Pediatrics 2011 Skowronski e276 89

DOI: 10.1542/peds.2010-2777; originally published online July 18, 2011; 2011;128;e276Pediatrics

Sabaiduc and Martin PetricScheifele, Brian J. Ward, Scott A. Halperin, Naveed Z. Janjua, Tracy Chan, Suzana Danuta M. Skowronski, Travis S. Hottes, Mei Chong, Gaston De Serres, David W.

Aged 6 to 23 MonthsRandomized Controlled Trial of Dose Response to Influenza Vaccine in Children

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Randomized Controlled Trial of Dose Response toInfluenza Vaccine in Children Aged 6 to 23 Months

WHAT’S KNOWN ON THIS SUBJECT: Infants and toddlers aged 6 to23 months experience high rates of influenza hospitalization, highestin those younger than 1 year. In North America, they arerecommended to receive influenza vaccine annually at a per-injectiondose half that recommended for older children and adults.

WHAT THIS STUDY ADDS: This randomized controlled trial ininfants and toddlers shows that compared with 0.25-mL half-dosing, administration of 2 full 0.5-mL doses of trivalentinactivated influenza vaccine can increase antibody responsewithout increasing reactogenicity in previously unimmunizedinfants aged 6 to 11 months.

abstractOBJECTIVES: We assessed whether 2 full versus 2 half-doses of triva-lent inactivated influenza vaccine (TIV) could improve immunogenicitywithout increasing reactogenicity in infants (aged 6–11 months) andtoddlers (aged 12–23 months).

METHODS: Previously unimmunized infants and toddlers were sepa-rately randomly assigned to receive 2 full (0.5-mL) or 2 half (0.25-mL)doses of 2008–2009 split TIV. Sera were collected at enrollment and at27 to 45 days after the second injection. Parents recorded adverseevents after each injection. The primary immunogenicity outcome wassuperiority (1-sided, � � 0.025) of the full versus the half-dose basedon a �10% increase in rates of seroprotection (hemagglutination in-hibition titer of�40). The primary reactogenicity outcomewas fever of�38°C within 3 days of either injection.

RESULTS: In per-protocol analyses, 252 participants (full dose: n �124; half-dose: n� 128) were included. In toddlers, postimmunizationseroprotection rates exceeded 85% for all 3 vaccine components with-out significant difference by dose. In infants, the full dose inducedhigher responses for all 3 vaccine components, meeting the 10% test ofsuperiority for the H3N2 (75.4% vs 47.6%; � � 27.8% [95% confidenceinterval (CI): 11.2–44.5]; P� .02) and B/Yamagata (70.2% vs 41.3%;� �28.9% [95% CI: 11.9–45.9]; P� .02) components but not H1N1 (71.9% vs54.0%; � � 18.0% [95% CI: 1.0–34.9]; P� .2). Rates of fever were notincreased among full- versus half-dose recipients in either age group(5.6% vs 12.7% combined).

CONCLUSIONS: Administration of 2 full TIV doses may improve immu-nogenicity without increasing reactogenicity in infants. Current TIVdosing recommendations for young children warrant additional eval-uation. Pediatrics 2011;128:e276–e289

AUTHORS: Danuta M. Skowronski, MD, FRCPC,a Travis S.Hottes, MSc,a Mei Chong, MSc,a Gaston De Serres, MD,PhD,b David W. Scheifele, MD,c Brian J. Ward, MDCM,d

Scott A. Halperin, MD,e Naveed Z. Janjua, MD, MSc, DrPH,a

Tracy Chan, BSc, RMCCM,a Suzana Sabaiduc, BSc,a andMartin Petric, PhD, FCCMa

aBritish Columbia Centre for Disease Control, Vancouver, BritishColumbia, Canada; bInstitut National de Santé Publique duQuébec, Québec, Canada; cVaccine Evaluation Centre, Child andFamily Research Institute, Vancouver, British Columbia, Canada;dVaccine Research Unit, Montreal General Hospital, McGillUniversity Health Centre, Montréal, Québec, Canada; andeCanadian Center for Vaccinology, Dalhousie University, IWKHealth Centre, Halifax, Nova Scotia, Canada

KEY WORDSinfluenza, influenza vaccine, randomized controlled trial,immunologic dose-response relationship, children, infants, child,influenza vaccines/immunology, influenza vaccines/adverse effects,influenza vaccines/administration, dosage

ABBREVIATIONSTIV—trivalent inactivated influenza vaccineHA—hemagglutininWHO—World Health OrganizationHI—hemagglutination inhibitionMN—microneutralizationGMT—geometric mean titerNML—National Microbiology LaboratoryNA—neuraminidase

Drs Skowronski, De Serres, Scheifele, Ward, and Halperin designedthe study and oversaw data collection; Dr Petric, Ms Sabaiduc, andMs Chan oversaw and performed laboratory testing; Ms Chong, MrHottes, and Drs Skowronski and Janjua analyzed the data; and allthe authors had access to the data (including statistical reportsand tables), take responsibility for the study, contributed to thewriting of the article, and reviewed and approved the finalmanuscript. Dr Skowronski serves as the guarantor.

This trial has been registered at www.clinicaltrials.gov(identifier NCT00710866).

www.pediatrics.org/cgi/doi/10.1542/peds.2010-2777

doi:10.1542/peds.2010-2777

Accepted for publication Apr 19, 2011

Address correspondence to Danuta M. Skowronski, MD, FRCPC,Epidemiology Services, British Columbia Centre for Disease Control,655 W 12th Ave, Vancouver, British Columbia, Canada V5Z 4R4.E-mail: [email protected].

(Continued on last page)

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Children younger than 2 yearsexperience high rates of influenza-associated hospitalization, estimatedto range from 100 to 500 per 100 000children during epidemic seasons; thehighest rates are seen among infantsless than 1 year of age.1–3 On the basisof these rates, advisory committees inNorth America recommend that in-fants (aged 6–11 months) and tod-dlers (aged 12–23 months) receive aninfluenza vaccine annually.4,5

Although recommendations else-where (eg, the United Kingdom) permitadult-dose (0.5 mL) trivalent inacti-vated influenza vaccine (TIV) adminis-tration in young children,6 advisorycommittees in North America recom-mend that one-half the adult dose beadministered per injection to childrenyounger than 3 years of age.7,8 The ra-tionale for this recommendation pri-marily has been the concern that a fulldose may be associated with higherrates of fever (up to 50%) and febrileconvulsions in young children.9 How-ever, this perception was on the basisof historical observations with wholevirus influenza vaccines.9 Current split-virus TIVs are much better tolerated,with mild fever reported in 12% orfewer of vaccinated children aged 1 to5 years. However, only limited dataexist for children aged 6 to 23months.8,10–14 In a 2004 Canadian tele-phone survey of 690 immunized infantsand toddlers, the only symptoms re-ported in more than 5% of the childrenwere fussiness (21%), fever (11%), de-creased eating or drinking (8%), anddrowsiness (7%).14 Serious adverseevents are rare among immunizedchildren aged 6 to 23 months, with fe-brile convulsion predominating.13

Studies show variable antibody re-sponse to the recommended half-doseof TIV in infants and toddlers, particu-larly the B component.15–21 Antibody re-sponses are lowest in infants.20

Vaccine effectiveness estimates for in-

fants and toddlers are limited and vari-able.17,22–28 Despite an improved safetyprofile and suboptimal immunogenic-ity and effectiveness, the recommen-dation to halve the per-injection doseof TIV for infants and toddlers has per-sisted for decades without reevalua-tion. Other studies have evaluateddose response to the influenza vaccinein older children (aged�7 years) andthe elderly, showing improved immu-nogenicity without greater reactoge-nicity when antigen content is in-creased.29–32 No studies to date haveassessed the impact of increasing to afull 0.5-mL dose of split TIV in infantsand toddlers, as is currently the rec-ommended practice for children aged3 to 9 years.7,8 Here, we report a studyto determine whether giving 2 fulldoses of split TIV to previously unim-munized infants and toddlers can im-prove immunogenicity without in-creasing reactogenicity comparedwith 2 half-doses.

PATIENTS AND METHODS

Study Design

A randomized controlled trial calledTITRE I (TIV Infant-Toddler Response Eval-uation I) was conducted at 5 sites in 3Canadian provinces (British Columbia,Quebec, and Nova Scotia). Childrenaged 6 to 23 months were enrolled be-tween September 1 and December 31,2008, after obtaining written informedconsent from the parent or guardian.At enrollment, participants were ran-domly assigned to receive 2 spaceddoses of 0.25 mL (half-dose) or 0.5 mL(full dose) of a 2008–2009 commer-cially available TIV, provided free bySanofi Pasteur (Lyon, France) (Vaxi-grip) and containing 15 �g hemagglu-tinin (HA) of each of the followingWorld Health Organization (WHO)-recommended antigens per 0.5 mL:A/Brisbane/10/07 (H3N2); A/Brisbane/59/07 (H1N1); and B/Florida/4/06(Yamagata lineage). Centralized ran-

dom assignment was conducted viathe Internet. Participants were block–randomly assigned by site and age(aged 6–11 months [infants] and12–23 months [toddlers]). Partici-pants received the same (half or full)dose at both visits by intramuscularinjection.

At enrollment, �3 mL of blood werecollected before giving the first vacci-nation. The protocol specified a secondvaccination 4 to 6 weeks later; at theanalysis phase, participants receivingtheir second vaccination at an intervalof 25 to 49 days were included. Collec-tion of�3 mL of blood was scheduledat 30 to 42 days after the second vacci-nation; blood collected from 27 to 45days after the second dose were in-cluded in the analysis. Antipyretic oranalgesic medication use 24 hours be-fore to 7 days after each vaccinationwas recorded.

Assignment blinding extended to inves-tigators and study staff receivingadverse-event information as well asto parents. Study analysts and labora-tory personnel remained blinded todose assignment until the main analy-sis was complete. Approval was pro-vided by research ethics boards atHealth Canada and the affiliated insti-tutions of the investigators at eachsite.

Population

Participants were aged 6 to 23 monthsat enrollment. Those considered ineli-gible were children with a history oflaboratory-confirmed influenza, previ-ous influenza vaccination, allergy toany vaccine component, bleeding dis-order, or compromised immunity, andthose who received immune globulinor other blood products or who werescheduled to receive a live vaccine dur-ing the study period. Enrollment wasdelayed for children given a nonlivevaccine within the previous 14 days orlive vaccine within the previous 28

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days and those who had febrile illnesswithin the previous 72 hours.

Immunogenicity

Antibody titers were measured usingrepresentative noninactivated refer-ence virus strains for each of the 3 vac-cine components, as well as B/Bris-bane/60/08 of the alternate (B/Victoria) lineage (the subsequent2009–2010 TIV component) (Appendix1). Paired sera were tested in dupli-cate by hemagglutination inhibition(HI) and microneutralization (MN) as-says at the British Columbia Centre forDisease Control in Vancouver per stan-dard protocol (Appendix 1).

HI and MN titers were summarized atthe subject level as the geometricmean titer (GMT) of duplicate tests. Ti-ters less than 10were assigned a valueof 5; titers were truncated at 10 240.Participants missing paired sera for agiven strain were excluded from anal-yses for that strain.

Group GMTs, GMT ratios (postimmuni-zation GMT to preimmunization GMT),seroprotection rates (proportion withHI titers�40),33,34 and seroconversionrates (proportion with preimmuniza-tion HI titers�10 and more than four-fold postimmunization rise, or with ti-ters less than 10 preimmunizationincreasing to 40 postimmunization)33

were estimated for each group and ex-plored by MN.

Reactogenicity

Parents were given a thermometer, adevice to measure local reactions, anda memory aid to record solicited andunsolicited adverse events after im-munization for days 0 to 7 after eachinjection. Solicited adverse events in-cluded bedtime axillary tempera-ture, irritability, sleep disturbance,drowsiness, decreased appetite andlocal tenderness, pain, redness,swelling, and induration. Parentswere also asked to record the high-

est temperature taken at any othertime of the day; the highest daily tem-perature was included in the analy-sis. At 2 to 3 and 8 to 10 days aftereach dose, study personnel con-tacted the parent to collect adverse-event information recorded in thememory aid. Symptoms were catego-rized using 4-point scales (none,mild, moderate, or severe) de-scribed on the memory aid and indi-cated in Appendix 2. Parents were in-structed to report any seriousadverse events throughout the studyperiod and were queried at each con-tact. Serious adverse events werefurther assessed for causality.

Statistical Methods

Initial sample-size calculations (1-sided; � � 0.05; � � 0.20) indicatedthat 150 participants per group wouldenable detection of increases of atleast 10% in seroprotection rates forinfluenza A components (from 80% to90%), 15% for the influenza B compo-nents (from 60% to 75%), and 10% forfever (from 10% to 20%). To be conser-vative, superiority was assessed onthe basis of the 1-sided test, with � �0.025 corresponding to a 95% confi-dence interval around differences. Theprimary immunogenicity outcome wastest of superiority of the full- versushalf-dose of TIV on the basis of HI assayusing the Wald method for �10% in-crease in sero-protection rate for eachcomponent. The primary reactogenic-ity outcome was a test of a less than10% increase between the full doseversus the half-dose based on the Waldmethod for rate of temperature 38°Cor higher within 3 days after either in-jection. Per-protocol and intention-to-treat analyses were performed; withparticipant attrition of less than 10% inboth groups, per-protocol analysesare presented. For antibody estimates,95% confidence intervals were calcu-lated using the exact (Clopper-Pearson) method. Comparisons were

performed using the Fisher’s exacttest for proportions and t test orMann-Whitney U test for continuousvariables.

RESULTS

Study Population

Enrollment totaled 267 subjects, but 15were excluded because of protocol vi-olations (Appendix 3). Baseline charac-teristics of the 252 participants (n �128 half-dose; n � 124 full dose; n �126 infants; n� 126 toddlers) includedin per-protocol analyses are pre-sented in Table 1. There were slightlymore white participants in the half-dose group andmore children with un-derlying conditions (mainly asthma) inthe full-dose group but no other signif-icant differences.

Immunogenicity

HI Assay

Preimmunization titers were low forall 3 vaccine strains in both age groups(Table 2 and Fig 1). Overall, postimmu-nization seroprotection rates for the 3strains were higher for full-dose com-pared with half-dose recipients, butthe superiority of the full dose couldnot be concluded in combined infantand toddler analysis (Table 2 and Fig 1).Full-dose minus half-dose differencesin seroprotection rates were 10.7%(95% confidence interval: �0.1–21.5)for H1N1, 16.6% (95% confidence inter-val: 5.9–27.2) for H3N2, and 14.0% (95%confidence interval: 2.9–25.0) forB/Yamagata. The lower bounds of these95% confidence intervals do not meetthe specified 10% superiority marginfor any of the vaccine strains. Thus, su-periority of the full-dose over the half-dose regimen cannot be concluded inthe analysis of infants and toddlerstogether.

Postimmunization responses to the 3vaccine components were higher intoddlers than in infants for all immu-



nogenicity outcomes (Table 2). How-ever, the full dose was not superior tothe half-dose for any vaccine compo-nent in the toddler group. Seroprotec-tion rates exceeded 85% for all 3vaccine components in toddlers re-gardless of dose received.

On the other hand, among infants fulldoses elicited substantially higher re-sponses for all vaccine components.Seroprotection rates ranged between40% and 55% in the half-dose groupand between 70% and 75% in the full-dose group (Table 2; Fig 1B and C). Thefull-dose seroprotection rate was statis-tically superior to the half-dose rate atthe 10%margin for theH3N2 (�� 27.8%[95% confidence interval: 11.2–44.5];P � .02) and B/Yamagata (� � 28.9%[95% confidence interval: 11.9–45.9];P � .02) antigens but not H1N1 (� �17.96% [95% confidence interval: 1.0–34.9]; P� .2). Virtually no antibody to thealternate B/Brisbane/60/08 (Victoria lin-eage) virus was induced in any group(Fig 1). All of the above findings were

similar by intention-to-treat analyses.Conclusions related to superioritywere not altered when the few partici-pants who met seroprotective thresh-olds for a given component before im-munization were excluded.

MN Assay

Preimmunization MN titers also werelow for all strains in both age groups(Table 3; Fig 1). Postimmunization MNresponses generally were higher fortoddlers than for infants (Table 3; Fig1B and C). MN seroprotection rateswere higher among full-dose com-pared with half-dose recipients, nota-bly among infants and for the H3N2component among toddlers.

Postimmunization seroprotection andseroconversion ratesmeasured by MNwere similar to those measured by HIfor the H1N1 and B/Yamagata compo-nents, but for H3N2 the responses byMN were appreciably lower than by HI(Tables 2 and 3; Fig 1). The discrepancybetween HI and MN seroprotection

rates for the H3N2 component wasgreater among infants given the fulldose (75.4% vs 50.9%; � � 24.5%) ver-sus the half-dose (47.6% vs 36.5%;� �11.1%); the reverse was true for tod-dlers given the full dose (91.7% vs82.0%; � � 9.7%) versus the half-dose(88.1% vs 64.4%; � � 23.7%). The in-crease in H3N2 seroprotection rateswith full doses was thus greater by HIthan MN for infants (HI� � 27.8% vsMN� � 14.4%) but smaller by HIthan MN for toddlers (HI� � 3.6% vsMN� � 17.6%). Vaccine-inducedcross-reactivity to the B/Victoria lin-eage was again virtually nil (Fig 1).

Adverse Events After Immunization

Primary Reactogenicity Outcome:Fever

Among infants, full-dose and half-dosevaccine recipients had fever of 38°C orhigher by day 3 after the first injectionat rates of 1.5% and 1.5%, respectively,and after the second injection at rates

TABLE 1 Baseline Characteristics of Participants Included in the Per-Protocol Analyses

Variable Full Dose (N� 124) Half-Dose (N� 128) Overall (N� 252) Pa

Range of dates, enrollment Sep 22–Dec 29, 2008 Sep 22–Dec 30, 2008 Sep 22–Dec 29, 2008Range of dates, second immunization Oct 20–Feb 3, 2009 Oct 20–Feb 4, 2009 Oct 20–Feb 4, 2009Site, n (%)1 30 (24.2) 32 (25.0) 62 (24.6) .9382 28 (22.6) 26 (20.3) 54 (21.4)3 27 (21.8) 28 (21.9) 55 (21.8)4 30 (24.2) 29 (22.7) 59 (23.4)5 9 (7.3) 13 (10.2) 22 (8.7)Mean age at enrollment, mean (SD), mo 13.2 (5.1) 12.8 (5.0) 13.0 (5.0) .317Age group, n (%)6–11 mo 61 (49.2) 65 (50.8) 126 (50.0) .70812–23 mo 63 (50.8) 63 (49.2) 126 (50.0)

Female, n (%) 63 (50.8) 71 (55.5) 134 (53.2) .528Ethnicity, n (%)White 89 (71.8) 107 (83.6) 196 (77.8) .028Asian 10 (8.1) 10 (7.8) 20 (7.9)Other 25 (20.2) 11 (8.6) 36 (14.3)

Mean child birth order, mean (SD) 1.8 (0.8) 1.8 (0.9) 1.8 (0.8) .778Mean total children for primary caregiver, mean (SD) 1.8 (0.8) 1.9 (0.9) 1.8 (0.9) .672Length, mean (SD), cm 76.8 (6.7) 75.3 (6.9) 76.0 (6.8) .165Weight, mean (SD), kg 10.2 (1.7) 9.9 (1.8) 10.1 (1.8) .318Underlying conditions, n (%) 9 (7.3) 2 (1.6) 11 (4.4) .030Reactive airway disease or asthma, n (%) 7 (5.6) 1 (0.8) 8 (3.2) .040Temperature at first dose, mean (SD), °C 35.9 (0.4) 35.9 (0.4) 35.9 (0.4) .599Prophylactic medication�24 h before first dose, n (%) 3 (2.4) 5 (3.9) 8 (3.2) .722Prophylactic medication�24 h before second dose, n (%) 1 (0.8) 3 (2.3) 4 (1.6) .622a P value for comparison between the half-dose and full-dose groups (Fisher’s exact test for categorical variables and Mann-Whitney U test for continuous variables).

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of 0% and 9.2%, respectively (Table 4).Among toddlers, corresponding feverrates for full-dose and half-dose recip-ients were 1.6% and 3.2%, respectively,after the first injection and 7.9% and13.1% , respectively, after the secondinjection (Table 5). Fever rates wereslightly higher among toddlers than in-fants, but these differences were notsignificant. Overall, 5.6% of full-doseand 12.7% of half-dose recipients hadfevers of 38°C or higher by day 3 aftereither dose, a difference of �7.1%(95% confidence interval: �14.2 to0.04) (Appendix 4). All of the rate differ-ences were significantly below the al-lowed 10% increase in reactogenicityfor the full dose (P � .001 for infantand combined analyses, P � .005 fortoddlers). Excluding those with thehighest temperature measured by analternate route (all rectally and at sec-

ond dose) did not alter these findings(Appendix 4). Findings were similar inthe intention-to-treat analyses.

Other Adverse Events

The most commonly reported local re-actions by day 3 after either dose areshown by age group in Tables 4 and 5and for infants and toddlers combinedin Appendix 4. Local reactions gener-ally were less common in infants (Ta-ble 4) than toddlers (Table 5) andmorecommon with full doses versus half-doses, but none of these differenceswere significant. In the combined in-fant and toddler analysis, the mostcommonly reported local reactions inboth dose groups were redness (23%full dose; 21% half-dose) and tender-ness (23% full dose; 26% half-dose):few (�5%) reported moderate or se-vere reactions with either dosage.

Swelling (15% full dose; 9% half-dose)and induration (14% full dose; 6% half-dose) were less frequently reportedbut were more common after fulldoses (respective P values � .12 and.06). Irritability, decreased appetite,drowsiness, and sleep disturbancewere reported in more than 35% ofparticipants but were infrequently(�5% of all participants) rated as se-vere, and significant differences be-tween full doses and half-doses werenot observed. Most solicited adverseevents had onset by day 3 after im-munization, with few additional re-ports to day 7 thereafter (data notpresented).

Unsolicited adverse events (regard-less of causality assessment) are alsoshown in Tables 4 and 5 and in Appen-dix 4 for infants and toddlers com-

TABLE 2 Pre- and Postimmunization (27–45 Days After the Second Dose) Titers to 2008–2009 Influenza Vaccine Viruses (With 95% Confidence Intervalsin Parentheses, Where Applicable), as Measured by an HI Assay, Overall, at Age 6 to 11 Months, and at Age 12 to 23 Months

A/Brisbane/59/07 (H1N1)a A/Brisbane/10/07 (H3N2)a B/Florida/4/06 (Yamagata)a

Full Dose(N� 117)(57, 60)b

Half-Dose(N� 122)(63, 59)b

Full Dose(N� 117)(57, 60)b

Half-Dose(N� 122)(63, 59)b

Full Dose(N� 117)(57, 60)b

Half-Dose(N� 122)(63, 59)b

PreimmunizationGMT, moOverall 6.4 (5.4–7.6) 5.5 (5.0–6.2) 6.1 (5.2–7.1) 5.2 (4.9–5.5) 6.1 (5.4–6.9) 6.2 (5.3–7.1)6–11 5.6 (4.7–6.7) 5.3 (4.8–5.8) 5.5 (4.6–6.5) 5.0 (5.0–5.0) 5.4 (5.1–5.8) 5.6 (4.8–6.6)12–23 7.2 (5.3–9.8) 5.8 (4.7–7.1) 6.7 (5.2–8.6) 5.4 (4.8–6.1) 6.7 (5.4–8.5) 6.8 (5.3–8.7)Seroprotection rate, %, moOverall 5.1 (1.9–10.8) 2.5 (0.5–7.0) 3.4 (0.9–8.5) 0.8 (0.0–4.5) 4.3 (1.4–9.7) 4.9 (1.8–10.4)6–11 1.8 (0.0–9.4) 1.6 (0.0–8.5) 1.8 (0.0–9.4) 0.0 (0.0–5.7) 0.0 (0.0–6.3) 1.6 (0.0–8.5)12–23 8.3 (2.8–18.4) 3.4 (0.4–11.7) 5.0 (1.0–13.9) 1.7 (0.0–9.1) 8.3 (2.8–18.4) 8.5 (2.8–18.7)

PostimmunizationGMT, moOverall 78.4 (61.0–100.7) 56.6 (44.6–71.8) 79.3 (65.0–96.8) 47.3 (38.8–57.6) 82.9 (65.0–105.7) 51.8 (40.8–65.8)6–11 44.1 (32.5–59.8) 33.0 (23.9–45.6) 55.2 (42.5–71.7) 30.5 (23.6–39.5) 45.7 (35.0–59.8) 25.5 (19.1–34.1)12–23 135.3 (95.6–191.6) 100.6 (75.1–134.7) 111.8 (84.7–147.7) 75.4 (58.1–97.9) 145.9 (102.8–206.9) 110.5 (83.6–146.1)GMT ratio, moOverall 12.2 (9.8–15.2) 10.2 (8.2–12.7) 13.0 (10.9–15.7) 9.1 (7.5–11.0) 13.6 (10.8–17.1) 8.4 (6.7–10.6)6–11 7.8 (5.8–10.4) 6.2 (4.5–8.5) 10.0 (7.8–12.8) 6.1 (4.7–7.9) 8.4 (6.2–11.3) 4.5 (3.2–6.3)12–23 18.7 (13.9–25.2) 17.4 (13.8–21.9) 16.8 (12.9–21.7) 13.9 (10.8–17.8) 21.6 (15.9–29.4) 16.3 (13.2–20.1)Seroprotection rate, %, moOverall 81.2 (72.9–87.8) 70.5 (61.6–78.4) 83.8 (75.8–89.9) 67.2 (58.1–75.4) 80.3 (72.0–87.1) 66.4 (57.3–74.7)6–11 71.9 (58.5–83.0) 54.0 (40.9–66.6) 75.4 (62.2–85.9) 47.6(34.9–60.6) 70.2 (56.6–81.6) 41.3 (29.0–54.4)12–23 90.0 (79.5–96.2) 88.1 (77.1–95.1) 91.7 (81.6–97.2) 88.1 (77.1–95.1) 90.0 (79.5–96.2) 93.2 (83.5–98.1)Seroconversion rate, %, moOverall 80.3 (72.0–87.1) 70.5 (61.6–78.4) 81.2 (72.9–87.8) 67.2 (58.1–75.4) 80.3 (72.0–87.1) 65.6 (56.4–73.9)6–11 70.2 (56.6–81.6) 54.0 (40.9–66.6) 73.7 (60.3–84.5) 47.6 (34.9–60.6) 70.2 (56.6–81.6) 39.7 (27.6–52.8)12–23 90.0 (79.5–96.2) 88.1 (77.1–95.1) 88.3 (77.4–95.2) 88.1 (77.1–95.1) 90.0 (79.5–96.2) 93.2 (83.5–98.1)

a Passaged reference viruses (see Appendix 1).b Sample size, overall (aged 6–11 months, aged 12–23 months).



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enta

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titr

e ≥4

0

HI, half-dose MN, half-dose HI, full-dose MN, full-doseB

0

10

20

30

40

50

60

70

80

90

100


Perc

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f par

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ants

with

titr

e ≥ 4

0

HI, half-dose MN, half-dose HI, full-dose MN, full-doseC

A/Brisbane/10/07(H3N2)a B/Brisbane/60/08(Victoria)a

A/Brisbane/10/07(H3N2)a B/Brisbane/60/08(Victoria)a

B/Brisbane/60/08(Victoria)aA/Brisbane/10/07(H3N2)a

FIGURE 1Postimmunization (27–45 days after the second dose) seroprotection rates to 2008–2009 influenza vaccine viruses and B/Brisbane/60/2008, according tostudy arm, strain, and assay overall (A), 6 to 11months (B), and 12 to 23 months (C). a Passaged reference viruses (see Appendix 1).

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bined. A significant difference in therates of unsolicited adverse eventswas observed in combined analysisonly for the miscellaneous category(higher for half-dose), none of whichwould explain the between-group feverdifferential. One serious adverse eventwas reported: a toddler in the half-dose group was hospitalized withpneumonia 28 days after the first vac-cination. The event was deemed un-likely related to the vaccine.

Parent Acceptability

At the time of final blood draw, parents(still blinded) were asked to rate theacceptability of the dose and scheduletheir child received by indicatingagreement on a 4-point Likert scalewith the following statement: “Givenmy child’s experience with this vac-cine, and if I had another child of the

same age, I would be comfortable withhim/her receiving the same vaccineand doses.”

Fifty-four percent of parents whosechild received the half-dose regimenstrongly agreed, and 46% agreed withthis statement. Likewise, 53% of par-ents whose child received the full dosestrongly agreed with this statement,and 46% agreed (P � .95). Only 1 par-ent, whose child received the full dose,disagreed.

DISCUSSION

In this randomized controlled trial, wefound increased antibody responsesamong previously unimmunized in-fants given 2 full doses rather thanhalf-doses of the 2008–2009 TIV. Sero-protection rates in the full-dose groupwere more than 10% higher for all TIV

components among children aged 6 to11 months and were statistically supe-rior for 2 of 3 vaccine components(H3N2:� � 28% and B/Yamagata:� �29%). We did not observe a similar in-crease in HI antibody responses in tod-dlers, among whom seroprotectionrates exceeded 85% in both dosinggroups. Meanwhile, rates of feverwerenot increased among full-dose recipi-ents, infants, or toddlers, and parentacceptability of increased dosing waslikewise comparable.

As noted by at least 1 other study,20

vaccine-induced antibody responsewas substantially lower among in-fants younger than 1 year of age, thepediatric group at highest risk ofinfluenza-related hospitalization anddeath.2,35 Possible interference frompersistent maternal antibody is not

TABLE 3 Pre- and Postimmunization (27–45 Days After the Second Dose) Titers to 2008–2009 Influenza Vaccine Viruses (With 95% Confidence Intervalsin Parentheses, Where Applicable), as Measured by an MN Assay, Overall, at Age 6 to 11 Months, and at Age 12 to 23 Months

A/Brisbane/59/07 (H1N1)a A/Brisbane/10/07 (H3N2)a B/Florida/4/06 (Yamagata)a

Full Dose(N� 117)(56, 61)b

Half-Dose(N� 122)(63, 59)b

Full Dose(N� 118)(57, 61)b

Half-Dose(N� 122)(63, 59)b

Full Dose(N� 118)(57, 61)b

Half-Dose(N� 122)(63, 59)b

PreimmunizationGMT, moOverall 6.6 (5.4–8.0) 5.6 (5.0–6.3) 6.9 (6.0–8.0) 6.2 (5.8–6.7) 5.7 (5.1–6.4) 5.9 (5.2–6.8)6–11 5.5 (4.6–6.7) 5.4 (4.9–5.9) 6.3 (5.4–7.4) 6.5 (6.0–7.0) 5.2 (4.9–5.5) 5.5 (4.7–6.3)12–23 7.7 (5.5–10.9) 5.8 (4.7–7.2) 7.5 (5.9–9.5) 6.0 (5.2–6.9) 6.2 (5.1–7.7) 6.5 (5.2–8.1)Seroprotection rate, %, moOverall 6.0 (2.4–11.9) 2.5 (0.5–7.0) 3.4 (0.9–8.5) 0.8 (0.0–4.5) 2.5 (0.5–7.3) 4.9 (1.8–10.4)6–11 1.8 (0.0–9.6) 1.6 (0.0–8.5) 1.8 (0.0–9.4) 0.0 (0.0–5.7) 0.0 (0.0–6.3) 1.6 (0.0–8.5)12–23 9.8 (3.7–20.2) 3.4 (0.4–11.7) 4.9 (1.0–13.7) 1.7 (0.0–9.1) 4.9 (1.0–13.7) 8.5 (2.8–18.7)

PostimmunizationGMT, moOverall 124.8 (90.2–172.5) 78.9 (59.6–104.4) 84.3 (65.5–108.5) 44.7 (36.3–55.1) 109.9 (82.8–145.8) 61.3 (46.9–80.0)6–11 57.6 (39.1–84.9) 43.0 (29.5–62.6) 48.9 (35.9–66.6) 29.9 (23.3–38.3) 54.2 (37.9–77.5) 29.9 (21.4–41.6)12–23 253.5 (161.9–397.0) 150.9 (105.6–215.6) 140.4 (98.4–200.3) 68.7 (50.4–93.7) 212.6 (146.7–308.0) 131.8 (94.5–183.8)GMT ratio, moOverall 19.0 (14.5–24.9) 14.1 (11.0–18.2) 12.2 (9.6–15.5) 7.2 (5.8–8.9) 19.3 (14.7–25.2) 10.3 (8.0–13.3)6–11 10.4 (7.3–15.0) 8.0 (5.6–11.4) 7.7 (5.8–10.2) 4.6 (3.5–6.0) 10.5 (7.2–15.2) 5.5 (3.8–7.8)12–23 32.9 (23.2–46.6) 25.9 (19.2–34.9) 18.8 (13.1–26.8) 11.5 (8.5–15.5) 34.1 (24.4–47.6) 20.4 (15.6–26.5)Seroprotection rate, %, moOverall 76.9 (68.2–84.2) 69.7 (60.7–77.7) 66.9 (57.7–75.3) 50.0 (40.8–59.2) 78.0 (69.4–85.1) 64.8 (55.6–73.2)6–11 62.5 (48.5–75.1) 54.0 (40.9–66.6) 50.9 (37.3–64.4) 36.5 (24.7–49.6) 64.9 (51.1–77.1) 44.4 (31.9–57.5)12–23 90.2 (79.8–96.3) 86.4 (75.0–94.0) 82.0 (70.0–90.6) 64.4 (50.9–76.4) 90.2 (79.8–96.3) 86.4 (75.0–94.0)Seroconversion rate, %, moOverall 76.1 (67.3–83.5) 69.7 (60.7–77.7) 66.1 (56.8–74.6) 50.0 (40.8–59.2) 78.0 (69.4–85.1) 63.9 (54.7–72.4)6–11 60.7 (46.8–73.5) 54.0 (40.9–66.6) 50.9 (37.3–64.4) 36.5 (24.7–49.6) 64.9 (51.1–77.1) 42.9 (30.5–56.0)12–23 90.2 (79.8–96.3) 86.4 (75.0–94.0) 80.3 (68.2–89.4) 64.4 (50.9–76.4) 90.2 (79.8–96.3) 86.4 (75.0–94.0)

a Passaged reference viruses (see Appendix 1).b Sample size, overall (age 6–11 months, age 12–23 months).



supported by the low preimmuniza-tion titers we observed in theseinfants. Immaturity of the immunesystem may instead contribute tosuboptimal vaccine responses in in-fants. This finding also may relate to

a lack of previous exposure to theinfluenza virus early in life, althoughbaseline titers measured in thisstudy also were low for childrenolder than 1 year of age. Current dos-ing recommendations are histori-

cally predicated on boosting preex-isting immunity in adults and olderchildren primed through previousnatural exposures, a profile less cer-tain in the very young.9 In our study,GMTs and GMT ratios were slightly

TABLE 4 Adverse Events by Day 3 After Immunization: Infants Aged 6 to 11 Months

Dose 1 Dose 2 Either Dose

Full Dose,n� 61

Half-Dose,n� 65

Pa Full Dose,n� 61

Half-Dose,n� 65

Pa Full Dose,n� 61

Half-Dose,n� 65

Pa

Adverse event, n (%)Any event 44 (72.1) 51 (78.5) .535 38 (62.3) 36 (55.4) .472 50 (82.0) 54 (83.1) 1.000Solicited 43 (70.5) 48 (73.8) .695 36 (59.0) 34 (52.3) .478 49 (80.3) 51 (78.5) .829Unsolicitedb 12 (19.7) 17 (26.2) .406 6 (9.8) 15 (23.1) .057 17 (27.9) 28 (43.1) .095

Solicited adverse events after immunizationRedness 10 (16.4) 7 (10.8) .438 12 (19.7) 3 (4.6) .012 15 (24.6) 9 (13.8) .173Moderate to severec 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASevered 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASwelling 5 (8.2) 2 (3.1) .262 5 (8.2) 1 (1.5) .107 7 (11.5) 3 (4.6) .196Moderate to severec 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASevered 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NAInduration 3 (4.9) 3 (4.6) 1.000 7 (11.5) 1 (1.5) .029 8 (13.1) 3 (4.6) .119Moderate to severec 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASevered 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NATenderness 10 (16.4) 9 (13.8) .805 7 (11.5) 8 (12.3) 1.000 13 (21.3) 13 (20.0) 1.000Moderate to severee 1 (1.6) 0 (0.0) .484 0 (0.0) 2 (3.1) .497 1 (1.6) 2 (3.1) 1.000Severee 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NAFever

�37.5°C 1 (1.6) 1 (1.5) 1.000 1 (1.6) 7 (10.8) .063 2 (3.3) 7 (10.8) .166�38°C 1 (1.6) 1 (1.5) 1.000 0 (0.0) 6 (9.2) .028 1 (1.6) 7 (10.8) .063�39°C 0 (0.0) 0 (0.0) NA 0 (0.0) 3 (4.6) .245 0 (0.0) 3 (4.6) .245Excluding rectal/tympanicFever

�37.5°C 1 (1.6) 1 (1.5) 1.000 1 (1.6) 4 (6.2) .366 2 (3.3) 4 (6.2) .681�38°C 1 (1.6) 1 (1.5) 1.000 0 (0.0) 3 (4.6) .245 1 (1.6) 4 (6.2) .366�39°C 0 (0.0) 0 (0.0) NA 0 (0.0) 1 (1.5) 1.000 0 (0.0) 1 (1.5) 1.000Irritability 33 (54.1) 35 (53.8) 1.000 20 (32.8) 27 (41.5) .359 36 (59.0) 41 (63.1) .716Moderate to severee 18 (29.5) 18 (27.7) .846 9 (14.8) 15 (23.1) .263 21 (34.4) 25 (38.5) .712Severee 1 (1.6) 2 (3.1) 1.000 0 (0.0) 1 (1.5) 1.000 1 (1.6) 2 (3.1) 1.000Decreased appetite 15 (24.6) 15 (23.1) 1.000 9 (14.8) 19 (29.2) .057 21 (34.4) 29 (44.6) .277Moderate to severee 2 (3.3) 5 (7.7) .441 0 (0.0) 4 (6.2) .12 2 (3.3) 8 (12.3) .097Severee 0 (0.0) 1 (1.5) 1.000 0 (0.0) 0 (0.0) NA 0 (0.0) 1 (1.5) 1.000Drowsiness 24 (39.3) 21 (32.3) .459 16 (26.2) 17 (26.2) 1.000 28 (45.9) 28 (43.1) .858Moderate to severee 2 (3.3) 5 (7.7) .441 3 (4.9) 7 (10.8) .326 4 (6.6) 12 (18.5) .061Severee 0 (0.0) 1 (1.5) 1.000 0 (0.0) 1 (1.5) 1.000 0 (0.0) 2 (3.1) .497Sleep disturbance 26 (42.6) 25 (38.5) .717 19 (31.1) 22 (33.8) .85 34 (55.7) 31 (47.7) .379Moderate to severee 11 (18.0) 15 (23.1) .516 7 (11.5) 17 (26.2) .043 16 (26.2) 25 (38.5) .183Severee 0 (0.0) 5 (7.7) .058 0 (0.0) 2 (3.1) .497 0 (0.0) 5 (7.7) .058

Unsolicited adverse events after immunizationb

Upper respiratory 4 (6.6) 6 (9.2) .745 4 (6.6) 7 (10.8) .532 8 (13.1) 12 (18.5) .471Ocular 0 (0.0) 1 (1.5) 1.000 0 (0.0) 0 (0.0) NA 0 (0.0) 1 (1.5) 1.000Gastrointestinal 1 (1.6) 2 (3.1) 1.000 0 (0.0) 3 (4.6) .245 1 (1.6) 5 (7.7) .209Rash 1 (1.6) 1 (1.5) 1.000 1 (1.6) 0 (0.0) .484 2 (3.3) 1 (1.5) .610Teething 6 (9.8) 6 (9.2) 1.000 2 (3.3) 5 (7.7) .441 8 (13.1) 10 (15.4) .802Miscellaneous 0 (0.0) 3 (4.6) .245 0 (0.0) 1 (1.5) 1.000 0 (0.0) 4 (6.2) .120

NA indicates not applicable.a Fisher’s exact test.b Includes all unsolicited adverse events after immunization, regardless of causality assessment.c Moderate to severe reaction refers to maximum measurement of more than 20 mm.d Severe reaction refers to maximum measurement of 50 mm or more.e See Appendix 3 for scale.

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higher, but responses were other-wise comparable between full-doseand half-dose recipients aged 12 to23 months. The minimal antibody ad-vantage conferred by the full dose in

toddlers is consistent with recentdose-sparing studies36,37 in youngadults in whom comparable antibodyresponses also have been found withhalf-doses or full doses. On the other

hand, superior response to the fulldose in infants highlights the needfor additional studies of improvedvaccine dosing and/or formulationsfor such young children.

TABLE 5 Adverse Events by Day 3 After Immunization: Toddlers Aged 12 to 23 Months

Dose 1 Dose 2 Either Dose

Full Dose(N� 63)

Half-Dose(N� 63)

Pa Full Dose(N� 63)

Half-Dose(N� 61)b

Pa Full Dose(N� 63)

Half-Dose(N� 61)b

Pa

Adverse event, n (%)Any event 45 (71.4) 47 (77.0) .541 45 (71.4) 39 (63.9) .443 58 (92.1) 53 (86.9) .392Solicited 43 (68.3) 42 (68.9) 1.000 44 (69.8) 39 (63.9) .568 56 (88.9) 50 (82.0) .316Unsolicitedc 9 (14.3) 11 (18.0) .631 11 (17.5) 8 (13.1) .620 18 (28.6) 17 (27.9) 1.000

Solicited adverse events after immunizationRedness 10 (15.9) 13 (20.6) .645 6 (9.5) 12 (19.7) .131 13 (20.6) 17 (27.9) .404Moderate to severed 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASeveree 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASwelling 10 (15.9) 5 (7.9) .271 5 (7.9) 5 (8.2) 1.000 12 (19.0) 8 (13.1) .466Moderate to severed 0 (0.0) 1 (1.6) 1.000 0 (0.0) 1 (1.6) .492 0 (0.0) 1 (1.6) .492Severee 0 (0.0) 1 (1.6) 1.000 0 (0.0) 0 (0.0) NA 0 (0.0) 1 (1.6) .492Induration 6 (9.5) 3 (4.8) .491 5 (7.9) 3 (4.9) .718 9 (14.3) 5 (8.2) .396Moderate to severec 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASeveree 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NATenderness 11 (17.5) 18 (28.6) .204 9 (14.3) 10 (16.4) .806 15 (23.8) 20 (32.8) .320Moderate to severef 2 (3.2) 1 (1.6) 1.000 3 (4.8) 1 (1.6) .619 4 (6.3) 2 (3.3) .680Severef 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NAFever

�37.5°C 2 (3.2) 5 (7.9) .44 7 (11.1) 10 (16.4) .442 9 (14.3) 12 (19.7) .479�38°C 1 (1.6) 2 (3.2) 1.000 5 (7.9) 8 (13.1) .392 6 (9.5) 9 (14.8) .419�39°C 0 (0.0) 0 (0.0) NA 2 (3.2) 2 (3.3) 1.000 2 (3.2) 2 (3.3) 1.000Excluding rectal/tympanicFever

�37.5°C 2 (3.2) 5 (7.9) .440 6 (9.5) 9 (14.8) .419 8 (12.7) 11 (18.0) .462�38°C 1 (1.6) 2 (3.2) 1.000 4 (6.3) 7 (11.5) .359 5 (7.9) 8 (13.1) .392�39°C 0 (0.0) 0 (0.0) NA 2 (3.2) 2 (3.3) 1.000 2 (3.2) 2 (3.3) 1.000Irritability 27 (42.9) 25 (39.7) .857 28 (44.4) 22 (36.1) .365 38 (60.3) 36 (59.0) 1.000Moderate to severef 7 (11.1) 10 (15.9) .603 10 (15.9) 11 (18.0) .813 15 (23.8) 18 (29.5) .544Severef 1 (1.6) 0 (0.0) 1.000 1 (1.6) 0 (0.0) 1.000 2 (3.2) 0 (0.0) .496Decreased appetite 17 (27.0) 18 (28.6) 1.000 18 (28.6) 19 (31.1) .845 27 (42.9) 26 (42.6) 1.000Moderate to severef 4 (6.3) 4 (6.3) 1.000 8 (12.7) 6 (9.8) .778 11 (17.5) 9 (14.8) .808Severef 2 (3.2) 0 (0.0) .496 1 (1.6) 1 (1.6) 1.000 2 (3.2) 1 (1.6) 1.000Drowsiness 17 (27.0) 19 (30.2) .844 10 (15.9) 11 (18.0) .813 21 (33.3) 25 (41.0) .458Moderate to severef 1 (1.6) 3 (4.8) .619 4 (6.3) 2 (3.3) .68 5 (7.9) 4 (6.6) 1.000Severef 0 (0.0) 0 (0.0) NA 1 (1.6) 0 (0.0) 1.000 1 (1.6) 0 (0.0) 1.000Sleep disturbance 23 (36.5) 22 (34.9) 1.000 24 (38.1) 26 (42.6) .715 34 (54.0) 33 (54.1) 1.000Moderate to severef 11 (17.5) 7 (11.1) .446 11 (17.5) 11 (18.0) 1.000 19 (30.2) 15 (24.6) .549Severef 0 (0.0) 0 (0.0) NA 4 (6.3) 0 (0.0) .119 4 (6.3) 0 (0.0) .119

Unsolicited adverse events after immunizationc

Upper Respiratory 3 (4.8) 1 (1.6) .619 5 (7.9) 2 (3.3) .440 8 (12.7) 3 (4.9) .206Ocular 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NAGastrointestinal 3 (4.8) 4 (6.3) 1.000 4 (6.3) 4 (6.6) 1.000 7 (11.1) 7 (11.5) 1.000Rash 1 (1.6) 3 (4.8) .619 1 (1.6) 0 (0.0) 1.000 2 (3.2) 3 (4.9) .677Teething 3 (4.8) 1 (1.6) .619 2 (3.2) 1 (1.6) 1.000 5 (7.9) 2 (3.3) .440Miscellaneous 0 (0.0) 2 (3.2) .496 0 (0.0) 1 (1.6) .492 0 (0.0) 3 (4.9) .116

NA indicates not applicable.a Fisher’s exact test.b Denominators differ because of missing data.c Includes all unsolicited adverse events after immunization, regardless of causality assessment.d Moderate to severe reaction refers to maximum measurement of more than 20 mm.e Severe reaction refers to maximum measurement of 50 mm or more.f See Appendix 3 for scale.



In this study, we found virtually no an-tibody induced to the alternate B/Victo-ria lineage that was not included as a2008–2009 TIV component. This sug-gests that exposing immunologicallynaïve infants to TIV containing 1 B/lin-eage is insufficient to induce primingto the other B/lineage, an observationthat requires additional evaluation. Ithas been suggested that ether treat-ment of the viral antigen used for HItesting can enhance sensitivity for in-fluenza B responses but at the expenseof specificity.38,39 Absent internation-ally standardized protocols or vali-dated correlation with clinical protec-tion, the use of ether in somelaboratories but not others, some-times specified in the methods andsometimes not, can complicate the in-terpretation and comparison acrosspublished immunogenicity data. Forthese results, we did not ether treatthe viral antigen used for HI testing,but the same approach was used forall relevant comparisons.

The use of noninactivated viruses fur-ther supported MN comparisons.Postimmunization results were com-parable by HI and MN for the H1N1 andB/Yamagata vaccine components butnot the H3N2 component. The patternof the full-dose versus half-dose in-crease for H3N2 became less markedin infants butmore so in toddlerswhenmeasured by MN versus HI. A degree oflaboratory variability in influenza anti-body assay results is widely recog-nized. Postimmunization HI and MN re-sponses typically are well-correlatedfor homologous viruses,40 but vaccine-induced HI responses may exceed MNfor heterologous strains.41 Sequencingof the HA protein of the A/Brisbane/10/07 (H3N2) strain used after serialpassage in our study showed fewamino acid differences at antigenicsites (Leu210Pro and Asn112Ser insites B and D, respectively) comparedwith the posted WHO reference strain.

The viral antigen used in our assay didnot lead to reduced titers when testedwith control ferret anti-sera, suggest-ing that these mutations did not have amajor impact on the observed results(Appendix 1).

There are several limitations to thisstudy. The target sample size was notachieved at 1 site, limiting power andinterpretation. However, 2 strikingtrends were apparent, including bothdose-response and age-related differ-ences that were consistent across all 3vaccine components by both HI andMNassays. The consistency of these dataargues strongly against their beingchance findings. By convention, we de-fined seroprotection rates on the basisof a threshold HI titer of 1:40, but wealso explored this on the basis of MN. Itshould be understood, however, thatthe 1:40 HI threshold used to approveinfluenza vaccines annually has notbeen specifically evaluated for infantsand toddlers nor is a seroprotectivethreshold known for MN. Furthermore,the 1:40 HI threshold corresponds gen-erally to a 50% protective level inadults.33,34 Infants and toddlers whohad previously been immunized wereexcluded, and baseline antibody titerswere low; consequently, our resultsapply to immunologically naïve infantsand toddlers but may not apply tothose who have been previously immu-nized or infected or to children aged 24to 35 months for whom half-dosingalso is currently recommended. Sea-sonal influenza activity was delayed inCanada during the 2008–2009 season,peaking in late February/early March,so that infection is unlikely to have sub-stantially influenced our findings.42 Thefollow-up period in this study was 45days or less, and caution is requiredwhen extrapolating results to longerperiods. Finally, fever was defined forthis study on the basis of axillary tem-perature for parental ease and childcomfort, but this route generally gives

lower temperature recordings thantympanic or rectal measures. Thislikely explains the low baseline tem-peratures we found in both studygroups (Table 1). However, the mostimportant comparison was betweengroups on the basis of the same routeof measure. This comparison showedthe full-dose regimen did not inducemore fever than the half-dose regimen.All other indicators of systemic reac-tion were consistent with this conclu-sion, as was parent acceptability.

CONCLUSIONS

Despite a decades-long recommenda-tion to halve the dose of split TIV ad-ministered to infants and toddlers,this is the first study to evaluate doseresponse on immunogenicity and re-actogenicity. By administering 2 0.5-mLdoses as given to older children, thisstudy suggests an opportunity to im-prove protection of highly vulnerableinfants, without increase in reactoge-nicity. Although cost-effectivenessanalyses are needed, the incrementalcost associated with full dosing wouldbe limited to that of the vaccine itselfbecause such a program changewould not require an additional medi-cal visit. Additional studies are neededto confirm these findings in a largersample, with additional seasons’ prod-ucts, further age stratification, andwith longer follow-up to assess anti-body duration. Relevance to pandemicas well as seasonal vaccine recom-mendations should be assessed. Inparticular, additional investigation ofthe lower response of infants to thecurrently recommended half-dose ap-proach is urgently required. If con-firmed, these results have significantimplications for influenza vaccine dos-ing recommendations in this veryyoung age group.

ACKNOWLEDGMENTSFunding for this study was providedby the Public Health Agency of Can-

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ada (6273-15-2008/4160872) as wellas the Ministère de la Santé et desServices Sociaux du Québec. Thefunders had no role in study design,data collection, analysis, decision topublish, or preparation of the manu-script. The views expressed hereindo not necessarily represent the

views of the Public Health Agency ofCanada. Vaccine was provided with-out charge from Sanofi Pasteur(Vaxigrip).

We thank the staff of the study sitesfor their diligence and Leslie Love forcoordination nationally. Yan Li of theNational Microbiology Laboratory

kindly provided reference virusesused in the antibody assays. Wethank Drs Nicole Le Saux, MonikaNaus, and Wendy Vaudry for servingas the data-monitoring safety com-mittee for this trial. We thank Dr Jen-nifer Gardy for assistance with virussequencing and interpretation.

REFERENCES

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33. Committee for Proprietary Medicinal Products(CPMP). Note for guidance on harmonization ofrequirementsforinfluenzavaccines.London,UK:EuropeanAgency for the EvaluationofMedicinalProducts [article online], 1997. CPMP/BWP/214/96 (circular 96–0666):1–22. Available at:

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APPENDIX 1: LABORATORYMETHODS

Viruses

Reference viruses were obtainedfrom the National Microbiology Labo-ratory (NML) in Winnipeg, Canada,and passaged in Madin Darby caninekidney (MDCK) cells at the British Co-lumbia Centre for Disease Control.A/Brisbane/59/07 (H1N1) was usedat passage 2 (P2) and A/Brisbane/10/07 (H3N2) was used at P3 for bothHI and MN. The HA and neuramini-dase (NA) genes of all viruses weresequenced to assess homology withthe reference strain. Differences be-tween study viruses and referencestrains are summarized below, withresidue numbering beginning withthe N-terminal methionine residues.

The HA protein sequence of the NMLA/Brisbane/59/07 (H1N1) virus (P2)differed from the WHO referencestrain by 1 amino acid in antigenicregion B (Asp/Ile203Asn), and the NAprotein sequence was identical tothe reference strain. The HA se-

quence of the NML A/Brisbane/10/07(H3N2) virus (P3) differed from theWHO reference strain by 2 amino ac-ids in antigenic regions B and D(Leu210Pro and Asn112Ser, res-pectively), and the NA protein se-quence was identical to the refer-ence strain.

B/Florida/4/06 (Yamagata) (vaccinecomponent) and B/Brisbane/60/08(Victoria) (alternate nonvaccine lin-eage) viruses used for both HI and MNassays were passaged twice (P2) inMDCK cells. The HA sequence of theB/Florida/4/06 (Yamagata) virus (P2)showed a mixture of wild-type geno-type (identical to the reference) andmutant genotype at position 429(Gly429Asp); the NA sequence wasidentical to the WHO posted refer-ence strain. The HA sequence of theB/Brisbane/60/08 (Victoria) virus(P2) also showed a mix of wild-typegenotype (identical to the reference)and mutant genotypes (Thr214Alaand Thr277Ile); the NA sequenceswere identical.

Deposition of Viral NucleotideSequences in GenBank

Nucleotide sequences of the abovestudy virus segments were depositedinto GenBank under the following ac-cession numbers: NML A/Brisbane/59/07 (H1N1): CY065747 (HA),CY065749 (NA); NML A/Brisbane/10/07(H3N2): CY065751 (HA), CY065752 (NA);NML B/Florida/4/06 (Yamagata):CY073895 (HA), CY073896 (NA); andNML B/Brisbane/60/08 (Victoria):CY073893 (HA), CY073894 (NA).

HI Assay

All sera were frozen at �20°C or lessuntil prepared for testing. In prepara-tion for the HI assay, sera were treatedwith a receptor-destroying enzyme toremove nonspecific agglutinins, andfurther hemadsorbed with 50% turkeyerythrocytes. Sera were serially di-luted beginning at 1:10 with phosphatebuffered saline and 25 �L of each se-rum dilution was reacted with 25�L ofantigen containing 4 HI units of virusfor 30 minutes. To each mixture, 50 �L

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of 0.5% turkey erythrocytes wereadded, and after mixing, the prepara-tions were incubated for 30 minutes.The HI titer was the inverse of the high-est dilution at which detectable HI ac-tivity still was present. All sera wereassayed in duplicate.

MN Assay

The same study viruses were used forthe MN assay as for the HI assay. Viraltiters were determined by tissue cul-ture infective dose 50 on the basis ofthe Karber method.1 The sera were in-activated by heating at 56°C for 30min-utes. The sera were serially diluted be-ginning at 1:10, and to each dilution100 infectious units of virus wereadded. The plates were incubated for 2hours at 37°C to allow for virus-antibody interaction. The contents ofeach well were then transferred ontomicrotiter plates with confluentmonolayers of MDCK cells. After 3hours of additional incubation at37°C, the medium in each well wasremoved and replaced by fresh me-dium (MegaVir; HyClone, Logan,Utah) containing L-1-tosylamido-2-phenylethyl chloromethyl ketone(TPCK)-treated trypsin. The plate wasthen again incubated at 37°C andmonitored for the appearance of cy-topathic effects on days 3 and 5. TheMN titer was defined as the serumdilution in the well immediately pre-ceding the wells with cytopathic ef-fects. MN was conducted in duplicateup to 2 times until intra-assay con-cordance was achieved (twofold orless) and GMTs reported.

Reference

1. Karber G. Beitrag zur kollektiven be-handlung pharmakologischer reihen-versuche. Arch Exp Path Pharmacol.1931;162(4):480–483

APPENDIX 3: RESPONSE SCALESFOR PARENT-MEASURED ADVERSEEVENTS AFTER IMMUNIZATION

Local and systemic reactions were mea-sured for days 0 to 7 after each immuni-zation by parents of study participants.Responseswere categorized into 4-pointscales (none, mild, moderate, or severe)described as follows:

● Axillary temperature: none (�37.5°C),mild (�37.5°C to �38.0°C), moderate(�38.0°C to �39.0°C), or severe(�39.0°C).

● Local redness, swelling, or indura-tion: mild (�0 mm but �20 mm),moderate (�20 mm and�50 mm),or severe (�50 mm).

● Local pain or tenderness: mild (mi-nor reaction when injection sitetouched), moderate (child cries orprotests when injection sitetouched), or severe (child cries

when injected limb moved or move-ment of injected limb reduced).

● Irritability: mild (easily consolable),moderate (requires increased at-tention), or severe (inconsolable).

● Sleep disturbance: mild (less sleepor woke once more than usual),moderate (less sleep or woke re-peatedly), or severe (less sleep orvirtually sleepless night).

● Drowsiness: mild (noticeable butdoes not interfere with usual dailyactivities), moderate (interfereswith daily activities), or severe(prevents usual daily activities).

● Decreased appetite: mild (eating orfeeding less than usual), moderate(eating or feeding much less thanusual), or severe (not eating orfeeding at all).

APPENDIX 2 Participant Flow Chart



APPENDIX 4 Adverse Events by Day 3 After Immunization: Infants and Toddlers Combined

Adverse Event Dose 1 Dose 2 Either Dose

Full Dose(N� 124), n(%)

Half-Dose(N� 128), n(%)

Pa Full-dose(N� 124), n(%)

Half-Dose(N� 126), n(%)b

Pa Full Dose(N� 124), n(%)

Half-Dose(N� 126), n(%)b

Pa

Any event 89 (71.8) 98 (77.8) .309 83 (66.9) 75 (59.5) .240 108 (87.1) 107 (84.9) .716Solicited 86 (69.4) 90 (71.4) .782 80 (64.5) 73 (57.9) .302 105 (84.7) 101 (80.2) .407Unsolicitedc 21 (16.9) 28 (22.2) .340 17 (13.7) 23 (18.3) .389 35 (28.2) 45 (35.7) .224Solicited AEFIsRedness 20 (16.1) 20 (15.6) 1.000 18 (14.5) 15 (11.9) .579 28 (22.6) 26 (20.6) .760Moderate-severed 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASeveree 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASwelling 15 (12.1) 7 (5.5) .075 10 (8.1) 6 (4.8) .313 19 (15.3) 11 (8.7) .122Moderate-severed 0 (0.0) 1 (0.8) 1.000 0 (0.0) 1 (0.8) 1.000 0 (0.0) 1 (0.8) 1.000Severee 0 (0.0) 1 (0.8) 1.000 0 (0.0) 0 (0.0) NA 0 (0.0) 1 (0.8) 1.000Induration 9 (7.3) 6 (4.7) .434 12 (9.7) 4 (3.2) .041 17 (13.7) 8 (6.3) .060Moderate-severed 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NASeveree 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NATenderness 21 (16.9) 27 (21.1) .426 16 (12.9) 18 (14.3) .854 28 (22.6) 33 (26.2) .557Moderate-severef 3 (2.4) 1 (0.8) .364 3 (2.4) 3 (2.4) 1.000 5 (4.0) 4 (3.2) .748Severef 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NAFever� 37.5°C 3 (2.4) 6 (4.7) .5 8 (6.5) 17a (13.5) .090 11 (8.9) 19 (15.1) .173

�38°C 2 (1.6) 3 (2.3) 1.000 5 (4.0) 14b (11.1) .054 7 (5.6) 16 (12.5) .078�39°C 0 (0.0) 0 (0.0) NA 2 (1.6) 5c (4.0) .447 2 (1.6) 5 (4.0) .447

Excluding rectal/tympanic Fever� 37.5°C 3 (2.4) 6 (4.7) .500 7 (5.6) 13 (10.3) .244 10 (8.1) 15 (11.9) .400�38°C 2 (1.6) 3 (2.3) 1.000 4 (3.2) 10 (7.9) .167 6 (4.8) 12 (9.5) .221�39°C 0 (0.0) 0 (0.0) 2 (1.6) 3 (2.4) 1.000 2 (1.6) 3 (2.4) 1.000Irritability 60 (48.4) 60 (46.9) .900 48 (38.7) 49 (38.9) 1.000 74 (59.7) 77 (61.1) .897Moderate-severef 25 (20.2) 28 (21.9) .759 19 (15.3) 26 (20.6) .324 36 (29.0) 43 (34.1) .416Severef 2 (1.6) 2 (1.6) 1.000 1 (0.8) 1 (0.8) 1.000 3 (2.4) 2 (1.6) .682

Decreased appetite 32 (25.8) 33 (25.8) 1.000 27 (21.8) 38 (30.2) .150 48 (38.7) 55 (43.7) .443Moderate-severef 6 (4.8) 9 (7.0) .597 8 (6.5) 10 (7.9) .808 13 (10.5) 17 (13.5) .560Severef 2 (1.6) 1 (0.8) .618 1 (0.8) 1 (0.8) 1.000 2 (1.6) 2 (1.6) 1.000Drowsiness 41 (33.1) 40 (31.3) .788 26 (21.0) 28 (22.2) .878 49 (39.5) 53 (42.1) .701Moderate-severef 3 (2.4) 8 (6.3) .217 7 (5.6) 9 (7.1) .797 9 (7.3) 16 (12.7) .206Severef 0 (0.0) 1 (0.8) 1.000 1 (0.8) 1 (0.8) 1.000 1 (0.8) 2 (1.6) 1.000Sleep disturbance 49 (39.5) 47 (36.7) .698 43 (34.7) 48 (38.1) .601 68 (54.8) 64 (50.8) .529Moderate-severef 22 (17.7) 22 (17.2) 1.000 18 (14.5) 28 (22.2) .142 35 (28.2) 40 (31.7) .582Severef 0 (0.0) 5 (3.9) .060 4 (3.2) 2 (1.6) .445 4 (3.2) 5 (4.0) 1.000

Unsolicited AEFIsc

Upper respiratory 7 (5.6) 7 (5.5) 1.000 9 (7.3) 9 (7.1) 1.000 16 (12.9) 15 (11.9) .850Ocular 0 (0.0) 1 (0.8) 1.000 0 (0.0) 0 (0.0) NA 0 (0.0) 1 (0.8) 1.000Gastrointestinal 4 (3.2) 6 (4.7) .749 4 (3.2) 7 (5.6) .540 8 (6.5) 12 (9.5) .486Rash 2 (1.6) 4 (3.1) .684 2 (1.6) 0 (0.0) .245 4 (3.2) 4 (3.2) 1.000Teething 9 (7.3) 7 (5.5) .613 4 (3.2) 6 (4.8) .749 13 (10.5) 12 (9.5) .836Miscellaneous 0 (0.0) 5 (3.9) .060 0 (0.0) 2 (1.6) .498 0 (0.0) 7 (5.6) .014

AEFI indicates adverse event following immunization; NA, not applicable.a Fisher’s exact test.b Denominators differ because of missing data.c Includes all unsolicited AEFIs, regardless of causality assessment.d Moderate-severe reaction refers to maximum measurement of more than 20 mm.e Severe reaction refers to maximum measurement of�50 mm.f See Appendix 3 for scale.

(Continued from first page)

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2011 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: Dr De Serres has received research grant funding for unrelated studies from Sanofi Pasteur and GlaxoSmithKline; Dr Scheifele hasreceived research grant funding for unrelated studies from Sanofi Pasteur, GlaxoSmithKline, and Wyeth; Dr Ward currently shares a CIHR team grant withGlaxoSmithKline investigators; and Dr Halperin has received research grant funding for unrelated studies from Sanofi Pasteur, GlaxoSmithKline and Novartis.The other authors have indicated they have no financial relationships relevant to this article to disclose.

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DOI: 10.1542/peds.2010-2777; originally published online July 18, 2011; 2011;128;e276Pediatrics

Sabaiduc and Martin PetricScheifele, Brian J. Ward, Scott A. Halperin, Naveed Z. Janjua, Tracy Chan, Suzana Danuta M. Skowronski, Travis S. Hottes, Mei Chong, Gaston De Serres, David W.

Aged 6 to 23 MonthsRandomized Controlled Trial of Dose Response to Influenza Vaccine in Children

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