Influenza Vaccine: Issues and Opportunities

VACCINE RECOMMENDATIONS CHALLENGES AND CONTROVERSIES

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INFLUENZA VACCINE: ISSUES AND OPPORTUNITIES Kathleen M. Neuzil, MD, MPH; Marie R. Griffin, MD, MPH; and William Schaffner, MD

Influenza is the most important acute upper respiratory infection that removes people from work and obliges them to seek medical care. It affects all age groups from the youngest through the old. It can produce repeated infections throughout life, is highly communicable, and is responsible for annual community epidemics of varying severity. In addition to its acute respiratory presentation, influenza also is a systemic infection that predisposes particularly to pulmonary and cardiac complications. Therein lies its capacity to kill. The deaths accompanying seasonal influenza epidemics are designated “excess mortality” for two reasons. First, during the epidemic the number of deaths in the population exceeds the demographer’s statistical expectation of mortality during that period. Second, after the epidemic, there is little or no compensatory reduction in mortality below the expected rate. Thus, influenza does not cause an earlier death only among those who might have been expected to die in the near future; most of the deaths produced by influenza would not have happened had the flu not run through the community. Thus, these deaths represent a genuine ”excess” mortality. Influenza is paradoxical. Despite its dire capacities, most influenza infections are self-limited. Influenza can resemble numerous other acute winter respiratory infections, all casually referred to as the flu. As a From the Division of Infectious Diseases, University of Washington School of Medicine, and VA Puget Sound Health Care System, Seattle, Washington (KMN);the Department of Preventive Medicine (MRG, WS); Division of General Internal Medicine (MRG), and the Division of Infectious Diseases (WS), Vanderbilt University School of Medicine, Nashville, Tennessee (MRG, WS)

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consequence, its potential severity often goes unappreciated by the lay populace and even some physicians. This lack of awareness of its potential to produce serious disease is a barrier to implementing a successful vaccination program. Although admittedly still imperfect, influenza prevention is effective. Annual vaccination remains the mainstay of prevention. The limitations of influenza vaccination are well known; among others, there must be a good antigenic match between the dominant circulating wild virus and the viral product in the vaccine, and there is a yearly race by the manufacturers to have sufficient quantities of vaccine available at the appropriate time. Furthermore, patients need a better understanding that influenza vaccine cannot prevent every winter respiratory infection. Indeed, even physicians often need reminding that the principal function of the vaccine is the prevention of the most severe complications of influenza: pneumonia, hospitalization, and death. In addition, among young healthy persons, the vaccine has been effective in preventing infections entirely and reducing sick days from work and the need for medical care. In this article, we address some of the issues commonly raised about influenza and its prevention, and review developments that have enhanced the prevention, diagnosis, and treatment of this unwelcome annual viral HEALTHY YOUNG ADULTS AND ANNUAL INFLUENZA VACCINE

Although influenza is responsible for about 20,000 deaths and 200,000 hospitalizations each year in the United States, few of these serious events occur in healthy young adults. The attack rate of influenza is high in all age groups, however, and on average, 10% of adults experience influenza illness each year. Although the hospitalization rate among healthy young adults is estimated to be only 2 to 4 per 10,000 persons per year? 58 a substantial number of persons who have influenza illness miss work or school, visit a health care provider, or are prescribed antibiotics for influenza-associated illness. A report from the National Health Interview Survey estimated that 27% to 34% of adults 18 to 64 years of age with influenza visited a health care pr0vider.l In one health mainatenance organization, influenza was estimated to result in 5 to 7 outpatient visits per 100 adults annually? It is likely that this rate of outpatient visits is mirrored by a similar rate of antibiotic prescriptions, as has been demonstrated in older ~hildren.5~ The efficacy of influenza vaccine is generally quoted to be 70% to 90% in healthy young adults.18 A recent Cochrane Systematic Review evaluated trials of influenza vaccine among healthy persons, at least 75% of whom were age 14 to 60 years?* Overall, the vaccine was 65% effective in preventing serologically confirmed cases of influenza and rose to 72% when there was a good match between the antigen in the

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vaccine and the dominant circulating virus. In these same studies, vaccine participants had 29% fewer episodes of acute respiratory illness overall, and 37% fewer episodes when there was a good vaccine match. Three trials also evaluated time missed from work; they estimated that influenza illness resulted in an average of 3 to 4 days lost from work and that vaccine saved 0.4 working day per recipient. Thus, there are ample reasons for healthy young adults to get influenza vaccine each year. RISKS VERSUS BENEFITS OF INFLUENZA VACCINE

The currently available inactivated influenza vaccine does not contain any live virus. Placebo-controlled trials have demonstrated that development of viral respiratory symptoms following immunization is coincidental and unrelated to vaccine. Therefore, to dispel a common misconception, one cannot get the flu from influenza vaccine. The most frequent side effect of influenza vaccination is soreness at the injection site lasting 1to 2 days. Systemic symptoms including fever, malaise, and myalgias have been reported to occur 6 to 12 hours after immunization and last 1 to 2 days, but these symptoms occur primarily in young children. Indeed, recent placebo-controlled trials using splitvirus vaccine in healthy adults and in elderly persons found no excess of these systemic symptoms associated with the vaccine. As with any vaccine, immediate hypersensitivity reactions (including anaphylaxis) occur rarely. With influenza vaccine, these reactions are likely related to small amounts of egg protein in the vaccine. In persons with asthma, influenza vaccine rarely can cause a transient decrease in expiratory flow rates. In a crossover trial of 262 persons age 18 to 75 years (mean 52 years) with stable medically treated asthma (910/, taking maintenance inhaled corticosteroids, 17% taking maintenance oral steroids), 4.3% developed a 20% or greater drop in peak expiratory flow in the 72 hours after receiving the vaccine versus 1.2% after These small differences did not translate into any differences in asthma-related medications, physician visits, or hospitalizations. The 1976 swine influenza vaccine was associated with an increased frequency of Guillain-Barr6 syndrome (GBS), with a rate of about 10 cases per million persons vaccinated. Adverse events occurring this rarely are extremely difficult to detect. Over several years, surveillance studies have suggested that this level of risk did not exist for subsequent vaccines. Lasky et alG reported an overall relative risk for GBS of 1.7 (95% confidence interval [CI] 1.0 to 2.8) during the 6 weeks following influenza immunization in a study of the 1992-1993 and 1993-1994 influenza seasons combined. This risk is consistent with one or two excess cases of GBS per million vaccinations. Thus, if influenza vaccine does cause GBS, it is rare. In addition, this level of risk is similar to the risk of anaphylaxis associated with many preventive and therapeutic products.

RECOMMENDED AGE FOR UNIVERSAL ANNUAL INFLUENZA VACCINE

Hospitalization rates for influenza-associated illness are highest at the extremes of age, but begin to rise well before age 65. This is due in part to the increasing prevalence of high-risk conditions in the fourth and fifth decades of life. Close to 25% of those age 50 to 64 have a chronic medical condition that places them at high risk of serious influenza-related morbidity. In addition, there is some evidence that smokers are predisposed to influenza and, when infected, develop more severe 39, disease.26* Influenza vaccination long has been recommended for persons younger than age 65 years who have high-risk medical conditions, because influenza-associated serious morbidity is relatively high in these persons (2 to 6 hospitalizations per 1000 persons per yearB). Such riskbased recommendations, however, have been much less successfully implemented than have age-based recommendations. National survey data indicate that 65.5% of persons age 65 years and older received influenza vaccine in 1997.8Immunization rates, however, were substantially lower (only about 30% to 40%) for persons younger than age 65 years with high-risk condition’s. Thus, both the American Academy of Family Physicians and the Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) now recommend that all adults age 50 years and older receive influenza immunization annually.lO, RAPID INFLUENZA TESTS AND NEW ANTI-FLU DRUGS

Amantadine hydrochloride (available since 1976) and rimantadine hydrochloride (available since 1993) are effective therapeutic and prophylactic agents against influenza A, but not against influenza B virus infections. After influenza A viruses enter cells, these drugs inhibit the uncoating of influenza A viruses by blocking the ion-channel activity of the viral M 2 protein, inhibiting replication. Zanamivir and oseltamivir, both approved by the Food and Drug Administration (FDA) in 1999 for treatment and not for prophylaxis, are members of a new class of antiviral agents that selectively inhibit the neuraminidase of both influenza A and B viruses, effectively inhibiting the release of viral progeny from infected cells. The appropriate treatment of patients with viral respiratory illness depends on accurate and timely diagnosis. Surveillance for the presence of influenza in the community or in specific institutions is also important in deciding when to initiate prophylaxis. In 1999, the FDA approved three laboratory tests (Flu OIA, QuickVue, and ZstatFlu) for the rapid diagnosis of both influenza A and B. Another test, Directigen Flu A, has been available for several years for the detection of influenza A only.

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Reported sensitivities range from 65% to 83%, but in practice vary with the age of the person being tested, the duration of symptoms, and handling of the specimens. Specificities of all the tests are reported to be over 90%. These tests cost between $15 and $20 each, and can help with diagnosis and in guiding antiviral (versus antibiotic) treatment; however, a negative test does not rule out influenza.l8* 50 One study of children whose respiratory infections were assessed in an emergency room setting showed encouraging results when a rapid influenza diagnostic test was The detection of influenza A resulted in a reduction of antibiotic use among children who were managed as outpatients. Among patients who required admission, antibiotic use was reduced in duration and the use of antiviral medication was enhanced.63The availability of these tests and new drugs for influenza treatment promise an increased awareness of the burden of influenza illness in the community and assure more appropriate treatment and prevention, especially yearly immunization. All four antiviral drugs can shorten the duration of fever and the severity of other symptoms associated with influenza if initiated 24 to 48 hours after onset. Little 9ata are available on prevention of complications. The drugs differ in the types of viruses inhibited, route of administration, dose, and the ages for which treatment is approved (Table 1). To date, the neuraminidase inhibitors have limited clinical experience and relatively high costs. Nevertheless, their effectiveness against both influenza A and B, early evidence suggesting only limited development of resistance, and their side effect profiles offer potential advantages over the older drugs. To reduce emergence of resistance, treatment with amantadine and rimantadine should be stopped as soon as clinically warranted, generally in 3 to 5 days. Recommended length of treatment for the neuraminidase inhibitors is 5 days. At the usual dose of 200 mg per day, amantadine causes nausea, dizziness, insomnia, and difficulty with concentration in 5% to 10% of young adults. More serious central nervous system effects, such as seizures and confusion, are less frequent. All these effects are more common in elderly persons and patients with renal disease and seizure disorders. Reducing the dose is recommended in these groups; however, side effects are still common at recommended doses in frail, elderly nursing home residents. Rimantidine has similar but less frequent side effects. Dosage reductions also are suggested for some groups (see Table 1).Zanamivir is administered locally as an inhaled powder and has little systemic absorption. Its side effect profile was similar to placebo. Both caution and the ready availability of a fast-acting bronchodilator are advised in persons with asthma or other chronic lung disease, however, because of the possibility of inducing bronchospasm. Oseltamivir, which is administered orally, was associated with significantly more nausea and vomiting than placebo, but these symptoms were rarely severe enough to cause discontinuation of therapy. Rimantidine or amantadine prophylaxis should be considered in several situations: (1)Prophylaxis is recommended as an adjunct to be given concurrently with vaccination when vaccine is given after influ-

21y

Same as amantidine, but less frequent 100 mg twice daily < age 65 100 or 200 mg daily age 65 + Lower dose for elderly nursing home residents, severe liver disease and creatinine clearance
21 y

Anxiety, poor concentration, confusion, seizures

100 mg twice daily < age 65 5100 mg daily age 65 + Consult package insert for creatinine clearance 550 mL/min

Possible bronchospasm in those with chronic lung disease, including asthma 2 inhalations (each 5 mg) twice daily, 12 h apart

212 y

214 y*

75 mg twice daily. Consider dosage reduction with creatinine clearance <30 mL/min.

Nausea, vomiting

218 y

Influenza A and B Oral (capsule)

Influenza A and B Oral inhalation

Influenza A Oral (tablet, syrup)

Influenza A Oral (tablet, capsule, SyrUP) rl y

‘Many experts believe it is appropriate for treatment of children >1 year.

Dose in adults

Ages for which treatment is approved Ages for which prophylaxis is approved Major adverse effect

Viruses inhibited Route of administration

Oseltamivir

Rimantadine

Zanamivir

Amantadine

Table 1. COMPARISON OF ANTIVIRAL AGENTS FOR INFLUENZA

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enza is already in the community. In this situation, prophylaxis is continued for 2 weeks, until the development of vaccine-associated immunity. (2) Prophylaxis is recommended for unvaccinated household members and other caregivers who have close contact with high-risk persons in the home. (3) Prophylaxis is recommended for high-risk persons for whom influenza vaccine is contraindicated. (4)Prophylaxis should be considered as supplemental protection for immunodeficient persons, including those with advanced HIV infection, who have poor antibody responses to vaccination. (5) Prophylaxis has been useful in controlling outbreaks of influenza among high-risk institutionalized persons. Once an outbreak is recognized in this setting, prophylaxis should be considered for all high-risk patients, regardless of previous influenza vaccine, and for all unvaccinated staff who care for high-risk persons. Prophylaxis generally is continued through the peak of the epidemic for those in the community and until the end of the outbreak in institutional settings. *

PREGNANT WOMEN AND INFLUENZA VACCINE

Routine influenza immunization of pregnant women is a controversial and emotionally charged issue. Recent guidelines by the ACIP urge physicians to consider influenza immunization for otherwise healthy pregnant women. Yet influenza vaccine remains a category C drug, and package inserts from certain manufacturers raise concern about the routine use of the vaccine during pregnancy. In weighing the benefits and risks of any vaccine during pregnancy, the CDC and the American College of Obstetricians and Gynecologists (ACOG) favor vaccination under certain conditions. These include situations where (1)the risk for disease exposure is high; (2) infection poses a special risk to the mother or fetus; and (3) the vaccine is unlikely to cause harm. Because influenza affects 10% of adults and up to 30% of children annually, avoiding influenza exposure during pregnancy is impractical, if not possible. Therefore, quantifying the risks of both influenza illness and influenza vaccine to both the pregnant women and her fetus is key to making an informed decision regarding immunization. Historically, pregnancy has been recognized as a risk factor for increased mortality from influenza. In the influenza pandemic of 1918, pregnant women hospitalized with influenza pneumonia had overall mortality rates as high as 51%, with the highest mortality rates in the late stages of pregnancy.34,79 Similarly, 50% of women of childbearing age who died from influenza during the 1957 pandemic in selected United States cities were pregnant, and 10% of all influenza deaths 30, 46 Most of the during that season occurred among pregnant women.27* deaths occurred during the second half of pregnancy. Since 1957, influenza-associated excess mortality among pregnant women has not been quantified, although there are case reports of women in the second and

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third trimester and early puerperium with serious illness and death following influenza infection.5,43, 49, 67,71 Two large retrospective cohort studies addressed the occurrence of excess morbidity among pregnant women during more recent influenza seasons. Mullooly et aP5examined outpatient visits for acute respiratory illness (AM) among pregnant and nonpregnant members of a large prepaid practice in Oregon. They calculated the difference in AM visits during periods with moderate to high influenza activity during the years 1975,1976,1978,and 1979 to a corresponding period in 1977 when there was low influenza activity. Pregnant and nonpregnant women had 23.7 and 10.2 A N visits per 1000 women, respectively, attributable to epidemic influenza annually. Hospitalizations and deaths were too infrequent to study. A more recent study examined serious morbidity attributable to influenza among women age 15 to 44 years enrolled in the Tennessee Medicaid program between 1974 and 1993.59Nonpregnant women and women in the early postpartum period had similar rates of acute cardiopulmonary hospitalizations while influenza virus was circulating. The risk of such hospitalizations was higher in pregnant women and increased with stage of pregnhcy, however. Women in the second and third trimester of pregnancy, with no other identified medical risk factors, experienced one and two excess acute cardiopulmonaryhospitalizations per 1000 women, respectively, in an average influenza season, a rate comparable to that seen in other high-risk groups for whom vaccine is recommended. There were no deaths from acute cardiopulmonary causes during influenza season among pregnant women in this study. An assessment of the impact of influenza in pregnancy would be incomplete without consideration of the effect of influenza on the fetus. In the pandemics of 1918 and 1957, 50% of women with influenzaassociated pneumonia experienced interruption of their pregnan~y.2~~ 30, 79 Case reports since then describe stillbirths or neonatal deaths associated with maternal influenza. Influenza virus has been isolated from the placenta or fetal tissues in two of these ~ases.3~’82 Further studies are needed that quantify the effects of maternal influenza on subsequent fetal outcome. The physiologic changes of pregnancy support the concern for increased risk of serious disease with any respiratory illness. Parturient women have less pulmonary reserve; baseline oxygen consumption increases by 15% to 25% while the functional residual capacity of the lung decreases. Cardiac output increases by 1.5 liters per minute after the first 10 weeks of pregnancy, with increased maternal heart rate and stroke volume.bs,71 Similarly, adverse fetal outcome from maternal influenza is biologically plausible. Studies confirm that the fetus tolerates maternal pneumonia or high fever poorly, and pneumonia during pregnancy increases the chances of preterm labor in otherwise uncomplicated pregnanciesF8 Available data indicate that pregnant women in their second or third trimester have no major reactions to influenza vaccine, and that

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they achieve antibody levels comparable to those of age-matched control^?^, 74 Few data are available that address the effect of influenza, or the effect of influenza vaccine, on fetal ~utcomes.'~ Animal reproductive studies with influenza vaccine have not been conducted, hence the FDA category C rating. Because all available influenza vaccine in the United States contains a mercury-based preservative, thimerosal, one recent concern relates to a potential harmful effect of thimerosal on the developing fetus, or the cumulative effect in vaccines given to children younger than 6 months. In a joint statement, the American Academy of Pediatrics and the US Public Health Service provide reassurance that there is a substantial safety margin incorporated into all the acceptable mercury exposure limits." Furthermore, mercury deposited intramuscularly should be less bioavailable to a developing fetus than an oral or intravenous exposure. Any theoretical risk could be eliminated with the use of thimerosal-free influenza vaccine, currently available in Europe. Overall, the current data identify pregnant women as a high-risk group for influenza and support the recommendation for routine immunization. Some experts prefer to administer influenza vaccination during the second trimester to,avoid a coincidental association of vaccine with spontaneous abortion, which is common in the first trimester, and because exposures to vaccines traditionally have been avoided during the first trime~ter.~

YOUNG CHILDREN AS A HIGH-RISK G R O U P Influenza is a common disease of childhood; during epidemics, the attack rates can exceed 40% in preschool children and 30% in school-age children. The disease can be severe in healthy children younger than 3 years of age, leading to hospitalizations for lower respiratory tract disease, nonspecific febrile illness, or central nervous system complications, including encephalitis and febrile seiz~res.4~,81 Young children had high mortality rates during the influenza pandemics of the past century, and a 20-year hospital-based study identified influenza as the causative agent in 10% to 36% of children younger than 6 years of age who were hospitalized for lower respiratory tract illness during influenza season.4I Indeed, during influenza epidemics in Houston from 1978 through 1981, the high hospitalization rates among children younger than 5 years were second only to rates among persons 65 years and 01der.l~ Despite the recognized complications of influenza infection in young children, measuring the pediatric disease burden of interpandemic influenza on a population level has been difficult. Respiratory syncytial virus (RSV) is recognized as the most frequent cause of lower respiratory tract disease that leads to hospitalization in infants and young children, and RSV often circulates concurrently with influenza virus. Mullooly et a1 attempted to overcome the potential confounding influence of RSV by comparing the rates of pediatric hospitalization for influenza-related conditions in two influenza A epidemic years to rates

in a nonepidemic year. The excess rates of hospitalization of healthy children during the two influenza seasons were approximately 10 per 10,000 children younger than 4 years, and 2 per 10,000 children 5 to 14 years.% Two recent population-based studies of healthy children examined young children by smaller age groups, and both controlled for the effect of RSV. The first study involved healthy children enrolled in the Tennessee Medicaid program over a 19-year period. The average annual rate of hospitalization for cardiopulmonary conditions attributable to influenza was estimated by calculating the excess hospitalization when influenza virus was circulating compared to other winter months. There were 77, 19, 9, and 4 influenza-associated hospitalizations per 10,000 children younger than 1 year, 1 to less than 3 years, 3 to less than 5 years, and 5 to less than 15 years, res~ectively.5~ The second study involved children with a different socioeconomic background enrolled in one of two West Coast health maintenance organizations over 5 years.36Similarly, these authors found that when hospitalization rates during periods of influenza virus were compared to baseline winter rates, healthy children younger than 2 years had excess hospitalizations for acute respiratory disease from 17 to 22 per 10,000. Currently, influenza vascine is recommended for children older than 6 months of age with high-risk medical conditions, but is not recommended routinely for otherwise healthy children. Nevertheless, the excess rates of hospitalization in children younger than 2 years in these recent studies were similar to rates in adults for whom influenza virus vaccine is recommended routinely. Cumulatively, the consistency of these findings across multiple influenza seasons and among children from varying populations argues for designating children younger than age 2 as a high-risk group for influenza. Recognizing that young children are at high risk for influenzarelated complications should engender discussion about routine influenza immunization. Unfortunately, there currently is no available licensed vaccine for children at highest risk those in the first 6 months of life during influenza season. Until better vaccines are available, the emphasis should be preventing exposure of young infants to influenza virus. To that end, influenza vaccine is recommended for those who live or work with persons at high risk for serious influenza-associated morbidity. These recommendations should include family members and other caretakers of infants and young children. Further research is needed to determine whether broadening the coverage of influenza virus vaccine to include pregnant women will provide protection to the newborn through the transfer of maternal antibody. For children age 6 to 24 months, the decision regarding universal immunization will rest on feasibility and economics.48The current influenza vaccine must be given annually, and young children require two doses of the inactivated vaccine the first year they are vaccinated for optimal immunogenicity. Furthermore, up to 16 immunizations currently are recommended before the age of 2 years. The practical issue of adding

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two injections that can be given only a narrow time frame to the already crowded immunization schedule will be challenging. In summary, current data support the designation of children younger than 2 years as a high-risk group for influenza. At the very least, their parents, older siblings, and other close contacts should be encouraged to receive annual influenza vaccine. Furthermore, the parents of children age 6 months to 2 years should be informed that their children are at risk for serious complications of influenza, and allowed to make individual informed decisions regarding influenza immunization for their children. REDUCING VIRUS TRANSMISSION THROUGH IMMUNIZATION The major goal of the influenza vaccine policy in the United States is to protect individuals from complications of influenza. Because many of the highest risk individdals are at the end of the transmission chain, immunization of these groups cannot be expected to alter the course of an epidemic. An alternative strategy for preventing influenza-related morbidity and mortality is to direct vaccination toward members of the community, predominantly healthy children and adults, who are integral to the dissemination of the virus. Inactivated viral vaccines can decrease transmission by limiting viral shedding among infected individuals and reducing the number of individuals in a population susceptible to infection. In adults challenged with wild-type virus 1 to 2 months after vaccination, those who had received inactivated vaccine shed significantly less virus than those who had received placebo.72Live-attenuated viral vaccines appear to be even more effective than inactivated vaccines in restricting replication of influenza virus in children and adults.13,38 Children play an important role in the spread of influenza, with school-aged children being the main introducers of influenza into households. Children more frequently acquire and shed influenza than do adults, as demonstrated by a 3-year community-based study of the occurrence of influenza. The arrival of influenza in a community is associated with both school absenteeism and an influx of children with febrile respiratory illness into health care facilities. During both pandemic and interpandemic periods, school-age children have the highest attack rates for influenza, reaching 50% to 60% in some studies.21 One mathematical model predicted that immunizing 50% or 90% of schoolchildren in a community will result in attack rates that are 50% to 70% and 16% to 33% of baseline, respecti~ely.~~ A clinical study performed during the fall and winter of 1968-1969 tested this hypothesis. Nearly 86% of all schoolchildren in Tecumseh, Michigan, received inactivated influenza vaccine directed against the Hong Kong influenza variant. Mean rates of respiratory illness in Tecumseh were compared to rates in Adrian, Michigan, a demographically similar community in

which schoolchildren were not targeted for vaccination. Overall, rates of illness were three times lower in Tecumseh as compared to Adrian. The protection from illness was not limited to school-aged children, as every age group experienced a lower rate of illness, suggesting that immunizing schoolchildren led to decreased transmission of influenza v i r ~ s . 5 ~ There is additional evidence that widespread use of influenza vaccine can produce a ”herd immunity” that limits the spread of viruses during influenza epidemics. Annual immunization of servicemen with influenza virus vaccine has reduced substantially or eliminated influenza from military establishments when epidemics continued among civilians.5I In studies of American and Japanese servicemen, vaccination of troops in barracks reduced the occurrence of influenza in the unvaccinated men living in the same quarters. Among civilian populations, the spread of influenza was affected by a mass immunization campaign in 1969 that reached only 29 of 40 communities in the Northern Territory of Australia before the onset of the influenza Among 29 communities that participated in the immunization campaign, influenza illness occurred in only 4 communities, with attack rates of 5% to 28% (mean, 15%).By comparison, influenza occurred in 17 of 20 communities in which residents were not immunized; the attack rates in those communities varied from 6% to 100% (mean, 65%). Although not randomized, all communities studied had similar social and demographic characteristics. Vaccination of health care workers is advocated to prevent transmission of influenza virus to patients. Two randomized trials studied the effect of influenza vaccination of health care workers on the mortality of elderly people in long-term care facilities. In the first study, 60% of health care workers received influenza vaccine in the targeted facilitiesa These targeted facilities had significantly lower total patient mortality and influenzalike illness among residents as compared to control facilities. Similarly, in the second study, 51% of health care workers received vaccine in targeted facilities, compared to only 5% in control facilities? The crude patient mortality was 13.6%in facilities with higher immunization rates compared with 22.4% in control facilities. Although these two studies lend support to the hypothesis that immunization of nursing home staff decreased both transmission of influenza and related mortality, methodologic problems render the evidence weak. In both studies, there were substantial differences in baseline characteristics of the two populations that could account for the findings. Furthermore, in the first study, the unit of randomization was the long-term care facility, so that the appropriate analysis (by facility) could not be done because of the limited sample size (four facilities). In the second study, there was no decrease in nonfatal influenzalike infections in homes with the high staff immunization rates, bringing into question a causal relationship between immunization and lower overall mortality. Thus, although the results are intriguing, further study is needed to determine whether immunization of health care workers can reduce influenza virus transmission, and

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what proportion of health care workers must be immunized to achieve this goal. INVESTIGATIONAL LIVE-ATTENUATED INTRANASAL VACCINES

Although decreasing the morbidity associated with influenza infection through vaccination is a laudable goal, it is a challenging one. The influenza virus is capable of antigenic change, requiring that the influenza strains to be included in the vaccine must be selected on a yearly basis, and must be chosen sufficiently early in the year to allow adequate production of the new vaccine by early fall. Clinical trials have demonstrated that the effectiveness of the vaccine is enhanced when the vaccine strain and the circulating strain match. Because it is generally accepted that the immunogenicity provided by any given vaccine lasts no longer than 1 year, individuals must receive the new vaccine annually; young children receiving influenza vaccine for the first time require two doses for adequate immun~genicity.'~ The proportion of the population that receives vaccine varies considerably. Although vaccination rates among adults over age 65 years in this country now approach 70%, among younger high-risk patient's and health care workers, vaccination rates are a dismal 30% to 40%. The rate of delivery of influenza vaccine to high-risk children represents the lowest compliance rate of any recommended vaccine in pediatric^.^^ The intranasally administered, cold-adapted, live-attenuated vaccines have two theoretical advantages that can help to overcome the limitations of our current method of influenza control. Substantial research efforts over many years have been directed at developing an influenza vaccine that could be applied directly to the respiratory mucosa, thereby more closely resembling natural infection. The live-attenuated, cold-adapted influenza vaccine replicates in the cooler tissues of the upper airway and does not produce a systemic infection. In addition, the vaccine induces a mucosal IgA immune response and systemic humoral and cellular immune responses that lead to enhanced protection against influenza strains that have undergone antigenic drift or shift. Furthermore, it is anticipated that the ease of intranasal administration will enhance the acceptability of annual influenza immunization. In a recent study of children age 15 to 71 months, intranasal vaccine was 93% effective in preventing culture-confirmed influenza. The vaccinated children had significantly fewer febrile episodes, including 30% fewer episodes of febrile otitis media? This study was continued for a second year, during which there was circulation of a variant influenza strain. Despite the poor match between the vaccine and circulating viruses, the efficacy of the intranasal vaccine remained high, at 87%.The protection afforded by the live-attenuated vaccine against the variant 73 influenza strain matched the protection conferred by natural infe~tion.~, Similarly, in a study of healthy adults younger than 65 years, Nichol

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et a1 showed that intranasally administered live-attenuated vaccine significantly reduced the numbers of severe febrile illnesses and febrile upper respiratory tract illnesses, and that recipients of these vaccines missed fewer days of work and had fewer health care provider visits than placebo recipients.61Similar to the pediatric experience, the protection of adults occurred despite significant antigenic drift of the circulating virus from the vaccine virus. These results suggest that the liveattenuated influenza vaccine elicits an immune response that is broadly cross-reactive against antigenically variant viruses. These studies did not directly compare the live virus vaccine to the standard inactivated preparation. A 5-year study comparing the trivalent inactivated vaccine with an earlier, bivalent live-attenuated vaccine showed they had approximately equivalent effectiveness.zzTrials are ongoing to determine if administration of both vaccines to patients can confer protection that is superior to either vaccine alone. Some theoretical concerns about the live vaccines include possible genetic instability, enhanced replication of attenuated virus if inadvertently given to immunosuppressed patients, and the concern for bacterial superinfection if replicatiOn of the attenuated virus disrupts the nasal m ~ c o s a Live-attenuated, .~~ cold-adapted vaccines, however, generally have been well-tolerated by immunocompetent children and adults? 61 and a recent study demonstrated that the live-attenuated influenza virus vaccine was well tolerated by human immunodeficiency virus (HN)infected Prolonged shedding of the vaccine was not observed and increases in HIV viral load were not detected. PERSONS WITH HIV The incidence of cardiopulmonary complications following influenza infection is known to be increased in older persons, and those with certain medical conditions. Although persons infected with HIV might be expected to have more severe illness due to influenza virus infection than HIV-negative persons, the course of influenza in HIV-infected populations has not been well delineated. Several case reports and a small case series suggest that influenza A can cause prolonged illness with occasional severe complications in HIV-infected individuals.25,66, 69, T / Whether HIV-infected persons are more or less susceptible to influenza infection has been debated, but is not re~olved.'~, l6 A retrospective cohort study of young and middle-aged women enrolled in Tennessee's Medicaid program found that women with HIV infection had a risk of influenza-attributable hospitalizations at least as high as women with other high-risk medical conditions. In this population, there were estimated to be 33 (95% CI 7 to 59) excess hospitalizations attributable to influenza yearly for every 1000 HIV-infected This estimate was based on relatively small numbers of HIV-infected women and merits confirmation in a more typical HN-infected population. The paucity of reports of influenza morbidity in HIV-infected indi-

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viduals is the result of multiple factors. Influenza infections in HIVinfected individuals can be of limited occurrence or severity; they can occur coincident with infections with other pathogens that dominate the clinical picture; or they can predispose to secondary bacterial or opportunistic infection. Given the marked immune defects associated with acquired immunodeficiency syndrome and the frequency and severity of other viral infections in these patients, one would expect influenza to be an important pathogen in this population. HIV-infected persons receiving antiretroviral therapy represent an enlarging population with an increasing life expectancy toward whom preventive measures should be directed. Historically, excess mortality has been the hallmark of epidemic influenza. Such epidemics generally have shown an increased case fatality rate at the extremes of age, with the exception of the 1918 pandemic, in which a high case fatality rate was seen in young adults. After decades of decline, pneumonia and influenza mortality rates again have increased in the 25- to 44-year age group, presumably a consequence of HIV infection. These pneumonia and influenza deaths among young adults occur seasonally'as do such deaths in other age g r o ~ p s It . ~is possible that these seasonal peaks correlated with influenza epidemics. Although the contribution of influenza to HIV-related mortality has not been determined, it is intriguing to consider that influenza infections can affect the incidence and severity of severe bacterial or opportunistic pneumonias in these patients. Influenza infection is known to predispose to many secondary complications, including bacterial pneumonia, exacerbation of chronic pulmonary diseases, and congestive heart failure, in other high-risk populations.6° Physicians hesitate to give inactivated vaccines to HIV-infected patients because of concerns that resultant antigenic stimulation can increase viral load in these individuals. In addition, persons with marked immune deficits have suboptimal antibody responses. Although early studies suggested transient increases in viral load after influenza 83 other prospective studies of influenza immunization irnmunizati~n,~~, have not demonstrated adverse effects on HIV viral load or disease progression.28,29, 33 Most of these studies were conducted before the introduction of highly active antiretroviral therapy; however, a few investigations involving patients treated with potent antivirals have appeared.31,70 In general, their results confirm that influenza vaccination can increase HIV viral load briefly, especially among patients who had a response to antiretroviral therapy with less than 400 RNA copies/mL before vaccination. Direct comparisons with the effect of natural influenza on viral load are not available. The serologic response of HIV-infected individuals to several vaccines, including inactivated influenza vaccine, can be lower than the 52 Antibody responses in response in uninfected, age-matched HIV-infected individuals are inversely related to CD4 counts, however, and patients with less advanced disease can mount better antibody responses than untreated HIV-infected patients.28, 35, 44 In a recent ran337

domized, double-blind, placebo-controlled trial of predominantly young men with HIV infection, those who received influenza vaccine had modest serologic responses. Nevertheless, the vaccine was highly effective, with 10 of 47 placebo recipients and none of the 55 vaccine recipients having symptomatic laboratory-confirmed influenza A?6 Information is limited regarding influenza illness and vaccine efficacy among persons infected with HIV, but recent evidence suggests that the benefits of vaccination outweigh the risks. HIV-infected individuals can suffer serious consequences of influenza infection, whereas the vaccine is unlikely to cause harm. References 1. National Center for Health Statistics. Current estimates from the National Health Interview Survey, 1994. Vital and health statistics. Series 10, No. 193. Washington, DC: Government Printing Office, 1995. (DHHS publication no. [PHS] 961521). 2. Barker WH, Mullooly JP: Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol 112798-811,1980 3. Belshe RB, Gruber WC, Mendelman PM, et al: Efficacy of vaccination with live attenuated, cold-adapted, trivaent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr 136168-175,2000 4. Belshe RB, Mendelman PM, Treanor JJ, et a l The efficacy of live attenuated, coldadapted, trivalent, intranasal influenzavirus vaccine in children [see comments]. N Engl J Med 338:1405-1412,1998 5. Bisno AL, Griffin JP, Van Epps KA, et al: Pneumonia and Hong Kong influenza: A prospective study of the 1968-1969 epidemic. Am J Med Sci 261:251-265, 1971 6. Carman WF, Elder AG, Wallace LA, et al: Effects of influenza vaccination of healthcare workers on mortality of elderly people in long-term care: a randomised controlled trial. Lancet 355:93-97, 2000 7. Centers for Disease Control Increase in pneumonia mortality among young adults and the HIV epidemic-New York City, United States. MMWR Morb Mortal Wkly Rep 37593-596,1988 8. Centers for Disease Control Influenza and pneumococcal vaccination levels among adults aged >65 years-United States, 1997. MMWR Morb Mortal Wkly Rep 47(38):797-802, 1998 9. Centers for Disease Control: Prevention and control of influenza. MMWR Morb Mortal Wkly Rep 48:l-28, 1999 10. Centers for Disease Control and Prevention: Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 49 (RP-3):l-38,2000 11. Centers for Disease Control: Recommendations regarding the use of vaccines that contain thimerosal as a preservative. h4MWR Morb Mortal Wkly Rep 48:996998,1999 12. Chadwick EG, Chang G, Decker MD, et al: Serologic response to standard inactivated influenza vaccine in human immunodeficiency virus-infected children. Pediatr Infect Dis J 13:206-211, 1994 13. Clements ML, Betts RF, liemey EL, et a l Resistance of adults to challenge with influenza A wild-type virus after receiving live or inactivated virus vaccine. J Clin Microbiol 23:73-76, 1986 14. Cohen JP, Macauley C: Susceptibility to influenza A in HIV-positive patients. JAMA 261:245, 1989 15. Committee on Infectious Diseases, American Academy of Pediatrics: 1997 Red Book Report of the Committee on Infectious Diseases, ed 24. Elk Grove Village, IL, American Academy of Pediatrics, 1997 16. Couch RB: Editorial response: Influenza, influenza virus vaccine, and human immunodeficiency virus infection. Crit Infect Dis 28:548-551,1999

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Address reprint requests to William Schaffner, MD Chairman, Department of Preventive Medicine A-1124 Medical Center North Vanderbilt University School of Medicine Nashville, Tennessee 37232-2637 e-maik [email protected]