* Live attenuated influenza vaccine (LAIV) or

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5 Target Groups for Influenza Vaccination Influenza Season Persons at Increased Risk for Influenza-Related Complications Persons Who Live With or Care for Persons at High Risk for Influenza-Related Complications Inactivated Influenza Vaccine ONLY Inactivated OR Live Influenza Vaccine* Children age 6 59 months. Children and adolescents (age 6 months 18 years) who are receiving long-term aspirin therapy. Adolescents who will be pregnant during the influenza season. Children and adolescents (age 6 months 18 years) who have chronic disorders of the pulmonary or cardiovascular systems. Children and adolescents (age 6 months 18 years) who have any condition that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders). Trivalent inactivated influenza vaccine (TIV) should not be administered to persons with a history of hypersensitivity, including anaphylaxis, to any of the components of TIV or to eggs. Healthy household contacts and caregivers of children aged 0 59 months and persons at high risk for severe complications from influenza. Health-care workers. * Live attenuated influenza vaccine (LAIV) or FluMist should be administered to healthy VFC-elibible patients age 5 18 years. The following patients should not be vaccinated with LAIV: Persons age <5 years. Persons with asthma, reactive airway disease, or other chronic disorders of the pulmonary or cardiovascular systems; persons with other underlying conditions, including diabetes, renal dysfunction, and hemoglobinopathies; or persons with known or suspected immunodeficiency diseases or who are receiving immunosuppressive therapies. Children and adolescents receiving aspirin or other salicylates. Persons with a history of Guillain-Barre Syndrome (GBS). Pregnant adolescents. Persons with a history of hypersensitivity, including anaphylaxis, to any of the components of LAIV or to eggs.

6 PRIVATE VACCINES FOR CHILDREN (VFC) PROVIDERS Influenza Vaccine Dosage Chart Inactivated and Live Influenza Vaccine Age Dose No. of Doses Route and Site Presentation Brand 6-35 months 0.25 ml 1 or 2 * IM in anterolateral aspect of thigh (or in deltoid if muscle mass is sufficient) Single-dose syringes Fluzone Pediatric, Preservative-Free, Inactivated 6 months & older 0.25 ml (6-35 months) 0.5 ml (3 years & older) 1 or 2 * IM in anterolateral aspect of thigh (or in deltoid if muscle mass is sufficient) Multi-dose vials Fluzone Preservative-Containing, Inactivated 36 months & older 0.5 ml 1 or 2 * IM in anterolateral aspect of thigh (or in deltoid if muscle mass is sufficient) Single-dose syringes Fluzone Preservative-Free, Inactivated 36 months & older 0.5 ml 1 or 2 * IM in anterolateral aspect of thigh (or in deltoid if muscle mass is sufficient) Single-dose vials Fluzone Preservative-Free, Inactivated 5 years-49 years Healthy persons ONLY 0.5 ml 1 or 2 * 1 spray in each nostril Single-dose nasal sprayers FluMist Preservative-Free, Live, Attenuated Vaccine * Two doses are recommended for children younger than 9 years of age who have never before received influenza vaccine, either live or inactivated. Administer live, nasal spray influenza doses at least 6 weeks apart. For optimal protection, both doses should be administered before December.

7 INFLUENZAVACCINE INACTIVATED WHAT YOU NEED TO KNOW Why get vaccinated? Influenza ( flu ) is a contagious disease. It is caused by the influenza virus, which spreads from person to person through coughing or sneezing. Other illnesses have the same symptoms and are often mistaken for influenza. But only the influenza virus can cause influenza. Anyone can get influenza. For most people, it lasts only a few days. It can cause: fever sore throat chills fatigue cough headache muscle aches Some people get much sicker. Influenza can lead to pneumonia and can be dangerous for people with heart or breathing conditions. It can cause high fever and seizures in children. Influenza kills about 36,000 people each year in the United States, mostly among the elderly. Influenza vaccine can prevent influenza. 2 Inactivated Influenza vaccine There are two types of influenza vaccine: An inactivated (killed) vaccine, or flu shot, has been used in the United States for many years. It is given by injection. A live, weakened vaccine was licensed in It is sprayed into the nostrils. This vaccine is described in a separate Vaccine Information Statement. Influenza viruses are always changing. Therefore, influenza vaccines are updated every year, and an annual vaccination is recommended. For most people influenza vaccine prevents serious influenzarelated illness. It will not prevent influenza-like illnesses caused by other viruses. It takes about 2 weeks for protection to develop after the vaccination, and protection can last up to a year. Inactivated influenza vaccine may be given at the same time as other vaccines, including pneumococcal vaccine. Some inactivated influenza vaccine contains thimerosal, a preservative that contains mercury. Some people believe thimerosal may be related to developmental problems in children. In 2004 the Institute of Medicine published a report concluding that, based on scientific studies, there is no evidence of such a relationship. If you are concerned about thimerosal, ask your doctor about thimerosal-free influenza vaccine. 3 Who should get inactivated influenza vaccine? Inactivated influenza vaccine can be given to people 6 months of age and older. It is recommended for people who are at risk of complications from influenza, and for people who can spread influenza to those at high risk (including all household members): People at high risk for complications from influenza: People 65 years of age and older. Residents of long-term care facilities housing persons with chronic medical conditions. People who have long-term health problems with: - heart disease - kidney disease - lung disease - metabolic disease, such as diabetes - asthma - anemia, and other blood disorders People with certain muscle or nerve disorders (such as seizure disorders or severe cerebral palsy) that can lead to breathing or swallowing problems. People with a weakened immune system due to: - HIV/AIDS or other diseases affecting the immune system - long-term treatment with drugs such as steroids - cancer treatment with x-rays or drugs People 6 months to 18 years of age on long-term aspirin treatment (these people could develop Reye Syndrome if they got influenza). Women who will be pregnant during influenza season. All children 6-59 months of age. People who can spread influenza to those at high risk: Household contacts and out-of-home caretakers of children from 0-59 months of age. Physicians, nurses, family members, or anyone else in close contact with people at risk of serious influenza. Influenza vaccine is also recommended for adults years of age and anyone else who wants to reduce their chance of getting influenza. A yearly influenza vaccination should be considered for: People who provide essential community services. People living in dormitories or under other crowded conditions, to prevent outbreaks. People at high risk of influenza complications who travel to the Southern hemisphere between April and September, or to the tropics or in organized tourist groups at any time.

8 4 The best time to get influenza vaccine is in October or November. Influenza season usually peaks in February, but it can peak any time from November through May. So getting the vaccine in December, or even later, can be beneficial in most years. Some people should get their flu shot in October or earlier: - people 50 years of age and older, - younger people at high risk from influenza and its complications (including children 6 through 59 months of age), - household contacts of people at high risk, - health care workers, and - children younger than 9 years of age getting influenza vaccine for the first time. Most people need one flu shot each year. Children younger than 9 years of age getting influenza vaccine for the first time should get 2 doses, given at least one month apart. 5 6 When should I get influenza vaccine? Some people should talk with a doctor before getting influenza vaccine Some people should not get inactivated influenza vaccine or should wait before getting it. Tell your doctor if you have any severe (life-threatening) allergies. Allergic reactions to influenza vaccine are rare. - Influenza vaccine virus is grown in eggs. People with a severe egg allergy should not get the vaccine. - A severe allergy to any vaccine component is also a reason to not get the vaccine. - If you have had a severe reaction after a previous dose of influenza vaccine, tell your doctor. Tell your doctor if you ever had Guillain-Barré Syndrome (a severe paralytic illness, also called GBS). You may be able to get the vaccine, but your doctor should help you make the decision. People who are moderately or severely ill should usually wait until they recover before getting flu vaccine. If you are ill, talk to your doctor or nurse about whether to reschedule the vaccination. People with a mild illness can usually get the vaccine. What are the risks from inactivated influenza vaccine? A vaccine, like any medicine, could possibly cause serious problems, such as severe allergic reactions. The risk of a vaccine causing serious harm, or death, is extremely small. Serious problems from influenza vaccine are very rare. The viruses in inactivated influenza vaccine have been killed, so you cannot get influenza from the vaccine. Mild problems: soreness, redness, or swelling where the shot was given fever aches Vaccine Information Statement Inactivated Influenza Vaccine (6/30/06) 42 U.S.C. 300aa-26 If these problems occur, they usually begin soon after the shot and last 1-2 days. Severe problems: Life-threatening allergic reactions from vaccines are very rare. If they do occur, it is within a few minutes to a few hours after the shot. In 1976, a certain type of influenza (swine flu) vaccine was associated with Guillain-Barré Syndrome (GBS). Since then, flu vaccines have not been clearly linked to GBS. However, if there is a risk of GBS from current flu vaccines, it would be no more than 1 or 2 cases per million people vaccinated. This is much lower than the risk of severe influenza, which can be prevented by vaccination. 7 What if there is a severe reaction? What should I look for? Any unusual condition, such as a high fever or behavior changes. Signs of a serious allergic reaction can include difficulty breathing, hoarseness or wheezing, hives, paleness, weakness, a fast heart beat or dizziness. What should I do? Call a doctor, or get the person to a doctor right away. Tell your doctor what happened, the date and time it happened, and when the vaccination was given. Ask your doctor, nurse, or health department to report the reaction by filing a Vaccine Adverse Event Reporting System (VAERS) form. Or you can file this report through the VAERS web site at or by calling VAERS does not provide medical advice. 8 The National Vaccine Injury Compensation Program In the event that you or your child has a serious reaction to a vaccine, a federal program has been created to help pay for the care of those who have been harmed. For details about the National Vaccine Injury Compensation Program, call or visit their website at 9 How can I learn more? Ask your immunization provider. They can give you the vaccine package insert or suggest other sources of information. Call your local or state health department. Contact the Centers for Disease Control and Prevention (CDC): - Call (1-800-CDC-INFO) - Visit CDC s website at department of health and human services Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases

9 INFLUENZAVACCINE LIVE, INTRANASAL WHAT YOU NEED TO KNOW Why get vaccinated? Influenza ( flu ) is a contagious disease. It is caused by the influenza virus, which spreads from infected persons to the nose or throat of others. Other illnesses can have the same symptoms and are often mistaken for influenza. But only an illness caused by the influenza virus is really influenza. Anyone can get influenza, but rates of infection are highest among children. For most people, it lasts only a few days. It can cause: fever sore throat chills fatigue cough headache muscle aches Some people get much sicker. Influenza can lead to pneumonia and can be dangerous for people with heart or breathing conditions. It can cause high fever and seizures in children. Influenza kills about 36,000 people each year in the United States. Influenza vaccine can prevent influenza. 2 Live, attenuated influenza vaccine (nasal spray) There are two types of influenza vaccine: Live, attenuated influenza vaccine (LAIV) was licensed in LAIV contains live but attenuated (weakened) influenza virus. It is sprayed into the nostrils rather than injected into the muscle. It is recommended for healthy children and adults from 5 through 49 years of age, who are not pregnant. Inactivated influenza vaccine, sometimes called the flu shot, has been used for many years and is given by injection. This vaccine is described in a separate Vaccine Information Statement. Influenza viruses are constantly changing. Therefore, influenza vaccines are updated every year, and annual vaccination is recommended. For most people influenza vaccine prevents serious influenza-related illness. It will not prevent influenzalike illnesses caused by other viruses. It takes about 2 weeks for protection to develop after vaccination, and protection can last up to a year. 3 Who can get LAIV? Live, intranasal influenza vaccine is approved for healthy children and adults from 5 through 49 years of age, including those who can spread influenza to people at high risk, such as: Household contacts and out-of-home caretakers of children from 0-59 months of age. Physicians and nurses, and family members or any one else in close contact with people at risk of serious influenza. Influenza vaccine is also recommended for anyone else who wants to reduce their chance of getting influenza. LAIV may be considered for: People who provide essential community services. People living in dormitories or under other crowded conditions, to prevent outbreaks. 4 Who should not get LAIV? LAIV is not licensed for everyone. The following people should check with their health-care provider about getting the inactivated vaccine (flu shot). Adults 50 years of age or older or children younger than 5. People who have long-term health problems with: - heart disease - kidney disease - lung disease - metabolic disease, such as diabetes - asthma - anemia, and other blood disorders People with a weakened immune system. Children or adolescents on long-term aspirin treatment. Pregnant women. Anyone with a history of Guillain-Barré syndrome (a severe paralytic illness, also called GBS). Inactivated influenza vaccine (the flu shot) is the preferred vaccine for people (including health-care workers, and family members) coming in close contact with anyone who has a severely weakened immune system (that is, anyone who requires care in a protected environment).

10 Some people should talk with a doctor before getting either influenza vaccine: Anyone who has ever had a serious allergic reaction to eggs or to a previous dose of influenza vaccine. People who are moderately or severely ill should usually wait until they recover before getting flu vaccine. If you are ill, talk to your doctor or nurse about whether to reschedule the vaccination. People with a mild illness can usually get the vaccine. 5 When should I get influenza vaccine? The best time to get influenza vaccine is in October or November, but LAIV may be given as soon as it is available. Influenza season usually peaks in February, but it can peak any time from November through May. So getting the vaccine in December, or even later, can be beneficial in most years. Most people need one dose of influenza vaccine each year. Children younger than 9 years of age getting influenza vaccine for the first time should get 2 doses For LAIV, these doses should be given 6-10 weeks apart. LAIV may be given at the same time as other vaccines. 6 What are the risks from LAIV? A vaccine, like any medicine, could possibly cause serious problems, such as severe allergic reactions. However, the risk of a vaccine causing serious harm, or death, is extremely small. Live influenza vaccine viruses rarely spread from person to person. Even if they do, they are not likely to cause illness. LAIV is made from weakened virus and does not cause influenza. The vaccine can cause mild symptoms in people who get it (see below). Mild problems: Some children and adolescents 5-17 years of age have reported mild reactions, including: runny nose, nasal congestion or cough headache and muscle aches fever abdominal pain or occasional vomiting or diarrhea Some adults years of age have reported: runny nose or nasal congestion sore throat cough, chills, tiredness/weakness headache These symptoms did not last long and went away on their own. Although they can occur after vaccination, they may not have been caused by the vaccine. Severe problems: Life-threatening allergic reactions from vaccines are very rare. If they do occur, it is within a few minutes to a few hours after the vaccination. Vaccine Information Statement Live, Attenuated Influenza Vaccine (6/30/06) 42 U.S.C. 300aa-26 If rare reactions occur with any new product, they may not be identified until thousands, or millions, of people have used it. Over four million doses of LAIV have been distributed since it was licensed, and no serious problems have been identified. Like all vaccines, LAIV will continue to be monitored for unusual or severe problems. 7 What if there is a severe reaction? What should I look for? Any unusual condition, such as a high fever or behavior changes. Signs of a serious allergic reaction can include difficulty breathing, hoarseness or wheezing, hives, paleness, weakness, a fast heart beat or dizziness. What should I do? Call a doctor, or get the person to a doctor right away. Tell your doctor what happened, the date and time it happened, and when the vaccination was given. Ask your doctor, nurse, or health department to report the reaction by filing a Vaccine Adverse Event Reporting System (VAERS) form. Or you can file this report through the VAERS website at or by calling VAERS does not provide medical advice. 8 The National Vaccine Injury Compensation Program In the event that you or your child has a serious reaction to a vaccine, a federal program has been created to help pay for the care of those who have been harmed. For details about the National Vaccine Injury Compensation Program, call or visit their website at 9 How can I learn more? Ask your immunization provider. They can give you the vaccine package insert or suggest other sources of information. Call your local or state health department. Contact the Centers for Disease Control and Prevention (CDC): - Call (1-800-CDC-INFO) - Visit CDC s website at department of health and human services Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases

11 Influenza Vaccine Immunogenicity in 6- to 23-Month-Old Children: Are Identical Antigens Necessary for Priming? Emmanuel B. Walter, Kathleen M. Neuzil, Yuwei Zhu, Mary P. Fairchok, Martha E. Gagliano, Arnold S. Monto and Janet A. Englund Pediatrics 2006;118; DOI: /peds This information is current as of November 16, 2006 The online version of this article, along with updated information and services, is located on the World Wide Web at: PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, Copyright 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN: Online ISSN: Downloaded from by on November 16, 2006

12 ARTICLE Influenza Vaccine Immunogenicity in 6- to 23-Month- Old Children: Are Identical Antigens Necessary for Priming? Emmanuel B. Walter, MD, MPH a, Kathleen M. Neuzil, MD, MPH b, Yuwei Zhu, MD, MS c, Mary P. Fairchok, MD d,e, Martha E. Gagliano, MD f, Arnold S. Monto, MD g, Janet A. Englund, MD d a Duke Clinical Research Institute and Department of Pediatrics, Duke University Medical Center, Durham, North Carolina; b Program for Appropriate Technology in Health and Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, Washington; c Department of Biostatistics, Vanderbilt University, Nashville, Tennessee; d Division of Pediatric Infectious Diseases, Allergy, and Rheumatology, University of Washington and Children s Hospital and Regional Medical Center, Seattle, Washington; e Department of Pediatrics, Madigan Army Medical Center, Tacoma, Washington; f Duke University Affiliated Physicians, Durham, North Carolina; g School of Public Health, University of Michigan, Ann Arbor, Michigan Financial Disclosure: This study was funded by an unrestricted grant from Sanofi Pasteur, the vaccine division of the Sanofi-Aventis Group (Swiftwater, PA). Dr Walter is a speaker for; Drs Neuzil, Fairchok, and Monto have received research support from; and Dr Englund has received research support, consulting fees, and honoraria from Sanofi-Aventis Group. ABSTRACT OBJECTIVES. Immunoprophylaxis with influenza vaccine is the primary method for reducing the effect of influenza on children, and inactivated influenza vaccine has been shown to be safe and effective in children. The Advisory Committee on Immunization Practices recommends that children 6 to 23 months of age who are receiving trivalent inactivated influenza vaccine for the first time be given 2 doses; however, delivering 2 doses of trivalent inactivated influenza vaccine 4 weeks apart each fall can be logistically challenging. We evaluated an alternate spring dosing schedule to assess whether a spring dose of trivalent inactivated influenza vaccine was capable of priming the immune response to a fall dose of trivalent inactivated influenza vaccine containing 2 different antigens. PATIENTS AND METHODS. Healthy children born between November 1, 2002, and December 31, 2003, were recruited in the spring and randomly assigned to either the alternate spring schedule or standard fall schedule. The licensed trivalent inactivated influenza vaccine was administered in the spring; the fall vaccine had the same A/H1N1 antigen but contained drifted A/H3N2 antigen and B antigen with a major change in strain lineage. Reactogenicity was assessed by parental diaries and telephone surveillance. Blood was obtained after the second dose of trivalent inactivated influenza vaccine for all of the children and after the first dose of trivalent inactivated influenza vaccine in the fall group. The primary outcome of this study was to demonstrate noninferiority of the antibody response after a spring-fall dosing schedule compared with the standard fall dosing schedule. Noninferiority was based on the proportion of subjects in each group achieving a hemagglutination-inhibition antibody titer of 1:32 after vaccination to 2 of the 3 antigens (H1N2, H3N2, and B) contained in the vaccine. For each antigen, the antibody response was proposed to be noninferior if, within the upper bound of 95% confidence interval, there was 15% difference between peds doi: /peds This work was presented in part at the 43rd Annual Meeting of the Infectious Diseases Society of America; October 6-9, 2005; San Francisco, CA (abstracts 63 and 1007). The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense. Key Words inactivated influenza vaccine, children, immunogenicity Abbreviations ACIP Advisory Committee on Immunization Practices TIV trivalent inactivated influenza vaccine HA hemagglutinin HAI hemagglutination inhibition GMT geometric mean titer Accepted for publication May 11, 2006 Address correspondence to Emmanuel B. Walter, MD, MPH, Duke Children s Primary Care, 4020 N Roxboro Rd, Durham, NC walte002@mc.duke.edu PEDIATRICS (ISSN Numbers: Print, ; Online, ). Copyright 2006 by the American Academy of Pediatrics e570 WALTER et al Downloaded from by on November 16, 2006

13 the proportion of children in the fall and spring groups with postvaccination titers 1:32. RESULTS. A total of 468 children were randomly assigned to either the spring (n 233) or fall (n 235) trivalent inactivated influenza vaccine schedule. Excellent response rates to A/H1N1, as measured by antibody levels 1:32, were noted in both the spring (86%) and fall groups (93%). The A/H1N1 response rate of the spring group was noninferior to that of the fall group. Noninferiority of the spring schedule was not met with respect to the other 2 influenza antigens: for A/H3N2 the response was 70% in the spring group versus 83% for the fall group, and the response to B was 39% in the spring group versus 88% for the fall group. After 2 doses of vaccine, the geometric mean antibody titers also were less robust in the spring group for both A/H3N2 and B antigens. For each of the 3 vaccine antigens, the respective geometric mean antibody titers for the spring group versus the fall group were: A/H1N1, and ; A/H3N2, and ; and B, and However, a significantly higher proportion of children in the spring group achieved potentially protective levels of antibody to all 3 antigens after their first fall dose of trivalent inactivated influenza vaccine than children in the fall group after receiving their first fall dose. For influenza A/H1N1, there was an antibody level 1:32 in 86% of children in the spring group versus 55% of children in the fall group. Likewise, for influenza A/H3N2, 70% of children in the spring group and 47% of children in the fall group had antibody levels 1:32; for influenza B, the proportions were 39% of children in the spring group and 16% of children in the fall group. Reactogenicity after trivalent inactivated influenza vaccine in both groups of children was minimal and did not differ by dose. CONCLUSIONS. Although the immune response to the identical A/H1N1 vaccine antigen was similar in both groups, priming with different A/H3N2 antigens and B antigens in the spring produced a lower immune response to both antigens than that shown in children who received 2 doses of the same vaccine in the fall. However, 70% of children in the spring group had a protective response to the H3N2 antigen after 2 doses. Initiating influenza immunization in the spring was superior to 1 dose of trivalent inactivated influenza vaccine in the fall. The goal of delivering 2 doses of influenza vaccine a month apart to vaccine-naive children within the narrow flu vaccination season is a challenge not yet met; thus far, only about half of children aged 6 to 23 months of age are receiving influenza vaccine. By using the spring schedule, we were able to administer 2 doses of trivalent inactivated influenza vaccine to a higher proportion of children earlier in the influenza vaccination season. In years when there is an ample supply of trivalent inactivated influenza vaccine, and vaccine remains at the end of the season, priming influenza vaccine-naive infants with a spring dose will lead to the earlier protection of a higher proportion of infants in the fall. This strategy may be particularly advantageous when there is an early start to an influenza season as occurred in the fall of A priming dose of influenza vaccine in the spring may also offer other advantages. Many vaccine-naive children may miss the second dose of fall trivalent inactivated influenza vaccine because of vaccine shortages or for other reasons, such as the potential implementation of new antigens at a late date. Even with seasonal changes in influenza vaccine antigens, by giving a springtime dose of trivalent inactivated influenza vaccine, such children would be more protected against influenza than would children who were only able to receive 1 dose in the fall. In summary, our data suggest that identical influenza antigens are not necessary for priming vaccine-naive children and that innovative uses of influenza vaccine, such as a springtime dose of vaccine, could assist in earlier and more complete immunization of young children. HEALTHY CHILDREN 2 years of age are at a substantially increased risk for influenza-related hospitalization. 1 5 Immunoprophylaxis with influenza vaccine is the primary method for reducing the effect of influenza on children, and inactivated influenza vaccine has been shown to be safe and effective in children Consequently, the Advisory Committee on Immunization Practices (ACIP) recommended that, beginning in fall 2004, children aged 6 to 23 months receive trivalent inactivated influenza vaccine (TIV). 11,12 For influenza vaccine-naive children in this age group, 2 doses of vaccine are necessary to achieve a protective response However, delivering 2 doses of vaccine to all previously unvaccinated 6- to 23-month-old children between September and November is logistically challenging. For example, in the fall of 2003, the proportion of children aged 6 to 23 months who received 1 dose of vaccine was nearly twice that of children receiving 2 doses of vaccine by December 7 (27% vs 15%). 14 Partial immunization with influenza vaccine frequently occurs in vaccine-naive high-risk children as well. 15 As an alternative to delivering 2 doses of TIV in the fall, we sought to learn whether a springtime dose of the TIV from the previous year could prime infants sufficiently so that only a single dose of TIV would be required in the fall. We reported previously that antibody responses and the rates of reactogenicity were similar in 6- to 23- month-old children receiving the standard 2-dose regimen of TIV 1 month apart in the fall versus an alternative regimen in which a spring dose of TIV was followed in 6 months by a fall dose of TIV containing identical influenza antigens. 13 In the current study, we examined PEDIATRICS Volume 118, Number 3, September 2006 Downloaded from by on November 16, 2006 e571

14 whether the administration of the influenza vaccine from the previous year for the first dose in the spring would adequately prime for the second fall dose when 2 of the 3 TIV vaccine antigens had changed. Thus, the primary goal of our study was to compare the immunogenicity of 2 doses of TIV with different A/H3N2 and B vaccine antigens administered in a spring-fall schedule with the immunogenicity of 2 doses of TIV containing the same vaccine antigens administered in a standard fall schedule. METHODS Study Design This study was a prospective, randomized, open-label clinical trial conducted at 3 clinics near Seattle, WA (Skagit Valley Pediatrics, Madigan Army Medical Center, and Virginia Mason Medical Center), 3 pediatric practices in Durham, NC (Duke Children s Primary Care, Durham Pediatrics, and Regional Pediatrics), and 1 pediatric practice in Chapel Hill, NC (Chapel Hill Pediatrics). All of the children were enrolled between April 1, 2004, and June 30, The study protocol was approved by each institutional review board, and informed consent was obtained from a parent or guardian. Sitespecific randomization was allocated by an investigator not involved in patient recruitment or patient care and performed in blocks of 10 by using random-number tables. In this open-label trial, children were randomly assigned to either the spring or fall group. Those randomly assigned to the spring group received their first dose of TIV in the spring and 2 doses of TIV in the fall (a total of 3 doses), whereas children in the fall group received no vaccine in the spring and 2 doses of TIV in the fall (Table 1). Thus, all of the children received 2 doses of TIV in the fall. To evaluate the primary outcome, blood samples were obtained 4 weeks after the second dose of influenza vaccine in both groups. Blood samples were also taken before the first dose of vaccine in the spring group and 4 weeks after the first dose of vaccine in the fall group. The primary outcome of this study was to demonstrate noninferiority of the antibody response after a spring-fall dosing schedule compared with the standard TABLE 1 Study Design Group Spring Fall Spring group Fall group Day 0 Day 30 Day 60 Enroll TIV TIV TIV Sera Sera Enroll TIV TIV Sera Sera fall dosing schedule. Noninferiority was based on the proportion of subjects in each group achieving a titer of 1:32 after vaccination to 2 of the 3 antigens (H1N2, H3N2, and B) contained in the vaccine. For each antigen, the antibody response was proposed to be noninferior if, within the upper bound of 95% confidence interval, there was 15% difference between the proportion of children in the fall and spring groups with postvaccination titers 1:32. A sample size of 214 per group was initially calculated for this study to have 80% power in favor of noninferiority between the spring and fall groups. Assuming a 1-sided of.05, we anticipated seroprotection rates in the fall group of 80% and expected 5% lower rates in the spring group for each included antigen, with a maximum margin of 15%. Secondary study objectives included the following: determining the children s immune status against antigens contained in the TIV before any dose of TIV was given (spring group only), characterizing the seroconversion rate in children receiving 2 doses of vaccine separated by 6 months (spring group only), comparing the proportion of seroresponders after 1 injection (fall group) versus 2 injections (fall group and spring group), and comparing reactogenicity between the 2 groups. Population Healthy children born between November 1, 2002, and December 31, 2003, were eligible for enrollment. Inclusion criteria included parental informed consent, availability for all of the study visits, and telephone access. Subjects with acute febrile illnesses were eligible for enrollment, but immunization was deferred for 24 hours after the last temperature of 38 C axillary. Exclusion criteria included birth before 36 weeks gestation, previous receipt of influenza vaccine of any kind, allergy to eggs or egg products, history of Guillain-Barré syndrome, immunosuppression as a result of underlying illness or treatment, any acute or chronic condition that, in the opinion of the investigator, would render vaccination unsafe or ineffective, history of receiving immunoglobulin or other blood product within 3 months before enrollment, receipt of a live virus vaccine (eg, measles, mumps, and rubella vaccine or varicella vaccine) within the preceding 4 weeks, or need to obtain a live virus vaccine within the consecutive 4 weeks. Simultaneous administration of a live virus vaccine was permitted. 12 Children were referred for inclusion in the study by their health care practitioners. Documented medical reasons for exclusion from the study were noted for 8 children, including children with the following conditions: cleft lip and palate with impending surgical procedure, sleep apnea, Down syndrome, perinatal stroke and esophageal atresia, pulmonary hypertension, biliary atresia, lymphatic malformation and severe gastroesoph- e572 WALTER et al Downloaded from by on November 16, 2006

15 ageal reflux with gastrostomy and tracheostomy, and a complicated hemangioma. Children were not excluded from participation in the study on the basis of their prevaccination titer. Vaccine Single lots of licensed and trivalent inactivated preservative-free influenza vaccine (TIV) provided by Aventis-Pasteur (Swiftwater, PA) were used throughout the trial. The TIV contained A/New Caledonia/20/99 (H1N1), A/Panama/ 2007/99 (H3N2), and B/ HongKong/1434/2002 antigens, whereas the TIV contained the H1N1, A/Wyoming/03/2003 (H3N2), and B/Jiangsu/10/2003 strains. Vaccine was prepackaged in 0.25-mL syringes and administered intramuscularly in the thigh with a 25-gauge needle using standard sterile technique. Each 0.25-mL dose of vaccine contained a total of 22.5 g of hemagglutinin (HA), representing 7.5 g of HA per strain of influenza antigen. Immunogenicity Sera were stored frozen at 20 C or less until analyzed at the University of Michigan. Hemagglutination-inhibition (HAI) antibody titers were determined in duplicate, with all of the paired specimens run in the same test. Antigens were provided by the Centers for Disease Control and Prevention (H1N1, H3N2, and B/Jiangsu/10/ 2003, ether extracted). Sera were treated with receptordestroying enzyme (Denke Seiken Co Ltd, Tokyo, Japan). To inactivate the receptor-destroying enzyme, sera were heated to 56 C for 30 minutes. Twenty-five microliters of diluted sera were incubated with an equal volume of antigen diluted to contain 4-8 HA units, and 50 L of a 0.5% suspension of chicken red blood cells were then added to the mixture. Antibody response was defined as an HAI titer 1:32, which has been correlated with protection against influenza. 16,17 Reactogenicity Prospective evaluation of reactogenicity was obtained by using a parental diary. Parents were requested to record daily axillary temperatures, any local reactions (pain, tenderness, redness, and swelling at the site of TIV), and systemic reactions (irritability, alteration in sleep behavior, emesis, and change in appetite) for 5 days after vaccination. In addition, parents were contacted by telephone between 3 and 5 days after vaccination to confirm temperatures and any adverse reactions. Reactogenicity data were obtained by using both parental diaries and nurse telephone interviews after all of the study visits, including the enrollment visit. At the enrollment visit, children in the spring group received TIV and may have received concomitant routine childhood immunizations, but children in the fall group received whatever vaccinations were scheduled at that visit. Children in both the spring and fall groups were followed for 5 days after the enrollment visit. By capturing reactogenicity data from children in the fall group who received other pediatric vaccines, reactogenicity from a comparison group not receiving TIV was available for analysis. Parents were again contacted 6 months after the last dose of vaccine to elicit information about any serious adverse reactions. Statistics Descriptive and exploratory analyses were used to evaluate demographic characteristics stratified by different vaccine regimen groups. Univariate analyses were performed to assess the associations among reactogenicity, concomitant vaccines, and groups. Antibody titers were expressed as log 2, and geometric mean titers (GMTs) were reported. Any titer 1:8 was assigned a minimum value of 4. Vaccination titers 1:32 were considered positive. Seroconversion rate was defined as the number of subjects with a fourfold rise divided by the number of paired preimmunization and post second-dose subjects. All of the comparisons were done by using a 2 test for contingency tables and a t test for continuous variables. There was no adjustment for multiple comparisons. Noninferior tests were done by using StatXact 6.0 (Cytel Corporation, Cambridge, MA), and the remaining analyses were performed by using SAS 9.1 (SAS Institute, Inc, Cary, NC). RESULTS Subjects Children aged 6 to 23 months were enrolled between April and June Overall, 468 children were enrolled: 233 in the spring group and 235 in the fall group. We excluded 6 subjects (2 spring and 4 fall) from data analysis, because they either did not receive any study vaccines or did not provide any information about vaccine reactogenicity. Thus, 462 children were included in the final analysis, with 231 in each group (Fig 1). Children in the spring and fall groups were similar with respect to gender and race/ethnicity: female, 53% vs 48%; white, 65% vs 62%; black, 14% vs 16%; and other race/ethnicity, 21% in both groups. Although the average age at enrollment did not vary between the 2 study groups (8.8 months, spring group, vs 9.0 months, fall group), the average ages at the time of the first and second doses of TIV were significantly different, per the study design. The mean age at the time of receipt of the first dose of TIV was 8.8 months for the spring group and 13.0 months for the fall group (P.01). Children in the spring group were also younger than those in the fall group when they received the second dose of TIV: 13.0 vs 14.2 months (P.01). Altogether, 432 children received 2 immunizations (220 spring and 212 fall), and 212 children in the spring PEDIATRICS Volume 118, Number 3, September 2006 Downloaded from by on November 16, 2006 e573

16 FIGURE 1 Follow-up and procedures for children enrolled. group received 3 doses of TIV. Because of the slight variation in the number of subjects with adequate blood samples or returned diaries after each dose of vaccine, the number of subjects analyzed for immunogenicity or reactogenicity at each time point is not identical (Fig 1). An adequate blood sample was obtained from 417 children (214 spring and 203 fall) after the second dose of TIV, and paired blood sample results were available for 404 subjects (205 spring and 199 fall). Reactogenicity data were recorded and analyzed on 1079 immunizations from a total of 1089 doses of TIV. Based on influenza surveillance in both North Carolina and Washington, influenza disease activity was initially detected in late January 2005, well after the period when study participants were vaccinated. In the spring group, 95% of children received their second dose of vaccine by October 21, 2004, whereas 95% of children in the fall group received their first dose of vaccine by October 13, 2004, and their second dose of vaccine by November 18, Immunogenicity Primary Outcome For the influenza A/H1N1 antigen, the antibody responses after 2 doses of vaccine were comparable between the spring and fall groups; however, for the A/H3N2 and B antigens, the responses in the spring group were less robust than those in the fall group (Fig 2). Excellent response rates to A/H1N1, as measured by antibody levels 1:32, were noted in both the spring (86%) and fall groups (93%). The A/H1N1 response rate of the spring group was noninferior to that of the fall group (P.001). Noninferiority of the spring schedule was not met with respect to the other 2 influenza antigens: for A/H3N2, the response was 70% in the spring group versus 83% for the fall group (P.336), and the response to B was 39% in the spring group versus 88% for the fall group (P 1.0). After 2 doses of vaccine, the GMTs for antibodies were also less robust in the spring group for both A/H3N2 and B antigens (Fig 3). For each of the 3 vaccine antigens, the respective GMTs for the e574 WALTER et al Downloaded from by on November 16, 2006

17 FIGURE 2 Seroresponse rate before vaccine (spring group only), after 1 dose of TIV (fall group only), or after 2 doses of TIV in young children receiving the spring or fall regimen. FIGURE 3 HAI antibody titers before administration of vaccine (spring group only), after 1 dose of TIV (fall group only), or after 2 doses of TIV in young children receiving either the spring or standard fall regimen. spring group versus the fall group were: A/H1N1, and (P.174); A/H3N2, and (P.022); and B, and (P.001). Secondary Outcomes At baseline, most of the children in the spring group were seronegative to all 3 of the vaccine antigens (Fig 2). The proportion of children with antibody levels 1:32 was 14% for A/H1N1, 27% for A/H3N2, and 3% for B antigens. The GMTs were 7.5 for A/H1N1, 14.6 for A/H3N2, and 4.9 for B (Fig3). In the spring group, we were able to determine the fourfold seroconversion rate for children with titers 1:8 before receiving any influenza vaccine. The fourfold seroconversion rates comparing preimmunization and post second dose were 87% against A/H1N1 antigens, 57% against A/H3N2 antigens, and 37% against B antigens. In contrast to children at baseline, antibody titers 1:32 to both A/H1N1 and A/H3N2 were noted in approximately half of the children in the fall group after receipt of a single dose of vaccine, whereas antibody titers to influenza B were noted in only 16% of the children (Fig 2). A significant increase in antibody between the first and second dose of TIV was noted for each of the 3 vaccine antigens in the fall group (P.001 for each antigen). After receiving 2 doses of vaccine, 80% of the children in the fall group had titers 1:32 for each of the 3 vaccine antigens, demonstrating a need for a second dose of vaccine to achieve adequate protections. A significantly higher proportion of children in the spring group achieved potentially protective levels of antibody to all 3 of the antigens after their first fall dose of TIV than children in the fall group after receiving their first fall dose (Fig 2). For influenza A/H1N1, there was an antibody level 1:32 in 86% of children in the spring group versus 55% of children in the fall group. Likewise, for influenza A/H3N2, 70% of children in the spring group and 47% of children in the fall group had antibody levels 1:32; for influenza B, the proportions were 39% of children in the spring group and 16% of children in the fall group (P.001 for each antigen). Reactogenicity Overall, TIV was well tolerated with relatively low rates of reactions. Moderate-to-severe fever (ie, temperature 38 C axillary) was reported during the first 3 days after PEDIATRICS Volume 118, Number 3, September 2006 Downloaded from by on November 16, 2006 e575

18 3.8% of the doses of TIV were received. There were 6 episodes (0.6%) of fever 39.5 C noted after receipt of any dose of TIV. Local reactions were also minimal after receipt of TIV. Moderate-to-severe pain and tenderness at the injection site were noted after 4% of doses. Redness was noted after 0.6% of doses and swelling after 0.3% of doses. Other moderate-to-severe symptoms reported after receipt of TIV included: irritability (16%), changes in sleep patterns (11%), vomiting (3%), and change in appetite (4%). Moderate-to-severe fever was twice as common in children who received routine immunizations but no influenza vaccine (fall group at enrollment, 8%) than in children who received TIV either alone or with other concomitant immunizations (4%; P.021). Reports of irritability after any TIV were comparable to the rates seen in the fall group receiving routine immunizations other than TIV. No serious adverse events were recorded after any dose of vaccine. There were no significant differences in the rate of moderate and severe reactions reported between the spring and fall groups, with the exception of vomiting after the second dose of TIV. Moderate-to-severe vomiting after a second dose of TIV was reported in 6 children in the fall group and no children in the spring group (P.04). Rates of moderate-to-severe reactions were comparable after dose 1, dose 2, or dose 3 of vaccine and did not increase after subsequent doses of TIV (Fig 4). In general, rates of moderate-to-severe reactions also did not vary when stratified according to the age of the child ( 12 months of age versus 12 months of age). Irritability after receipt of TIV was reported more frequently in children 12 months of age (18.2% vs 12.4%; P.01). DISCUSSION TIV currently contains vaccine antigens from 2 A subtypes, H3N2 and H1N1, and 1 B subtype. Between the and seasons, there was a change in vaccine composition for both the influenza A/H3N2 and B subtypes, whereas the H1N1 subtype remained unchanged. The change in the A/H3N2 subtype reflected an antigenic drift, whereas the change in the B antigen reflected a major change in the strain lineage. 18 In this study in young children, we have demonstrated that a springtime priming dose of TIV followed by a fall dose containing different influenza A/H3N2 and influenza B antigens produced a less robust immune response to the changed antigens when compared with 2 antigenically identical doses of vaccine delivered a month apart in the fall. Despite this finding, children in the spring group had higher levels of antibody than did children in the fall group after a single dose of vaccine, suggesting that priming did occur. Our study confirmed that the immune response to the unchanging A/H1N1 antigen was similar between the spring and fall groups. The response verified data from our previous study, which revealed that the time interval between influenza vaccine doses in toddlers receiving the vaccine for the first time does not affect immunogenicity when antigens remain the same. 13 This finding has been noted with other vaccines, such as hepatitis B, where the timing of antigen administration is not as important as the delivery of sequential doses Although the HAI antibody responses to drifted A/H3N2 after 2 different TIV preparations were less robust in children in the spring group than those of children who received 2 doses of identical A/H3N2 antigen in the fall group, 70% of children in the spring group developed protective levels of antibody to this antigen after receipt of 2 doses of vaccine. The proportion of children in the spring group with serologic protection against A/H3N2 was markedly better than that of the fall group after just a single dose of TIV in the fall. This suggests that the spring A/H3N2 antigen primed the immune response to the drifted fall A/H3N2 antigen. The antibody responses to B antigen were remarkably lower in those children in the spring group, who were primed with a B antigen from a different major lineage, suggesting that priming with a significantly different influenza antigen is not as successful as priming with a closely related antigen. Although previous studies have FIGURE 4 Reactogenicity as shown by dose of TIV compared with that of subjects in the fall group not receiving TIV at the enrollment visit. Reactogenicity was assessed for 3 days only and was based on moderate-to-severe symptoms. e576 WALTER et al Downloaded from by on November 16, 2006