Adverse Events Reported Following Live, Cold-Adapted, Intranasal Influenza Vaccine

ORIGINAL CONTRIBUTION

Hector S. Izurieta, MD, MPH Context In June 2003, the US Food and Drug Administration licensed a trivalent live, Penina Haber, MPH attenuated influenza vaccine (LAIV-T) for intranasal administration to healthy per- Robert P. Wise, MD, MPH sons 5 to 49 years of age. Although prelicensure testing involved 20 228 vaccinees, clinical trials were not of sufficient size to detect rare adverse events reliably. John Iskander, MD, MPH Objective To identify adverse events reported following LAIV-T administration af- Douglas Pratt, MD, MPH ter licensure. ChrisAnna Mink, MD, MPH Design, Setting, and Participants All adverse events reported to the US Vaccine Soju Chang, MD, MPH Adverse Event Reporting System (VAERS) during the 2003-2004 and the 2004-2005 influenza seasons. M. Miles Braun, MD, MPH Main Outcome Measures Numbers and proportions of reported adverse events Robert Ball, MD, MPH and reporting rates of adverse events per 100 000 vaccinees. NNUAL INFLUENZA VACCINA- Results Approximately 2 500 000 persons received LAIV-T during the first 2 post- tion is the primary method licensure seasons. As of August 16, 2005, VAERS received 460 adverse event reports for protection against influ- for vaccinations received from August 2003 through July 2005. No fatalities were re- enza illness.1 Until the 2002- ported. There were 7 reports of possible anaphylaxis, 2 reports of Guillain-Barre´ syn- 2003A influenza season, the only li- drome, 1 report of Bell palsy, and 8 reports of asthma exacerbation among individuals with a prior asthma history. Events in individuals for whom the vaccine was not indi- censed influenza vaccine in the United cated accounted for 73 reports (16%). States was the inactivated, trivalent in- jectable vaccine, with recommenda- Conclusions Reports to VAERS in the first 2 seasons of LAIV-T use did not identify tions emphasizing use among individu- any unexpected serious risks with this vaccine when used according to approved indications. Like many vaccines and other medical products, LAIV-T may rarely cause als for whom influenza is of particular anaphylaxis. Secondary transmission of the vaccine virus merits further investigation. 1,2 concern. In June 2003, the US Food Reports of asthma exacerbations in vaccinees with prior asthma history highlight the and Drug Administration (FDA) li- risks of vaccine use inconsistent with approved labeling. censed a trivalent live, attenuated in- JAMA. 2005;294:2720-2725 www.jama.com fluenza vaccine (LAIV-T [FluMist, MedImmune Vaccines Inc, Gaithers- issues.4,5 Currently, the vaccine manu- health coordinators.4,5,7 Manufacturers burg, Md]) for intranasal use among facturer is conducting a large postli- are required by law to report adverse healthy persons 5 to 49 years of age.3 censure study in a health maintenance events. Reports are sent electronically, by Each dose contains live attenuated in- organization to monitor medically mail, or by fax, and are received fluenza virus reassortants of the 3 attended and serious adverse events in by a VAERS contractor who enters strains recommended by the US Pub- a total of 60 000 LAIV-T recipients 5 the information into a database. The lic Health Service for the correspond- to 49 years of age.6 contractor will contact the reporter if ing influenza season.2,3 The Vaccine Adverse Event Report- basic information is not included. During prelicensure clinical trials, ing System (VAERS), jointly operated by LAIV-T was administered to 20 228 the FDA and the Centers for Author Affiliations: Center for Biologics Evaluation and persons aged 6 months to 93 years.3 Research, Food and Drug Administration, Rockville, Disease Control and Prevention since Md (Drs Izurieta, Wise, Pratt, Mink, Chang, Braun, and Although the number of vaccinees 1990, accepts reports of adverse events Ball); and National Immunization Office, Office of the studied during clinical trials was rela- Chief Science Officer, Centers for Disease Control and from any source. Although a few re- tively large, postlicensure administra- Prevention, Atlanta, Ga (Ms Haber and Dr Iskander). ports are sent by vaccine recipients Corresponding Author: Hector S. Izurieta, MD, MPH, tion of the vaccine to much larger Vaccine Safety Branch, Division of Epidemiology, Of- or their parents, most originate populations could reveal new safety fice of Biostatistics and Epidemiology, Center for Bio- from health care clinicians. They may logics Evaluation and Research, Food and Drug Ad- submit reports to VAERS directly or ministration, 1401 Rockville Pike, Second Floor, Suite For editorial comment see p 2763. 200S, HFM-222, Rockville, MD 20852-1448 (hector through manufacturers or state [email protected]).

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All serious reports are reviewed by FDA physicians who evaluate whether Box. Criteria for Review of Selected Conditions Following LAIV-T further follow-up investigation is needed. Administration The objective of this study of ad- Neurological Event verse events reported to VAERS during the first 2 influenza seasons following Any report specifying a diagnosis/disorder of the nervous system LAIV-T licensure was to describe the Possible Anaphylaxis9 characteristics of reported adverse events Includes: (a) events with signs or symptoms developing within 4 hours after vac- and to identify new or unexpected ad- cination, involvement of 1 or more organ systems (cutaneous, respiratory, car- verse events, including rare events. diovascular, and/or gastrointestinal) and treated with epinephrine, parenterally administered antihistamines, corticosteroids, intravenous fluids or bronchodila- METHODS tors or, if untreated, with involvement of more than 1 organ system; or (b) occur- We reviewed all reported adverse ring more than 4 hours after vaccination, with involvement of more than 1 organ events that followed LAIV-T adminis- system and treated tration during the 2003-2004 and the Possible Secondary Transmission 2004-2005 influenza seasons (August Possible transmission of the vaccine virus to a contact either during administra- 1, 2003, through July 31, 2005) and tion of the vaccine or from a vaccine recipient received by VAERS through August Influenzalike Illness 16, 2005. Reports are classified in VAERS as Events describing fever and cough, unless diagnosed otherwise either serious or nonserious accord- Asthma ing to the information provided in the Events with either a diagnosis of asthma/reactive airway disease or else describing report. The Code of Federal Regula- wheezing, stridor, or bronchospasm, provided the report did not specify determi- tions defines serious adverse events as nation of an alternative diagnosis death, life-threatening illness, hospi- Other Events talization or prolongation of hospitalization, permanent disability, or any As specified in the report event for which a medical interven- tion was required to prevent one of these outcomes.8 No causal relation to vaccination is implied by submission of described in the Box. Reports requir- were considered serious; no deaths were an adverse event report. ing clarification or additional informa- reported. Age (stated in 410 reports) Manufacturers are required to send tion were investigated by telephone in- ranged from 2 to 70 years (mean age, 26 all reports of adverse events to the FDA terviews with reporters or by requesting years). Of 448 reports that specified sex, according to a specific timetable.8 additional medical records. 256 (57%) occurred in females. Events that are serious adverse events Because VAERS is a government- and not included in the vaccine label sponsored surveillance system, insti- Allergic Events are usually expedited in accordance tutional review board approval and in- Fifty-four reports (12%) were classi- with the Code of Federal Regulations.In formed consent were not required. fied as allergic events (TABLE). Accord- addition, during the first 2 seasons fol- ing to criteria described in the Table, lowing licensure, at the request of the RESULTS 7 reports were possible anaphylaxis FDA, the vaccine manufacturer also ex- Approximately 2 500 000 persons re- events, including 4 in individuals who pedited reporting of other adverse ceived LAIV-T during the first 2 influ- developed throat swelling (2 reported events of interest. The events of pri- enza seasons following licensure. Of as serious) and 1 serious event in an in- mary interest for this review, based on these, approximately 500 000 were vac- dividual who reported periorbital swell- severity, data from clinical trials, and cinated during the 2003-2004 influ- ing. None of these events resulted in adverse event experiences with other enza season and approximately hospitalization. The age of individuals vaccines, included neurological events, 2 000 000 were vaccinated during the with possible anaphylaxis ranged from possible anaphylaxis,9 possible second- 2004-2005 season (Kimber Poffen- 10 to 49 years. The interval from vac- ary transmission of the vaccine virus to berger, MedImmune, written commu- cination to symptom onset was less than a contact, influenzalike illness, and pos- nication, April 18, 2005). VAERS re- 3 hours for all cases, and 20 minutes sible asthma (BOX). ceived a total of 460 adverse event or less for 5 of the cases. Although no All reports and medical records were reports during the study period; a ma- one had a reported prior history of ana- reviewed by 2 medical epidemiologists jority (283 reports) were received dur- phylaxis or known allergy to any of the and were classified according to criteria ing the first season. Forty reports (9%) vaccine components, 5 cases had prior

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history of hypersensitivity including There were 47 reports of other aller- Of these, 3 reports, including 1 of gen- contact dermatitis, hypersensitivity to gic symptoms, mainly rash, urticaria, eralized urticaria, 1 of a generalized other drugs, and seasonal allergy. or edema, mostly in the face and neck. itchy rash, and 1 of rash on the back and chest, were reported as serious. The interval from vaccination to onset of Table. Summary of All Intranasal Influenza Vaccine Reports by Main Condition, VAERS, 2003-2005 symptoms was between 1 and 3 days No. (%) for all 3 reports. None of these events resulted in hospitalization. All Reports All Serious Reports Main Conditions (N = 460) (n = 40) Respiratory Events Respiratory (n = 217) Influenzalike illness 67 (14.6) 2 (5) There were 217 reports (47%) of res- Vaccine failure 4 (0.9) 0 piratory events (Table). Sixty-seven Rhinitis 40 (8.7) 0 events were influenzalike illnesses; Pharyngitis, tracheitis 42 (9.1) 1 (2.5) none of these events resulted in hospi- Secondary transmission 22 (4.8) 1 (2.5) talization. Two events required emer- Sinusitis 12 (2.6) 0 gency department treatment and were Asthma 12 (2.6) 5 (12.5) reported as serious, 1 in a 39-year-old Pneumonia 10 (2.2) 5 (12.5) man with dehydration 3 days after Other respiratory 8 (1.7) 1 (2.5) vaccination and another in a 5-year- Constitutional (n = 67) old boy with a high fever who tested Weakness/tiredness 21 (4.6) 0 positive for influenza 1 month af- Fever 14 (3.0) 1 (2.5) ter vaccination. None of 40 rhinitis Headache 13 (2.8) 1 (2.5) events resulted in hospitalization or Dizziness 12 (2.6) 1 (2.5) were reported as serious. Of the 42 Arthritis 7 (1.5) 1 (2.5) pharyngitis/tracheitis cases, 1 case, tra- Allergic (n = 54) Possible anaphylaxis 7 (1.5) 3 (7.5) cheitis in an 8-year-old boy with onset Other allergic 47 (10.2) 3 (7.5) 22 days after vaccination, resulted in Abdominal symptoms (n = 33) 33 (7.2) 1 (2.5) hospitalization. There were 10 reports Ear-nose-throat (n = 18) of pneumonia with onset intervals Epistaxis 13 (2.8) 0 between 1 and 45 days after vaccina- Nose ulcer, redness 2 (0.4) 0 tion. Two of them, 1 in a 30-year-old Ear infection 2 (0.4) 0 man with onset 7 days after vaccina- Oral herpes simplex 1 (0.2) 0 tion and 1 in a 10-year-old boy with Ocular (n = 7) onset 2 days after vaccination, resulted Edema 3 (0.7) 0 in hospitalization. In 3 other pneumo- Retinal hemorrhage 1 (0.2) 1 (2.5) nia events (in a 9-year-old boy, a Eye pain 3 (0.7) 0 Neurological (n = 10) 13-year-old boy, and a 9-year-old girl) Guillain-Barre´ syndrome* 3 (0.7) 3 (7.5) the patients were not hospitalized, but Bell palsy 1 (0.2) 1 (2.5) were reported as serious events. Febrile seizures 1 (0.2) 1 (2.5) Among 12 sinusitis reports, none was Encephalomyelitis 1 (0.2) 1 (2.5) reported as serious. Encephalitis 1 (0.2) 1 (2.5) Other† 3 (0.7) 0 Possible Secondary Transmission Cardiovascular (n = 10) There were 22 reports of possible sec- Pericarditis‡ 3 (0.7) 2 (5) ondary transmission of the vaccine vi- Myocardial infarction 1 (0.2) 1 (2.5) rus from vaccinees to nonvaccinees. Chest pain/discomfort 6 (1.3) 0 None of the events resulted in hospi- Other (n = 44)§ Vaccine administration error ࿣ 18 (3.9) 0 talization. Among 18 cases in which age Other reports 26 (5.7) 3 (7.5) was reported, ages ranged from 3 to 64 Abbreviation: VAERS, US Vaccine Adverse Event Reporting System. years. Among 17 reports for which this *One of 3 reports of Guillain-Barre´ syndrome was excluded from analysis because of lack of supportive information. information was available, the inter- †Includes 1 report each of dystonic tongue, paresthesia of tongue, and ataxia. ‡One report of viral pericarditis; the other report of pericarditis was of unknown origin (cultures not performed). val from exposure to a vaccinated per- §Includes (serious) chickenpox, group A streptococcal infection, a psychiatric condition, rash/erythema, taste perver- sion, and irritability. son to symptom onset ranged from a ࿣If the reason for reporting is either a technical vaccine administration error or the vaccination of a person for whom the few hours to 15 days. Thirteen of the vaccine was not indicated, but without known adverse consequences. events (59%) were transmission to a

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health care clinician who adminis- facial weakness, progressive limb weak- nosed with “viral” gastroenteritis lead- tered the vaccine. Of them, 6 events re- ness, and loss of most reflexes. The lum- ing to ileus with onset 6 days after portedly occurred among military medi- bar puncture found high protein con- vaccination. No cultures were per- cal personnel exposed to vaccinees who centration (273 mg/100 mL) in the formed. already had respiratory symptoms at the cerebrospinal fluid and no pleocyto- time of LAIV-T vaccination. One pos- sis. She was hospitalized and recov- Constitutional Symptoms sible secondary transmission event re- ered. Guillain-Barre´ syndrome was also Of 67 reports (15%) of constitutional ported as serious concerned a 3-year- reported in a previously healthy 50- symptoms, the most frequently re- old girl with influenzalike symptoms year-old man with symptom onset 1 day ported events included weakness/ followed by lobar pneumonia 3 days af- after vaccination. His son and wife had tiredness (21), fever (14), headache ter her mother received LAIV-T. Only had a gastrointestinal illness approxi- (13), dizziness (12), and arthritis (7) 1 report of suspected secondary trans- mately 2 weeks earlier. (Table). mission included laboratory analysis to Bell palsy was reported in a 40-year- distinguish between vaccine and wild- old woman with onset of symptoms 5 Ear, Nose, Throat, type strains. Fifteen days after a pedia- days after vaccination. No cause was and Ocular Symptoms trician received LAIV-T, her 4-year- identified. Although she reported a prior Of a total of 18 reports (4%), 13 were old child developed influenzalike episode of Bell palsy approximately 20 epistaxis, 2 were nasal ulcer or red- symptoms. The Centers for Disease years ago, this could not be confirmed. ness, 2 were ear infections, and 1 was Control and Prevention influenza labo- Acute disseminated encephalomyelitis oral herpes simplex. None were seri- ratory analysis revealed that the child’s (ADEM) was reported in a 14-year-old ous. Seven reports (2%) described ocu- isolate was wild-type influenza boy with a prior history of asthma. On lar symptoms, including 3 reports of eye A(H3N2) similar to A(H3N2) viruses the day of vaccination he had an upper edema, 3 reports of eye pain, and 1 (se- that had been circulating and did not respiratory tract infection. Two days rious) report of retinal hemorrhage in contain any gene of the vaccine strain. postvaccination, he developed confu- a 9-year-old boy 1 day after vaccina- There was no report of possible sec- sion, followed by hyperreflexia and men- tion. For the latter report, the ophthal- ondary transmission to an immuno- ingismus. Magnetic resonance imaging mologist reported bleeding in the retina suppressed individual. was consistent with ADEM, and a na- but no detachment. None of these sal swab was negative for influenza vi- events resulted in hospitalization. Possible Asthma ruses. He was treated as an inpatient with Of 12 asthma episodes reported, 9 were corticosteroids and improved within 24 Vaccination of Persons for Whom among children 6 to 15 years of age and hours. Laboratory-confirmed enterovi- the Vaccine Was Not Indicated 3 in adults. The interval from vaccina- rus encephalitis was reported in a 39- There were 73 reports (16%) involv- tion to symptom onset ranged from a year-old pediatric nurse with onset 10 ing individuals for whom the vaccine few hours to more than a month. In 6 days after vaccination. Another report was not indicated according to the asthma events, the interval was4 days concerned a 4-year-old boy with no prior product label. Of them, 21 were out- or less. Eight of the 12 reports in- history of seizures who experienced fe- side the recommended age, 47 had pre- volved asthma exacerbations among brile seizures approximately 26 hours af- existing chronic conditions, and 5 were persons with prior asthma history. Five ter receiving LAIV-T. He recovered with- both outside the recommended age and were reported as serious. out sequelae. There were 3 nonserious had preexisting chronic conditions. The reports of other neurological condi- most frequent adverse events reported Neurological Events tions, including dystonic tongue 3 days among persons for whom the vaccine Ten neurological events (2%) were re- after vaccination in a 10-year-old boy was not indicated were influenzalike ill- ported, and 7 were reported as serious with prior history of a similar episode, ness, rhinitis, and other respiratory (Table). Two of the reports were Guil- tongue paresthesia in a 41-year-old man symptoms (31 reports). lain-Barre´ syndrome (GBS), both con- 1 day after vaccination, and ataxia and Of the 26 total reports among indi- firmed by a neurologist. The first was vertigo in a 52-year-old individual with viduals outside the recommended age in a previously healthy 21-year-old onset 11 days after vaccination. (including 5 who also had chronic con- woman who received LAIV-T in De- ditions), 7 were younger than 5 years cember 2004. The day following im- Abdominal Symptoms and 19 were 50 years or older. munization she developed fever and There were no reports of intussuscep- Among 52 reports for individuals myalgias (her mother, who was not vac- tion among 33 reports (7%) of abdomi- with preexisting chronic conditions (in- cinated, had similar symptoms as well nal symptoms, which included abdomi- cluding 5 who were also outside the rec- as pneumonia). About 10 days post- nal pain, vomiting, and diarrhea. There ommended age), 16 patients had a prior vaccination, she developed paresthe- was only 1 serious report, of hospital- history of bronchospasm. Eight re- sia in her extremities, and 8 days later ization, in a 46-year-old man diag- ports involved asthma exacerbations af-

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ter vaccination. Three of these events events. In addition, epistaxis, although about virus isolation and characteriza- were serious: 1 report involved a 14- among the more frequent events, also tion, and in it the virus found was a wild- year-old boy with onset 2 days after vac- was not investigated during clinical type influenza A(H3N2) virus. The other cination who had status asthmaticus trials. However, because of the limita- reports of suspected secondary trans- and was hospitalized; another report in- tions inherent in passive surveillance— mission were not assessed with virus iso- volved a 6-year-old boy with onset 3 including underreporting, reporting of lation and characterization. In the ab- days after vaccination with symptoms solely temporal associations, uncon- sence of viral characterization, reports lasting for 7 days; and the remaining re- firmed diagnoses, lack of denominator of possible secondary transmission port was of a 7-year-old boy with on- data and unbiased comparison groups, events may represent coincidental, natu- set of wheezing within 4 days after and possible reporting, surveillance, or rally occurring respiratory infections. Be- vaccination. source bias—data from VAERS require cause reporting delays and lack of labo- Among 8 reports concerning indi- cautious interpretation.4,5,7 The rates of ratory resources hinder the role of viduals with a prior history of chronic spontaneous adverse event reports can VAERS in the investigation of second- cardiovascular disease, 1 serious case be higher within the months following ary transmission, any further investiga- involved a 42-year-old man with a his- initial marketing of a new product,10 and tion of this potential risk would have to tory of uncontrolled hyperlipidemia serious adverse events are more likely take place in settings other than who was hospitalized with a myocar- to be reported. VAERS.3-5 The fact that more than half dial infarction 2 days after vaccina- According to the package insert, of these reports were of transmission to tion. He underwent cardiac catheter- LAIV-T is contraindicated for individu- a health care worker who administered ization. Among 10 reports from als with a history of anaphylactic reac- the vaccine may reflect preferential re- individuals with preexisting meta- tions or hypersensitivity to any of its porting related to concerns of the medi- bolic conditions (including 8 with thy- components, including eggs or egg prod- cal community regarding this potential roid disease), 1 (a 48-year-old woman ucts.3 In this review, none of the re- risk.2,3 who had pneumonia 7 days after vac- ports of possible anaphylaxis described With regard to the 2 GBS reports, both cination) was serious. There were no a prior history of anaphylaxis or hyper- diagnoses were confirmed by a neurolo- hospitalizations. Among the remain- sensitivity to a vaccine component. The gist. In 1 case, the short interval be- ing 14 individuals with chronic condi- 5 reports of possible anaphylaxis with tween vaccination and symptom onset, tions (4 with chronic neurological con- onset within 20 minutes after vaccina- and the patient’s recent exposure to fam- ditions, 4 with chronic respiratory tion are consistent with causal associa- ily members with gastrointestinal ill- diseases, 2 with pernicious anemia, 2 tion. This rate of 2 anaphylaxis reports ness, which provides an alternative non- with sarcoidosis, 1 with fibromyalgia, per million vaccinees is within the range vaccine etiology, make the association and 1 with lupus), none resulted in hos- from 1 per 20 000 to 1 per million esti- with the vaccine less likely.14,15 For the pitalization. One report, in a 48-year- mated by the Institute of Medicine for second case, the etiology of the GBS can- old woman who had a prior history of anaphylaxis after measles-mumps- not be identified. Although the pa- Bell palsy, was classified as serious. rubella vaccination and is somewhat tient’s respiratory infection of un- higher than the 0.65 cases per million known origin presents an alternative Vaccine Administration Error doses reported for all childhood and ado- nonvaccine etiology, the interval from There were a total of 18 reports (4%) lescent vaccinations in 4 health main- vaccination to onset is compatible with in which the only reason for reporting tenance organizations.9,11 Although this prior research on GBS and inactivated in- was an error in vaccine administra- estimate of anaphylaxis incidence in fluenza vaccine.14,15 As for the ADEM re- tion with no known adverse conse- VAERS could be affected by underre- port, the short time interval does not ap- quences. These included administra- porting, serious events are more likely pear to support vaccine causation.16 tion of 2 doses instead of 1 to children to be reported.4,5,12 Because of the route of administra- 9 years of age or older (10 reports), im- Shedding of vaccine virus following tion of this vaccine and timing of the ad- proper handling of vaccine (5 re- LAIV-T administration has been ob- verse events, the VAERS reports of epi- ports), and vaccination of a pregnant served in clinical trials, particularly staxis, nose ulcer, and ocular symptoms woman (2 reports). among children, and transmission of are potentially compatible with vaccine vaccine virus has been documented in causation. The 73 reports of vaccina- COMMENT a child care setting in a clinical trial in tion to persons for whom it was not in- A major strength of VAERS is that it is Finland.13 The per-protocol rate of trans- dicated, and the 18 reports of vaccine ad- national in scope. VAERS may allow de- mission was 1.75% (1/57), with an up- ministration errors, underscore the tection of rare events that would be un- per boundary of the 95% confidence in- complexity of marketing a vaccine that likely to be detected even in large clini- terval of 8.05%. Among the 22 reports requires a new route of administration cal trials. In the case of LAIV-T, these of secondary transmission in VAERS, and is indicated for healthy people be- included anaphylaxis and neurological only 1 report provided information longing to a specific age group.

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Although data from a large commu- cine when used according to ap- Author Contributions: Dr Izurieta had full access to all of the data in the study and takes responsibility for nity-based trial did not support the hy- proved indications. Like many vac- the integrity of the data and the accuracy of the data pothesis that LAIV-T is associated with cines and other medical products, analysis. an increase in asthma events in chil- LAIV-T may rarely cause anaphylaxis. Study concept and design: Izurieta, Haber, Wise, Mink, Ball. 17 dren, the 8 reports of asthma exacer- As with other vaccines, LAIV-T could Acquisition of data: Izurieta, Braun. bations among persons with prior his- carry the risk of anaphylaxis or other Analysis and interpretation of data: Izurieta, Haber, Wise, Iskander, Pratt, Mink, Chang, Braun, Ball. tory in our study are consistent with allergic events. Continued monitor- Drafting of the manuscript: Izurieta, Haber, Wise. findings from a small multicenter, pro- ing of neurological events, such as GBS, Critical revision of the manuscript for important in- spective, randomized, double-blind, pla- appears warranted. Determination of tellectual content: Izurieta, Haber, Wise, Iskander, Pratt, Mink, Chang, Braun, Ball. cebo-controlled safety study among the risk of secondary transmission of Statistical analysis: Izurieta, Chang. moderate and severe asthmatics 9 to 17 the vaccine virus would require a fo- Administrative, technical, or material support: Izurieta, years of age. In that study, 2 of 24 cused clinical study. Wise, Iskander, Braun, Ball. Study supervision: Izurieta, Haber, Wise, Iskander, LAIV-T recipients (days 2 and 3 post- The reports of asthma exacerbations Pratt, Mink, Braun, Ball. vaccination) and 0 of 24 placebo recipi- in vaccinees with prior asthma history Financial Disclosures: None reported. ents had asthma exacerbations within 28 highlight the potential risks of not fol- Funding/Support: The study was implemented by Food 18 and Drug Administration (FDA) and Centers for Dis- days. Additionally, a significant in- lowing the approved indications and ease Control and Prevention (CDC) scientists and the crease in asthma or reactive airways dis- support the need for continued close sur- only funds used were from CDC and FDA budgets. This study had no external sponsors. ease was observed for children 12 to 59 veillance for asthma exacerbations fol- Acknowledgment: We wish to thank the US Vaccine months of age following the first dose lowing use of this vaccine. The finding Adverse Event Reporting System (VAERS) staff, par- of LAIV-T in a randomized, double- of a high proportion of vaccine admin- ticularly Marla Sidey-Vener, RN, and Steve Gordon, 19 PharmD, for assistance on VAERS reports follow-up; blind, placebo-controlled trial. istration errors and the reports of use Elaine Miller, RN, Frank Destefano, MD, MPH, Wal- among persons for whom this vaccine ton Kim, MS, and Roseanne English (CDC), and Ann CONCLUSIONS McMahon, MD, MSc, and Jane Woo, MD, MPH (FDA) was not indicated underscore the need for their helpful comments and discussion; and Scott Reports to VAERS in the first 2 sea- for the clinician to follow the package Harper, MD, MPH, MSc, Alexander Klimov, PhD, ScD, and Nancy Cox, PhD (CDC), for their comments and sons of LAIV-T use did not identify any insert indications regarding vaccine ad- for contributing information on their investigation of unexpected serious risk with this vac- ministration and patient eligibility. secondary transmission of the vaccine virus.

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