PEDIATRICS Vol. 121 No. 3 March 2008, pp. 508-516 (doi:10.1542/peds.2007-1064)
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ARTICLE |
Safety and Immunogenicity of Concurrent Administration of Live Attenuated Influenza Vaccine With Measles-Mumps-Rubella and Varicella Vaccines to Infants 12 to 15 Months of Age
a School of Population Health, University of Melbourne and Murdoch Children's Research Institute, Victoria, Australia
b Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
c Kentucky Pediatric Research, Bardstown, Kentucky
d Pediatric Clinical Trials International, Columbus, Ohio
e Division of Infectious Diseases, Epidemiology, and Immunology, Emory University, Atlanta, Georgia
f School of Medicine, Boston University Medical Center, Boston, Massachusetts
g Discipline of Paediatrics, University of Adelaide and Children, Youth, and Women's Health Service, Adelaide, Australia
h Princess Margaret Hospital for Children, Subiaco, Australia
i Infectious Diseases, Children's Memorial Hospital, Chicago, Illinois
j Departments of Clinical Development and Biostatistics, MedImmune, Gaithersburg, Maryland
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ABSTRACT |
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OBJECTIVE. This study evaluated the safety, tolerability, and immunogenicity of live attenuated influenza vaccine administered concurrently with measles-mumps-rubella vaccine and varicella vaccine to healthy children 12 to 15 months of age.
METHODS. Children were assigned randomly to receive (1) measles-mumps-rubella vaccine, varicella vaccine, and intranasal placebo on day 0, followed by 1 dose of live attenuated influenza vaccine on days 42 and 72; (2) measles-mumps-rubella, varicella, and live attenuated influenza vaccines on day 0, followed by a second dose of live attenuated influenza vaccine on day 42 and intranasally administered placebo on day 72; or (3) 1 dose of live attenuated influenza vaccine on days 0 and 42, followed by measles-mumps-rubella and varicella vaccines on day 72. Serum samples were collected before vaccination on days 0, 42, and 72. Reactogenicity events and adverse events were collected through day 41 after concurrent vaccinations and through day 10 after administration of live attenuated influenza vaccine or placebo alone.
RESULTS. Among 1245 (99.5%) evaluable children, seroresponse rates and geometric mean titers for measles-mumps-rubella vaccine and varicella vaccine were similar with concurrent administration of live attenuated influenza vaccine or placebo (seroresponse rates of 
96% for measles-mumps-rubella vaccine and 82% for varicella vaccine in both groups). Hemagglutinin-inhibiting antibody geometric mean titers and seroconversion rates to influenza strains in live attenuated influenza virus vaccine were similar after the vaccine was administered alone (seroconversion rates of 98%, 92%, and 44% for H3, B, and H1 strains, respectively) or with measles-mumps-rubella and varicella vaccines (seroconversion rates of 98%, 96%, and 43%). The incidences of reactogenicity events and adverse events were similar among treatment groups.
CONCLUSIONS. Concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella vaccine and varicella vaccine provided equivalent immunogenicity, compared with separate administration, and was well tolerated.
Key Words: live attenuated influenza virus vaccine • varicella vaccine • measles-mumps-rubella vaccine • immunogenicity • concurrent vaccinations • children
Abbreviations: AE—adverse event • CI—confidence interval • GMT—geometric mean titer • HAI—hemagglutination-inhibiting • LAIV—live attenuated influenza vaccine • MMR—measles-mumps-rubella • RE—reactogenicity event
The advisory committee on Immunization Practices currently recommends that healthy children receive >25 vaccine doses during their first 2 years to prevent infections, including influenza.1 This schedule frequently necessitates concurrent administration of vaccines.
Although seroresponse rates and adverse reactions after administration of combinations of live attenuated vaccines are similar to those observed with separate administration,2 immunogenicity, safety, and lack of interference with concurrent administration of multiple live vaccines must be established. Because of this theoretical risk, the Centers for Disease Control and Prevention recommends that live vaccines that are not administered concurrently be administered at intervals of >4 weeks.2 Currently recommended vaccines for infants and young children that use live attenuated viruses as the immunogens include measles, mumps, rubella, varicella (frequently given as a combined product), and rotavirus vaccines.
Live attenuated influenza vaccine (LAIV, FluMist; MedImmune, Gaithersburg, MD) is currently approved for healthy children 2 years of age. Several studies have established that the frozen LAIV (and the recently licensed, refrigerator-stable formulation, referred to as cold-adapted influenza vaccine, trivalent) is immunogenic, efficacious, and well tolerated in young children.3–9 It is important to demonstrate that concurrent administration of LAIV does not adversely affect the immune response to LAIV or other pediatric live vaccines. The objective of this study was to evaluate the safety, tolerability, and immunogenicity of concurrent administration of LAIV with measles-mumps-rubella (MMR) and varicella vaccines in healthy infants 12 to 15 months of age.
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METHODS |
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Study Design
This randomized, placebo-controlled trial was conducted over 2 study seasons at 44 sites in the United States and 3 sites in Australia. To avoid potentially confounding factors in the interpretation of immune responses, children were enrolled outside periods of peak influenza activity in their respective regions. Study seasons in the United States were May through October, 2001 and 2002, and those in Australia were November 2000 through May 2001 and November 2001 through May 2002.
Eligible children were prospectively assigned randomly, in a 1:1:1 ratio, to 1 of 3 groups, as follows: MMR/varicella group, concurrent administration of MMR vaccine, varicella vaccine, and intranasal placebo treatment on day 0, followed by a single dose of LAIV on days 42 and 72; MMR/varicella/LAIV group, concurrent administration of MMR, varicella, and LAIV vaccines on day 0, followed by a second dose of LAIV on day 42 and intranasal placebo treatment on day 72; LAIV group, a single dose of LAIV on days 0 and 42, followed by concurrent dosing with MMR and varicella vaccines on day 72. Randomization was stratified according to season and site by using a block size of 6 and was achieved with a predefined randomization schedule that assigned a treatment group to each unique participant number. Each participant was assigned a unique participant number that was maintained throughout the trial. The MMR/varicella and MMR/varicella/LAIV groups were double-blinded with respect to treatment for the duration of the study. Because no injectable placebo treatments were used, treatment assignment to the LAIV group was unblinded after randomization.
The study was conducted in accordance with the Declaration of Helsinki, the US Code of Federal Regulations governing the protection of human subjects, and the International Conference on Harmonisation Guidance for Good Clinical Practice. The study protocol and informed consent documents were approved by the institutional review board or independent ethics committee of each site. Written informed consent was obtained from each subject's parent or legal guardian.
Study Participants
Eligible subjects were children 12 to 15 months of age who were in good health (determined by medical history and physical examination) and up to date with the primary series of recommended vaccines (according to standard clinic practice and local vaccine availability). Exclusion criteria included previous vaccination against or diagnoses of measles, mumps, rubella, or varicella; hypersensitivity to egg, egg protein, or any component of the study vaccines or placebo treatment; known or suspected immunosuppression or immunosuppressed household member; acute febrile (>100.0°F oral) illness or clinically significant upper respiratory illness within 72 hours before enrollment; receipt of aspirin (acetylsalicylic acid) or aspirin-containing products in the month before enrollment; receipt of any intranasally administered medication within 2 weeks before enrollment; receipt of any live virus vaccine within 1 month before enrollment through 30 days after the final visit; receipt of any inactivated vaccine within 2 weeks before enrollment through 30 days after the final visit; receipt of any blood product within 3 months before vaccination; and history of 2 episodes of medically attended wheezing or medically attended wheezing illness or bronchodilator medication use within 4 weeks before enrollment.
Vaccines
LAIV vaccine (MedImmune Vaccines, Mountain View, CA) was supplied in intranasal sprayers with a total volume of 0.5 mL, containing allantoic fluid stabilized with sucrose/phosphate/glutamate and 
107 median tissue culture infectious doses of each of the 3 attenuated vaccine strains grown in pathogen-free chicken eggs, that is, A/New Caledonia/20/99 (H1N1), A/Sydney/05/97 (H3N2), and B/Yamanashi/166/90. Vaccine was stored frozen at –15°C or below until just before intranasal administration (0.25 mL into each nostril). Excipient placebo was supplied in intranasal sprayers with a total volume of 0.5 mL, containing allantoic fluid from pathogen-free eggs, stabilized with sucrose/phosphate/glutamate. MMR vaccine (M-M-RII; Merck, Whitehouse Station, NJ) and varicella virus vaccine (Varivax; Merck) were supplied as single-dose vials of lyophilized vaccine.10,11
Study Evaluations
The primary objective was to compare the immune responses to measles, mumps, rubella, and varicella antigens in the MMR/varicella/LAIV and MMR/varicella groups and to compare the immune responses to the 3 strains of influenza (A/H1N1, A/H3N2, and B) in the MMR/varicella/LAIV and LAIV groups. Serum samples were obtained before vaccination on day 0 and on day 42 (for MMR and varicella vaccine responses) and day 72 (for LAIV responses).
Immunogenicity to mumps, measles, rubella, and varicella antigens was assessed and validated by Merck Research Laboratories (West Point, PA), using antigen-specific enzyme-linked immunosorbent assays to detect serum antibody (immunoglobulin G), before and after vaccination with MMR and varicella vaccines. Seroresponse criteria for measles, mumps, rubella, and varicella assays were predefined as 255 mIU/mL, 10 mumps antibody units per mL, 10 IU/mL, and 5 glycoprotein enzyme-linked immunosorbent assay units per mL, respectively.
Immunogenicity to influenza viruses was evaluated at MedImmune through measurement of serum hemagglutination-inhibiting (HAI) titers to each of the strains contained in the vaccine, using standard assay procedures.12 The HAI titer was defined as the reciprocal of the highest dilution of the test serum that inhibited hemagglutination completely. A titer of <4 was assigned to serum samples for which no inhibition could be detected, even at the lowest dilution tested (1:4 dilution). A fourfold or greater difference in titer between 2 serum samples was considered significant.13
A secondary objective of this study was to evaluate the safety and tolerability of concurrent administration of LAIV with MMR and varicella vaccines. An adverse event (AE) was defined as any unfavorable and unintended sign, symptom, disease, or worsening of a pre- existing condition associated temporally with vaccine administration. Reactogenicity events (REs) were predefined solicited AEs occurring after study vaccination, including injection site reactions and fever (>100.6°F rectal or aural, >100.0°F oral, or >99.6°F axillary). Serious AEs were defined as AEs that resulted in death, were life-threatening, required hospitalization or prolonged existing hospitalization, resulted in a persistent or significant disability, or required medical intervention to prevent one of these outcomes. To conduct the key safety comparisons between the MMR/varicella and MMR/varicella/LAIV groups (whether LAIV vaccine potentiated AEs associated with MMR/varicella vaccines), AEs and REs were recorded for 42 days after concomitant vaccination. To evaluate whether MMR/varicella vaccines potentiated REs associated with LAIV vaccine (MMR/varicella/LAIV versus LAIV alone), REs were recorded for 10 days after intranasal vaccination alone. Significant new medical conditions and serious AEs were recorded for 6 months after vaccination. REs, AEs, concomitant medication use, and health care provider visits were recorded daily by parents or guardians on assessment worksheets. Parents or guardians of children in the MMR/varicella and MMR/varicella/LAIV groups also recorded the presence and size of injection site reactions. Study staff members contacted parents or guardians by telephone to collect information regarding AEs, REs, and significant new medical conditions, 3, 14, 28, and 42 days after concurrent administration of MMR/varicella vaccines and LAIV or placebo and 3 and 10 days after administration of LAIV or placebo alone.
Statistical Analyses
A sample size of 300 evaluable subjects per treatment group was required to provide overall power of 94% to demonstrate equivalent immune responses between the treatment groups and to provide 88% power to decrease the probability of an increase of >10% in the incidence of REs. The immunogenicity population included children who received all scheduled treatments, and data were analyzed according to treatment received. The safety population included children with any RE or AE data for the visit/dose-specific safety evaluation period. Data for subjects in the safety population were analyzed according to treatment received. The primary end points were to demonstrate equivalent immunogenicity of MMR vaccine and varicella vaccine after concurrent administration with intranasally administered LAIV or placebo and to demonstrate equivalent immunogenicity of intranasally administered LAIV administered alone or concurrently with MMR and varicella vaccines.
Equivalent immunogenicity of MMR and varicella vaccines with or without LAIV was evaluated by determining postvaccination seroresponse rates for measles, mumps, rubella, and varicella antigens in baseline seronegative children in the MMR/varicella/LAIV group, compared with those in the MMR/varicella group, and by comparing postvaccination geometric mean titers (GMTs) for measles, mumps, rubella, and varicella antigens in children in the MMR/varicella/LAIV group with GMTs for those in the MMR/varicella group regardless of baseline antibody titers. The definitions for seroresponse and for baseline seronegativity for measles, mumps, rubella, and varicella antigens are presented in Table 1. In the immunogenicity analysis, equivalent seroresponse was achieved if the lower limit of the 2-sided exact 95% confidence interval (CI) for the rate difference (MMR/ varicella/LAIV minus MMR/varicella) was greater than –5 percentage points for measles, mumps, and rubella and greater than –10 percentage points for varicella. Equivalence based on the ratio of GMTs (MMR/varicella/LAIV GMT/MMR/varicella GMT) was achieved if the lower limit of the 2-sided 95% CI for the ratio was >0.5.
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Equivalent immunogenicity of LAIV administered alone or concurrently with MMR/varicella vaccines was evaluated by determining postvaccination (dose 2) seroconversion rates for each of the vaccine strains among baseline seronegative children who received MMR/varicella/LAIV vaccines, compared with those who received LAIV, and postvaccination (dose 2) GMTs for each of the vaccine strains among children who received MMR/varicella/LAIV vaccines, compared with those who received LAIV, regardless of baseline serostatus. The definitions for seroconversion and for baseline seronegativity for influenza strains are presented in Table 1. Equivalent seroconversion was achieved if the lower limit of the 2-sided 95% CI for the rate difference (MMR/varicella/LAIV minus LAIV) was greater than –10 percentage points for all strains. GMTs were considered equivalent if the lower limit of the 2-sided 95% CI for the ratio (MMR/varicella/LAIV GMT/LAIV GMT) was >0.5.
CIs for differences in seroresponse/seroconversion rates were constructed by using the method described by Miettinen and Nurminen.14 CIs for all GMTs were based on the percentile-based bootstrap technique and included stratification according to season (1, 2) and continent (Australia or North America), to control for potential previous exposure to the antigens under study that might vary according to these factors.
Incidence rates of REs were analyzed with 2-sided, exact, unconditional, 90% CIs for the rate difference.15 No formal statistical comparisons were performed for other AEs. All immunogenicity summaries and statistical analyses were performed with SAS 8 (SAS Institute, Cary, NC).
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RESULTS |
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Study Participants
Of 1251 children assigned randomly, 1245 were evaluable for safety and immunogenicity, including 411 in the MMR/varicella group, 422 in the MMR/varicella/LAIV group, and 412 in the LAIV group. All treatment groups were well matched with regard to age, gender, and ethnicity (Table 2). Data from 1 study site (n = 6) were excluded from the analysis because the documentation of data did not meet good clinical practices standards.
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A total of 1046 children (84.0%) completed the study. Subject disposition is presented in Fig 1. Ninety-eight subjects (7.9%) across the 3 treatment groups failed to meet continuing eligibility criteria and were withdrawn from the study. Of these, 49 children (50%; MMR/varicella/LAIV: 24; LAIV: 25) were withdrawn because of a local measles outbreak and subsequent unblinding of participants at 1 site; as specified in the study protocol, children who received MMR/varicella/LAIV vaccines or LAIV alone were offered open-label, measles-containing vaccine. Other reasons for failure to meet continuing eligibility criteria included history of
2 wheezing illnesses (n = 11), vaccine administered outside the dosing window (n = 3), varicella infection (n = 3), receipt of other vaccine (n = 7), randomization error (n = 8), egg allergy (n = 2), wheezing or bronchodilator use within 4 weeks (n = 14), and use of a product containing salicylate (n = 2).
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For the evaluation of immunogenicity, 8 subjects assigned randomly to the LAIV group received the treatment regimen for the MMR/varicella/LAIV group and were summarized as MMR/varicella/LAIV subjects. The immunogenicity population therefore consisted of 411 subjects in the MMR/varicella group, 430 subjects in the MMR/varicella/LAIV group, and 404 subjects in the LAIV group.
Immunogenicity
More than 90% of evaluated subjects in the MMR/varicella/LAIV and MMR/varicella groups were seronegative for measles, mumps, rubella, and varicella antigens at baseline. Equivalent seroresponse rates were demonstrated in baseline seronegative subjects for MMR and varicella vaccines, with and without concomitant LAIV administration (Table 3). Antigen-specific GMTs for MMR and varicella with and without concurrent LAIV administration and for the MMR/varicella and MMR/varicella/LAIV groups were within the equivalence criteria. The postvaccination rubella GMT was higher in the MMR/varicella group than in the MMR/varicella/LAIV group, but both exceeded the seropositive threshold of 10 IU. In contrast, the postvaccination measles titer was slightly higher in the MMR/varicella/LAIV group, compared with the MMR/varicella group (95% CI: 1.04–1.39).
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Equivalent immunogenicity was also demonstrated against the 3 influenza strains contained in the vaccine (A/H1N1, A/H3N2, and B) after 2 doses of LAIV with and without concurrent administration of MMR and varicella vaccines in baseline seronegative subjects (Table 4). Strain-specific seroconversion rates (more than fourfold increase in HAI titer) in subjects who were seronegative at baseline were similar in the MMR/varicella/LAIV and LAIV groups for each of the influenza strains. Strain-specific GMTs after 2 doses of LAIV were also comparable between the MMR/varicella/LAIV and LAIV groups.
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Safety
All vaccine regimens were generally well tolerated. During the 42 days after the first dose of LAIV or placebo concurrent with MMR and varicella vaccines, only runny nose/nasal congestion occurred significantly more frequently among subjects who received LAIV, compared with placebo (Table 5). Nearly one half of all children in the MMR/varicella/LAIV and MMR/varicella groups experienced
1 AE (47% and 49%, respectively) (Table 5). The most frequently reported AEs during the 42 days after concurrent vaccination with MMR/varicella/LAIV vaccines or MMR/varicella vaccines were diarrhea (17% vs 15%) and otitis media (8% vs 11%). Respiratory AEs occurred less frequently in the MMR/varicella/LAIV group than in the MMR/varicella group, with more than twice as many children in the MMR/varicella group reporting wheezing (2.5%), compared with the MMR/varicella/LAIV group (1.2%).
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Irritability and fever were significantly more frequent within 10 days after vaccination in subjects who received LAIV concurrent with MMR and varicella vaccines than in subjects who received LAIV alone (Table 6). There were no significant differences in REs within 10 days after the second dose of LAIV whether the first dose was administered concurrent with MMR and varicella vaccines or alone;
1 AE was reported by 25% and 32% of children, respectively, within 10 days after vaccination (Table 6). Respiratory events occurred less frequently in the MMR/varicella/LAIV group than in the LAIV group (1.5% vs 4.1%, respectively). No AE was reported with a frequency of >10%.
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No deaths were reported during the study. Nine reported serious AEs were considered to be possibly related to study vaccine. In the MMR/varicella group, there were 2 cases of croup, 1 case of pneumonia, and 1 case of bronchiolitis. In the MMR/varicella/LAIV group, there was 1 case each of croup and bronchiolitis. In the LAIV group, there was 1 case each of a viral chest infection, bronchiolitis, and bronchospasm. Nine children experienced 9 significant new medical conditions, including asthma (1 in the MMR/varicella group and 3 in the LAIV group), speech delay (2 in the LAIV group), excessive language delay (1 in the MMR/varicella group), cerebral palsy (1 in the MMR/varicella/LAIV group), and seizures (1 in the LAIV group).
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DISCUSSION |
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Influenza is associated with a significant excess of outpatient visits, hospitalizations, and rare deaths among young children each year.16–20 Routine annual influenza vaccination is now recommended for children between the ages of 6 months and 59 months, adding multiple vaccinations to the pediatric immunization schedule.21
The Advisory Committee on Immunization Practices recommends that injectable or nasally administered live vaccines not administered on the same day should be administered >4 weeks apart whenever possible, to minimize the potential for interference.22 This recommendation is supported by the observation that immunization with a live measles vaccine can block the immune responses to a live smallpox vaccine if the measles vaccine is administered within 15 days after smallpox vaccine dosing but not if the vaccines are administered simultaneously, presumably because of the action of interferon induced in response to the initial live virus vaccine.23,24 Similarly, administration of varicella vaccine within 28 to 30 days after receipt of MMR vaccine, but not simultaneous administration, has been associated with an increased risk of breakthrough varicella disease.25,26 However, concomitant administration of live vaccines can produce interference; concomitant administration of 2 live oral vaccines (polio vaccine and rotavirus vaccine) has been associated with a >40% reduction in seroresponse rates to a live oral rotavirus vaccine.27,28 Because it is common practice for children to receive several vaccines during the same office or clinic visit, it is important to establish the safety and immunogenicity of concomitantly administered live virus vaccines.
To date, limited data have been published on the impact on other vaccines of concurrent administration of either inactivated or live influenza virus vaccines, with respect to the immune responses of children or adults. The findings of the current study indicate equivalent immunogenicity with concurrent administration of MMR and varicella vaccines with LAIV, compared with separate administration. Seroresponse rates and ratios of antigen-specific antibody titers for measles, mumps, rubella, and varicella antigens present in the vaccines were similar, regardless of whether MMR and varicella vaccines were administered concurrently with LAIV or concurrently with placebo. Similarly, responses elicited by 2 intranasal doses of LAIV were not affected by concomitant administration of subcutaneously administered MMR and varicella vaccines. The serum HAI responses to the 3 LAIV strains observed in this study are consistent with findings from other LAIV studies, including the lower immune response to the A/H1N1 strain.3,29,30 Overall, although the presence of antibody responses after the administration of LAIV is predictive of protection, the lack of an antibody response is not indicative of the absence of protection.31
REs reported after vaccinations in this study were generally typical of those observed in a young pediatric population after vaccination. The increased incidence of fever seen in children treated with MMR/varicella/LAIV vaccines, compared with those treated with LAIV alone, can be attributed in large part to receipt of MMR and varicella vaccines, because an increased incidence of fever was reported in previous studies of concurrent immunization with MMR and varicella vaccines.32,33 Of note, respiratory AEs (including wheeze) were less frequent in the MMR/varicella/LAIV group than in the MMR/varicella group in the 42 days after vaccination.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Concomitant administration of live vaccines (MMR, varicella, and LAIV vaccines) to children 12 to 15 months of age did not affect significantly the seroresponse rates for MMR and varicella vaccines with simultaneous administration of LAIV. Strain-specific seroconversion rates for each of the 3 LAIV vaccine strains were not altered by concomitant administration of MMR and varicella vaccines. Concurrent administration of MMR vaccine, varicella vaccine, and intranasally administered LAIV was generally well tolerated. These findings suggest that LAIV can be administered concomitantly to young children with MMR and varicella vaccines in routine clinical practice with no diminution of immunogenicity or safety. This is important because LAIV offers potential benefits to young children, such as a broad immune response that includes both systemic and mucosal antibody responses and cellular immune responses,34 protection against strains that are antigenically "drifted" from the vaccine strains,4,35–38 and needle-free, intranasal administration.
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ACKNOWLEDGMENTS |
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This study was supported by MedImmune.
The LAIV Study Group included Parisa Arman, San Miguel Medical Clinic (Panorama City, CA); Russell T. Bain, Suncoast Clinical Research (New Port Richey, FL); Marshall Benbow, Southwest Children's Research Associates (San Antonio, TX); David Bernstein, Cincinnati Children's Hospital Medical Center (Cincinnati, OH); Mark Blatter, Primary Physicians Research (Pittsburgh, PA); Stan Block, Kentucky Pediatric/Adult Research (Bardstown, KY); William Borkowsky, Bellevue Hospital (New York, NY); Gerald Bottenfield, R/D Clinical Research (Lake Jackson, TX); Kevin Browngoehl, Drexel Hill Pediatrics (Drexel Hill, PA); Robert J. Carson, Pediatric Associates of Mt Carmel (Cincinnati, OH); Milo Hilty, Pediatric Clinical Trials International (Columbus, OH); Jeffrey A. Hirschfield (St Petersburg, FL); David Hudson, Tennessee Pediatrics (Hendersonville, TN); Louise Iwaishi, Hawaii Pacific Health (Honolulu, HI); Jerome Kaltman, Lake Forest Pediatric Associates (Lake Forest, IL); Harry Keyserling, Emory University School of Medicine (Atlanta, GA); James C. King, University of Maryland at Baltimore (Baltimore, MD); Leonard Krilov, Winthrop University Hospital (Mineola, NY); Erik Lamberth, Pennridge Pediatrics (Sellersville, PA); Stephen Lambert, Murdoch Children's Research Institute (Victoria, Australia); Thomas Latiolais, ARK-LA-TEX Children's Clinic (Bossier City, LA); John Lauzon, Owensboro Pediatrics (Owensboro, KY); Stephen Luber, Rockwood Clinic (Spokane, WA); Colin Marchant, Boston University Medical Center (Boston, MA); Eugenia Marcus, Pediatric Health Care at Newton-Wellesley (Newton, MA); Helen Marshall, University of Adelaide and Children, Youth, and Women's Health Service (Adelaide, Australia); Douglas Mitchell, Center for Pediatric Research (Norfolk, VA); Sharon Nachman, Stony Brook University School of Medicine (Stony Brook, NY); Corazon Oca, Southland Clinical Research (Fountain Valley, CA); Terry Nolan, University of Melbourne and Murdoch Children's Research Institute (Victoria, Australia); William Parker, Willis Knighton Medical Center (Shreveport, LA); Michael E. Pichichero, University of Rochester Medical Center (Rochester, NY); Bernard Pollara, University of South Florida (Tampa, FL); Keith Reisinger, Primary Physicians Research (Pittsburgh, PA); Peter Richmond, Princess Margaret Hospital for Children (Subiaco, Australia); Jose Romero, Creighton University (Omaha, NE); Mark Sawyer, University of California, San Diego, Pediatric Pharmacology Research Unit (La Jolla, CA); Mark Schane, Longmont Medical Research Network at Longmont Clinic (Longmont, CO); Richard Schwartz, Advanced Pediatrics (Vienna, VA); Shelly Senders, Senders & Associates Pediatrics (University Heights, OH); Peter Short, East Coast Clinical (Salisbury, MA); Rafael Solis, San Miguel Medical Clinic (North Hollywood, CA); Malcom J. Sperling, Edinger Medical Group (Fountain Valley, CA); Craig A. Spiegel, Radiant Research (Bridgeton, MO); Tibisay Villalobos, Affinity Health Group (Tifton, GA); Emmanuel B. Walter, Duke Children's Primary Care (Durham, NC); Peter Wright, Vanderbilt Medical Center (Nashville, TN); Ram Yogev, Children's Memorial Hospital (Chicago, IL).
We thank the participating children and their parents, the study nurses and coordinators, and the clinical testing laboratory staff members. We thank Dr John Boslego and Dr Florian Schoedel of Merck Research Laboratories for their assistance with the analysis and interpretation of serologic responses to the MMR and varicella antigens and CSL Ltd for assistance in the conduct of this study. We also thank David P. Greenberg, MD, who was the central safety monitor for this study, Colin Hessel, MS, and Stephen Chan, BS, who conducted the statistical analysis and programming, and Catherine Grillo, MS, Gerard P. Johnson, PhD, and Janet Stead, BM, BS, who provided medical writing and editorial assistance on behalf of MedImmune.
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FOOTNOTES |
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Accepted Aug 15, 2007.
Address correspondence to Terry Nolan, MBBS, PhD, School of Population Health, University of Melbourne, Level 2, 723 Swanston St, Carlton, Melbourne, Victoria 3010, Australia. E-mail: t.nolan{at}unimelb.edu.au
Financial Disclosure: Drs Nolan, Bernstein, Block, Hilty, Keyserling, Marchant, Marshall, Richmond, Yogev, and Mendelman and the LAIV Study Group participated in this research study, which was sponsored by MedImmune. The Murdoch Children's Research Institute has received research grant support from MedImmune. Dr Bernstein is a consultant for MedImmune and has received honoraria for speaking engagements on behalf of MedImmune. Dr Block has served as a consultant and speaker for and has received research grant support from MedImmune. Dr Marchant has received research and grant support from GlaxoSmithKline, MedImmune, and Merck, has served on the speakers bureaus for GlaxoSmithKline and Sanofi Pasteur, and has served as a consultant for GlaxoSmithKline, MedImmune, Merck, and Sanofi Pasteur. Dr Marshall has been the principal investigator for several studies sponsored by the pharmaceutical industry, including MedImmune. Iksung Cho and Julie Cordova are current and former employees of MedImmune, respectively. Dr Mendelman is a former employee of and current consultant for MedImmune.
This trial has been registered at www.clinicaltrials.gov (identifier NCT00192491).
| What's Known on this Subject Childhood vaccines are often administered concurrently. There is a theoretical possibility that components of one vaccine may alter immune responses to another. The concurrent use of live attenuated influenza virus vaccine with other live vaccines for children has not been investigated.
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| What This Study Adds Intranasally administered live attenuated influenza virus vaccine can be administered concomitantly with measles-mumps-rubella and varicella vaccines to young children in routine clinical practice without reducing the immunogenicity or safety of any of the vaccines.
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REFERENCES |
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