by the tion with A/Hong Kong/213/03 vaccines are so-called split vaccines, US Centers for Disease Control and (H5N1) genetically engineered virus which contain the hemagglutinin Health Canada because it has been vaccine, indicating that there was (HA) and neuraminidase (NA) of the proven to reduce hospitalization in cross-protection against several mutat- 12,13 most current epidemic subtypes of these groups. ed subtypes of H5N1. This might influenza A and influenza B. The three In the next pandemic, whatever the mean it will be possible to manufac- most likely candidate antigens are virus happens to be, vaccine will be ture an effective or partially effective mass produced by vaccine manufactur- distributed to priority groups based on vaccine in advance and stockpile it 17 ers from viruses grown in hens’ eggs. the BC Pandemic Influenza Prepared- prior to any H5N1 pandemic. “Seed” strains for this mass produc- ness Plan. These groups are the same According to the BC Pandemic tion are created by a process called as those who now are prioritized to Influenza Preparedness Plan, organiza- “reverse genetics” and recombination, receive influenza vaccine. In order of tion and implementation of vaccine by which a virus can be constructed in priority, they are: administration is to be carried out by vitro, resulting in a progeny that has 1. Health care workers. each regional health authority. The the required surface HA and NA anti- 2. Essential service workers and secu- type and dose of vaccine will depend gens (with egg-toxic genes removed) rity personnel. on what the pandemic virus is. Recent combined with a fast egg-growing 3. High-risk medical patients, such as evidence suggests that purified HA 4 “backbone” virus. Since vaccines for the frail elderly and individuals with protein from the avian H5N1 virus influenza were first introduced, the chronic underlying organ diseases. does not elicit a very strong antibody A/PR/8 strain, a very good replicator 4. Infants andchildren under 2 years of response unless it is given at higher 18,19 in fertilized hens’ eggs, has been the age. antigen dose and with an adjuvant. backbone strain. Egg adaptation has 5. Healthy adults and older children. Such a dose is accompanied by more 19 been greatly enhanced by the technol- While Canada is expected to be local skin reaction. Others have sug- ogy of reverse genetics, andnow a seed self-sufficient in vaccine manufactur- gested that a whole virus vaccine strain can be made in as little as 4 ing in the event of a pandemic, there (used until the 1980s) might improve weeks, whereas previously this took is always the possibility of vaccine the immune response to H5N1, but no months of egg adaptation. Obviously, shortage. In a recent study, a lower dose comparative studies have been pub- rapid vaccine manufacture and distrib- (0.1 mL instead of the usual 0.5 mL) lished yet. The current recommenda- ution in the early stages of a pandem- of trivalent inactivated vaccine inject- tions for influenza vaccination sched- ic will be the most critical factor in ed intradermally in adults instead of ules and doses are in effect for a reducing morbidity and mortality. The intramuscularly (the same technique pandemic until better data on vaccine World Health Organization has devel- used for a Mantoux test), stimulated a strength and formulation are forth- oped a strategy to make this as effi- protective serum antibody level equal coming. 5 cient as possible. to or better than the 0.5 mL intramus- Since a pandemic may occur with- 14,15 The safety, efficacy, and effective- cular dose, and possibly also a con- in the next several years, physicians ness of influenza vaccine have been comitant cell-mediated response be- should take every opportunity to im- 6- determinedby multiple clinical trials. cause of the stimulation of potent munize their high-risk patients with 9 To summarize, illness rates are immune-mediating dendritic cells in pneumococcal vaccine. (An estimated 16 reduced by approximately 75% to the skin. This dose-sparing strategy one-third of all deaths from the 90% in younger persons, and by 50% may be useful in extending the vaccine 1918–19 pandemic were caused by in the frail elderly. In the latter group, supply in a pandemic situation. combined viral and bacterial pneu- although vaccine does not prevent There are also some encouraging monia and one-third from bacterial infection as it does in persons with data from avian influenza vaccination pneumonia initially triggered by prior more robust systems, it does reduce of ferrets (animals that are highly sus- infection with influenza.) Although 250 BC MEDICAL JOURNAL VOL. 49 NO. 5, JUNE 2007 Use of vaccines and antiviral drugs in the next influenza pandemic pneumo coccal polysaccharide vaccine the statistically significant differences ily members have occurred in poultry does not reduce the incidence of pneu- between placebo and NAI are only seen workers. Human-to-human transmis- 23- monia and hospitalization, it is asso- if the drug is started within 36 hours). sion is not efficient at this time. 25 ciated with a decrease in mortality due The earlier an NAI can be started after The optimal dosage of oseltamivir 20 to pneumonia in elderly patients. the onset of symptoms, the less ill- for effective treatment of H5N1 avian Pneumococcal vaccination rates in ness occurs. For example, oseltamivir influenza is not clearly established. adults in BC at present are inappropri- given within 12 hours of symptom Animal studies suggest that a higher ately low. onset rather than 48 hours has resulted dose and longer course may be re - 26 30 Antiviral drugs in 3 fewer days of symptoms. quired, possibly because the virus is There are three influenza antiviral drugs currently licensed in Canada: the proton channel inhibitor amantadine (Symmetrel), which targets in flu enza A only, and the viral neura min idase H5N1 causes a “cytokine storm,” an inhibitors (NAIs) zanamivir (Relenza; over-stimulation of the immune response treatment dose 10 mg [two inhalations] ϫ b.i.d. 5 days) and oselta mivir (Tam- that is uncontrolled and deleterious, with iflu; treatment dose 75 mg [one cap- ϫ severe lung edema and hemorrhage sule] b.i.d.
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