Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine (HibMenCY-TT; MenHibrix®): A Review
The meningococcal groups C and Y and Haemophilus b (Hib) tetanus toxoid conjugate vaccine (HibMenCY-TT) contains Neisseria meningitidis serogroup C and Y capsular polysaccharide antigens, and Hib capsular polysaccharide [polyribosyl-ribitol-phosphate (PRP)]. The HibMenCY-TT vaccine is available in the USA for use as active immunization to prevent invasive disease caused by N. meningitidis serogroups C (MenC) and Y (MenY), and Hib in children 6 weeks–18 months of age. HibMenCY-TT is the first meningococcal vaccine available for use in the USA that can be administered to infants as young as 6 weeks of age. In a randomized, controlled, phase III clinical trial, the HibMenCY-TT vaccine, administered to infants at 2, 4, 6 and 12–15 months of age, was immunogenic against MenC and MenY, and met the prespecified criteria for immunogenicity. Anti-PRP antibodies, which have been shown to correlate with protection against Hib invasive disease, were also induced in the infants who received the HibMenCY-TT vaccine, with induced levels of this antibody noninferior to those occurring in the control group of infants who received a Hib tetanus toxoid conjugate vaccine at 2, 4, and 6 months and a single dose of Hib conjugated to N. meningitidis outer membrane protein at 12–15 months. In several randomized, controlled clinical trials, HibMenCY-TT was coadministered with vaccines that are routinely administered to infants and toddlers in the USA. These vaccines included: diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated poliovirus vaccine combined; 7-valent Streptococcus pneumoniae polysaccharide conjugate vaccine; measles, mumps and rubella vaccine; and varicella vaccine. Coadministration of these vaccines did not interfere with the immunogenicity of the HibMenCY-TT vaccine. Similarly, immune responses to the coadministered vaccines were not affected by the HibMenCY-TT vaccine. The tolerability profile of the HibMenCY-TT vaccine in infants and toddlers in the phase III trial was considered to be clinically acceptable and comparable to that of the Hib conjugate vaccines received by the control group.
Meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine: a summary
Administered to infants at 2, 4, 6 and 12–15 months of age (four doses in total), with the first dose given as early as 6 weeks of age
Effective as active immunization to prevent invasive disease caused by Neisseria meningitidis serogroups C and Y and Haemophilus influenzae type b in infants and toddlers in a phase III study
Antibody persistence demonstrated for up to 5 years after the fourth dose of the vaccine in a phase II study
Clinically acceptable tolerability profile: injection site
pain, redness, and swelling are the most common local events; irritability, drowsiness, loss of appetite, and fever are the most common systemic events
Bacterial meningitis is a serious threat to global health and accounts for an estimated 170,000 deaths worldwide each year [1, 2]. Neisseria meningitidis, a Gram-negative diplococcus, is the only encapsulated bacterium responsible for large epidemics of bacterial meningitis worldwide [3, 4]. Although the nasopharynx is commonly colonized by N. meningitidis, the presence of this pathogen is not usually associated with disease symptoms. However, in some cases, meningococci may spread to epithelial cells and invade local tissue, with rapidly developing, potentially devastating and often long-term sequelae. Importantly, in the event of meningococci entering the bloodstream, life-threatening meningococcal meningitis and fulminant septicaemia may develop [3, 5, 6]. N. meningitidis is a leading cause of meningitis and septicaemia in the USA and many other industrialized countries, and is the most common cause of bacterial meningitis in paediatric patients [7, 8, 9, 10].
Based on differences in the capsular polysaccharide antigens, N. meningitidis is classified into 13 serogroups. The majority of cases of meningococcal disease are caused by serogroups A, B, C, W-135, Y and X [3, 11]. Outbreaks of extensive meningococcal disease have cyclic fluctuations, with an incidence and serogroup distribution varying across different geographical regions and disease peaks generally occurring every 5–8 years [12, 13]. Extensive outbreaks of meningococcal disease occur cyclically in the meningitis belt of sub-Saharan Africa, with up to 1 % of the population affected during epidemics . Although the incidence of meningoccal disease is currently considered to be low in industrialized countries (0.5–6 per 100,000 of the overall population), the disease is more common in children aged under 1 year (incidence of 5.38 cases per 100,000 of this population between 1998 and 2007 in the USA) . In the EU, the incidence of meningococcal disease in infants under 1 year of age is 17 cases per 100,000 . N. meningitidis serogroups C (MenC) and Y (MenY) are thought to be responsible for 38 % of cases in the USA  and yet are the most common vaccine-preventable serogroups . Surveillance of meningococcal disease outbreaks is essential for assessing local epidemiology and developing prevention strategies, including the formulation of effective, well tolerated and cost-effective vaccines, which are a public health priority [1, 7, 10, 15].
The first vaccines developed for the prevention of meningococcal disease consisted of purified capsular polysaccharides from meningococcal serogroups. Although these plain polysaccharide vaccines have been widely used to elicit immune protection in various groups, including travellers, military personnel and at-risk populations, most [with the exception of N. meningitidis serogroup A (MenA) vaccines] are associated with suboptimal immunogenic responses in infants and young children . Furthermore, the T-cell independent immune responses elicited by these vaccines are not usually sustained and immune memory is not induced. In addition, for serogroups A, C, W-135 and Y, immunological hyporesponsiveness may be induced [7, 16, 17, 18, 19].
Conjugate vaccines, consisting of capsular polysaccharides covalently linked to carrier proteins containing T-cell epitopes (e.g. tetanus toxoid), have been developed to overcome the limitations of the plain vaccines and they provide advantages in children, including better immunogenicity in infants, T-cell dependency, induction of immune memory and the induction of higher bacterial titres, with the potential for a more durable antibody response . Immunization of individuals aged ≥2 years with high-risk medical conditions is recommended by the Advisory Committee on Immunization Practices (ACIP) in the USA  and two tetravalent conjugated meningococcal vaccines using diphtheria toxoid or cross-reacting mutant diphtheria toxoid (CRM197) as a carrier protein for protection against MenA, C, W-135 and Y are licensed for use in the USA and some other countries . In addition, a quadrivalent MenA, C, W-135,Y conjugate vaccine using tetanus toxoid (meningococcal group A, C, W-135, and Y conjugate vaccine; Nimenrix®) has been developed and is available for the immunization of children aged ≥12 months in the EU . Until recently, no meningococcal vaccine was approved for use in infants aged <9 months in the USA [7, 23].
To help address an unmet need for a vaccine for the prevention of meningoccal disease in young children in the USA where MenC and MenY are more commonly associated with the disease in this population than other serogroups, a new vaccine consisting of capsular polysaccharide MenC and MenY antigens conjugated to tetanus toxoid and Haemophilus influenzae type b (Hib) capsular polysaccharide [polyribosyl-ribitol-phosphate (PRP)] [meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine; HibMenCY-TT: MenHibrix®] has been developed and has undergone clinical evaluation in infants and toddlers [20, 23]. This combination vaccine also provides protection against invasive Hib disease, which commonly presents as meningitis . Hib was the leading cause of bacterial meningitis in the USA among children <5 years of age before the introduction of effective vaccines but has been virtually eliminated through routine infant vaccination .
The HibMenCY-TT vaccine is approved in the USA for use as active immunization to prevent invasive disease caused by MenC and MenY and Hib in children 6 weeks–18 months of age . This is the first meningococcal vaccine that can be administered to infants as young as 6 weeks of age in the USA  and offers healthcare providers an option of combining MenC, MenY and Hib immunization, without the need for additional injections. The ACIP has recently recommended the use of the HibMenCY-TT vaccine for routine vaccination against MenC and MenY in infants aged 6 weeks–18 months who are at increased risk for meningococcal disease, such as those with persistent complement component pathway deficiencies, or functional or anatomical asplenia, including sickle cell disease . The vaccine is also recommended by the ACIP for healthy infants residing in communities where there are outbreaks of MenC or MenY meningococcal disease . This article reviews the immunogenicity and tolerability of the HibMenCY-TT vaccine in healthy infants and toddlers. The main focus of the review is a fully published, randomized, phase III trial of the immunogenicity and safety of the HibMenCY-TT vaccine in healthy infants aged 6–12 weeks at enrolment .
Sources: Medical literature (including published and unpublished data) on meningococcal groups C and Y and Haemophilus influenzae type b HibMenCY-TT and was identified by searching databases (including MEDLINE from 1946 and EMBASE from 1996) [searches last updated 4 April 2013], bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug.
Search terms: MEDLINE and EMBASE search terms were meningococcal groups C and Y and Haemophilus influenzae type b tetanus toxoid conjugate vaccine, MenHibrix®, HibMenCY-TT vaccine, immunization.
Selection: Studies in infants and children who received HibMenCY-TT (MenHibrix®) vaccination. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred.
Keywords: Meningococcal groups C and Y and haemophilus b tetanus toxoid conjugate vaccine, Haemophilus influenzae type b–Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine, HibMenCY-TT vaccine, immunization, immunogenicity, protective efficacy, reactogenicity, safety, tolerability.
2 Mechanism of Action
In early- and late-phase clinical trials (Sect. 3), the HibMenCY-TT vaccine elicited the production of bactericidal antibodies specific to the capsular polysaccharides of the MenC and MenY serogroups, thereby potentially conferring protective immunity against both MenC and MenY meningococcal disease [7, 24, 26].
PRP is an important virulence factor for Hib and specific anti-PRP levels correlate with protection against invasive disease caused by this pathogen . Results of passive antibody studies  and an efficacy study that investigated an unconjugated Hib polysaccharide vaccine  led to the acceptance of an anti-PRP concentration of 0.15 μg/ml as the level conferring minimal protection against invasive disease caused by Hib. Findings of another efficacy study of an unconjugated Hib polysaccharide vaccine demonstrated that an anti-PRP concentration of ≥1.0 μg/mL is predictive of long-term protection against Hib disease for a period of at least one year [29, 30]. In clinical studies of the HibMenCY-TT vaccine, these antibody levels were used to evaluate the effectiveness of vaccines at conferring protection against Hib (see Sect. 3) .
The immunogenicity of the HibMenCY-TT vaccine has been evaluated in more than 7,500 healthy infants and toddlers in a clinical trial programme  consisting of several randomized phase II controlled trials and a pivotal randomized, controlled phase III trial  [NCT002 89783; study 009/010 (hereafter referred to as the phase III trial)]; the phase III trial examined the formulation and vaccination schedule currently approved for use in the USA [7, 24]. Studies have been conducted in the USA, Mexico, Australia, Belgium and Germany, with more than 3,000 study participants located in the USA [7, 14]. In most studies, infants were aged approximately 2 months at the time of the first vaccination [7, 20, 23, 31, 32, 33, 34]. Data relating to the phase III trial reviewed in this section are from both the fully published report of the study  and the US prescribing information .
Protective efficacy rates (based on humoral responses) and immune-mediated responses as well as other immunogenicity data, including results of studies evaluating the persistence of antibody responses to the MenC, MenY and Hib antigens, are reviewed in this section. N. meningitidis serum bactericidal activity (using human complement) was measured for serogroups C (hSBA-MenC) and Y (hSBA-MenY) in several studies, including the main phase III study . Although bactericidal titres of ≥1:4 are regarded as protective against MenC, and the same is assumed for MenY, a threshold of ≥1:8 was often used in these studies, including the phase III study . Rabbit complement was used as the exogenous complement source in earlier studies [31, 32, 33]. An anti-PRP concentration of 0.15 μg/mL or 1.0 μg/mL (predictive of longer term protection ) was generally used to assess protection against invasive disease caused by Hib [23, 31, 32, 33, 34]. When possible, the immunogenicity of HibMenCY-TT was compared with that of other meningococcal conjugate vaccines and Hib conjugate vaccines.
3.1 Phase II Trials
Several published phase II studies have evaluated the immunogenicity of the HibMenCY-TT vaccine administered as a primary vaccination to infants aged 2, 3 and 4  or approximately 2, 4 and 6 months [31, 32, 34]. Most of the studies were randomized, controlled, multicentre and nonblind in design, and included evaluations of three different doses or formulations of the vaccine [31, 33] as well as assessments of its immunogenicity after administration of a fourth dose to toddlers at age 12–15 months [32, 35, 36, 37]. In several studies, infants were randomized to receive primary vaccination with HibMenCY-TT or a licensed Hib tetanus toxoid conjugate vaccine (HibTT; ActHIB®) [31, 32, 34], a MenC vaccine containing 10 μg of MenC polysaccharide conjugated to CRM197 adsorbed onto aluminium phosphate [31, 32, 33] or HibMenC (Menitorix®) , with a fourth dose of HibMenCY-TT or Hib conjugated to N. meningitidis outer membrane protein (HibOMP; PedvaxHIB®) administered at 12–15 months . Study participants also received routine vaccinations, including: diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated poliovirus vaccine combined (DTaP-HBV-IPV; Pediarix®); and 7-valent Streptococcus pneumoniae polysaccharide conjugate vaccine (PCV7; Prevnar®) [31, 32, 34] during the primary vaccination period, as well as measles, mumps and rubella vaccine (MMR®II) and varicella vaccine (Varivax®) .
HibMenCY-TT was shown to be highly immunogenic and produced protective levels of MenC, MenY and Hib antibodies when administered as a three-dose course of primary vaccinations to infants aged 2, 4 and 6 months [31, 32, 34] or 2, 3 and 4 months  in studies conducted in the USA, Australia, Belgium and Germany. MenC, MenY and Hib antibodies, at levels conferring disease protection, persisted up to the time of a fourth booster vaccination with HibMenCY-TT during the second year of life [32, 35]. Administration of a challenge dose indicated that the vaccine had induced immune memory .
In the first phase II study (n = 609) (reported by Marchant et al. ) to demonstrate the immunogenicity of the licensed formulation of HibMenCY-TT given at 2, 4 and 6 months, high levels of bactericidal antibodies against MenC and MenY were induced. One month after primary vaccination, hSBA titres of ≥1:8 were detected in significantly (p < 0.05) greater proportions of infants who received the HibMenCY-TT vaccine [95.9 % (MenC) and 89.4 % (MenY)] compared with a nonrandomized control group of children aged 3–5 years who had received a single dose of a tetravalent meningococcal ACWY polysaccharide vaccine (MPSV4) in whom corresponding Men C and MenY response rates were 30.2 and 47.5 %, respectively. In addition, the immunogenicity of the vaccine in terms of Hib immune responses (defined as anti-PRP concentrations of ≥1.0 μg/mL) was noninferior to that in the control group of infants who received the licensed HibTT vaccine, with 93.5 % of infants in the HibMenCY-TT group having a response compared with 85.8 % in the HibTT control group .
In infants who received a fourth booster dose HibMenCY-TT at 12–15 months (following primary vaccination), robust immune responses occurred and persistent immunity to the three vaccine antigens (MenC, Men Y and Hib) was evident during the third  year of life, with >96 % of infants who received four doses of the HibMenCY-TT vaccine having serological evidence of protection against MenC and >83 % having protection against Men Y one year after the fourth dose in the study conducted in the USA . At the same timepoint, anti-PRP concentrations of ≥0.15 μg/mL and ≥1.0 μg/mL were detected in 100 and 75.9 % of infants, respectively.
Data are also available regarding the persistence of antibodies elicited by three- and four-dose schedules of the HibMenCY-TT vaccine in the study conducted in the USA  at 3  and 5  years. Protective antibodies against MenC, MenY and Hib were shown to persist for up to 3  and 5  years after the fourth dose of the HibMenCY-TT vaccine in most children, thus demonstrating that the vaccine was immunogenic in the longer term. The primary endpoint indicating protective antibody levels at the 5-year assessment was the hSBA titre ≥1:8 for MenC and MenY, and for Hib it was an anti-PRP concentration of ≥0.15 μg/mL . At the 5-year assessment, hSBA-MenC and hSBA-MenY protective antibodies were achieved in 82.9 and 69.5 %, respectively, of children who had received 4 doses of HibMenCY-TT at approximately 2, 4, 6 and 12–15 months; anti-PRP concentrations of ≥0.15 μg/mL were reported in 98.8 % of the children in this group. By comparison, of the children who had received four doses of the HibTT vaccine at corresponding vaccination times, 21.1 and 18.4 % had protective hSBA-MenC and hSBA-MenY protective antibodies, and anti-PRP concentrations of ≥0.15 μg/mL occurred in 92.3 % of patients. In the third group of children who had received HibTT for three doses at approximately 2, 4 and 6 months, followed by a single dose of the HibMenCY-TT vaccine at 12–15 months, hSBA-MenC and hSBA-MenY protective antibodies were detected in 73.5 and 54.3 % of children, and 97.3 % of children had anti-PRP concentrations of ≥0.15 μg/mL . The presence of natural antibodies against MenC and MenY in the HibTT group who did not receive meningoccal vaccine antigens may be explained by the gradual acquisition of natural immunity during childhood .
3.2 Phase III Randomized, Controlled Trial
Demographic characteristics of infants enrolled in the total vaccinated cohort and the according to protocol immunogenicity US and Mexican immunogenicity cohorts in the primary vaccination phase (doses 1, 2 and 3) of the phase III randomized, controlled trial of the meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine (HibMenCY-TT) vaccine (administered at 2, 4, 6 and 12–15 months) in infants aged 6–12 weeks at enrolment 
Total vaccinated cohorta
US immunogenicity cohort (cohort 1)
Mexican immunogenicity cohort (cohort 3)
HibMenCY-TT (n = 3,136)
HibTT/Hib-OMP (n = 1,044)
HibMenCY-TT (n = 522)
HibTT/HibOMP (n = 173)
HibMenCY-TT (n = 135)
HibTT/HibOMP (n = 46)
Mean age (days) at dose 1
African origin (%)
Immunogenicity of the meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate (HibMenCY-TT) vaccine administered at 2, 4, 6 and 12–15 months to healthy US infants aged 6–12 weeks at enrolment in the phase III randomized, controlled trial [23, 24]. Results presented are for the according to protocol cohort for whom serological results were available for immunological evaluations postdose 3 and postdose 4
Seroconversion rates (95 % CI)
Fold increase from baseline in GMTs (95 % CI)
PD3 (n = 491)
PD4 (n = 331)
PD3 (n = 481)
PD4 (n = 342)
98.8 (97.4, 99.6)
Infants within each cohort were randomized 1:1:1:1 to be in one of three groups receiving the HibMenCY-TT vaccine; infants in these three groups received three separate doses of HibMenCY-TT vaccine from one of three lots (lot A, B or C) and then HibMenCY-TT (lot D) was administered at 12–15 months of age; the fourth group of infants received the HibTT vaccine for 3 consecutive doses and then HibOMP at 12–15 months (Table 1). This vaccine schedule was studied because it is the standard schedule for the conjugate Hib vaccination that is currently recommended by the ACIP . All vaccines were administered intramuscularly as an 0.5 mL dose into the right upper thigh. The HibMenCY-TT vaccine contained 5 μg of MenC polysaccharide and 5 μg of MenY polysaccharide conjugated to tetanus toxoid, and 2.5 μg of Hib PRP also conjugated to tetanus toxoid in each 0.5 mL dose. The HibTT vaccine contained 10 μg of Hib PRP conjugated to tetanus toxoid per 0.5 mL dose; the HibOMP vaccine contained 7.5 μg of PRP conjugated to 125 μg N. meningitidis OMP per 0.5 mL dose . Infants in the control group did not receive monovalent MenC vaccination because these vaccines are not licensed in the USA for clinical use. However, controls in Australia received a single dose of monovalent MenC conjugate vaccine after study completion, to comply with Australian national immunization recommendations .
The study was double-blind in regard to the individual lots of HibMenCY-TT vaccine and single-blind in regard to the comparison of the HibMenCY-TT with the HibTT vaccine. Parents or guardians were blinded in terms of the vaccine, whereas the study personnel were not because the two vaccines had different physical presentations. Parents of the study participants were blinded until the toddler vaccination phase had been completed (42 days after dose 4). The according to protocol (immunogenicity) cohorts were used for evaluations of the immunogenicity of the HibMenCY-TT vaccine. In the US cohort (cohort 1), the immunogenicity of serogroup C and Y responses was shown if the lower limit of the 95 % confidence interval (CI) in the percentage of infants with hSBA-MenC or hSBA-MenY titre of ≥1:8 was ≥90 % after administration of dose 4 and if the lower limit of the 95 % CI of the postdose 4/predose 4 GMT ratio was ≥2 .
Consistent with the evaluation of vaccines with an established standard such as Hib conjugate vaccines, and in contrast to vaccines licensed for the prevention of meningococcal disease in the USA, noninferiority was the objective for evaluation of the immunogenicity of the Hib component of the HibMenCY-TT vaccine . Noninferiority of anti-PRP responses in the group of infants randomized to receive the HibMenCY-TT vaccine compared with these responses in the HibTT/HibOMP group was established if the lower limit of the 2-sided standardized asymptotic 95 % CI on the difference between vaccine groups in the percentage of infants with anti-PRP concentrations of ≥1.0 μg/mL was −10 % or higher .
A secondary objective was the immunogenicity of MenC and MenY 1 month after dose 3, with the preset hypothesis that the lower limit of the 95 % CI of the percentage of infants with a bactericidal titre of ≥1:8 was to be ≥90 % or ≥85 % for MenC and MenY, respectively. Between-group differences of statistical significance could be concluded if the asymptotic standardized 95 % CI for the difference in percentages of infants attaining specific cut-offs did not include 0 or if the between-group 95 % CI for the GMT or geometric mean antibody concentration (GMC) ratio did not contain 1 .
Nine pairwise comparisons of different vaccine lots (three comparisons per antigen) were conducted to assess the lot-to-lot consistency of the vaccine. The consistency of different lots was established if the 2-sided 95 % CI on the GMC or GMT ratio between lots was within the 0.5–2.0 interval for every comparison .
3.2.1 Lot-to-Lot Consistency
The consistency of the different lots of HibMenCY-TT vaccine was demonstrated in the phase III trial for eight of nine comparisons. For the ninth comparison, the predefined criteria for consistency was exceeded marginally (95 % CI 1.14–2.27). Nevertheless, the criterion used to define immunogenicity for pooled lots of the vaccine was met for the individual lots and the criteria (for hSBA titres) for lot-to-lot consistency were met before administration of dose 4 . Furthermore, the 3 pairwise comparisons for antibodies (measured by enzyme-linked immunosorbent assay) specific for serogroup Y polysaccharide (anti-PSY GMC ratios) were all within the prespecified interval (0.5–2.0), thereby providing evidence of sufficient comparability to justify the pooling of data for the evaluation of other objectives .
3.2.2 Neisseria Meningitidis Antibody Responses
The HibMenCY-TT vaccine was highly immunogenic in healthy infants in terms of immunogenicity to both MenC and MenY antigens. After administration of doses 3 and 4 of the HibMenCY-TT vaccine, the prespecified immunogenicity criteria for MenC and MenY were met in the vaccinated infants included in the US according to protocol immunogenicity cohort in the phase III trial. At months 2, 4 and 6 after vaccination, ≥95.8 % patients in the HibMenCY-TT group had bactericidal titres of ≥1:8 (Table 2). Moreover, vaccinated individuals had robust and sustained responses to both MenC and MenY antigens, with bactericidal titres of ≥1:8 present in ≥92.8 % of patients prior to dose 4 and in ≥98.5 % of patients after dose 4 (Table 2) .
Furthermore, an increase in MenY antibody levels was seen in the infants in the HibTT/HibOMP group, with titres of ≥1.8 reported in 72.5 % of patients after dose 4 (i.e. HibOMP). This phenomenon was not evident for MenC after dose 4. In addition, after dose 4, a positive anti-MenY response (measured using the anti-MenY polysaccharide enzyme-linked immunosorbent assay) occurred in 97.3 % (≥2 μg/mL) and 99.4 % (≥0.3 μg/mL) of infants who had received the HibMenCY-TT vaccine, but did not occur in recipients of the Hib control vaccine, indicating that the presence of hSBA-MenY titres between doses 3 and 4 of the vaccine were not due to anti-MenY polysaccharide-specific antibodies .
The HibMenCY-TT vaccine was also immunogenic when used as a four-dose series in the subgroup of infants in the Mexican cohort, with immunogenicity results consistent with those reported for the US cohort. The majority of infants who received the HibMenCY-TT vaccine had bactericidal titres against MenC and MenY of ≥1.8, as well as an anti-PRP concentration of ≥1.0 μg/mL four weeks after dose 3 and four weeks after the fourth dose .
3.2.3 Haemophilus Influenzae Type b Antibody Responses
The noninferiority of the HibMenCY-TT vaccine compared with the control Hib vaccine in terms of induction of anti-PRP antibodies was demonstrated in the phase III trial in the according to protocol immunogenicity cohort. One month after administration of dose 3, the noninferiority criterion was met, with the lower limit of the 95 % CI above the predefined limit of −10 % (between-group difference 5.10 %; 95 % CI 1.20–10.49) . At this timepoint, 96.3 % of infants who received HibMenCY-TT and 91.2 % of recipients of the control Hib vaccine had reached the ≥1 μg/mL cut-off concentration for anti-PRP antibody concentrations; corresponding percentages of infants with anti-PRP antibody concentrations of ≥0.15 μg/mL at the same timepoint were 100 and 98.2 % . Anti-PRP responses were robust and sustained at the assessment 6 weeks after dose 4, with anti-PRP antibody concentrations of ≥1 μg/mL achieved in 99.2 % of infants in each group and concentrations of ≥0.15 μg/mL achieved in 100 % of infants in each group .
One month after dose 3, the anti-PRP antibody GMC was significantly higher in the infants who received HibMenCY-TT than in the control Hib group: 11.0 (95 % CI 10.0–12.1) versus 6.5 μg/mL (95 % CI 5.3–7.9), with 95 % CIs for the GMC ratio not including 1 [23, 24].
3.3 Coadministration of HibMenCY-TT with Other Vaccines
The immune responses and high levels of seroprotection produced by the HibMenCY-TT vaccine were not compromised in infants who also received recommended immunization schedules of vaccines routinely given to infants and toddlers in the USA and other countries in phase II trials [31, 32, 33, 34, 35, 38] and the phase III trial . As noted earlier in this section, the coadministered vaccines were DTaP-HBV-IPV, PCV7, MMR vaccine and varicella vaccine. These findings suggest that the HibMenCY-TT vaccine may be added to existing vaccination schedules without the need for additional injections. Similarly, immune responses to the coadministered vaccines were not affected by the HibMenCY-TT vaccine. In two fully published analyses [38, 39] and in the fully published report of the phase III trial  there was no reported evidence of an interference in immune responses to vaccination with DTaP-HBV-IPV and PCV7 in infants, or MMR and varicella vaccines in toddlers compared with immune responses achieved in the control groups who received Hib conjugate vaccines.
Across the published studies, including the phase III trial, reactogenicity and safety data indicate that the HibMenCY-TT vaccine administered as a three- or four-dose series has a clinically acceptable tolerability profile. Fully published long-term (>5 years) tolerability data are currently limited; however, no serious adverse events considered as possibly related to administration of the HibMenCY-TT vaccine were reported in children up to 5 years after vaccination in one antibody persistence study .
The most common solicited local and systemic reactions observed after each dose in both the HibMenCY-TT and the Hib vaccine treatment groups included irritability, drowsiness and pain in the total vaccinated cohort in the phase III trial. Fever (defined as body temperature >40 °C) occurred in ≤0.2 % of patients in both groups after each dose of the vaccine. There was a tendency for redness at the injection site and swelling (any grade) to increase in incidence with subsequent doses of the vaccine, although this increase in incidence was not evident for drowsiness, irritability and loss of appetite (Fig. 1) .
Irritability, pain, redness and swelling of any grade occurred at a lower incidence in the HibMenCY-TT group compared with the comparator group (Fig. 1), with the greatest between-group difference seen after the first dose of each vaccine. Five (0.4 %) of the HibMenCY-TT recipients and 2 (0.6 %) of the HibOMP recipients had a large swelling at the site of the injection. There was no involvement of the adjacent joints in individuals with local swelling for whom data are available. During the entire study, ≥1 serious adverse event was recorded in 134 (5.2 %) of 3,136 patients in the HibMenCY-TT group and in 65 (6.2 %) of 1,044 patients in the Hib group. Two serious adverse events of fever (with onset on the day of the first dose of vaccine and resolution the day after) were documented in the HibMenCY-TT group; these events were deemed by the investigator to be vaccine-related. Grade 3 adverse events were reported in <7 % of infants in the HibMenCY-TT group compared with ≤13.2 % of infants in the control group. The incidence of pain of grade 3 severity after doses 1, 2 and 4 was significantly (p ≤ 0.01) lower with HibMenCY-TT (6.9, 5.5 and 1.7 %) than with HibTT (13.2, 8.0 and 5.5 %) .
Solicited local and systemic adverse events recorded for the US participants in the phase III trial of HibMenCY-TT vaccine are reported in the US prescribing information . The incidence of local injection site pain, redness and swelling in recipients of the HibMenCY-TT vaccine ranged from 15 to 46 %, depending on the event and specific dose in the schedule, according to the US prescribing information. This analysis also included the total vaccinated cohort i.e. all study participants who received ≥1 dose of either vaccine, although the number of study participants (n = 2,009, for the first dose) differs from that in the fully published report of the phase III trial. This is explained by the fact that 2,776 infants were included in the total vaccinated cohort and 2,009 is the number of infants in the total vaccinated cohort with documented data for one dose of the vaccine. Other common solicited systemic events in the HibMenCY-TT group included irritability (incidence 62–71 %), drowsiness (49–63 %), loss of appetite (30–34 %) and fever (11–26 %) . The US prescribing information should be referred to for additional data on the tolerability of the HibMenCY-TT vaccine .
In a pooled analysis that included >8,500 infants who had received a four-dose series of HibMenCY-TT or Hib vaccines (at age 2, 4, 6 and 12–15 months) in two primary vaccination and two fourth-dose studies, the safety profile of the HibMenCY-TT vaccine was similar to those of the comparator Hib vaccines . In all of the studies, the infants also received routine age-appropriate vaccines (see Sect. 3). Solicited local and general symptoms occurred at a similar incidence after vaccination with HibMenCY-TT or Hib vaccines. In addition, the incidence of certain solicited symptoms (e.g. irritability and pain at the injection site) was significantly (p < 0.05) lower with HibMenCY-TT than with Hib vaccines. No statistically significant differences between the HibMenCY-TT and Hib vaccines in the incidence of serious adverse events, new onset of chronic disease, rash, or adverse events that led to emergency room visits were reported. The only exception to this was in regard to viral gastroenteritis and anaemia .
During post-approval use of the Haemophilus b conjugate vaccine (tetanus toxoid conjugate) [Hiberix®] in the US and other countries, the following types of adverse events were reported: general disorders and administration site conditions; immune system disorders; nervous system disorders; respiratory, thoracic and mediastinal disorders, skin and subcutaneous tissue disorders. These events are of relevance to the use of the HibMenCY-TT vaccine as the Haemophilus b capsular polysaccharide tetanus toxoid conjugate is one of the component antigens in the HibMenCY-TT vaccine . However frequency estimations were/are not possible as these events are reported voluntarily from a population of uncertain size.
5 Dosage and Administration
The HibMenCY-TT vaccine is indicated for active immunization to prevent invasive disease caused by N. meningitidis serogroups C and Y and Hib . The vaccine is approved for use in children 6 weeks to 18 months of age. HibMenCY-TT vaccine is available as a single-dose vial of lyophilized vaccine that is reconstituted with a saline diluent to produce a clear and colourless 0.5 mL solution and administered by intramuscular injection immediately after reconstitution. When reconstituted with the accompanying saline diluent, each 0.5 mL dose of the HibMenCY-TT vaccine is formulated to contain 5 μg of purified N. meningitidis C capsular polysaccharide conjugated to approximately 5 μg of tetanus toxoid, 5 μg of purified N. meningitidis Y capsular polysaccharide conjugated to approximately 6.5 μg of tetanus toxoid, and 2.5 μg of purified Haemophilus b capsular polysaccharide conjugated to approximately 6.25 μg of tetanus toxoid. Each dose also contains 96.8 μg of Tris (trometamol) hydrochloride, 12.6 mg of sucrose, and ≤0.72 μg of residual formaldehyde. The HibMenCY-TT vaccine does not contain preservatives. The anterolateral aspect of the thigh is the preferred administration site for most infants less than 1 year of age. The deltoid muscle is usually large enough in older children for administration of the vaccine by intramuscular injection .
The HibMenCY-TT vaccine is given as a four-dose series, with every 0.5 mL dose administered at 2, 4, 6, and 12–15 months of age . The initial dose may be administered as early as 6 weeks of age and the final (fourth) dose given as late as age 18 months. In the phase III trial, the HibMenCY-TT vaccine was administered concomitantly with vaccines licensed in the USA and routinely recommended for use in paediatric patients. If the HibMenCY-TT vaccine is given concomitantly with other vaccines, they should be administered with separate syringes and at different injection sites . The HibMenCY-TT vaccine should not be mixed with any other vaccine in the same syringe. The safety and effectiveness of the HibMenCY-TT has not been established in infants <6 weeks of age or in children 19 months to 16 years of age .
Local prescribing information should be consulted for information on contraindications (including a severe allergic reaction e.g. anaphylaxis), warnings, precautions, potential drug interactions, and use in special patient populations.
6 The Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine (HibMenCY-TT; MenHibrix®): Current Status
The HibMenCY-TT vaccine, currently approved for use in the USA, was highly immunogenic against MenC and MenY, and immune responses induced by the vaccine in terms of anti-PRP antibodies were noninferior to those achieved with comparator Hib conjugate vaccines when the vaccine was administered to infants at the recommended 2, 4, 6 and 12–15 months schedule, in a large phase III, randomized, controlled trial . In addition, the safety profile of HibMenCY-TT vaccine in this trial was considered clinically acceptable and comparable to that of the Hib conjugate vaccines . Immune responses to constituents of the HibMenCY-TT vaccine were not compromised when it was coadministered with other routinely used vaccines in several clinical trials. Moreover, the HibMenCY-TT vaccine did not interfere with immune responses produced by the coadministered vaccines. These findings suggest that the HibMenCY-TT vaccine may be incorporated in several paediatric vaccine schedules without interference with immune responses achieved with other vaccines. Initial published data from a phase II study indicate that protective antibodies against MenC, MenY and Hib persist for up to 5 years after the fourth dose of the vaccine . Further long-term data are needed to confirm long-term antibody persistence and protective efficacy in recipients of the HibMenCY-TT vaccine, and to more clearly define its long-term tolerability profile.
The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit.
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