To the Editor: In their report on the use of inactivated andlive attenuated influenza vaccines to prevent antigenicallydrifted influenza, Ohmit et al. (Dec. 14 issue)1 conclude thatthe live attenuated vaccine was less efficacious than the inactivatedvaccine in their study population of healthy adults. This conclusionis not warranted, for three reasons. First, the study was nota head-to-head comparison of the two vaccines. The design wasactually that of two separate studies: a comparison of inactivatedvaccine with injectable placebo and a comparison of live attenuatedvaccine with intranasal placebo. Second, 1800 participants wereestimated to be needed to achieve the planned statistical powerof the study, but only 876 participants were included in theper-protocol analyses. Consequently, none of the analyses involvingthe live attenuated vaccine had significant results. Third,the only apparent superiority in efficacy of the inactivatedvaccine over the live attenuated vaccine was for type B influenza.Despite the random assignment of participants to study interventions,these results could easily have been affected by the chanceoccurrence of more infections with viruses of the Victoria lineage(not included in the vaccine) in the group receiving live attenuatedvaccine than in the group receiving inactivated vaccine.
Thomas G. Boyce, M.D., M.P.H. Mayo Clinic College of Medicine Rochester, MN 55905 boyce.thomas{at}mayo.edu
Dr. Boyce reports receiving speaking fees from Sanofi Pasteurand MedImmune.
References
Ohmit SE, Victor JC, Rotthoff JR, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med 2006;355:2513-2522. [Free Full Text]
To the Editor: King et al. (Dec. 14 issue)1 report the beneficialeffects of school-based influenza vaccination. The study waswell designed, but we wonder why the serious adverse event ofasthmatic exacerbation 36 days after vaccination was judgedto be unrelated to the vaccine by investigators who were awareof study-group assignments. Asthmatic exacerbations in personswith a history of asthma have been considered one type of adverseevent that can occur after the administration of live attenuatedintranasal influenza vaccine.2 The interval from vaccinationto the onset of symptoms may range from a few hours to morethan a month. Children 18 months to 4 years of age are alsoreported to have a higher relative risk of asthmatic events15 to 42 days after vaccination than earlier.3 We are concernedthat the lack of blinding may have affected the assessment ofcausality for adverse events.
Takashi Takahashi, M.D. Tsugiyasu Kanda, M.D. Nobuo Yamaguchi, M.D. Kanazawa Medical University Kahoku-gun 920-0293, Japan taka2si{at}kanazawa-med.ac.jp
References
King JC Jr, Stoddard JJ, Gaglani MJ, et al. Effectiveness of school-based influenza vaccination. N Engl J Med 2006;355:2523-2532. [Free Full Text]
Izurieta HS, Haber P, Wise RP, et al. Adverse events reported following live, cold-adapted, intranasal influenza vaccine. JAMA 2005;294:2720-2725. [Erratum, JAMA 2005;294:3092.] [Free Full Text]
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-e407. [Free Full Text]
Drs. Ohmit and Monto reply: Although we do not use the term"head to head" in describing our study, we disagree with Dr.Boyce's statement that it was actually two studies. Participantswere randomly assigned to one of the study groups as they wereenrolled, and since the trial was double-blind, all observerswere unaware of whether the participant was receiving vaccineor placebo. The percentage of persons in each group who reportedinfluenza-like illnesses did not differ among groups, indicatingthat the route of vaccine administration did not bias the reportingof illness. Although the planned number of participants in thestudy was not achieved, insufficient power cannot be used toexplain our results, since the community attack rate was higherthan that assumed in the sample-size calculations and sincethe required number of end points occurred. The only differencebetween the per-protocol population (876 participants) mentionedby Dr. Boyce and the intention-to-treat population (1247 participants)was the timing of collection of the postintervention blood specimens,which made the increase in antibody titer (the serologic endpoint) not useful in the larger group. We did not stress theserologic end point in our analyses, mainly because it put thelive attenuated influenza vaccine at a disadvantage1; instead,we focused on the end points related to virus identification:isolation of the virus in cell culture and through real-timepolymerase chain reaction (PCR).
To say that the differences in efficacy were related to typeB only is incorrect, and to explain the differences as beingrelated to B-lineage differences is only speculation. In theanalyses that considered outcomes associated with type A influenzaonly, the efficacies of the live attenuated influenza vaccineand the inactivated vaccine, calculated with the use of culture-onlyend points, were identical; however, when the combined cultureand PCR results were examined, the efficacy of the live attenuatedinfluenza vaccine was reduced. In contrast, in a single yearin which drifted viruses circulated, analyses using multipleend points showed that the inactivated vaccine was consistentlyefficacious.
Suzanne E. Ohmit, Dr.P.H. Arnold S. Monto, M.D. University of Michigan School of Public Health Ann Arbor, MI 48109 sohmit{at}umich.edu
References
Treanor JJ, Kotloff K, Betts RF, et al. Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine 1999;18:899-906. [CrossRef][ISI][Medline]
Dr. King replies: As noted by Takahashi et al., the unblindednature of our study could have biased the investigators. However,the study design was not intended to definitively assess vaccinesafety. Site investigators, all of whom had extensive experiencein conducting clinical trials, made assessments of the possiblerelationship of adverse events to immunization. It is difficultto assign causation of wheezing to a vaccine in patients withasthma, who naturally have occasional exacerbations. This vaccinehas been administered safely to over 2000 school-age childrenwith asthma, who have had no increase in asthmatic exacerbationsas compared with recipients of parenteral influenza vaccine.1Also, despite clear recommendations that children with asthmashould receive a yearly influenza vaccine, the proportion whoare immunized is low2 in a population of children in whom wild-typeinfluenza is likely to be a greater risk than vaccine-inducedasthmatic exacerbation.
James C. King, Jr., M.D. University of Maryland School of Medicine Baltimore, MD 21201 jking{at}peds.umaryland.edu
Dr. King reports receiving, since the publication of his article,consulting fees from MedImmune.
References
Fleming DM, Crovari P, Wahn U, et al. Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J 2006;25:860-869. [CrossRef][ISI][Medline]
Gnanasekaran SK, Finkelstein JA, Lozano P, Farber HJ, Chi FW, Lieu TA. Influenza vaccination among children with asthma in Medicaid managed care. Ambul Pediatr 2006;6:1-7. [CrossRef][ISI][Medline]
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