Immunogenicity and reactogenicity of DTPa-HBV-IPV/Hib vaccine as primary and booster vaccination in...

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Immunogenicity and reactogenicity of DTPa-HBV-IPV/Hib vaccine asprimary and booster vaccination in low-birth-weight premature infantsLiliana Vazquez1, Fabiana Garcia1, Ricardo Ruttimann2, Gustavo Coconier1, Jeanne-Marie Jacquet ([email protected])3, Lode Schuerman3

1.Fundacion Centro de Estudios Infectologicos, Buenos Aires, Argentina2.GlaxoSmithKline Biologicals, Buenos Aires, Argentina3.GlaxoSmithKline Biologicals, Rixensart, Belgium

KeywordsCombination paediatric vaccines, DTPa,DTPa-HBV-IPV/Hib, Pre-term

CorrespondenceJeanne-Marie Jacquet, GSK Biologicals, Rue del’Institut 89, 1330 Rixensart, Belgium.Tel: +3226566758 |Fax: +3226569072 |Email: [email protected]

Received14 March 2008; revised 21 April 2008;accepted 25 April 2008.

DOI:10.1111/j.1651-2227.2008.00884.x

AbstractAim: To assess suitability of a combined DTPa-HBV-IPV/Hib vaccine (Infanrix hexaTM) for

immunization of low-birth-weight (<2.0 kg) preterm infants, with particular focus on the hepatitis B

response.

Methods: Open-label study in 170 preterm infants receiving primary vaccination at 2, 4 and

6 months of age and booster vaccination at 18–24 months. Enrolment and analysis were stratified in

two groups: infants with birth weight between 1.5 kg and 2.0 kg (low birth weight: LBW), infants with

BW <1.5 kg (very low birth weight: VLBW).

Results: One month after the three dose primary vaccination, 93.7% and 94.9% of infants in VLBW

and LBW groups, respectively, had anti-HBs antibody concentrations ≥ 10 mIU/mL. High

seroprotection and response rates (92.4–100%) to all vaccine antigens were observed. Those were

reinforced (>98%) by booster vaccination for all antigens except for HBs in VLBW children: only

88.7% of those had anti-HBs antibody concentrations ≥ 10 mIU/mL, compared with 96.5% of LBW

children (difference statistically not significant). The vaccine was well tolerated in both groups of

infants.

Conclusion: Preterm infants will benefit by the administration of a primary and booster vaccination with

DTPa-HBV-IPV/Hib vaccine.

INTRODUCTIONPreterm and low-birth-weight (LBW) infants are known tobe at high risk of vaccine-preventable disease but are lesslikely to receive immunizations on time (1,2). Medically sta-ble premature and LBW infants should receive full dosesof diphtheria, tetanus, acellular pertussis, hepatitis B, po-liovirus and Haemophilus influenzae type b (Hib) conju-gate vaccines at a chronological age consistent with therecommendations for full-term infants (1,3). Mild vaccine-attributable adverse events occur with similar frequenciesin both full-term and premature vaccine recipients and, al-though the immunogenicity of some childhood vaccines maybe decreased in the smallest premature infants, the antibodyconcentrations achieved are usually protective (1).

The introduction of multivalent combination vaccineshas been shown to be beneficial in terms of reducing the

AbbreviationsATP, according to protocol; GMC/T, geometric mean anti-body concentration/titre; DTPa-HBV-IPV/Hib, combinedhexavalent diphtheria-tetanus-acellular pertussis-hepatitisB-inactivated poliovirus/Hib vaccine; GA, gestationalage; Hib, Haemophilus influenzae type b; HBsAg, hep-atitis B virus surface antigen; LBW/VLBW, low/verylow birth weight; PT, pertussis toxoid; FHA, filamentoushaemagglutinin; PRN, pertactin; SAE, serious adverseevent.

number of injections and the associated pain and distressfor vaccinees (4,5), increasing compliance and vaccina-tion coverage (6). Although scarce, studies of the immuno-genicity and safety of DTPa combination vaccines in smallpreterm infants support their timely use in this popula-tion (7,8,9). The combined hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Hib(DTPa-HBV-IPV/Hib) vaccine, evaluated in term infants(10–16), has also shown to be immunogenic in preterm in-fants (17).

The primary aim of this study was to verify the suitabil-ity of the DTPa-HBV-IPV/Hib vaccine for immunization ofpreterm infants with a very low birth weight. The poten-tial impact of body weight at birth on the immune responseto vaccination was assessed via stratification of subjects ac-cording to this factor.

METHODSStudy design and subjectsEight centres were involved in this open-label study of theimmunogenicity, safety and reactogenicity of the hexavalentcombined DTPa-HBV-IPV/Hib vaccine in preterm infants.The study protocol was approved by local ethics committeesand conducted according to the guidelines of the Declara-tion of Helsinki and the principles of Good Clinical Practice.Following written informed consent provided by parents orguardians, male and female preterm infants born to mothers

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proven seronegative for hepatitis B virus surface antigen(HBsAg) after a gestation period between 24 and 36 weeks,with birth weight <2000 g, were enrolled for first vaccina-tion at 6–10 weeks of age. Enrolment was stratified accord-ing to birth weight so as to recruit two groups of infants:(i) infants with birth weight between 1.5 kg and less than2 kg (referred to as the LBW group); (ii) infants with a birthweight below 1.5 kg (referred to as the very low birth weight[VLBW] group).

Exclusion criteria were: participation in another trial; ahistory of infection with any of the diseases representedby the vaccine components; any previous vaccinations (ex-cept for Bacille Calmette-Guerin, anti-meningococcal andanti-pneumococcal vaccines) and immunosuppressive drugs(except for inhaled and topical corticosteroids) or immun-odeficient conditions; allergic disease; or any condition thatcould have potentially interfered with interpretation of studyoutcomes.

Study vaccineSubjects received the combined hexavalent DTPa-HBV-IPV/Hib vaccine (Infanrix hexaTM; GlaxoSmithKline Bio-logicals, Rixensart, Belgium) as a deep intramuscular injec-tion into the anterolateral region of the left thigh at 2, 4 and6 months of age, followed by a booster injection of the samevaccine at 18–24 months of age. The composition of theDTPa-HBV-IPV/Hib vaccine has been previously described(15).

Serological analysisBlood samples were drawn from all subjects before thefirst dose and 1 month after the third dose of theprimary vaccination series, and immediately before and1 month after the booster dose. Serum was stored at −20◦Cuntil serological analysis was undertaken. Methods andcut-offs for seroprotection (anti-HBs ≥10 mIU/mL; anti-PRP ≥0.15 �g/mL; anti-diphtheria ≥0.1 IU/mL; anti-tetanus≥0.1 IU/mL; anti-poliovirus types 1, 2 and 3 antibodytitres ≥8) or seropositivity (anti-PT, anti-FHA and anti-PRN antibody concentrations ≥5 EL.U/mL) were asdescribed (17). Results from samples with anti-HBs antibod-ies around the cut-off for seroprotection were retested forconfirmation. Samples seronegative for antidiphtheria anti-bodies were retested with the more sensitive in vitro neu-tralization assay on Vero cells (cut-off ≥ 0.016 IU/mL). Asthere is no established serological correlate of protection forpertussis antibodies, the response to pertussis antigens wasdefined as the appearance of antibodies in children seroneg-ative prior to vaccine administration (antibody concentra-tion <5 EL.U/mL), and in initially seropositive children,at least maintenance of prevaccination antibody concentra-tions for the primary series and at least two-fold increase ofantibody concentrations for the booster dose (15,17).

Reactogenicity assessmentDiary cards were distributed to parents or guardians torecord solicited local reactions (pain, redness and swellingat the injection site) and general symptoms (fever, irritabil-

ity/fussiness, drowsiness and loss of appetite) on the day ofeach vaccination and for the 3 subsequent days. The intensityof symptoms was graded from 1 to 3. Fever was defined asaxillary temperature ≥37.5◦C and grade 3 as axillary temper-ature >39.0◦C. Grade 3 symptoms were defined as: cryingwhen limb was moved (pain), redness or swelling >20 mm,inconsolable or persistent crying (irritability) and prevent-ing normal daily activities (all other symptoms). Unsolicitedsymptoms were reported during a 30-day follow-up periodafter each vaccination and serious adverse events (SAE)throughout the entire primary vaccination and booster vac-cination phases.

Statistical analysisImmunogenicity analyses were performed on the according-to-protocol (ATP) cohort, defined as vaccinated subjectswho met all eligibility criteria, complied with protocol-defined procedures and with antibody assay results avail-able. The safety analysis was performed on the total vacci-nated cohort.

Seropositivity, seroprotection or vaccine-response ratesand geometric mean antibody concentrations/titres (GMCs/GMTs) were calculated with 95% confidence intervals (CIs)for each antigen at each time point.

Differences in immunogenicity between the two groups ateach time point were assessed for each antigen. Standard-ized asymptotic 95% CI for the difference between groups inthe percentage of subjects with antibody concentration (ortitre) above the specified cut-offs or with a sero-responsewere calculated. The 95% CI for the GMT (or GMC) ra-tio between groups (LBW/VLBW) was calculated using aone-way analysis of variance (ANOVA) model on the log10

transformation of the antibody concentrations or titres(postprimary) of an ANCOVA model adjusted for baselineantibody GMC/T (postbooster).

The observation that the 95% CI on the GMC/GMTratios excluded 1 or that the 95% CI on the differencesin seroprotection/seropositivity/vaccine-response rates ex-cluded 0% was used to highlight possible differences be-tween groups.

The primary objective of the study was to explore whetherbody weight at birth impacted the response to the hepatitisB antigen after primary vaccination. With 150 subjects in theATP cohort for immunogenicity, the study had 90% power todetect a difference in anti-HBs seroprotection rates in favourof LBW infants, with a null hypothesis of 95% seroprotectionin the LBW group and 75% in the VLBW group (two-sidedt-test, � = 5%).

RESULTSOut of 169 infants enrolled and vaccinated (total vaccinatedcohort), 161 were included in the ATP immunogenicity co-hort for the primary vaccination phase. Reasons for elimina-tion were: study vaccine not administered according to thestudy protocol (n = 2); forbidden concomitant medicationduring the study (n = 1); development of pertussis beforecompletion of primary vaccination (n = 1); or serological

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data missing after the third vaccine dose (n = 4). In thebooster vaccination phase, 124 children were vaccinated and119 were included in the ATP immunogenicity cohort. Onesubject was lost to follow-up; one subject left the study aftera serious adverse event; two subjects had consent withdrawnafter booster vaccination; and one subject had received an-other vaccine before the booster.

DemographicsThe VLBW and LBW were similar with respect to genderand ethnic origin (Table S1). Here 77.2% of VLBW infantshad a gestational age (GA) of 30 weeks or less comparedto 11.0% of LBW infants, and 7.6% of VLBW infants were<0.75 kg at birth (Table S1).

Chronological age at the time of the first vaccine doseslightly tended to be higher in the VLBW group, but subjectsin this group were still of lower body weight compared tothe LBW group at that time. Here 11.4% of VLBW infantswere <1.5 kg at the time of the first vaccine dose, whereas amajority of LBW infants were >2.5 kg at the time of the firstvaccine dose.

IMMUNOGENICITYPrimary vaccinationOne month after the third vaccine dose, the anti-HBs sero-protection rate was similar in the two groups: 93.7% inthe VLBW group and 94.9% in the LBW group: differ-ence 1.3% [95% CI −6.8; 9.6] (Table 1). Anti-HBs anti-body GMC were also similar in both groups: GMC ratio(LBW group/VLBW) 1.3 [95%CI 0.7; 2.3]. 83.5% of subjectsin each group achieved anti-HBs antibody concentrations≥100 mIU/mL after primary vaccination.

At least 98% of infants in both groups had seroprotec-tive antibody concentrations against diphtheria, tetanus, Hiband poliovirus types 1, 2 and 3 (Table S2). At least 96.3% ofinfants in both groups mounted a response to filamentoushaemagglutinin (FHA) and pertactin (PRN) but there wasa trend for a lower response to pertussis toxoid (PT) in theVLBW group (92.4% in the VLBW group and 96.3% in theLBW group; Table S2). At least 94.6% of initially seronega-tive infants mounted a response to PT. The percentage ofinfants with anti-PRP antibodies ≥1 �g/mL, was signifi-cantly higher in the LBW group (80.8%) than in the VLBW

Table 1 Immune response to hepatitis B (95% CI) 1 month after primary vaccination, before and 1 month after booster vaccination (ATP cohort for immunogenicity)

Very low birth weight (%, (95%CI)) Low birth weight (%, (95%CI))

Primary Booster Primary Booster

Anti-HBs N Post N Pre N Post N Post N Pre N Post

% ≥10 mIU/mL 79 93.7 59 61.0 62 88.7 79 94.9 56 69.6 57 96.5(85.8–97.9) (47.4–73.5) (78.1–95.3) (87.5–98.6) (55.9–81.2) (87.9–99.6)

GMC mIU/mL 444.1 23.5 1026.5 576.4 32.7 1785.6(303.6–649.4) (15.7–35.3) (536.6–1963.8) (382.3–869.0) (21.6–49.4) (1027.0–3104.5)

Very low birth weight = <1.5 kg; Low birth weight = ≥1.5 kg and <2.0 kg; N = number of subjects with available results (both pre- and post-vaccination resultsfor pertussis vaccine response).

group (65.4%): between-group difference 15.4% [95% CI1.5; 28.9]. The anti-PT GMC (ratio 1.4 [95% CI 1.1–1.9])and anti-poliovirus type 3 GMT (ratio 1.7 [95% CI 1.1–2.7])were significantly higher in the LBW group than the VLBWgroup (Table S3). No other difference between groups wasdetected.

Booster vaccinationPrior to the booster dose, persisting anti-HBs seroprotectionrates in the VLBW and LBW groups were 61.0% and 69.6%,respectively. These rose to 88.7% and 96.5%, respectively,1 month after the booster dose (Table 1). In each groupthe increase in seroprotection rate between pre- and post-booster levels was statistically significant as evidenced byno overlap of the 95% CIs. However there was no statisti-cally significant difference in postbooster anti-HBs seropro-tection rates between groups: group difference 7.78% [95%CI −2.09; 18.56].

Of 9 infants who remained seronegative after the boosterdose, 7 had not attained postprimary vaccination anti-HBsconcentrations >100mIU/mL and 7 were VLBW infantsof 27 to 30 weeks GA. Five of these VLBW infants were>2.0 kg at the time of the first primary vaccination dose(Table 2). Three VLBW infants who failed to respond to thebooster dose also failed to mount an immune response fol-lowing primary vaccination (true nonresponders).

The lower postbooster seroprotection rate in theVLBW group was reflected in anti-HBs antibody GMCs(1026.5 mIU/mL vs. 1785.6 mIU/mL in the VLBW andLBW groups, respectively). Anti-HBs antibody concentra-tions ≥100 mIU/mL after the booster dose were similar inboth groups (85.5% of VLBW vs. 84.2% of LBW infants).Of 20 subjects with postprimary anti-HBS concentrations≤ 100 mIU/mL, only 7 achieved postbooster levels ≥100mIU/mL.

Prior to the booster dose, seroprotection rates againstdiphtheria, tetanus and polyribosyl ribitol phosphate (PRP)ranged between 55.6% and 78.9%, and seroprotection ratesagainst the polio types remained high (above 92%; Table S2).The significant difference between groups in the percent-age of subjects with anti-PRP antibody concentrations ≥1.0�g/mL observed after primary vaccination was not main-tained prior to the booster dose (14.8% [95% CI 7.0; 26.2]



Table 2 Characteristics of children with postbooster anti-HBs antibody concen-trations <10 mIU/mL (ATP immunogenicity cohort)

Birth Weight Anti-HBs GMC (mIU/mL)Gestational weight at Dose

Subject Group age (kg) 1 (kg) Postprimary Postbooster

88 VLBW 27 1.150 2.080 <10 <1099 VLBW 28 0.950 1.450 <10 <10120 VLBW 30 1.490 2.370 <10 <1042 VLBW 28 1.160 2.180 47 <1086 VLBW 29 1.200 3.040 66 <10112 VLBW 30 1.420 2.400 67 <10142 VLBW 30 0.955 1.615 527 <10121 LBW 31 1.900 3.670 38 <10133 LBW 32 1.825 3.00 870 <10

in the LBW group and 19.3% [95% CI 10.0; 31.9] in theVLBW group) or after the booster dose (100% [95% CI94.2; 100] vs. 98.2% [95% CI 90.6; 100], respectively). Thebooster dose elicited high seroprotection rates (over 98%) toall these antigens. A booster vaccine response to the threeacellular pertussis antigens was observed in at least 96.8%of VLBW subjects and 98.2% of the LBW subjects (TableS2 in Supplementary material online). A global trend forlower GMC/Ts following the booster in the VLBW groupwas observed versus the LBW group for all antibodies ex-cept PRP. The GMC/T ratios included ‘1’ for all antibodiesexcept diphtheria (ratio 1.69 [95%CI 1.16–2.47]).

Reactogenicity and safetyThe DTPa-HBV-IPV/Hib vaccine was generally well toler-ated in preterm infants. The incidence and intensity of so-licited local and general symptoms was similar between thetwo groups at each dose (overlap of 95% CIs), with the ex-ception of pain at dose 1, which was more common in theLBW group (borderline overlap of 95% CIs, Table S4).

Local symptoms of grade 3 intensity were within the samerange in each group following each dose. Overall grade 3local symptoms were reported by up to 10.7% of subjects inthe LBW group and 11.8% in the VLBW group.

Irritability was the most frequently reported solicited gen-eral symptom in both groups after primary and booster vac-cine doses (Table S5). Grade 3 fever (>39.0◦C) was reportedin only one child in the VLBW group after dose 1 and bythree subjects in the same group after the booster dose.Other grade 3 solicited general symptoms were reported in-frequently, by no more than 3.6% of subjects in either groupduring the primary vaccination course or 4.9% following thebooster dose. A majority of solicited general symptoms inboth groups were considered to be related to vaccination.

One child from the VLBW group had a swelling > 50 mmin diameter (55 mm) 1 day after the booster dose. No painor functional impairment was associated with the reaction,which lasted 1 day.

Thirty-four subjects experienced at least one serious ad-verse event (SAE) during the primary vaccination phase ofthis study, the majority of which involved infections (n =

28). Two subjects died. A twin boy (LBW group), born at31 weeks of gestation, birth weight 1.9 kg, died 62 days af-ter the first vaccination. No autopsy was performed and theultimate cause of death is unknown but was not consideredto be related to the study vaccine. The second death, con-sidered to be a possible case of sudden infant death syn-drome (SIDS), was that of a twin girl (VLBW group), born at32 weeks of gestation, birth weight 1.3 kg. She died 2 daysafter receiving the second dose of study vaccine at 3 monthsand 3 weeks of age. No autopsy was performed and thepossibility of a causal relationship with study vaccinationcould not be ruled out or confirmed. Both subjects who diedhad several SIDS risk factors, as discussed below. The otherSAEs reported during the primary vaccination phase weredetermined to be unrelated to the study vaccination. Twochildren in the VLBW group and three children in the LBWgroup experienced SAEs following booster vaccination.None was considered causally related to study vaccination.

DISCUSSIONCurrent guidelines recommend that vaccination of infantsborn before term should be performed without delay, at thesame age as infants born after a normal gestation period.Data on the use of DTPa-based combination vaccines inthis vulnerable population are scarce but support nonde-ferred vaccination (7). In this study of LBW preterm infants(<2.0 kg), high seroprotection and vaccine response rateswere observed after primary vaccination with the DTPa-HBV-IPV/Hib vaccine at 2, 4 and 6 months of age. Nosignificant differences were noted between the VLBW andLBW groups (birth weight below or above 1.5 kg) in terms ofseroprotection or vaccine response rates except for anti-PRPantibody concentrations ≥1.0 �g/mL observed in 65.4% ofVLBW infants and 80.8% of LBW infants after primaryvaccination.

Of note, seroprotection against hepatitis B, which wasthe primary objective of the study, was similar in the twogroups after primary vaccination. A similar percentage ofsubjects in both groups achieved anti-HBs concentrations≥ 100 mIU/mL after primary and booster vaccination, alevel that has shown some correlation with boostability inolder children (18). Fewer VLBW than LBW children withpostprimary concentrations <100 mIU/mL were able to re-spond satisfactorily to the booster dose (postbooster concen-tration ≥100 mIU/mL). Although no statistically significantdifference between groups was observed in terms of anti-HBs GMCs, the observed GMC was lower in VLBW infantsat all time points. A lower GMC after the last vaccine dosemay be of concern with regard to long-term persistence ofimmunity. However, the fact that the proportion of subjectswith anti-HBs concentrations ≥100 mIU/mL was similar inVLBW and LBW children (85.5% and 84.2%) suggest thatprotection in the long term may be similar in the two groups.A number of studies specifically evaluated the effect of birthweight on the response of preterm infants to hepatitis B vac-cination. These differ in design, vaccination schedule, thevaccine administered and importantly, the age vaccination



commenced (19,20,21,22,23). They show conflicting resultswith respect to the impact of body weight on the immuneresponse of preterm infants, some concluding an absence ofimpact (19,21,22) and others concluding some impact, al-though in conjunction with a number of other factors (23).

In contrast, the observed lower persistence before boostervaccination of anti-PRP and antitetanus antibodies inVLBW children, did not translate into a lower response tothe booster dose. Indeed all subjects in both groups reachedseroprotective concentrations postbooster with similarlyhigh antibody GMCs in both groups. Prior to the boosterdose, 64.5% of VLBW subjects and 80.0% of LBW sub-jects had persisting anti-PRP antibody concentrations ≥0.15�g/mL (difference not significant: 15.48 [95%CI −0.44;30.78]). However, >98.0% of subjects in both groups hadpostbooster anti-PRP antibody concentrations ≥1.0 �g/mL,indicating effective priming against Hib in both the LBWand VLBW groups.

Although a trend for a lower response to PT was seen af-ter primary vaccination, the response to that antigen wassimilar in the two groups after booster vaccination. Of note,long-term pertussis-specific immunity (humoral and cell me-diated) measured at 5–6 years of age after DTPa-Hep B(InfanrixTM-Hep B) vaccination in a 3-, 5- and 11-monthschedule was similar in children born before term and chil-dren born at term (24).

The immunogenicity results of this study are consistentwith a previous evaluation of primary and booster vacci-nation with the same hexavalent DTPa-HBV-IPV/Hib vac-cine in preterm (GA <37 weeks) infants in Spain (17,25,26).The study was also conducted in a 2-, 4- and 6-month pri-mary vaccination schedule with a booster dose at 18 monthsof age. Immunogenicity was assessed using the same assaysand parameters as this study. Enrolled infants were similarin terms of GA and a similar percentage of subjects wereof birth weight <1.5 kg. Postprimary seroprotection ratesagainst vaccine antigens were similar in the two studies: atleast 92.5% seroprotection against Hib, tetanus, diphtheriaand polio versus at least 93.7% in this study. The responseto pertussis antigens was also similar: 98.9% in the Spanishstudy versus at least 92.4% in this study. Of note, a lower re-sponse to PRP detected after the primary series was restoredto high levels by the booster, as seen in this study (26).

In both studies, the number of true nonresponders to hep-atitis B vaccine (subjects who failed to respond to primary orbooster vaccination) was similar, ranging between 5% and7% of preterm subjects. In our study, six subjects (four inthe VLBW group) who achieved anti-HBs antibody concen-trations ≥10 mIU/mL after primary vaccination failed to re-spond to the booster dose. Thus, of those who responded toprimary vaccination, 93% in the VLBW group and 96% inthe LBW group also responded to the booster dose.

Overall, the vaccine was well tolerated in preterm in-fants of low birth weight. A limitation of this study wasthat the methodology used to monitor safety did not allowspecific identification of cardiorespiratory adverse eventsknown to sometimes occur after vaccination of preterm in-fants (7,17,27). These events are considered to be predom-

inantly benign (7). Although 34 infants experienced SAEsduring the primary vaccination phase, this high frequencywas not unexpected in a population of preterm infants of lowbody weight at birth (<2.0 kg). The booster reactogenicitydata observed in this study were in line with previous expe-riences with this DTPa-HBV-IPV/Hib vaccine (28).

Two infants died during the course of the study, neitherwith an established diagnosis although one was consideredto be a case of SIDS. It has previously been established thatpremature infants are at a higher risk of SIDS, and that therisk increases with decreasing GA (29,30). Low body weightat birth, directly linked to GA, has also been identified asa significant risk factor (31). The relative risk of SIDS forpreterms relative to full terms was shown to be 2.64 for in-fants with a 1.5–2.5 kg body weight at birth and 3.68 for in-fants with a body weight at birth <1.5 kg (32). Both infantswho died in this study had several SIDS risk factors: prema-turity (both were born after a gestation of 31 or 32 weeks),low body weight at birth (both had birth weights <2.0 kg),age, as well as twin birth for both infants. Although theserisk factors are not independent, the infant with SIDS diag-nosis was clearly in a category at increased risk and died inthe age period of high susceptibility for sudden infant death(31). The potential relationship between vaccination withhexavalent vaccines and sudden unexpected deaths (includ-ing SIDS) has been reviewed at a larger scale by the Com-mittee for Proprietary Medicinal Products (CPMP) of theEuropean Agency for the Evaluation of Medicinal Productsand no evidence for a link between immunization with hex-avalent vaccines and sudden unexpected deaths was found(33).

In conclusion, this study confirms that primary vacci-nation of preterm infants according to the recommendedschedule for full-term infants can be done using the hex-avalent DTPa-HBV-IPV/Hib combination vaccine. It alsosuggests that the initially weaker immune response seen insome of those infants to hepatitis B vaccination may resultin a suboptimal booster response, although the two groupsevaluated in this study cannot be distinguished when the100 mIU/mL threshold for booster response to HBV isconsidered.

ACKNOWLEDGEMENTSThis study was supported by GlaxoSmithKline Biologicals,Belgium. Ruttimann, Jacquet and Schuerman are employ-ees of GlaxoSmithKline Biologicals and report ownershipof equity or stock options. Vazquez, Garcia and Coconierare consultants to GSK and have received travel grantsor honoraria within the past 3 years. The authors thankthe following investigators who participated in the study:Sanatorio de la Trinidad. San Isidro: Dr. Regina Valverde,Dr. Monica Gervasoni, Sanatorio de la Trinidad. Palermo:Dr. Marcelo de Caro, Dr. Adriana Gorestein, SanatorioOtamendi: Dr. Graciela Basso, Dr. Liliana Morales,Maternidad Sarda: Dr. Ana Galindo, Dr. Marcela Ortizde Zarate, Hospital Fernandez: Dr. Teresa Sepulveda,Dr. Alicia Serjan, Dr. Maria Buraschi, Hospital Posadas:Dr. Graciela Olsen, Dr. Arias, Dr. Vilma Oreiro, Hospital



Materno Infantil. San Isidro: Dr. Regina Valverde,Dr. Menendez, Dr. Blanca Sendra, Fundacion Cen-tro de Estudios Infectologicos: Dr. Oscar Podesta andDr Daniel Stamboulian. The authors thank MohammedBenaata and Valerie Haezebroeck for laboratory analyses,Simon Lancaster and Julia Donnelly for editorial assistancein the preparation of this manuscript and Silvia Damaso forconducting the data analysis.

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Supplementary materialThe following supplementary material is available for thisarticle:

Table S1 Summary of demographic characteristics (ATP co-hort for immunogenicity)Table S2 Seroprotection/vaccine-response rates (95% CI)1 month after primary vaccination, before and 1 month afterbooster vaccination (ATP cohort for Immunogenicity)Table S3 Antibody GMCs/GMTs (95% CI) 1 month afterprimary vaccination, before and 1 month after booster vac-cination (ATP cohort for Immunogenicity)Table S4 Incidence of solicited local injection site symptomswithin 4 days (Day 0–3) after vaccination (%)Table S5 Incidence of solicited general symptoms within4 days (Day 0–3) after vaccination (%)

This material is available as part of the online article from:http://www.blackwell-synergy.com/doi/abs/10.1111/j.1651-2227.2008.00884.x(This link will take you to the article abstract).

Please note: Blackwell Publishing are not responsible forthe content or functionality of any supplementary materialssupplied by the authors. Any queries (other than missingmaterial) should be directed to the corresponding authorfor the article.


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