previous studies showed that a novel , combined haemophilus influenzae type b ( hib ) and neisseria meningitidis serogroups c and y conjugate vaccine that uses tetanus toxoid as carrier protein ( hibmency - tt ) was immunogenic with an acceptable safety profile when administered to infants as a 3-dose primary series , with a fourth dose in the second year of life .
the vaccination schedule for hibmency - tt is consistent with the current hib immunization schedule recommended by the united states ( us ) advisory committee on immunization practices , which includes a fourth dose of hib at 12 to 15 mo of age . in australia , a fourth dose of hib conjugate vaccine
is routinely given at 1 y of age . according to these schedules , hibmency - tt
could potentially be coadministered with the combined measles , mumps , and rubella vaccine ( mmr ) and monovalent varicella vaccine ( var ) . to facilitate integration of hibmency - tt into toddler vaccination schedules , it is important to demonstrate a lack of immune interference and an acceptable safety profile when mmr , var , and hibmency - tt are given at the same time . in 2
randomized controlled studies , infants received either hibmency - tt or hib polysaccharide conjugated to tetanus toxoid ( hib - tt ; acthib , sanofi pasteur sa , lyon , france ) at 2 , 4 , and 6 mo of age , followed at 12 to 15 mo of age by 1 dose of hibmency - tt or hib polysaccharide conjugated to n. meningitidis outer membrane protein ( hib - omp ; pedvaxhib , merck and co. inc . ,
whitehouse station , nj , usa ) coadministered with mmr ( m - m - r ii ; merck and co. inc . ) and var ( varivax ; merck and co. inc . ) .
hib - omp was used for the toddler dose at the request of the us food and drug administration , because us prescribing information for hib - tt does not include immunogenicity data for children aged between 12 and 15 mo .
the hib , menc , and meny immunogenicity results from both studies were reported previously .
the designs of the studies were sufficiently similar to allow a pooled analysis of immune responses to the coadministered mmr and var in the hibmency - tt group relative to those in the hib - omp control group at 12 to 15 mo of age .
immunogenicity data available from australian children included in a phase ii randomized controlled study ( nct00134719 ) and us children enrolled in a phase iii randomized controlled study ( nct00289783 ) were assessed .
the studies , which were described in detail previously , were designed in a similar way within the context of each country s immunization schedule , with the pre - specified objective of pooling data for the primary objective of assessing the non - inferiority of mmr and var co - administered with hib - mency compared with co - administration with a licensed hib vaccine .
conditions to pool the data were therefore defined prospectively , and were determined on the grounds of comparable immunogenicity between studies and were met if the point estimates of the difference between the hibmency - tt and hib - omp groups were above the predefined noninferiority limits in each study in terms of anti - measles seroconversion , anti - mumps seroconversion , anti - rubella seroresponse , and anti - varicella seroconversion .
immunogenicity analyses were performed on the pooled according - to - protocol ( atp ) cohorts for immunogenicity from each study , defined as vaccinated children who met all eligibility criteria , complied with protocol - defined procedures , and had antibody assay results available for at least 1 antigen component .
cut - offs for seropositivity were defined as follows : anti - measles , enzyme - linked immunosorbent assay ( elisa ) value  150 miu / ml ; anti - mumps , neutralization test value  28 ed50 ; anti - rubella , elisa value  4 iu / ml ; anti - varicella fluorescent antibody membrane assay value  1:5 .
seroconversion for antibodies to measles , mumps , and varicella was defined as the presence of detectable levels of the relevant antibodies at 42 d post - vaccination in subjects who were seronegative before vaccination .
seroresponse for rubella was defined as the appearance of anti - rubella virus antibodies to a concentration  10 iu / ml in subjects who were seronegative before vaccination ( concentration < 4 iu / ml ) .
the coprimary objectives of the pooled immunogenicity analysis were to demonstrate noninferiority of mmr and var when coadministered with a dose of hibmency - tt compared with mmr and var coadministered with a dose of hib - omp in terms of anti - measles seroconversion , anti - mumps seroconversion , anti - rubella seroresponse , and anti - varicella seroconversion at 42 d ( range 3556 d ) after administration of the vaccines .
the pooling criterion prespecified in the study protocols stated that the data could be pooled if , in each individual study , the point estimate for the group difference in seroconversion / seroresponse rates ( hibmency - tt group minus hib - omp group ) was  -5% for measles , mumps , and rubella , and  -10% for varicella ( note : the individual studies were not adequately powered to demonstrate a lower limit higher than the noninferiority criterion ) .
assessment of noninferiority was based on standardized asymptotic 95% confidence intervals ( cis ) for the difference between groups ( hibmency - tt group minus hib - omp control group ) in percentage of subjects reaching the separate prespecified endpoints for each of the mmr and var components .
noninferiority would be demonstrated if the lower limit of the 95% ci was above -5% for measles , mumps , and rubella , and above -10% for varicella .
parents / guardians of subjects completed diary cards with any solicited symptoms specific to mmr and var vaccination : fever  38c measured by any route , rash / exanthem , parotid / salivary gland swelling , and any suspected meningeal signs or febrile convulsions over a 43-d follow - up period after vaccination
. subjects with symptoms of parotid swelling were to return to the study center to be medically examined to confirm the diagnosis of parotiditis .
as planned in the study protocols , the reactogenicity and safety analysis of these symptoms was performed on subjects in the pooled total vaccinated cohorts ( tvcs ) from both studies with safety data available ( i.e. , diary cards returned ) .
relative risk ( percentage of subjects reporting a specific symptom in hibmency - tt group over percentage in hib - omp group ) was calculated with exact 95% ci for each symptom .
p - values were calculated using a 2-sided exact stratified test conditional to number of cases and taking into account the study effect .
there were 1648 subjects in the pooled data set ( table 1 ) ; 1645 comprised the tvc ( 3 subjects were enrolled but did not receive study vaccines ) and 1257 comprised the atp cohort for immunogenicity .
mean age (  standard deviation ) in the australian study was 12.0  0.3 and 12.0  0.2 mo in the hibmency - tt and hib - omp groups , respectively , and 12.1  0.5 and 12.3  0.6 mo in the us hibmency - tt and hib - omp groups , respectively .
in the australian study , 49% of the hibmency - tt group and 47% of the hib - omp group were female ; in the us cohort , 47% and 48% , respectively , were female .
at least 94% in both australian groups were white / caucasian ; 7782% were white / caucasian in both us groups , and 7% and 11% were african - american in the us hibmency - tt and hib - omp groups , respectively .   for the us cohort ,
pneumococcal conjugate vaccine ( prevnar , pfizer inc . ) was a concomitant vaccine , in accordance with local recommendations .  
subjects excluded from according - to - protocol cohort for immunogenicity ( primary phase ) unless reason for exclusion was noncompliance with protocol - defined serum sampling windows or lack of availability of immunogenicity results at post - dose 3 time point .  
one subject in the hibmency - tt group developed varicella infection before administration of varicella vaccine .  
note : the number of subjects excluded for a specific reason does not take into account subjects already excluded because of reasons presented previously .
conditions to pool the data were met ( fig .  1 ) , with seroconversion rates to measles , mumps , and varicella and the seroresponse rate to rubella in both the hibmency - tt and hib - omp groups of both studies exceeding 93% 42 d after the fourth dose ( table 2 ) .
the pooled data indicated that seroconversion or seroresponse levels in both groups were at least 95% for measles and at least 99% for mumps , rubella , and varicella , with
antibody geometric mean concentrations / titers within the same range in both groups ( table 2 )
. statistical noninferiority of responses to mmr and var was demonstrated ( fig .  1 ) .
difference between the hibmency - tt and hib - omp groups in percentage of subjects who seroconverted for measles , mumps , and varicella and with a seroresponse to rubella 42 d post - fourth dose of hibmency - tt / hib - omp in the australian study ( aus ) , us immunogenicity cohort ( us ) , and pooled analysis ( pooled ) ( atp cohorts for immunogenicity ; subjects who were seronegative at baseline ) .
footnote : anti - measles seroconversion : post - vaccination antibody concentration  150 miu / ml in initially seronegative subjects ( < 150 miu / ml ) ; anti - mumps seroconversion : post - vaccination antibody titer  28 ed50 in initially seronegative subjects ( < 28 ed50 ) ; anti - rubella seroresponse : post - vaccination antibody concentration  10 iu / ml in initially seronegative subjects ( < 4 iu / ml ) ; anti - varicella seroconversion : post - vaccination antibody titer  1:5 in initially seronegative subjects ( < 1:5 ) ; * limit of non - inferiority varicella ; * * limit of non - inferiority measles , mumps , and rubella .
n indicates number of subjects with available serology results ; rate , seroconversion or seroresponse rate ( 95% confidence interval ) ; gmc / gmt , geometric mean concentration / titer ; anti - measles seroconversion , post - vaccination antibody concentration  150 miu / ml in initially seronegative subjects ( < 150 miu / ml ) ; anti - mumps seroconversion , post - vaccination antibody titer  28 ed50 in initially seronegative subjects ( < 28 ed50 ) ; anti - rubella seroresponse , post - vaccination antibody concentration  10 iu / ml in initially seronegative subjects ( < 4 iu / ml ) ; anti - varicella seroconversion , post - vaccination antibody titer  1:5 in initially seronegative subjects ( < 1:5 ) . there were no statistically significant differences between the hibmency - tt group and hib - omp group with respect to solicited symptoms specific to the coadministered mmr and var ( p  0.05 for all relative risks ) ( table 3 ) .
the most frequently reported solicited symptom during the 43-d period following administration of mmr and var was fever  38c ( 45.8% and 48.7% of subjects in the hibmency - tt and hib - omp groups , respectively ) , with a peak in incidence at around day 9 in both groups ( data not shown ) .
fever > 40.0c was infrequent ( < 2% in both groups ) . there were no reports of meningeal signs or febrile convulsions in the 43-d post - vaccination period .
parotid / salivary gland swelling was reported in 4 subjects in the hibmency - tt group ( 0.3% ) , with no reports in the hib - omp group ; all reports were from australia and all were considered by the investigator as related to vaccination .
two were categorized as grade 3 , defined as swelling with accompanying general symptoms , occurred 12 to 14 and 14 to 17 d after vaccine administration , and were medically reviewed as a requirement of the study . all parotid / salivary gland swelling episodes resolved without sequelae .
rashes were reported in 25.0% and 22.6% of subjects in the hibmency - tt and hib - omp groups , respectively .
n indicates number of subjects with the documented dose ; n/% , number / percentage of subjects reporting a specified symptom ; nc , not calculated because no events reported ; inf , infinity .
p - value , 2-sided exact stratified test conditional to number of cases ; fever , rectal or axillary / tympanic temperature  38.0c . grade 3 : meningeal signs / febrile convulsion that prevented normal , everyday activities ; parotid / salivary gland swelling , with accompanying general symptoms ; temperature > 40.0c ; rash with 200 or more papules , vesicles and/or crusts .
in 2 randomized controlled studies , 3 doses of hibmency - tt in infancy followed by 1 dose at 12 to 15 mo of age induced robust anti - hib and anti - meningococcal serogroups c and y immune responses and had an acceptable safety profile . here ,
pooled analysis of data from these studies demonstrated noninferiority of immunological responses to mmr and var when concomitantly administered with the fourth dose of hibmency - tt compared with coadministration with a fourth dose of monovalent hib - omp .
previous analyses showed the percentages of children with anti - polyribosylribitol phosphate ( prp ) antibody concentration  1.0 g / ml were high after the fourth hibmency - tt dose and consistent with the hib - omp control group , and that anti - prp geometric mean concentrations were significantly higher than in hib - omp recipients .
these results were in line with a study of hibmency - tt vs. monovalent hib - tt vaccine in which mmr and var were not coadministered with the fourth dose .
this suggests immune responses to hibmency - tt , mmr , and var are not compromised when administered together , although the possibility of interference can not be completely excluded because no group in the current study received a fourth dose without mmr or var , or received mmr and var alone .
the reactogenicity profile of mmr and var was comparable when coadministered with hibmency - tt or hib - omp , as indicated by similar incidences of mmr- and var - specific solicited symptoms in both groups .
also , the incidence of fever > 38.5c in the hibmency - tt and hib - omp groups was consistent with the incidence of fever  38.9c reported in a study in which a group of children aged 12 to 23 mo received mmr and var alone .
parotid / salivary gland swelling was reported in less than 1% of subjects in the hibmency - tt group , which was consistent with a review of various randomized studies involving 3 different mmr vaccines that also showed low incidence of this adverse event (  1.8% ) .
approximately one - third of enrolled infants in the us immunogenicity cohort were excluded from the atp cohort for immunogenicity because of noncompliance with the blood sampling schedule or insufficient blood samples . additionally , the majority of subjects in both studies were white / caucasian .
other potential limitations were the lack of a control group that did not receive m - m - r ii and varivax without the co - administration of licensed hib vaccine , and lack of blinding of study personnel to treatment group , which could have influenced the assessment of reactogenicity , although in this instance one might expect the bias to be against the investigational vaccine , which includes two additional antigens . also , the results of group comparisons should be interpreted with caution considering that there was no adjustment for multiplicity and the study was not powered for these comparisons , meaning that definite conclusions can not be made regarding the relative risk of a given adverse event . in conclusion , the results of this pooled analysis of data from 2 randomized controlled studies indicate that a dose of hibmency - tt at 12 to 15 mo of age , given as part of a 4-dose hibmency - tt series , can be administered with an acceptable safety profile without diminishing immune responses to mmr and var .
 a pooled analysis was conducted of 1257 toddlers who received a fourth dose of haemophilus influenzae type b - neisseria meningitidis serogroups c and y - tetanus toxoid conjugate vaccine ( hibmency - tt ) or hib conjugate vaccine ( hib polysaccharide conjugated to n. meningitidis outer membrane protein ) coadministered with measles - mumps - rubella ( mmr ) and varicella ( var ) vaccines ( nct00134719/nct00289783 ) . 
 noninferiority of immunological responses to mmr and var was demonstrated between groups and incidences of mmr- and var - specific solicited symptoms were similar , indicating that hibmency - tt can be coadministered with mmr and var . 
Introduction
Materials and Methods
Results
Discussion