Vaccinating Schoolchildren: Next Step Forward in the Battle Against Influenza?

Transcription

1 October 2009 Vaccinating Schoolchildren: Next Step Forward in the Battle Against Influenza? CME Course Director and Moderator Stephen I. Pelton, MD Professor of Pediatrics Boston University School of Medicine Chief, Division of Pediatric Infectious Diseases Boston Medical Center Boston, MA Faculty Terho J. Heikkinen, MD, PhD Assistant Professor of Pediatrics University of Turku Consultant in Pediatrics Turku University Hospital Turku, Finland Robert B. Belshe, MD Dianna and J Joseph Adorjan Endowed Professor of Infectious Diseases and Immunology Saint Louis University School of Medicine Edward Doisy Research Center St Louis, MO Prof. Asher Barzilai, MD, EMBA Head, Pediatric Infectious Disease Unit Head, Laboratory Wing The Edmond and Lily Safra Children s Hospital Sheba Medical Center Tel Hashomer, Israel CME Activity Release Date: October 2009 Expiration Date: October 31, 2010 Sponsored by Boston University School of Medicine Supported by an educational grant from MedImmune Produced by

2 Vaccinating Schoolchildren: Next Step Forward in the Battle Against Influenza? This monograph is based on a live symposium held in Brussels, Belgium, in June NEEDS ASSESSMENT Each year, influenza epidemics cause 3 to 5 million cases of severe illness and between 250,000 and 500,000 deaths worldwide. 1 While the very youngest and very oldest individuals are the most vulnerable to influenza and its potentially life-threatening complications, the highest attack rates occur among school-aged children and adolescents, who then serve as key vectors of disease transmission to other populations. 2 Overall annual attack rates of influenza within the pediatric population (vaccinated and unvaccinated) range from 10% to 40% in the United States and from 20% to 30% worldwide. 1-3 Healthy schoolchildren, along with healthy adults in the workforce, not only have the highest attack rates for influenza but also are the spreaders in the community and the introducers into the household. 4 Young children between the ages of 2 and 5 years are also recognized as a key source of influenza transmission. 5 Vaccination is the most effective way to prevent influenza-related morbidity and mortality. 6 Two types of influenza vaccine are available: live, attenuated vaccine, administered via intranasal spray, and trivalent inactivated vaccine, administered via intramuscular injection. Despite strong recommendations from national and international authorities for annual immunization of persons considered at increased risk for influenza and its complications, vaccination rates in many countries have not increased significantly over the past decade. 4 At the same time, the identified target groups for vaccination have increased significantly, most notably among the pediatric population. A growing body of research and clinical experience indicates that vaccinating children and adolescents of school age has a protective effect, within that age-group itself and throughout the population at large, and thus may be a more effective strategy than the traditional approach of vaccinating selected groups at high risk for influenza and its complications. 1. World Health Organization (WHO). Influenza. Fact Sheet No Available at: Accessed August 5, American Academy of Pediatrics Committee on Infectious Diseases. Prevention of influenza: Recommendations for influenza immunization of children, Pediatrics. 2008;121:e1016- e WHO Position paper. Influenza vaccines. Weekly Epidemiological Record. 2005; No. 33, August 19, Available at: Accessed August 5, Glezen WP. Universal influenza immunization and live attenuated influenza vaccination of children. Pediatr Infect Dis J. 2008;27(10 suppl):s104-s Brownstein JS, Kleinman KP, Mandl KD. Identifying pediatric age groups for influenza vaccination using a real-time regional surveillance system. Am J Epidemiol. 2005;162: Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recomm Rep. 2008;57(RR-7):1-60. LEARNING OBJECTIVES After taking part in this educational activity, participants should be able to: Describe the worldwide morbidity and mortality associated with influenza, identifying groups with highest attack rates and groups with highest incidence of complications, hospitalization, and death Summarize recent changes in official recommendations for annual influenza immunization of children and adolescents Evaluate and critique the rationale for universal pediatric immunization against influenza, including scientific findings on the herd immunity effect of immunizing the pediatric population against influenza Compare safety and efficacy data for the live, attenuated influenza vaccine (LAIV) and the trivalent inactivated influenza vaccine (TIV) in the pediatric population Provide appropriate responses to typical myths and misunderstandings about influenza and influenza vaccination Implement effective strategies for improving influenza immunization rates in the pediatric population, both in office- and clinic-based practice and in broader-based, population-wide immunization efforts TARGET AUDIENCE Pediatricians, primary care physicians, and other clinicians involved in the prevention, diagnosis, and treatment of pediatric influenza. ACCREDITATION STATEMENT Boston University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Boston University School of Medicine designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. To participate in this activity at no charge, please read the monograph and take the test. Fill in the answer sheet and submit it to BUSM CME before October 31, CME credit will be awarded if a score of 70% or better is achieved. Submit the answer sheet form via mail or fax to: Boston University School of Medicine, Continuing Medical Education, E.ESPIDHAY09, 72 East Concord Street, A305, Boston, MA 02118, Fax Your certificate will be mailed to you in 4-6 weeks. Or participate online to receive your certificate instantly, at: Enter E.ESPIDHAY09 in the Test Code Search field. If you submit your test online or by fax, please do not mail the original. For questions please contact BUSM CME at Estimated time to complete this activity is 1.0 hour. Program Code: E.ESPIDHAY09 Release Date: October 2009 Expiration Date: October 31, 2010 CME BETA TESTER/REVIEWER Rosemary Moleski, MD Pediatric Infectious Disease Fellow Boston Medical Center DISCLOSURE POLICY Boston University School of Medicine asks all individuals involved in the development and presentation of continuing medical education (CME) activities to disclose all relationships with commercial interests. This information is disclosed to CME activity participants. Boston University School of Medicine has procedures to resolve any apparent conflicts of interest. In addition, faculty members are asked to disclose when any unapproved use of pharmaceuticals and/or devices is being discussed. Stephen I. Pelton, MD, has been a consultant for sanofi-aventis and a member of the speakers bureaus for sanofi-aventis and MedImmune. Terho J. Heikkinen, MD, PhD, has been a consultant for MedImmune, Novartis, and GlaxoSmithKline. Robert B. Belshe, MD, has been a consultant for MedImmune and Novartis, and a member of the speakers bureaus for MedImmune and GlaxoSmithKline. Asher Barzilai, MD, EMBA, has nothing to disclose. Rosemary Moleski, MD, Boston University School of Medicine, has nothing to disclose. Lara Zisblatt, Boston University School of Medicine, has nothing to disclose. Lynne Callea, Haymarket Medical Education, has nothing to disclose. Marilyn Stearns, MD, Haymarket Medical Education, has nothing to disclose. DISCLOSURE OF OFF-LABEL USE Unlabeled/investigational uses of commercial products are discussed in this monograph. DISCLAIMER THESE MATERIALS AND ALL OTHER MATERIALS PROVIDED IN CONJUNCTION WITH CONTINUING MEDICAL EDUCATION ACTIVITIES ARE INTENDED SOLELY FOR PURPOSES OF SUPPLEMENTING CONTINUING MEDICAL EDUCATION PROGRAMS FOR QUALIFIED HEALTH- CARE PROFESSIONALS. ANYONE USING THE MATERIALS ASSUMES FULL RESPONSIBILITY AND ALL RISK FOR THEIR APPROPRIATE USE. TRUSTEES OF BOSTON UNIVERSITY MAKES NO WARRANTIES OR REPRESENTATIONS WHATSOEVER REGARDING THE ACCURACY, COMPLETENESS, CURRENTNESS, NONINFRINGEMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OF THE MATERIALS. IN NO EVENT WILL TRUSTEES OF BOSTON UNIVERSITY BE LIABLE TO ANYONE FOR ANY DECISION MADE OR ACTION TAKEN IN RELIANCE ON THE MATERIALS. IN NO EVENT SHOULD THE INFORMATION IN THE MATERIALS BE USED AS A SUBSTITUTE FOR PROFESSIONAL CARE. Cover image: Getty Images Haymarket Medical Education 25 Philips Parkway, Suite 105 Montvale, NJ mycme.com 2 October 2009

3 Vaccinating Schoolchildren: Next Step Forward in the Battle Against Influenza? Introduction Targeting schoolchildren for universal vaccination can help to control transmission of influenza virus and reduce influenzarelated morbidity and mortality for persons of all ages. 1 Influenza virus infection continues to be an important cause of morbidity and mortality throughout the world. 2 In the United States, 10 to 60 million cases of symptomatic influenza occur each year, leading to an annual average of 25 million outpatient visits, 200,000 hospitalizations, and 36,000 deaths. 1 Influenza causes a substantial burden of illness on children and their families. 3 Attack rates are consistently highest in children during annual influenza epidemics. 3 Influenza-related morbidity and hospitalization rates are greatest in the youngest children, and illness in the pediatric population results in substantial loss of productivity among their caregivers. 2,3 Children also are responsible for most influenza virus transmission throughout the community. 1 School-aged children play a particularly important role, beginning with child-to-child transmission at school, then dissemination of the virus to susceptible household contacts, to regular contacts in the local environment, and ultimately to the community at large. 1 There are three types of human influenza viruses: influenza A, influenza B, and influenza C. The two major types causing human disease are influenza A and influenza B. Influenza A includes the subtypes H1N1 and H3N2, which infect humans. Influenza A and influenza B are found together in most seasonal outbreaks. Both types are subject to antigenic drift changes in the antigenic profile due to point mutations that occur during viral replication. Influenza B is a more stable virus and generally causes local outbreaks of illness. Diagnosis of influenza is moderately reliable during a seasonal epidemic but more difficult without a prevalence of disease. 1 Laboratory culture and polymerase chain reaction tests are used to confirm the diagnosis, and in the outpatient setting, rapid point-of-care diagnostic tests are reasonably reliable. Administration of an influenza antiviral agent as chemoprophylaxis or early treatment is effective for reducing viral titers and limiting both the severity and the duration of influenza-like illness. Annual vaccination against influenza is the most effective method of reducing the impact of influenza virus infection and its complications. 1,4 The vaccine is a trivalent compound, containing the three strains of viruses commonly found in the United States: influenza A/H1N1, influenza A/H3N2, and influenza B. 1 Two types of vaccine an inactivated vaccine and a live-attenuated vaccine are approved for use in children. 4 Despite evidence from population-based studies of the burden of influenza illness in children, influenza vaccines are administered to healthy children only infrequently, reflecting the misperception that influenza is a benign disease in children. 5 References 1. Belshe RB. An introduction to influenza: lessons from the past in epidemiology, prevention, and treatment. Manag Care. 2008;17(10 suppl 10): Zangwill KM, Belshe RB. Safety and efficacy of trivalent inactivated influenza vaccine in young children: a summary for the new era of routine vaccination. Pediatr Infect Dis J. 2004;23: Heikkinen T, Silvennoinen H, Peltola V, et al. Burden of influenza in children in the community. J Infect Dis. 2004;190: Fiore AE, Shay DK, Broder K, et al. Centers for Disease Control and Prevention. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recomm Rep. 2009;58(RR-8): Neuzil KM, Mellen BG, Wright PF, Mitchel EF, Griffin MR. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med. 2000;342: October

4 Vaccinating Schoolchildren: Next Step Forward in the Battle Against Influenza? Influenza in Children: Strategies for Prevention Terho J. Heikkinen, MD, PhD Influenza virus infections cause considerable morbidity and mortality in the United States, and winter-month epidemics are associated with increased rates of hospitalization and death due to pneumonia, bacterial infection, and chronic obstructive pulmonary disease.1 While a small number of children die each year from influenza, most influenzarelated mortality occurs in the elderly population. Data for the through influenza seasons indicated that 22.1 deaths per 100,000 person-years occurred among persons age 65 and older, while the rates among children less than 1 year old and between 1 and 4 years of age were 0.3 and 0.2 per 100,000 person-years, respectively. 1 Influenza-associated Morbidity in the Pediatric Population Despite the low mortality rates associated with pediatric influenza, children may be three times more likely to become infected with an influenza virus than adults of any age group, including the elderly. 2 One study found a 17% incidence of influenza among children less than 14 years of age over two consecutive seasons; the highest incidence, up to 21%, was among children younger than 3 years old. 3 An increased risk of hospitalization for acute respiratory disorders parallels this increased incidence in the illness. 4 During influenza outbreaks from 1992 to 1997, hospitalization rates among children younger than 2 years of age and without high-risk conditions (eg, asthma, cardiovascular disease, or premature birth) were 12 times higher than those among their healthy 5- to 17-year-old counterparts (P<.001) and comparable to rates among children 5 to 17 years old with high-risk conditions. 4 Fortunately, the proportion of children in the United States who require hospitalization for influenza-related complications is low, about Figure 1. Pediatric hospitalizations, emergency departments, and outpatient visits due to laboratory-confirmed influenza during the season. 5 1 per 1000 children per year. 5 Yet that figure represents only a fraction of the burden that influenza and its treatment place on the health care system, since most children with influenza are treated as outpatients. During the influenza season, it was estimated that for every 1000 children aged 0 to 59 months with laboratory-confirmed influenza there were 95 influenza-related outpatient clinic visits and 27 Emergency Department (ED) visits but only 1.5 hospitalizations (Fig. 1). 5 Outpatient and ED visits were highest among children 6 to 23 months old (164 per 1000 children), whereas hospitalizations were highest among infants 5 months of age or younger (7.2 per 1000 children) (Fig. 1). 5 Role of Children in the Spread of Influenza Several factors contribute to children being responsible for most of the transmission of influenza virus in families and throughout the community. 6,7 For example, attack rates are highest in children, and viral shedding persists longer in children than adults, for up to 2 to 3 weeks. 6-8 In addition, viral titers in the nasopharyngeal mucosa are higher in children than in adults. 7 A study conducted during the 1976 influenza A epidemic in Houston, Texas, supports the role of children in the transmission of the virus. 8 Among more than 1800 patients, children 5 to 19 years of age accounted for 50.4% of cases in the early phase of the epidemic but only 25% to 35% in the intermediate and late phases (Fig. 2). 8 At that time, more than 30 years ago, researchers were suggesting that prophylaxis for school-aged children could be a means of controlling an influenza epidemic. 8 One of these researchers later documented the benefit of vaccination of schoolchildren by comparing mortality trends from 1949 to 1998 in Japan and the United States. 9 Over that 50-year period, excess mortality from influenza and pneumonia was nearly constant in the United States. In Japan, however, initiation of a mandatory influenza vaccination program for schoolchildren in 1962 resulted in a decrease of 50% in excess influenza-related mortality for the first 10 years and 40% from 1972 to 1987 by 10,000 to 12,000 deaths per year. When the Japanese vaccination law was relaxed in 1987 and then repealed in 1994, excess mortality due to influenza and pneumonia increased steadily to the values before Although the contribution of other factors to the decline in Japanese mortality during the years of mandatory vaccination cannot be ignored, it is equally difficult to ignore the sharp increase in excess mortality with the coincident end of mass immunization. Current National Policies for Influenza Immunization In North America, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) in the 4 October 2009

5 United States originally recommended immunization against influenza for patients at increased risk for complications, including children and adults with chronic cardiovascular or pulmonary conditions, pregnant women, residents of chronic care facilities, health care workers, household contacts, and persons aged 65 or older. 10 The possible addition of healthy infants and children to these targeted groups was first raised nearly 10 years ago following publication of several studies of pediatric morbidity related to influenza. 11 Subsequently, the ACIP first encouraged and then recommended vaccination against influenza for healthy children aged 6 to 23 months in 2002 and 2004, respectively. 10,12 The ACIP recommendation was expanded in 2006 to include children from 24 to 59 months of age and again in 2008 to include all school-aged children and adolescents aged 5 to 18 years. 13,14 Therefore, the CDC currently recommends that all infants and children from 6 months to 18 years of age be vaccinated against influenza annually. 15 The Public Health Agency of Canada has similar recommendations for high-risk individuals and, as of 2007, includes healthy children aged 6 to 23 months in its national policy for influenza vaccination. 16 In Europe, Finland is the only country to date with a national policy for immunization against influenza in children aged 6 months to 35 months of age. 17 During 2007, the first year after the policy was implemented, 43% of children in this age group received at least one dose of the influenza vaccine and approximately one third received both recommended doses. 18 Universal Recommendations for Influenza Immunization: A Feasible Goal? The feasibility of having all European countries adopt a universal immunization policy for healthy children was explored by the Summits of Independent European Vaccination Experts. 7 In their report, the Experts emphasized the high attack rates of influenza in children, the increased influenza-related morbidity among children, the burden of childhood influenza on health care systems, and the socioeconomic impact of influenza on affected children and their families as reasons Figure 2. Age distribution of patients with influenza during the influenza A epidemic in Houston in Obstacles to Universal Recommendations for Influenza Vaccination of Healthy Children Worldwide disparity in vaccine distribution and immunization recommendations Varying legislation and priorities for vaccinating healthy children among countries Underestimation of burden of influenza in children Vaccine efficacy in young children not convincingly established Differences among countries in health care related aspects (eg, reimbursements, patterns of child care) Logistical issues in administering vaccine Vaccine supply concerns Cost-effectiveness issues in different health care systems to support such a policy. They also cited increased outpatient visits for the treatment of acute otitis media, pneumonia, and sinusitis, as well as hospitalizations for more severe respiratory conditions and neurological complications. Given the total burden of influenza in children, it was the consensus of the Experts that all children aged 6 months to 3 years, with or without underlying medical conditions, should be considered a high-risk group, and annual immunization against influenza should be recommended for them. 7 However, the continent of Europe comprises 50 distinct countries, each with an independent governing body making health care decisions, and is therefore unlikely to accept a single-policy recommendation. Although most developed nations have recommendations for immunization against influenza similar to those of the United States, Canada, and Finland for elderly persons and high-risk individuals, including children, numerous obstacles stand in the way of a universal immunization policy (see Box). 7,19 There is a significant disparity in the rates of influenza vaccine distribution worldwide, from 344 doses to as little as 1 per 1000 population (2003 data). 19 Thus, immunization practice is inconsistent with existing recommendations, reducing the likelihood for inclusion of healthy children in those recommendations by many nations. In addition, many countries around the world have begun only recently to discuss expanding their target groups for influenza immunization. 7 Substantial differences also exist among nations in aspects of their health care systems such as reimbursement and patterns of child care. 7 These factors will necessitate careful evaluation of the benefits and disadvantages of new vaccination strategies. One of the most significant obstacles to universal recommendations is a failure on the part of health care professionals and the public alike to appreciate the burden of influenza in children. 7 In the United States, for example, vaccination rates are low even among children at high risk for complications, despite the very broad recommendations for pediatric October

6 Vaccinating Schoolchildren: Next Step Forward in the Battle Against Influenza? immunization. 15 Questions regarding vaccine efficacy have been raised, particularly surrounding the protective effect of a particular vaccine against circulating strains. 7 In addition, when children develop respiratory viral infections of different etiologies during the influenza season, there is a misperception that the influenza vaccine is ineffective. Logistical issues pose additional problems for universal immunization against influenza. It may be challenging to add another vaccine to the existing tight schedule of childhood immunizations. 7 The availability of seasonal influenza vaccine may not coincide with well-child visits for many infants and children and necessitate additional clinic visits. Two doses must be given for the initial vaccination, and, unlike most childhood vaccines, the influenza vaccine must be administered annually. In addition, vaccine supply may be an issue, even in vaccine-producing countries. 7 Finally, the cost-effectiveness of immunization for children over the age of 6 months has not been fully established. 20 A cost analysis of the impact of influenza vaccination in Finland used an estimated 122,000 annual cases of influenza among 750,000 children aged 6 months to 13 years. 20 In all age groups, influenza vaccination resulted in substantial savings from both a health care provider and a societal perspective. The savings in health care costs per vaccinated child were highest among children less than 5 years of age, exceeding 10 euros (about 14 USD), and total savings increased with each age group up to age 13 years, reaching about 4 million euros (about 5.6 million USD) (Fig. 3). The savings across all age groups were even higher from a societal perspective, including children 1 to 13 years of age. Conclusions Influenza is an important childhood illness, with infants and toddlers bearing the greatest burden of the disease and incurring disproportionately higher costs for outpatient visits, hospitalization, and treatment of complications. Only the United States, Canada, and Finland currently have immunization policies that recommend immunization against influenza for Savings per Vaccinated Child (euros) Savings/vaccinated child, provider perspective Total savings, provider perspective Savings/vaccinated child, societal perspective Total savings, societal perspective Age Group (years) Figure 3. Annual savings from health care provider and societal perspectives related to influenza vaccination of healthy children. 20 Reprinted from Vaccine. Copyright 2009, with permission from Elsevier Total Savings (million euros) children aged 6 months through 3 years or older, with or without medical conditions. Given the impact of influenza on children, their families, and society, it would be prudent for all countries to reconsider their current recommendations for influenza vaccination and to conduct local costeffectiveness analyses of vaccination of children to allow for variation in health care systems. Efforts should be continued and broadened to educate physicians and parents about the burden of influenza in children. References 1. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289: Monto AS, Sullivan KM. Acute respiratory illness in the community: frequency of illness and the agents involved. Epidemiol Infect. 1993;110: Heikkinen T, Silvennoinen H, Peltola V, et al. Burden of influenza in children in the community. J Infect Dis. 2004;190: Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med. 2000;342: Poehling KA, Edwards KM, Weinberg GA, et al. The underrecognized burden of influenza in young children. N Engl J Med. 2006;355: Belshe RB. An introduction to influenza: lessons from the past in epidemiology, prevention, and treatment. Manag Care. 2008;17(suppl 10): Heikkinen T, Booy R, Campins M, et al. Should healthy children be vaccinated against influenza? A consensus report of the Summits of Independent European Vaccination Experts. Eur J Pediatr. 2006;165: Glezen WP, Couch RB. Interpandemic influenza in the Houston area, N Engl J Med. 1978;298: Reichert TA, Sugaya N, Fedson DS, et al. The Japanese experience with vaccinating schoolchildren against influenza. N Engl J Med. 2001;344: Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2002;51(RR-3): McIntosh K, Lieu T. Is it time to give influenza vaccine to healthy infants? N Engl J Med. 2000;342: Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2003;53(RR-6): Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-10): Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recomm Rep. 2008;57(RR-7): Centers for Disease Control and Prevention. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recomm Rep. 2009;58(RR-8): National Advisory Committee on Immunization. Active immunizing agents: influenza vaccine, part 4. Available at: Accessed July 6, Rapola S. National immunization program in Finland. Int J Circumpolar Health. 2007;66: National Public Health Institute of Finland. [Influenssarokotukset ja rokotusohjelman uudistaminen. Influenssarokotuskattavuus 2007.] Available at ktl.fi/attachments/suomi/osastot/roko/roto/influ_kattavuus_julkinen. xsq2l.htm. Accessed July 6, The Macroepidemiology of Influenza Vaccination (MIV) Study Group. The macroepidemiology of influenza vaccination in 56 countries, Vaccine. 2005;23: Salo H, Kilpi T, Sintonen H, et al. Cost-effectiveness of influenza vaccination of healthy children. Vaccine. 2006;24: October 2009

7 Influenza Vaccination in Children: Efficacy and Effectiveness Robert B. Belshe, MD Annual vaccination is the most effective means of preventing influenza virus infection and its complications. 1 The United States currently has the most comprehensive recommendations for immunization against influenza. 1 Beginning with the influenza season, the US Centers for Disease Control and Prevention (CDC) recommended that in addition to individuals at high risk for complications of influenza, all children between the ages of 6 months and 18 years be vaccinated annually. 2 These new recommendations were developed after careful review of evidence that schoolchildren have the highest attack rates during outbreaks of influenza and account for the greatest source of transmission within the community. Adequate vaccination coverage among children has important public health implications, since it has the potential to reduce influenza rates among individuals in close contact with children as well as overall rates within communities. Influenza Vaccine Composition Influenza vaccine is recommended for any person over the age of 6 months who has no contraindications to vaccination, to reduce the possibility of developing influenza or transmitting it to others. 1 Two trivalent influenza vaccines are available in the United States: a trivalent inactivated influenza vaccine (TIV) administered by intramuscular injection and a live attenuated influenza vaccine (LAIV) administered as an intranasal spray. 1 A similar live attenuated vaccine has been used in Russia for several years. Viruses for TIV and LAIV are grown in eggs, and both vaccines contain strains of influenza viruses that are antigenically equivalent to the three strains considered most likely to circulate: influenza A/H3N2, influenza A/H1N1, and one of the two influenza B viruses. 1 Each year, one or more virus strains in the vaccine may be Figure 1. Efficacy of LAIV influenza virus vaccine for the prevention of culture-confirmed influenza in children aged 15 to 71 months. 4,5 changed based on global surveillance for influenza viruses and emergence and spread of new strains. During the preparation of TIV, the vaccine viruses are inactivated and, therefore, cannot cause influenza. LAIV contains live, attenuated viruses that replicate to a low level in the nose and have the potential to stimulate serum antibodies, secretory immunoglobulin A, and cellular immune responses that can cause mild signs or symptoms of influenza, such as runny nose, fever, or sore throat. Either TIV or LAIV can be used to vaccinate healthy nonpregnant persons between 2 and 49 years of age. TIV can be given to any healthy person 6 months of age or older, including pregnant women and individuals with high-risk conditions. 1 LAIV should not be administered to individuals with underlying chronic disease, including asthma or recurrent wheezing, or to children less than 5 years old who have recurrent wheezing. To ensure adequate response, children aged 6 months to 8 years should receive two doses of vaccine (with a 4-week or longer interval between doses), if they have not been vaccinated previously. Clinical Trials of TIV in Children Children 6 months of age or older typically are protected against specific influenza virus strains after receiving the recommended number of doses of influenza vaccine. 1 Only five clinical trials have evaluated the effectiveness of TIV in children 6 months to 9 years of age. 3 Analysis of pooled data from these trials, which comprised 1323 healthy children, found that only 38 of 787 children (4.8%) who received two doses of influenza vaccine developed influenza infection or illness, compared with 80 of 536 infants given placebo (14.9%). 3 Overall, the vaccine efficacy rate was 69%. One dose of TIV is not expected to provide protection to children less than 9 years of age who had not been previously vaccinated. Clinical Trials of LAIV in Children Several clinical trials have evaluated the safety and efficacy of LAIV in children, 4-6 including its efficacy relative to TIV. 6 In a 2-year, double-blind, placebo-controlled trial of children 15 to 71 months old in the United States, a single dose of LAIV or placebo was administered to 288 children and two doses (60 days apart) or placebo were administered to 1314 others in year 1. 4,5 The following year, 85% of the children were given a single dose of LAIV or placebo according to the original randomization. 5 All children were monitored with viral cultures for influenza during the two subsequent influenza seasons. During year 1 there was an outbreak of both influenza A/H3N2 and influenza B, and both antigens were well matched with the LAIV administered. 4 Culture-confirmed influenza infection was document- October

8 Vaccinating Schoolchildren: Next Step Forward in the Battle Against Influenza? ed for 18% of the children given placebo and for only 1% of those given two doses of LAIV, for a vaccine efficacy of 94% (Fig. 1). 4 The single-dose LAIV regimen was 89% effective, for a combined vaccine efficacy of 93% for all children treated. 4 In year 2, the circulating influenza strain, influenza A/H3N2/Sydney/5/97, was not well matched to strains in the administered LAIV. 5 Despite this major antigenic drift, only 1.6% of vaccinated children developed influenza infections compared with 14.1% of those given placebo, resulting in a vaccine efficacy of 87%. 5 LAIV was well tolerated in this study, with rhinorrhea or nasal congestion and low-grade fever as the only significant events associated with administration of the first dose of the vaccine in year 1. 4 Approximately 6.5% of children given the vaccine had a low-grade fever (mean temperature, 38.2 C [100.7 F]) that occurred only on day 2 after the first dose. 4 No significant differences in any signs or symptoms were observed between the two groups after administration of the second dose of the vaccine in year 1 or after revaccination in year 2. 4,5 Among four other trials of LAIV in children, one found an increased risk for wheezing events in children less than 3 years old. 6,7 These findings led to a randomized, double-blind trial to compare the safety and efficacy of LAIV and TIV. The study, conducted in the United States, Europe, Asia, and the Middle East, enrolled 8352 children between 6 months and 5 years of age. 6 Approximately 80% of the children had not been vaccinated previously and received two doses of vaccine; 21% had a parent- or guardian-reported history of wheezing. Over a 6-month surveillance period throughout the influenza season, there were 54.9% fewer cases of culture-confirmed influenza in the LAIV group than in the TIV group (153 vs 338 cases), resulting in attack rates of 3.9% and 8.6%, respectively (P<.001). There were fewer cases of influenza in the LAIV group according to the virus subtype: 89.2% fewer cases of influenza A/H1N1, 79.2% fewer cases of influenza A/H3N2 (both P<.001), and 16.1% fewer cases of influenza B (P=.19) (Fig. 2). Fewer children given LAIV developed acute otitis media (50.6% less, P=.004), lower respiratory illness (45.9% less, P=.046), and symptomatic influenza (50.6% less, P<.001) associated with positive influenza cultures. In this comparative trial, the incidence of wheezing within the first 42 days after administration of the first dose was somewhat higher among the children 6 to 11 months of age given LAIV than TIV (3.8% vs 2.1%, P=.076) but not among older children. 6 Rates of hospitalization for any cause were also higher for children 6 to 11 months of age given LAIV (6.1% vs 2.6%, P=.002). Thus, LAIV was shown to be a highly effective and safe vaccine for children 12 to 59 months of age with no history of asthma or wheezing. In a large community trial of LAIV conducted over a 4-year period, LAIV was found to be safe and well tolerated in children 18 months through 18 years of age. 8 Antibody Response to Influenza Vaccine and Protection from Antigenically Drifted Strains There is considerable evidence that TIV prevents influenza infection by increasing antibody titer, but only if the virus strain in the vaccine is Table. Cost-effectiveness analysis of TIV vs. LAIV in children 24 to 59 months old: total and incremental average costs per vaccinated child. 12 LAIV TIV Difference (LAIV vs TIV) Clinical outcomes measures per 100,000 vaccinated children Uncomplicated influenza Influenza + acute otitis media Influenza + lower respiratory infection Hospitalizations Emergency room visits Outpatient physician visits , Medical costs per vaccinated child Total vaccination costs $ $ $7.72 Total influenza direct costs $13.41 $ $15.80 Total influenza indirect costs $32.59 $ $37.72 Total average cost $ $ $45.80 LAIV = live attenuated influenza vaccine; TIV = trivalent inactivated influenza vaccine antigenically similar to the circulating strain. 9 The more recently developed LAIV has been protective even during influenza seasons in which the circulating virus differed antigenically from the virus in the vaccine. 9 These findings underscore the challenges of utilizing TIV in regions of the world with diverse circulating influenza strains. 10 An immunogenicity substudy of the international comparative trial of TIV and LAIV described previously found that the vaccines produced hemagglutinin-inhibiting (HAI) antibody to the antigenically equivalent influenza A/Nanchang strain in a comparable number of children. 11 However, significantly more children given LAIV than TIV developed HAI antibody, and had a higher titered response, to a panel of influenza A/H3N2 viruses, including influenza A/Sydney, A/Thessalonika, A/ Russia, and A/Johannesburg strains (P<.03). The apparently greater protective effect of LAIV was also borne out in a placebo-controlled trial in Asia, where there is significant variability in circulating influenza viruses each year. 10 In 3174 children between 1 and 3 years of age, the efficacy of LAIV after administration of two doses in year 1 was 72.9% against antigenically similar influenza subtypes and 70.1% against any subtype. In year 2, revaccination with one dose of LAIV provided 84.3% efficacy against antigenically similar subtypes and 64.2% efficacy against any influenza strain. Vaccine efficacy for those children who were not revaccinated in year 2 was 56.2% against all antigenically similar strains, indicating that the initial series of two doses of LAIV elicited an immune response capable of protecting against influenza for 2 years in many, but not all, children. Cost-Effectiveness of TIV and LAIV Cost-effectiveness analyses help formulary decision-makers, vaccine providers, health care policy groups, and payers develop influenza 8 October 2009

9 vaccine guidelines for children. 12 Clinical data from the international comparative trial of TIV and LAIV and published cost data were applied to a cost-effectiveness model to determine the relative cost and benefit of the two vaccines. 12 Due to higher acquisition costs, LAIV increased vaccination costs by $7.72 per child compared with TIV (Table). However, LAIV reduced the number of influenza cases, thereby lowering subsequent health care utilization and productivity losses of parents. Compared with children immunized with TIV, fewer children given LAIV contracted influenza, developed acute otitis media or lower respiratory tract infection, required hospitalization or Emergency Department treatment, and utilized outpatient services. With reduced health care utilization, parents of children given LAIV lowered influenza indirect costs by losing less time from work. Cost-effectiveness analysis determined that the use of LAIV resulted in a savings of $45.80 per vaccinated child, or $4.58 million per 100,000 children. The CDC recommends vaccination of healthy children between 6 months and 18 years of age against influenza to reduce the spread of influenza within families and in communities. 1,13 School-based immunization programs have been effective in two pilot programs in the United States. 13,14 One program used school-based clinics to vaccinate 9007 children 4 years of age or older (approximately 40% of all children in 50 schools), and 1878 school staff members. 14 An additional 1006 children were vaccinated during weekend clinics and community events. Another program identified 11 demographically similar clusters of elementary schools in four states, and selected one school in each cluster to participate in the vaccination program (intervention school) and two others to serve as controls. 13 LAIV was administered to 2717 students (approximately 45%) between 5 and 14 years of age. Based on information collected from questionnaires distributed to households of children in the intervention and control schools, fewer children and adults in intervention school households developed fever or influenza-like illness (P<.001) during the week of predicted peak influenza activity. Fewer children in the intervention schools Figure 2. Comparative efficacy of LAIV and TIV against culture-confirmed influenza in children 6 months to 5 years old in the United States. 6 had outpatient visits (P<.001) or were absent from elementary school (P<.001) or high school (P=.03), and their parents missed fewer work days due to their own influenza-like illness (P=.04). Summary Children are important vectors for the transmission of influenza within households and communities. Two vaccines are available for prevention of influenza in the United States: a trivalent inactivated vaccine (TIV) for children with chronic health conditions and a live attenuated influenza vaccine (LAIV) for healthy children. Large, controlled clinical trials have demonstrated the effectiveness of influenza vaccine in pediatric patients to reduce not only the clinical burden of illness but also the impact on health care utilization and productivity. Increasing immunization rates among healthy children should be an effective means of reducing the burden of influenza in children, their families, and the community. School-based influenza vaccination programs may be an effective and practical approach to vaccinate schoolchildren. References 1. Centers for Disease Control and Prevention. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recomm Rep. 2009;58(RR-8): Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recomm Rep. 2008;57(RR-7): Zangwill KM, Belshe RB. Safety and efficacy of trivalent inactivated influenza vaccine in young children: a summary for the new era of routine vaccination. Pediatr Infect Dis J. 2004;23: Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med. 1998;338: Belshe RB, Gruber WC, Mendelman PM, et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr. 2000;136: Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356: Bergen R, Black S, Shinefield H, et al. Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents. Pediatr Infect Dis J. 2004;23: Piedra PA, Gaglani MJ, Riggs M, et al. Live attenuated influenza vaccine, trivalent, is safe in healthy children 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in a community-based, nonrandomized, open-label trial. Pediatrics. 2005;116:e397-e Ohmit SE, Victor JC, Rotthoff JR, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med. 2006;355: Tam JS, Capeding MRZ, Lum LCS, et al. Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia. Pediatr Infect Dis J. 2007;26: Belshe RB, Gruber WC. Prevention of otitis media in children with live attenuated influenza vaccine given intranasally. Pediatr Infect Dis J. 2000;19:S66-S Luce BR, Nichol KL, Belshe RB, et al. Cost-effectiveness of live attenuated influenza vaccine versus inactivated influenza vaccine among children aged months in the United States. Vaccine. 2008;26: King JC Jr, Stoddard JJ, Gaglani MJ, et al. Effectiveness of school-based influenza vaccination. N Engl J Med. 2006;355: Gaglani M, Piedra P, Greger P, et al. Expansion of a school-based influenza vaccination and herd protection trial in central Texas second year of VIPS: Vaccines for Influenza Prevention in Schools. Presented at: 12th Annual Conference on Vaccine Research; April 27, 2009; Baltimore, MD. Abstract S8. October

10 Vaccinating Schoolchildren: Next Step Forward in the Battle Against Influenza? Current Approaches to Treatment and Prophylaxis of Influenza Prof. Asher Barzilai, MD, EMBA The burden of influenza illness on the pediatric population underscores the need for effective management, particularly in the youngest children affected so substantially. 1,2 Antiviral agents for influenza illness are now available, but prompt initiation of treatment and effective outcomes rely on the ability of the clinician to distinguish influenza from other viral infections. 1 The lack of specific signs and symptoms for influenza, underusage of rapid diagnostic tests in the outpatient setting, and simultaneous circulation of other respiratory viruses only serve to confound the accuracy of a clinical diagnosis. 1,2 Presentation and Recognition of Influenza The diagnosis of influenza usually is based on patient history, clinical signs and symptoms, and the local epidemiologic situation. 1 However, the predominant clinical symptoms of fever and cough are nonspecific and often typical of other respiratory or influenza-like illness. 3 Furthermore, the respiratory and systemic signs and symptoms of influenza in children can present as other illnesses, such as croup, bronchiolitis, pneumonia, or, occasionally, central nervous system (CNS) complications. 4 Laboratory confirmation of influenza virus in nasopharyngeal secretions is needed for a definitive diagnosis, as the symptoms of acute respiratory infection may predict influenza in only about 30% of patients. 3 To underscore the difficulty in diagnosing influenza, a study of children in the outpatient setting found that physicians made accurate clinical diagnoses in only 88 of 231 laboratory-confirmed cases of influenza (sensitivity, 38%). 1 Conversely, the physicians made a clinical diagnosis of influenza based on signs and symptoms in 276 children, of whom 88 had laboratory-confirmed influenza (positive predictive value, 32%). Figure 1. Clinical presentation of influenza in pediatric outpatients, by age group. 2 High fever, cough, and rhinorrhea are the most common symptoms of influenza in children. 2,4 Retrospective chart review of 683 children aged 2 to 4 years with influenza A or influenza B infection found that high fever was recorded for 89% to 94% of the children. 4 Rhinorrhea occurred as frequently as cough but was more commonly associated with influenza A infection. Ill appearance was also recorded more often for children with influenza A than influenza B. Vomiting or diarrhea was a presenting symptom in about one quarter of cases, and neither myalgia nor wheezing was a common symptom. 4 Another study found that fever 37.5 C occurred in 93% or more of 353 children aged 6 months to 13 years, and the highest fevers ( 39 C) occurred in the youngest children (less than 3 years of age) (Fig. 1). 2 While rhinorrhea was present in nearly 80% of all children, it also was more common in the youngest age group, while cough was common to all age groups. In contrast, headache, sore throat, and myalgia were noted more frequently in children 7 to 13 years of age than in younger children. 2 Based on such clinical trial evidence, a case definition for treating a child with the signs and symptoms of influenza would include a fever 37.8 C plus two or more of the following: cough, headache, myalgia, sore throat, or fatigue. 5 There should, in addition, be no evidence of bacterial infection. The benefits and limitations of diagnostic testing for influenza have been the topic of considerable discussion. 6 Laboratory testing, though time-consuming, can provide useful information to clinicians for more directed therapy and reduce both inappropriate antibiotic use and hospital admissions. However, 30% to 65% of cases of influenza may be missed unless a polymerase chain reaction (PCR) assay is used. In addition, a delay in obtaining test results may cause delay in diagnosis and therefore result in less effective treatment. Influenza rapid diagnostic tests (IRDTs) are available; however, they are less accurate than reverse transcriptase (RT) PCR, with a wide range of sensitivities but high specificities for the influenza virus. 7 Compared with RT-PCR, IRDT had a median sensitivity of only 26.7% but a median specificity of 97.2% for influenza A and B in children and young adults at three different outpatient sites in the United States, suggesting an advantage for prompt detection of the virus and improved management of the patient. 7 In the emergency room setting, IRDTs for influenza A and B were positive for 41.6% of pediatric cases. 8 Fewer laboratory tests (0.7% vs. 11.6%) and radiographs (0.7% vs. 8.6%) were ordered for children who were tested than for those who were not (P<.0001 for both). IRDT also reduced the use of antibiotics (7.6% vs 18.5%, P<.0001). 10 October 2009