UBC Faculty Research and Publications

Short and Long-Term Safety of the 2009 AS03- Adjuvanted Pandemic Vaccine De Serres, Gaston; Gariépy, Marie-Claude; Coleman, Brenda; Rouleau, Isabelle; McNeil, Shelly; Benoît, Mélanie; McGeer, Allison; Ambrose, Ardith; Needham, Judy; Bergeron, Chantal; Grenier, Cynthia; Sleigh, Kenna Marie; Kallos, Arlene; Ouakki, Manale; Ouhoummane, Najwa; Stiver, Grant; Valiquette, Louis; McCarthy, Anne; Bettinger, Julie A.; PHAC-CIHR influenza Research Network (PCIRN) Jul 31, 2012

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Short and Long-Term Safety of the 2009 AS03-Adjuvanted Pandemic VaccineGaston De Serres1,2*, Marie-Claude Garie´py1, Brenda Coleman3, Isabelle Rouleau1, Shelly McNeil4,Me´lanie Benoıˆt1, Allison McGeer3, Ardith Ambrose4, Judy Needham5, Chantal Bergeron6,Cynthia Grenier7, Kenna Sleigh8, Arlene Kallos5, Manale Ouakki2, Najwa Ouhoummane2, Grant Stiver8,Louis Valiquette7, Anne McCarthy6, Julie Bettinger5 on behalf of the PHAC-CIHR influenza ResearchNetwork (PCIRN)1 Centre de recherche du CHUQ-CHUL, Laval University, Quebec City, Quebec, Canada, 2 Institut national de sante´ publique du Que´bec (INSPQ), Quebec City, Quebec,Canada, 3 Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada, 4 Canadian Center for Vaccinology, Halifax, Nova Scotia, Canada, 5 Vaccine EvaluationCenter, BC Children’s Hospital and the University of British Columbia, Vancouver, British Columbia, Canada, 6 The Ottawa General Hospital, Ottawa, Ontario, Canada,7 Universite´ de Sherbrooke, Sherbrooke, Quebec, Canada, 8 University of British Columbia, Vancouver, British Columbia, CanadaAbstractBackground: This study assessed the short and the long term safety of the 2009 AS03 adjuvanted monovalent pandemicvaccine through an active web-based electronic surveillance. We compared its safety profile to that of the seasonal trivalentinactivated influenza vaccine (TIV) for 2010–2011.Methodology/Principal Findings: Health care workers (HCW) vaccinated in 2009 with the pandemic vaccine (Arepanrix Hfrom GSK) or HCW vaccinated in 2010 with the 2010–2011 TIV were invited to participate in a web-based active surveillanceof vaccine safety. They completed two surveys the day-8 survey covered the first 7 days post-vaccination and the day-29survey covered events occurring 8 to 28 days after vaccination. Those who reported a problem were called by a nurse toobtain details. The main outcome was the occurrence of a new health problem or the worsening of an existing healthcondition that resulted in a medical consultation or work absenteeism. For the pandemic vaccine, a six-month follow-up forthe occurrence of serious adverse events (SAE) was conducted. Among the 6242 HCW who received the pandemic vaccine,440 (7%) reported 468 events compared to 328 of the 7645 HCW (4.3%) who reported 339 events after the seasonal vaccine.The 2009 pandemic vaccine was associated with significantly more local reactions than the 2010–2011 seasonal vaccine (1%vs. 0.03%, p,0.001). Paresthesia was reported by 7 HCW (0.1%) after the pandemic vaccine but by none after the seasonalvaccine. For the pandemic vaccine, no clustering of SAE was found in the 6 month follow-up.Conclusion: The 2009 pandemic vaccine seems to have a good safety profile, similar to the 2010–2011 TIV, with theexception of local reactions. This surveillance was adequately powered to identify AE associated with an excess risk $1 per1000 vaccinations but is insufficient to detect rare AE.Trial Registration: ClinicalTrials.gov NCT01289418, NCT01318876Citation: De Serres G, Garie´py M-C, Coleman B, Rouleau I, McNeil S, et al. (2012) Short and Long-Term Safety of the 2009 AS03-Adjuvanted PandemicVaccine. PLoS ONE 7(7): e38563. doi:10.1371/journal.pone.0038563Editor: Benjamin J. Cowling, University of Hong Kong, Hong KongReceived February 2, 2012; Accepted May 9, 2012; Published July 3, 2012Copyright:  2012 De Serres et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Funding: This study was funded by the Public Health Agency of Canada (PHAC)/Canada Institutes for Health Research (CIHR) Influenza Research network (PCIRN)and by GlaxoSmithKline (GSK) Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing Interests: The authors have read the journal’s policy and have the following conflicts: Gaston De Serres has received research grant from GSK,Sanofi Pasteur. Shelly McNeil has research grants from GSK, Pfizer, and Sanofi and participated in clinical trials for GSK, Sanofi, Pfizer, Merck, Novartis. She hasreceived speaking fees/honoraria from Merck, GsK and Pfizer. Me´lanie Benoıˆt owned Janssen-ortho stocks and/or stock options and was an employee of Janssen-ortho (Johnson and Johnson) until 2009. Louis Valiquette has served on advisory boards for Abbott and Wyeth, and has received compensation to conduct clinicaltrials involving antibacterials from Genzyme, Wyeth, Merck, Pfizer, BioCryst, and Optimer. The other authors have declared that no competing interests exist. Thisdoes not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.* E-mail: gaston.deserres@ssss.gouv.qc.caIntroductionInfluenza vaccines are generally considered safe, but thefrequent changes to match the vaccine’s antigen to the influenzavirus’s antigenic shifts or drifts may affect their safety profile.Unexpected adverse events have been reported with influenzavaccines including the Guillain-Barre´ syndrome in the UnitedStates in 1976 [1], oculorespiratory syndrome (ORS) in Canada in2001 [2,3] and more recently febrile convulsions that led to thesuspension of the vaccination campaign in children aged 5 yearsand under in Australia in 2010 [4,5]. In Canada and Europe,manufacturers are required to conduct immunogenicity trials in 60healthy young adults and 60 elderly people to obtain their annuallicensure. These trials are so small they are only able to detectadverse events occurring at a very high frequency. When theannual fall mass vaccination campaign against seasonal influenzaPLoS ONE | www.plosone.org 1 July 2012 | Volume 7 | Issue 7 | e38563starts, several hundreds of thousands of people are vaccinated dailyover the first six weeks. At this pace, if an adverse event occurred,millions of doses may have been administered in the intervalbetween the detection of a signal and the investigation of thisAEFI. Relying on passive adverse event surveillance is insufficientand other mechanisms need to be put in place. [6] An activesurveillance system capable of rapid and economical collection ofsafety data on a large number of vaccinated people before or veryearly in the mass campaign could constitute an intermediate stepproviding some reassurance about the safety of the vaccine.For its pandemic vaccination in the fall of 2009, Canada choseArepanrixH, an AS03-adjuvanted monovalent influenza vaccinemanufactured by GlaxoSmithKline (GSK). [7] Despite theexperience gathered on nearly 40,000 individuals who werevaccinated in clinical trials, there were public concerns regardingthe safety of the AS03 adjuvant system. [8] While passivesurveillance of adverse events following immunizations (AEFI)was enhanced during the course of the mass vaccinationcampaign, an active electronic surveillance of a large number ofhealth care workers (HCW) was implemented to rapidly detectunexpected adverse events associated with this vaccine. HCWwere selected to participate as they were among the firstindividuals to receive the adjuvanted pandemic vaccine in thecampaign and because they constitute a well-defined, readilyaccessible group highly motivated to look for AEFI. Despite theinclusion of several thousands of HCW, this cohort was designedto detect AEFI occurring at a rate $1 per 1000 vaccinees. Thiswould have been sufficient for events like ORS in Canada in 2000or seizures in Australia in 2010 but not for rare events like theGuillain Barre Syndrome (GBS). [9,10] Many similar cohortstudies have been conducted in individuals who receivedadjuvanted pandemic vaccines but only AEFIs occurring withinthe first few weeks after vaccination have been collected.[11,12,13,14,15,16] Longer term assessment of the safety of theadjuvanted vaccine has been missing.The objective of this study was to assess the short and the longterm safety of the AS03 adjuvanted monovalent pandemic vaccinein Canada. We compared its safety profile to that of the seasonaltrivalent inactivated influenza vaccine (FluviralH, GlaxoSmith-Kline GSK) for 2010–2011.Table 1. Characteristics of the health care workers vaccinated with the monovalent 2009 AS03-adjuvanted pandemic vaccine orthe 2010–2011 trivalent inactivated seasonal vaccine.2009 2010–2011 P valuePandemic vaccine Seasonal vaccinen (%) n (%)Participants enrolled 6525 7645With valid email address 6242 (96%) 7549 (99%) ,0.0001Day-8 survey completed 4307(69%) 5825 (77%) ,0.0001Day 29 survey completed 4057(65%) 5724 (76%) ,0.0001Completed $1 survey 4984(80%) 6269 (83%) ,0.0001Completed both surveys 3308(53%) 5280 (70%) ,0.0001Demographics N = 3159* N = 6280Gender 0.20Female 73% 74%Male 27% 26%Age ,0.0001,30 33% 23%30–39 22% 24%40–49 20% 22%50–59 20% 23%60+ 4% 8%Type of occupation ,0.0001Physician 11% 13%Nurse 27% 19%Medical technician 6% 7%Other health professional 10% 16%Administration 11% 17%Other workers 34% 27%Vaccinated against pH1N1 100% 91% ,0.0001Ever vaccinated against seasonal influenza NA 91% NA*For 2009 this information was collected in only one site.NA: Not available.doi:10.1371/journal.pone.0038563.t001Safety of the AS03-Adjuvanted Pandemic VaccinePLoS ONE | www.plosone.org 2 July 2012 | Volume 7 | Issue 7 | e38563Methods2.1 Study Participants and ProceduresIn 2009, the surveillance was conducted in three hospitals(Quebec City, Toronto, and Halifax) whereas in 2010–2011, 7hospitals (Quebec City, 2 in Vancouver, Toronto, Halifax,Ottawa, and Sherbrooke) participated. All HCW immunized inthese institutions were invited to participate in the web-basedactive surveillance of vaccine safety. Participants had to sign ashort consent form, provide their email address and provide theirhome or cell phone number. In 2009, HCW received ArepanrixH,the AS03-adjuvanted monovalent influenza vaccine from Glaxo-SmithKline (GSK) whereas for 2010–2011, they were given theseasonal trivalent split inactivated influenza vaccine (FluviralH) alsofrom GSK.HCW were recruited between October 26th and November12th, 2009 and between October 15th, 2010 and January 18th,2011. In 2009, 8, 15 and 29 days post vaccination, participantswere sent an email message requesting them to complete astandardized electronic survey accessible by clicking on a personalhyperlink embedded in the email. The day 8 survey covered thefirst 7 days post vaccination; the day 15 survey collected dataabout events occurring 8 to 14 days after vaccination; and the day29 survey covered events occurring 15 to 28 days after vaccination.The 2010–2011 surveillance included only two surveys (one onday 8 and one on day 29); the latter covering the period from 8 to28 days post vaccination. During both years, if a participant failedto answer within 72 hours, a reminder email was sent. Non-responders were not contacted further.The main outcome was the occurrence of a new health problemor the worsening of an existing health condition that resulted in amedical consultation or work absenteeism. For each period,participants were asked if they developed the problem during thefollow-up period. Those who reported a problem on the websurvey were contacted by telephone by a trained nurse whoobtained a detailed history of the event. This additionalinformation was entered within 72 hours in the central databaseand monitored twice weekly for potential signals by a researchassistant.For the 2009 pandemic vaccine, after the completion of the 0–28 day follow-up survey, a six-month follow-up survey for theoccurrence of serious adverse events that occurred in the periodfrom one month to six months post-pandemic vaccination wasadded at the request of the vaccine manufacturer. For logisticalreasons, it was only conducted at the Quebec City site whichincluded 77% of the 2009 participants. The primary outcome wasthe occurrence of serious adverse events (SAE) defined as anyhealth condition requiring a hospitalization, or an event that waslife-threatening, resulting in persistent or significant disability/incapacity or an event resulting in a congenital anomaly/birthdefect. Participants who reported SAEs in the electronic surveywere contacted by a trained nurse to obtain a detailed historyregarding their reported SAE.Each year, this study was approved by the Research EthicsBoard (REB) of each participating site: Comite´ d’e´thique de larecherche du CHUQ (Que´bec), Comite´ d’e´thique de la rechercheen sante´ chez l’humain du Centre Hospitalier universitaire deSherbrooke (Sherbrooke), UBC C&W Research Ethics Board(Vancouver), IWK Health Centre Research Ethics Board(Halifax), Mount Sinai Hospital Research Ethics Board (REB)(Toronto), The Ottawa Hospital Research Ethics Board (Ottawa),University of British Columbia Clinical Research Ethics Board(Vancouver).2.2 AnalysesAEFI were classified into broad system categories. Thefrequency of AEFI was compared between the 2009 pandemicvaccine and the 2010–2011 seasonal vaccine during the first 7-daypost vaccine and those occurring between 8 and 28 days, using chisquare test. For 2009, the results of 8–28 day follow-up wereobtained by combining results from the 8–14 day survey and the15–28 day survey. Analyses were performed using SAS version 9.2(Inc., Cary, N.C., USA).ResultsA total of 6242 HCW vaccinated with the 2009 pandemicvaccine and 7549 vaccinated with the 2010–2011 seasonalinfluenza vaccine were enrolled and had a valid email address.(Table 1) Among them 53% and 70% respectively responded tothe two surveys and 80% and 83% responded to at least onesurvey. In 2009, demographic information was collected at only atone site whereas all sites collected it in 2010–2011. In both years,about three quarters of participants were women. The age rangedfrom 16 to 87 years with about two thirds being between 30 and60 years old while fewer than 8% were 60 years and older. Theoverall mean age was 39 years in 2009 and 41 years in 2010–2011.Compared to the active population in Canada, there was an over-representation of women but the mean age (40 years) was similar.[17] For both years, about 12% were physicians, 19–27% werenurses, 10–16% were other types of health professionals (phar-macists, physiotherapists, etc.) and 44%–45% were administrativeor other types of workers. In 2010–2011, 91% (95% CI: 90.6,92.0) of participants had been vaccinated against pandemicinfluenza the year before and 91% (95% CI: 90.0,91.5) hadreceived seasonal influenza vaccine at least once previously.Among HCW with a valid email address, for the 0–28 dayfollow-up, 508 (8.1%; 95% C.I: 7.5, 8.8) in 2009 and 386 (5.1%;95% CI: 4.6, 5.6) in 2010–2011 reported on their electronic surveyat least one event for which they missed work or had a medicalconsultation. After contact from research nurses to validate theevents, 85 of the 553 events reported after the 2009 pandemicvaccine were excluded for the following reasons: 49 wereerroneously reported and did not result in a medical consult orwork absenteeism (main outcome) and 36 could not be validatedeither because the HCW did not want to divulge informationabout the event or the HCW was not reached. In 2010–2011, 61of the 412 reported events were excluded after nurse follow up: 15did not meet the criteria for the main outcome and 44 could not bevalidated. After these exclusions, there were 440 HCW (7% ofparticipants; 95% CI: 6.4, 7.7) who reported 468 AEFIs after thepandemic vaccine and 328 HCW (4.3%; 95% CI: 3.9, 4.8)reported 339 AEFI after the seasonal vaccine. In both years about80% of cases missed work for their AEFIs and about 50%consulted a physician.As shown in Table 2, in the 28 days post vaccination, the 2009pandemic vaccine was associated with significantly more localreactions causing work absenteeism or medical consultation thanthe 2010–2011 seasonal vaccine (0.96% vs. 0.03%, p,0.0001).Fever alone was significantly less frequent with the 2009 pandemicvaccine (0.12% vs. 0.86%, p,0.0001) but general malaise with orwithout fever was similar with both vaccines. Upper respiratorytract infection was the most commonly reported health problemduring both years and was significantly more frequent with thepandemic than the seasonal vaccine (4.6% vs. 2.6%, respectively,p,0.0001). Similarly, there was more gastroenteritis reported afterthe pandemic vaccine than the seasonal vaccine (1.8% vs. 0.4%,p,0.0001). During the 8 to 28 day follow-up period, headache/Safety of the AS03-Adjuvanted Pandemic VaccinePLoS ONE | www.plosone.org 3 July 2012 | Volume 7 | Issue 7 | e38563Table2.Newhealthproblemortheworseningofanexistingconditionofsufficientsignificancetocauseamedicalconsultand/orworkabsenteeismbyfollow-upperiodandtypeofinfluenzavaccine.Follow-upperiodTotal0–7days8–28daysPandemicSeasonalRR(CI95%)PandemicSeasonalRR(CI95%)PandemicSeasonalRR(CI95%)20092010–201120092010–201120092010–2011n(%)n(%)n(%)n(%)n(%)n(%)Numberofrespondents430758254057572440575724Localreaction24(0.56)2(0.03)16.2(3.8,68.6)15(0.37)*0(0.0)–39(0.96)2(0.03)27.5(6.6,113.9)SystemicFeveronly3(0.07)30(0.52)0.1(0.04,0.4)2(0.05)19(0.33)0.2(0.03,0.6)5(0.12)49(0.86)0.1(0.06,0.4)Myalgia/fatiguewithorwithoutfeverbutnoothersymptoms45(1.04)64(1.10)0.9(0.6,1.4)25(0.62)50(0.87)0.7(0.4,1.1)70(1.73)114(1.99)0.9(0.6,1.2)Allergies8(0.19)4(0.07)2.7(0.8,9.0)4(0.10)2(0.03)2.8(0.5,15.4)12(0.30)6(0.10)2.8(0.98,9.2)RespiratoryUppertractinfection86(2.00)73(1.25)1.6(1.2,2.2)99(2.44)73(1.28)1.9(1.4,2.6)185(4.56)146(2.55)1.8(1.4,2.2)Lowertractinfection7(0.16)6(0.10)1.6(0.5,4.7)8(0.20)11(0.19)1.0(0.4,2.6)15(0.37)17(0.30)1.2(0.6,2.5)Asthma1(0.02)5(0.09)0.3(0.03,2.3)01(0.02)0.0(0.04,+Inf)1(0.02)6(0.10)0.2(0.03,1.9)Cardiacproblems3(0.07)1(0.02)4.1(0.4,39.0)3(0.07)2(0.03)2.1(0.4,12.7)6(0.15)3(0.05)2.8(0.7,11.3)Gastroenteritis26(0.60)11(0.19)3.2(1.6,6.5)47(1.16)12(0.21)5.5(2.9,10.4)73(1.80)23(0.40)0.2(0.03,0.6)Otherdigestiveproblems2(0.05)6(0.10)0.4(0.1,2.2)1(0.02)5(0.09)0.3(0.03,2.4)3(0.07)11(0.19)0.4(0.1,1.4)Non-traumaticmusculoskeletalproblems5(0.12)3(0.05)2.3(0.5,9.4)12(0.30)6(0.10)2.8(0.98,9.2)17(0.42)9(0.16)2.7(1.2,6.0)NeurologicalParesthesia/numbness3(0.07)0(0.0)–4(0.10)0–7(0.17)0–Migraine5(0.12)3(0.05)2.3(0.5,9.4)5(0.12)0–10(0.25)3(0.05)4.7(1.3,17.1)Urinaryproblems6(0.14)4(0.07)2.0(0.6,7.2)7(0.17)1(0.02)9.9(1.2,80.3)13(0.32)5(0.09)3.7(1.3,10.3)Allothers12(0.28)16(0.27)1.0(0.5,2.1)11(0.27)20(0.35)0.8(0.4,1.62)23(0.57)36(0.63)0.9(0.5,1.5)*Theselocalreactionsstartedinthe0–7dayperiodpostvaccinationbutwerereportedinthe8–28daysurvey.doi:10.1371/journal.pone.0038563.t002Safety of the AS03-Adjuvanted Pandemic VaccinePLoS ONE | www.plosone.org 4 July 2012 | Volume 7 | Issue 7 | e38563migraine and urinary problems were reported less frequently afterthe 2009 pandemic vaccine than with the 2010–2011 seasonalvaccine (Table 2).Only 3 of the 12 HCW (8 in 2009, 4 in 2010) who reportedallergic symptoms 0–7 days post vaccination had theirsymptoms occur shortly after vaccination and all 3 had receivedthe adjuvanted pandemic vaccine. The first case developedanaphylaxis within 30 minutes post-pandemic vaccine withgeneralized urticaria, swelling of the mouth and nausea. Thecase received adrenaline and was transferred to the emergencyroom. The second case developed urticaria starting 30 minutespost-vaccination followed by throat tightness an hour later. Thecase was transferred to the emergency room where antihista-mine, corticosteroids and antacid were administered. The casewas kept under observation for 4 to 5 hours and thendischarged. The last case presented at the emergency depart-ment with generalized urticaria and swelling of the lips whichstarted 5 hours post-vaccine.In the 28 days after the 2009 pandemic vaccine, seven HCWreported paresthesia described as numbness or tingling of sufficientsignificance to require consultation or work absenteeism. Thiscompared with zero reports following the 2010–2011 seasonalvaccine. (Table 3) While two HCW reported paresthesia in theirvaccinated arm, four reported numbness and tingling in theirlower limbs and one reported it in both upper limbs. For five of theseven HCW, symptoms started 0–7 days after vaccination.No HCW reported diagnoses compatible with an auto-immunedisease during the 28 days after receipt of the adjuvantedpandemic vaccine. In that same period, there were two SAE(hospitalization, life-threatening event, disability or stillbirth/congenital anomaly) reported for a rate of 0.32 per 1000 HCW(95% CI: 0.04,1.16) immunized. One was the first case ofanaphylaxis described above. The second SAE occurred in a 55–60 year old woman with a history of diabetes and hypertensionwho was hospitalized for an atrioventricular block that required apacemaker. In the 28 days after the 2010–2011 seasonal vaccine,no SAE were reported.In the six-month follow-up after the 2009 pandemic vaccine,emails were sent to the 4,812 HCW from the Quebec City site(77% of total 2009 participants) and 3,064 (63.4%) responded.Among 68 (2.9%) participants who initially reported a SAE in theone to six month period after their pandemic vaccination, 33 wereexcluded after follow up by a nurse: 19 had problems that did notmeet the SAE criteria, 11 had erroneously responded that theyhad a SAE and 3 could not be reached despite numerous attemptsthus no information was available about their problem. Among the35 HCW who met the criteria for SAE, 25 (57%) had beenhospitalized, 8 (20%) reported a life-threatening event and 9 (23%)had an event resulting in persistent or significant disability/incapacity. There were no congenital anomalies/birth defectsreported. Six HCW had conditions that met two criteria for a SAEwith hospitalization for respiratory infections (3), hospitalizationfor gastrointestinal infections (4) and hospitalization for cutaneousinfections (2) occurring most frequently. Otherwise the reporteddiagnoses affected only one patient, suggesting no cluster of SAEassociated with the vaccine. (Table 4).DiscussionIn this study, the 2009 pandemic AS03 adjuvanted vaccine usedin Canada was associated with a greater frequency of AEFI in the28 day follow-up period than the 2010–2011 unadjuvantedTable 3. Paresthesia of sufficient enough to cause work/school absenteeism or a medical consultation after the 2009 pandemicvaccine.Case Age group/SexInterval betweenvaccination andonset of symptoms SymptomsInterval betweenonset ofsymptoms andconsultationDays ofabsenteeism#1 35–39/Female ,1 day Numbness to both arms accompanied by lower limbsweaknessand shoulder blade pain leading to medical consultation. Nauseaand fatigue following vaccination. Shortness of breath3–4 days post-vaccination.3 days 2.5 days#2 30–34/Female 1 day Numbness to the left lower mandibula, lip and neck numbness.Tingling to the left side of the lips. Left axillary adenopathy.Headache2 days Not available#3 30–34/Female 2 days Dizziness and headache followed by tingling to the upper andlower limb extremities and abdomen. Loss of sensation andnumbness to both lower limbs.3 weeks Not available#4 45–49/Female 4 days Sudden fatigue with difficulty standing up, lower limbsnumbness, palpitation, feeling of passing out, and mild flusymptoms.Small (1 cm) local reaction 2 days post-vaccination4 days ,1 day#5 30–34/Male 7 days Numbness and pain at vaccinated site. Tingling and pain tothe left side of the thorax.11 days None#6 25–29/Female 12 days Tingling from left elbow to hand including finger tips.Symptoms increased in the morning. Vaccination sitetenderness12 hours post-vaccination.Not reported None#7 40–44/Female 14 days Hypoesthesia to both heels. Feet burning sensation andtingling when she showered (known past medical history).HeadacheNo consultationsoughtNotavailabledoi:10.1371/journal.pone.0038563.t003Safety of the AS03-Adjuvanted Pandemic VaccinePLoS ONE | www.plosone.org 5 July 2012 | Volume 7 | Issue 7 | e38563trivalent inactivated seasonal vaccine. While the increase in localreactions in 2009 can be attributed to the adjuvanted vaccine, theincreased occurrence of upper respiratory tract infections wasmore likely due to the second wave of 2009 A/H1N1 whichpeaked at the time the HCW were vaccinated [18]. Similarly, thegreater frequency of gastroenteritis seen during 2009 may havelargely been attributed to an epidemic of gastroenteritis occurringat the time of vaccination in Quebec City which had 77% of theparticipants in 2009. The six month post pandemic vaccinationfollow up did not find clusters of SAE that would have been asignal for concern.Both clinical trials and active surveillance studies have shownthat pandemic adjuvanted vaccines induce frequent localreactions [11,12,13,14,15,16,19,20]. Contrary to most otherstudies where participants were asked if they had a localreaction and how large it was, our study selected an outcomewith a more direct clinical significance. HCW were asked toreport AEFIs with sufficient clinical significance to seek medicaladvice or of enough severity to cause absence from work. Theremay have been some over-reporting in 2009 due to the mediacoverage and public concern over the pandemic, but theseendpoints were likely to have minimized this problem. With theadjuvanted vaccine, local reactions were nearly thirty timesmore likely to trigger this outcome than the seasonalvaccine(0.96% vs. 0.03%, p,0.001). When the MF-59 adju-vanted pandemic vaccine was administered to elderly patients,local reactions were also frequently seen and 0.36% of elderlyvaccinees consulted a general practitioner for this reason [13].This higher frequency is not unexpected as both AS03 andMF59 adjuvants are designed to increase local release ofchemokines to boost the immune response [21,22]. Localreactions are not life-threatening and during a pandemic, whererapid production of a large number of doses of antigen-sparingvaccines is critical, this should not be a reason to avoid usingadjuvanted vaccine. However, serious local reactions do leave along lasting unpleasant memory and could cause reduceduptake of the vaccine in subsequent years.Two patients had allergic symptoms within 30 minutes oftheir pandemic vaccine compared to none with the seasonalvaccine. The first patient met the Brighton Collaborationcriteria for anaphylaxis [23]. The second had urticaria andthroat tightness within 30 minutes of vaccination suggestinginvolvement of two systems as required for a diagnosis ofanaphylaxis but in the absence of objective evidence of throatswelling it does not meet the Brighton Collaboration criteria foranaphylaxis. With only one case of anaphylaxis occurring inalmost 6,000 vaccinated HCW our rate was 167 per milliondoses (95% CI: 4.2, 928). A review of anaphylaxis associatedwith PandemrixH or ArepanrixH concluded that fewer than 100of the worldwide reported cases in the GSK safety database metthe criteria for anaphylaxis and that the rate was within theexpected range of 1–10 per million doses [24]. Although ourpoint estimate was higher, our 95% confidence intervaloverlapped the expected range. The passive surveillance ofAEFI in Quebec received 20 times more anaphylaxis reportsafter Arepanrix than after the seasonal influenza vaccine for theprevious 6 years [25,26]. Using only passive surveillance datafor all of Canada, 135 cases of anaphylaxis that met theBrighton Collaboration criteria were reported after vaccinationwith Arepanrix for a rate of about 9 per million doses and onelot of the vaccine was pulled from the supply chain because of apotential association with these reports [27]. The evidenceindicates Canada experienced a higher rate of anaphylaxis afterArepanrix than that reported worldwide to the manufacturer.The risk of auto-immune disease after the adjuvanted pandemicvaccine was not specifically sought in this surveillance project, butno HCW reported diagnoses compatible with these diseases within28 days after vaccination.Another unexpected AEFI that emerged from our study was theparesthesia reported by seven participants (about 1 in 1000 HCW)after the adjuvanted pandemic vaccine compared to none after theseasonal vaccine. Again, our results are supported by passivesurveillance in Quebec, Canada, which in 2009, detected a strongsignal for paresthesia with an early onset after the pandemicvaccine [26,28]. Paresthesia is a frequent reason for consultation inneurology and we cannot rule out that this was coincidental ratherthan caused by the pandemic vaccine. However, paresthesia afterTable 4. Serious adverse events (SAE) reported for the period1–5 months after the 2009 AS03-adjuvanted monovalentpandemic vaccine.Diagnosis Number PercentageCancerBreast 1 3%Lung 1 3%Pancreas 1 3%Cervix (precancerous cells) 1 3%Gynecologic/obstetrical problemsOvarian cyst 1 3%Polymenorrhea 1 3%Ectopic pregnancy 1 3%Miscarriage (8 week pregnancy) 1 3%Fetal death (13 week pregnancy) 1 3%Hysterectomy for uterine fibroma 1 3%InfectionsRespiratory 3 9%Gastroenteritis 4 11%Cutaneous 2 6%Toxic shock syndrome 1 3%AbdominalCrohn’s disease 1 3%Intestinal abscess 1 3%Intestinal subocclusion 1 3%Cholecystitis 1 3%MusculoskeletalLumbar disc hernia 1 3%Sprained knee 1 3%OthersDepression 1 3%Anaphylactic shock 1 3%Chronic pericarditis 1 3%Eye/ear problem 2 6%Severe headache 1 3%Asthma 1 3%Vaso-vasectomy 1 3%No diagnosis 1 3%TOTAL 35 100%doi:10.1371/journal.pone.0038563.t004Safety of the AS03-Adjuvanted Pandemic VaccinePLoS ONE | www.plosone.org 6 July 2012 | Volume 7 | Issue 7 | e38563Pandemrix also was reported to the passive surveillance systems inSweden and in France [29,30]. It also occurred at a frequency of0.012% (6/49,138) (95% CI: 0.004%–0.026%) in French militarypersonal participating in an active surveillance of Pandemrix [14].Further investigation of this adverse event following AS03vaccination appears warranted.This study has several limitations. The main one is the nonconcomitant comparison of the pandemic and seasonal vaccines.The comparison may be biased because study populationsdiffered by their geography, the hospitals included, by otherfactors that may have changed between the two years. Theintense media attention during the pandemic may have causedover-reporting of AEFI, but the lower participation of HCW in2009 (53% answered the two surveys) compared to 2010–2011(70%) suggests that the impact was likely limited. We mayhypothesize that non-respondents were HCW who were notmotivated to respond because they did not experience an AEFI.However, we cannot rule out that answering an electronic surveywould have been difficult or impossible for HCW who were verysick, hospitalized or dead. The information about the AEFI wasreported by the HCW and was not validated with the attendinghealth care providers. Classification of AEFIs in broad categoriesmay also have obscured specific problems that would be moreapparent with a more detailed stratification. Ideally, activesurveillance for vaccine safety should include a group ofcomparable unvaccinated individuals to be in position to estimatethe risks attributable to the vaccine, from background rates. Inthis study, the rate of background diseases (like respiratoryinfections or gastroenteritis) was not similar in 2009 and 2010and this may affect the estimation of the greater reactogenicity ofthe adjuvanted pandemic compared to seasonal vaccine. Inaddition, public concerns and media attention about theadjuvanted pandemic vaccine may have lead to more compre-hensive symptom reporting in 2009 than in 2010–2011 with theseasonal vaccine. Nevertheless, the main findings about thepandemic vaccine do not seem to have been substantiallyaffected by these problems as we saw similar results in the passivesurveillance system. Finally, an active surveillance of severalthousand vaccinated individuals is unable to assess the risk ofrare adverse events such as the Guillain Barre Syndrome.In the six-month follow-up, 35 SAEs were reported after theadjuvanted pandemic vaccine. Although they occurred aftervaccination, they are likely unrelated to the vaccine but due toother background etiologies in effect at the same time the vaccinewas administered. The time-lapse from vaccination to VAEoccurrence and the absence of a cluster of cases with a singlediagnosis is reassuring but does not rule out the possibility of safetyissues. Proper assessment of the association between these delayedSAEs and the vaccine is very difficult: it would require a muchlarger sample size and the comparison of their frequencies to theirbaseline rate in the community.In conclusion, our surveillance has shown that the adjuvantedvaccine had a good safety profile, similar to that with the seasonalvaccine, with the exception of local reactions.Author ContributionsConceived and designed the experiments: GDS SM A. McGeer GS LV A.McCarthy JB. Performed the experiments: M-CG BC IR MB AA CB CGKS AK. Analyzed the data: MO NO. Contributed reagents/materials/analysis tools: GDS M-CG BC IR SM MB A. McGeer AA JN CB CG KSAK MO NO GS LV A. McCarthy JB. Wrote the paper: M-CG GDS.References1. Iskander J, Haber P, Herrera G (2005) Monitoring vaccine safety during aninfluenza pandemic. Yale J Biol Med 78: 265–275.2. 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(2011) Self-reported adverse reactions in 4337 healthcare workers immunizations againstnovel H1N1 influenza. BMC Res Notes 4: 297–302.13. Harmark L, van Hunsel F, Hak E, van Grootheest K (2011) Monitoring thesafety of influenza A (H1N1) vaccine using web-based intensive monitoring.Vaccine 29: 1941–1947.14. Mayet A, Ligier C, Gache K, Manet G, Nivoix P, et al. (2011) Adverse eventsfollowing pandemic influenza vaccine Pandemrix(R) reported in the Frenchmilitary forces–2009–2010. Vaccine 29: 2576–2581.15. Kiertiburanakul S, Malathum K, Watcharananan SP, Bunupuradah P, PiebpienP, et al. (2011) High coverage and safety of influenza A (H1N1) 2009monovalent vaccination among health care personnel in Thailand. Am J InfectControl 39: 525–528.16. Lapphra K, Dobson S, Bettinger JA (2010) Acceptability of Internet adverseevent self-reporting for pandemic and seasonal influenza immunization amonghealth care workers. Vaccine 28: 6199–6202.17. 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Expert review of vaccines 8: 483–492.22. Garcon N, Vaughn DW, Didierlaurent AM (2012) Development and evaluationof AS03, an Adjuvant System containing alpha-tocopherol and squalene in anoil-in-water emulsion. Expert review of vaccines 11: 349–366.23. Bonhoeffer J, Kohl K, Chen R, Duclos P, Heijbel H, et al. (2002) The BrightonCollaboration: addressing the need for standardized case definitions of adverseevents following immunization (AEFI). Vaccine 21: 298–302.24. Tavares F, Delaigle A, Slavin D, Bauchau V, Fries L, et al. (2011) Anaphylaxisfollowing H1N1 pandemic vaccines: safety data in perspective. Vaccine 29:6402–6407.25. Rouleau I, De Serres G, Benoıˆt M, Toth E, Me´nard S, et al. (2010) Anaphylaxisand allergic-like reactions following administration of AS03-adjuvated pandemicH1N1 vaccine: Surveillance summary from Quebec, Canada. Options for thecontrol of Influenza. Hong Kong SAR, China.26. Groupe Central ESPRI (2010) Surveillance des manifestations cliniquesinhabituelles survenues apre`s la vaccination contre la grippe A(H1N1) lors dela campagne de masse de l’automne 2009 au Que´bec. Que´bec, QC: Ministe`rede la Sante´ et des Services sociaux du Que´bec.Safety of the AS03-Adjuvanted Pandemic VaccinePLoS ONE | www.plosone.org 7 July 2012 | Volume 7 | Issue 7 | e3856327. Hardy S, Law B, Khromava A (2010) Approche sur l’innocuite´ axe´e sur le cyclede vie des vaccins. Pre´sentation par affiche. 9e confe´rence canadienne surl’immunisation, Centre des congre`s de Que´bec, 5–8 de´cembre.28. De Serres G, Rouleau I, Garie´py M-C, Coleman B, Wilkinson K, et al. (2010)Short and long-term active electronic surveillance of a large number ofhealthcare workers following administration of an adjuvanted pH1N1 vaccine.Hong Kong SAR, China.29. Agence Franc¸aise de se´curite´ sanitaire des produits de sante´ Bilan actualise´ depharmacovigilance des vaccins antigrippaux A/H1N1, mai 2010. [En ligne].Available: http://www.afssaps.fr/var/afssaps_site/storage/original/application/e41f68fbee043b89e1fc740dac52d2e1.pdf. Accessed 2010 Oct 25.30. Lakemedelsverket Medical Product Agency Final summary of adverse drugreaction reports in Sweden with Pandemrix through October 2009 - mid April2010. Stockholm June 2 2010. [En ligne]. Available: http://www.lakemedelsverket.se/english/All-news/NYHETER-2010/Final-summary-of-ADR-reports-in-Sweden-with-Pandemrix/. Accessed 2010 Oct 25.Safety of the AS03-Adjuvanted Pandemic VaccinePLoS ONE | www.plosone.org 8 July 2012 | Volume 7 | Issue 7 | e38563


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