Neisseria meningitidis is a leading cause of meningitis and septicemia globally, with 6 serogroups responsible for most human disease: A, B, C, W-135, X, and Y.1 In Australia, as elsewhere, the majority of this disease burden is borne by children less than 5 years of age.2
An increasing proportion of cases caused by serogroup C meningococci in the 1990s, both in Europe3 and Australia,4 spurred development and implementation of monovalent serogroup C (MenC) conjugate vaccines. At population level, MenC introduction has been consistently associated with a marked and sustained reduction in disease caused by serogroup C.5,6 This success has been attributed in large part to the vaccine's effect of impeding carriage,7 producing robust herd immunity.8
Recent changes in the dominance of meningococcal serogroups causing invasive disease in the United States,9 as well as outbreaks of imported infection,10 preempt the potential need for broader meningococcal serogroup coverage. Quadrivalent polysaccharide vaccines, previously licensed for travelers, are not immunogenic in the early years of life and may result in hyporesponsiveness to vaccine antigens with repeated administration.11
Two quadrivalent (A, C, W-135, Y) meningococcal conjugate vaccines have been licensed for use in a number of countries.12 In the United States, 1 of these products has recently been approved for use in children aged 9 to 23 months, as a 2-dose schedule. No quadrivalent meningococcal vaccine is yet licensed for administration as a single dose to children aged 12 months, the time point at which MenC conjugate vaccine is administered in a number of countries, including Australia.13 This study assessed the safety and immunogenicity of one dose each of alternative formulations of a meningococcal quadrivalent conjugate vaccine, given to toddlers aged 1 year.
MATERIALS AND METHODS
The study aimed to evaluate the safety of each of 5 different dose-ranging formulations of an investigational quadrivalent meningococcal conjugate vaccine (TetraMen-T), compared with a licensed adjuvanted meningococcal serogroup C conjugate vaccine (NeisVac-C, tetanus toxoid conjugate vaccine, Baxter vaccines, Deerfield, IL) administered as a single dose at 12 months of age. Furthermore, the immunogenicity of each of these formulations was investigated, and serogroup C responses were assessed in relation to the licensed comparator. The original study design contained 7 groups. Because of production issues with the formulation proposed for group 5, that group was eliminated rather than delaying study commencement, accounting for nonconsecutive numbering (Fig. 1).
This study was conducted at 5 vaccine research centers in Australia (Adelaide, Brisbane, Canberra, Melbourne, and Perth). In Melbourne, study staff conducted visits in participants' homes. At the remaining centers, participants attended a hospital-based clinical trial facility. Ethical approval for study conduct was obtained at each of the participating centers before study commencement.
The recruitment target was a total of 360 children, with 60 in each of 6 study groups. Those eligible for inclusion were 12 months (±21 days) of age and in good health. Participants were excluded if they had a history of serious acute or chronic medical conditions including seizures of any kind; past or family history of Guillain-Barré syndrome; immunologic impairment, including recent receipt of immunomodulatory products; history of meningococcal disease or vaccination; hypersensitivity to vaccine components; or bleeding disorders contraindicating intramuscular vaccine administration. Recent administration of antibiotics, investigational products, or vaccines was grounds for deferral.
Eligible children were randomly assigned to their study group, using an interactive voice response system. In Melbourne, parents were asked to sign a preconsent form at an initial home visit allowing their child to be randomized before the subsequent enrolment visit, where full written consent was obtained. At all other centers, randomization took place immediately after signed consent.
All children received a single dose of vaccine according to their allocated treatment group, administered intramuscularly into the anterolateral thigh (for children <12 months of age at enrolment) or deltoid muscle (for children ≥12 months of age). No concomitant vaccines were given. Participants were observed for immediate adverse events (AEs) for 30 minutes after immunization. Blood samples for immunogenicity assessment were collected before and 30 days (30–37 days) after vaccination.
TetraMen-T was presented as a single 0.5 mL liquid dose, containing 16, 28, or 40 μg of total polysaccharide in low-, medium-, or high-dose combinations. Two “low-dose” vaccines contained 4 μg each of serogroup A, C, Y, and W-135 polysaccharides, with either 22.1 (group 1) or 33.9 μg (group 4) of tetanus toxoid protein. The “medium-dose” vaccine comprised 10 μg each of A and W-135 polysaccharides, 4 μg of C and Y polysaccharides, and 36.6 μg of tetanus toxoid (group 2) Two “high-dose” vaccines included 10 μg of each polysaccharide and either 54.8 (group 3) or 84.8 μg (group 6) of protein carrier. The high/low tetanus toxoid content formulations of the low- and high-dose vaccines also differed slightly from each other in their chemical structure, using different variations in linker chemistry. The licensed comparator, NeisVac-C, contained 10 μg of de-O-acetylated serogroup C polysaccharide, with 10 to 20 μg of tetanus toxoid (group 7).
Solicited AEs were recorded on a safety diary card from day 0 to 7 after vaccination and rated in intensity where present from grade 1 to 3. Solicited injection site reactions included
* Tenderness—grade 1 = minor reaction to touch, grade 2 = cries and protests to touch, grade 3 = cries when injected limb moved or limb movement is reduced.
* Erythema—grade 1 = <2.5 cm, grade 2 = 2.5 to <5 cm, grade 3 = ≥5 cm.
* Swelling—grade 1 = <2.5 cm, grade 2 = 2.5 to <5 cm, grade 3 = ≥5 cm.
Solicited systemic reactions included
* Fever—grade 1 = 37.5°C to <38.0°C, grade 2 = 38.0°C to <39.0°C, grade 3 = ≥39°C.
* Vomiting—grade 1 = 1 episode per 24 hours, grade 2 = 2 to 5 episodes per 24 hours, grade 3 = ≥6 episodes per 24 hours or requiring parenteral hydration.
* Abnormal cry—grade 1 = <1 hours, grade 2 = 1 to 3 hours, grade 3 = >3 hours.
* Drowsiness—grade 1 = sleepier than usual or less interested in surroundings, grade 2 = not interested in surroundings or did not wake up for a feed/meal, grade 3 = sleeping most of the time or difficult to wake up.
* Loss of appetite—grade 1 = eating less than normal, grade 2 = missed 1 or 2 feeds/meals completely, grade 3 = refuses ≥3 feeds/meals or refuses most feeds/meals.
* Irritability—grade 1 = easily consolable, grade 2 = requiring increased attention, grade 3 = inconsolable.
Data on unsolicited AEs and concomitant medications were collected until the second study visit and followed up until resolution or trial termination. Serious AEs (SAEs) were reported throughout the study period.
Functional antibodies to each of the meningococcal serogroups contained in the vaccine (A, C, W-135 and Y) were measured in separate serum bactericidal assays containing either a human (hSBA) or baby rabbit (rSBA) complement source. Immunogenicity data were reported as proportions achieving threshold titers associated with protection against serogroup C after natural infection (hSBA ≥1:4)14 or conjugate vaccination (rSBA ≥1:8).15 Additional summary measures including the proportion with hSBA titer ≥1:8 and geometric mean titers (GMTs) facilitated comparison with previously studied vaccines. Antibody concentrations to tetanus toxoid were measured by enzyme-linked immunosorbent assay. All assays were validated and performed by Global Clinical Immunology at Sanofi Pasteur Inc, Swiftwater, Pennsylvania.
The study was designed as a modified double-blind protocol, in which treatment group was concealed from participants, investigators, and staff participating in safety assessments. Immunizers were not blinded to vaccine allocation, as the licensed comparator (NeisVac-C) was clearly distinguishable from study vaccine formulations. For this reason, the vaccinating staff member did not take part in any further procedures associated with assessment of vaccine safety, ensuring that all other staff remained blinded. Similarly, laboratory staff involved in assessment of immunogenicity had no knowledge of group allocation.
This was an exploratory study to provide preliminary safety and immunogenicity data on alternative formulations of TetraMen-T administered to toddlers. Therefore, no formal hypotheses were tested. A sample size of 60 participants per group allowed estimation of an AE event occurring with a frequency of 1 in 20 participants (5%) with a 95% confidence interval excluding zero. This group size further enabled estimation of a 17% decrease in seroresponse rate from an expectation of 95%, with 80% power.
Both according to protocol (ATP) and intention-to-treat analyses were performed. The safety analysis dataset included all available information, analyzed according to vaccine received. Missing data were not imputed. Continuous variables were described by summary statistics and categorical variables by frequency distributions, with estimates of precision. Antibody titers were log transformed to approximate a normal distribution, allowing reporting of GMTs. Statistical analyses were conducted using SAS version 9.1 software and STATA 11.
A total of 378 potential participants were randomized. At the study site that conducted home visits, participants were randomized before the enrolment visit. Four such participants were subsequently found to be ineligible and took no further part in the study; another 2 required deferral of first vaccination (one for acute fever, another for recent receipt of antibiotics) and were rerandomized before the next scheduled visit. One participant at another site was randomized in error, without consent. Subsequent disposition of the 373 subjects who were enrolled in the study is shown in Figure 1, with 368 continuing to completion. Among the 65 participants who recorded at least 1 protocol deviation (of whom 3 were not vaccinated), blood was collected outside the specified visit window in 47, antibiotics were received before visit 2 in 13, inclusion/exclusion criteria were breached in 6, blood samples were missing in 3, and a contraindicated vaccine was received by 1.
Enrolments occurred between April and September 2008; the final study visit took place in October 2008. Of the safety population of 368 participants, 51% were male, varying from 39% to 62% within groups. Participants ranged in age from 11 to 12 months at enrolment, with group means varying between 11.5 and 11.7 months (standard deviation, 0.5 months). The majority of children were Caucasian (91.8%), with a mixture of Asian, Pacific Islander, black, and other comprising the remainder.
Solicited injection site reactions were common, with approximately half of participants in each group reporting one or more events (Fig. 2). Tenderness was reported by one-third of subjects, as was erythema. Swelling was less common. Severe (grade 3) reactions were uncommon and not reported by more than a single participant in any group (Table 1). No apparent differences in the frequency of injection site reactions were observed between study groups (Fig. 2). All injection site reactions with the exception of 1 (swelling) were of onset within 3 days after immunization. The majority resolved within 3 days, with only 1 report of swelling (group 2) and 1 of erythema (group 1) extending to, but not beyond, the eighth day after immunization.
The majority of participants experienced at least 1 solicited systemic reaction (Fig. 3), of which irritability was the most common at around two-thirds, followed by abnormal crying and loss of appetite (approximately 40% for each). Fever, drowsiness, and vomiting were each reported by about 1 in 5 children. The most commonly reported grade 3 reactions were irritability (not more than 3 children per group), followed by crying and lost appetite (not more than 2 children per group) (Table 2) Not more than 1 child per group reported severe fever or vomiting, and none experienced severe drowsiness. Again, no significant between-group differences were observed. The majority of systemic reactions had an onset within 3 days after immunization, with most resolving in a matter of days. Solicited adverse reactions lasting 8 days or more included irritability in 14 children, abnormal crying in 5, loss of appetite in 5, and drowsiness in 1 child. The subset of children experiencing each of these events who had received the licensed comparator was 4, 0, 1, and 1, respectively.
A total of 931 unsolicited AEs were reported in 327 participants. The proportion of children who experienced an AE, reported by treatment group, ranged from 83.6% (group 2) to 93.4% (group 6) compared with 87.1% of children receiving the licensed comparator (group 7). Approximately one-third of these events were attributed to an infectious cause. The next most common reported conditions were classified as gastrointestinal, respiratory, and skin disorders, with no systematic differences observed between groups. Rates of unsolicited adverse reactions, or unsolicited AEs deemed related to vaccination, were also similar across treatment groups. The proportion of children reporting an AR ranged from 16.4% (group 3) to 31.1% (group 6), compared with 25.8% of those given NeisVac-C (group 7).
Seven SAEs were reported, of which 6 were considered unrelated. These included 2 cases of bronchiolitis, 1 unspecified viral illness, 1 breath-holding attack, and a case of tenosynovitis. The sixth unrelated SAE was a febrile convulsion, with onset within 9 days after vaccination in the context of an intercurrent viral illness. One participant experienced a monoarticular inflammatory arthritis with onset within 1 day after vaccination, for which no other cause could be found after extensive investigation, and was considered possibly related.
As the results of ATP and intention-to-treat analyses were concordant (data not shown), only ATP outcomes are reported.
Figure 4 shows reverse cumulative distribution plots of hSBA titers for each serogroup, reported by treatment allocation, from which proportions achieving titers ≥1:4 or 1:8 can be identified. For serogroup A, all 3 formulations containing 10 μg of the A capsular polysaccharide (groups 2, 3, and 6) were more immunogenic than those containing the 4-μg dose (groups 1, 4) (Fig. 4A). High background reactivity was evident from titers measured in group 7 participants, who did not receive a serogroup A vaccine. NeisVac-C (group 7) was more immunogenic for the serogroup C capsular polysaccharide than any of the TetraMen-T formulations studied. Participants with the highest titers against serogroup C received vaccines containing higher doses of tetanus toxoid carrier, regardless of serogroup C capsular polysaccharide content (groups 4, 6) (Fig. 4B). All of the studied TetraMen-T formulations were immunogenic for the serogroup W-135 capsular polysaccharide, those with higher polysaccharide content (groups 2, 3, 6) appearing more immunogenic than lower-content formulations. Baseline reactivity to this capsular polysaccharide was low (group 7) (Fig. 4C). There was no clear difference between alternative investigational formulations against serogroup Y (Fig. 4D).
Figure 5 shows proportions of participants achieving the threshold titer of at least 1:8, by rSBA. Distinct differences were observed between the 2 sets of assay results, with lower proportions of participants achieving the threshold titer of 1:8 against serogroup C in this assay using rabbit rather than human complement. Responses to serogroups A, W-135, and Y, on the other hand, were higher and more consistent by rSBA across all vaccine groups. Higher background activity against serogroup Y than A was also observed, unlike the hSBA findings. GMTs of antibody to each serogroup, reported by group, are shown in Table 3.
All participants had tetanus antibody concentrations ≥0.01 IU/mL before and after immunization. Levels ≥0.1 IU/mL were observed in 81.3% (group 3) to 89.8% (group 7) of subjects before vaccine administration, rising thereafter to a minimum of 95.8% (group 4) and maximum of 100% (groups 2 and 6). Geometric mean concentration rises within each group were close to 10-fold (data not shown).
All formulations of TetraMen-T evaluated in this study proved to be safe and well tolerated, with the majority of vaccine-associated AEs reported as mild and self-limiting. Using the many measures of immunogenicity employed, no consistent relationships were observed between the dose of either polysaccharide or carrier and serogroup-specific response for any antigen. The high-dose (group 6) formulation appeared to provide the best coverage for all 4 serogroups. Overall, the investigational vaccines were less immunogenic against the serogroup C capsular polysaccharide than the licensed comparator, with lower rSBA GMTs.
Because of the exploratory nature of the study, the precision of estimates of vaccine safety and immunogenicity was necessarily limited by sample size precluding identification of small variations in vaccine effects. Furthermore, interpretation of the clinical relevance of antibody titers measured is made uncertain by the absence of established population-level correlates of conjugate vaccine protection against any meningococcal serogroup other than C.6 Both rSBA and hSBA titers were assessed in this study; however, given that these 2 are less reliably correlated after vaccination than natural infection,16 it is not certain which will be more consistently predictive of protection in this age range. Although hSBA is often considered a “gold standard,” necessary reliance on diverse complement sources makes interlaboratory standardization difficult.16 Moreover, in the absence of persistence studies, no comment can be made from this study regarding the likely duration of vaccine protection.
Currently licensed vaccines have either a diphtheria or CRM197 carrier protein, and they have performed favorably in studies conducted in adults,17 adolescents,18 and young children.19 Demonstrated immunogenicity of one of these products after 2-dose administration at 9 and 12 months has been sufficient for licensure down to 9 months of age.20 Postlicensure surveillance of quadrivalent meningococcal vaccination in US adolescents has estimated vaccine effectiveness of 80% to 85% against invasive disease during the 3 to 4 years after immunization,21 a figure somewhat lower than anticipated. This finding reinforces the importance of both maintained high titers for direct protection22 and herd immunity for population impact6 against meningococcal disease, evidenced by MenC conjugate vaccines.
A recently published clinical trial of a quadrivalent meningococcal conjugate vaccine that included a group receiving a single dose at 12 months did not report hSBA titers of ≥1:8 in tables, making direct comparisons between study findings difficult.23 Administration of that vaccine according to a 2-dose (6, 12 months)23 or 3-dose (2, 4, 12 months) schedule resulted in higher postimmunization titers than those observed in the 1-dose (12 months) group.24
Another manufacturer is presently developing a tetanus-conjugated quadrivalent meningococcal conjugate vaccine for use across the age spectrum.25 A single dose given to children between 12 and 23 months of age has been found to elicit serogroup C responses that are noninferior to a MenC-CRM197 conjugate vaccine,26 together with robust responses to the other 3 serogroups. Similar immunogenicity has been observed when the vaccine is coadministered with either measles-mumps-rubella-varicella vaccine26 or routine infant schedule combinations.27 The superior immunogenicity of tetanus-conjugated vaccines is consistent with that observed for serogroup C–specific meningococcal conjugates, evident since early comparative clinical trials.28
Evaluation of TetraMen-T is ongoing, with a current clinical trial involving 580 participants examining immunogenicity and safety of the vaccine after several prime-boost schedules during the first year of life, compared with a single 12-month dose. Identification of optimal scheduling of quadrivalent meningococcal conjugates in this way will facilitate inclusion of these vaccines into national immunization programs seeking extended serogroup coverage against meningococci.
The authors are grateful for the contributions of parents and their children. Study staff in each center made valuable contributions: Adelaide: Dr. Susan Evans, Dr. Jan Walker, Dr. Rachel Chen, Mrs. Chris Heath, Mrs. Diana Weber, Mrs. Jane Tidswell, Mrs. Michelle Clarke, Ms. Susan Lee, Mrs. Louise DeGaris, Mrs. Sue Bourdon; Brisbane: Dr. Raymond Chuk, Dr. Rashmi Dixit, Kylie Berglund, Aaron Buckner, Fiona Canavan, Ria Halstead, Lisa Mulhearn, Nicholas O. Neill, Jane Yunus; Canberra: Sandra Gillett, Sarah Bunker, Gillian Fox; Melbourne: Marita Kefford, Dr. Karyn Alexander, Janet Briggs, Clare Brophy, Dr. Jenny Davey, Alice Holloway, Dr. Lana Horng, Clare Kohlman, Betty Lim, AnnMarie McEvoy, Liz McGrath, Elanna Nolan, Jacinta O'Keefe, Mairead Phelan, Dr. Briony Price, Dr. Nicole Rose, Jane Ryrie, Deborah Saunders, Jacinta Sonego, Judith Spotswood, Dr. Loretta Thorn, Marie West; Perth: Jennifer Kent, Jan Adams, Heidi Hutton, Larissa Rhind, Dr. Tanya Stoney; Sanofi Pasteur: Patrick McGinley, Melissa Vella, Anthony Yanni.
1. Stephens DS, Greenwood B, Brandtzaeg P. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet. 2007;369:2196–2210.
2. Tapsall J. Annual report of the Australian meningococcal surveillance programme, 2007—amended. Commun Dis Intell. 2009;33:1–9.
3. Ramsay M, Kaczmarski E, Rush M, et al.. Changing patterns of case ascertainment and trends in meningococcal disease in England and Wales. Commun Dis Rep CDR Rev. 1997;7:R49–R54.
4. Booy R, Jelfs J, El Bashir H, et al.. Impact of meningococcal C conjugate vaccine use in Australia. Med J Aust. 2007;186:108–109.
5. Simpkins D, Wood N, Jelfs J, et al.. Modern trends in mortality from meningococcal disease in Australia. Pediatr Infect Dis J. 2009;28:1119–1120.
6. Campbell H, Andrews N, Borrow R, et al.. Updated postlicensure surveillance of the meningococcal C conjugate vaccine in England and Wales: effectiveness, validation of serological correlates of protection, and modeling predictions of the duration of herd immunity. Clin Vaccine Immunol. 2010;17:840–847.
7. Maiden MC, Stuart JM. Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination. Lancet. 2002;359:1829–1831.
8. Trotter CL, Maiden MC. Meningococcal vaccines and herd immunity: lessons learned from serogroup C conjugate vaccination programs. Expert Rev Vaccines. 2009;8:851–861.
9. Rosenstein N, Perkins B, Stephens D, et al.. The changing epidemiology of meningococcal disease in the United States, 1992–1996. J Infect Dis. 1999:1894–1901.
10. Hahne SJ, Gray SJ, Jean F, et al.. W135 meningococcal disease in England and Wales associated with Hajj 2000 and 2001. Lancet. 2002;359:582–583.
11. Broker M, Veitch K. Quadrivalent meningococcal vaccines: hyporesponsiveness as an important consideration when choosing between the use of conjugate vaccine or polysaccharide vaccine. Travel Med Infect Dis. 2010;8:47–50.
12. Kimmel SR. Using the tetravalent meningococcal polysaccharide-protein conjugate vaccine in the prevention of meningococcal disease. Ther Clin Risk Manag. 2008;4:739–745.
13. Australian Government Department of Health and Ageing. The Australian Immunisation Handbook. 9th ed. Canberra, Australia: Australian Government Department of Health and Ageing; 2008.
14. Goldschneider I, Gotschlich E, Artenstein M. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med. 1969;127:1307–1323.
15. Andrews N, Borrow R, Miller E. Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England. Clin Diagn Lab Immunol. 2003;10:780–786.
16. Borrow R, Andrews N, Goldblatt D, et al.. Serological basis for use of meningococcal serogroup C conjugate vaccines in the United Kingdom: reevaluation of correlates of protection. Infect Immun. 2001;69:1568–1573.
17. Reisinger KS, Baxter R, Block SL, et al.. Quadrivalent meningococcal vaccination of adults: phase III comparison of an investigational conjugate vaccine, MenACWY-CRM, with the licensed vaccine, Menactra. Clin Vaccine Immunol. 2009;16:1810–1815.
18. Jackson LA, Jacobson RM, Reisinger KS, et al.. A randomized trial to determine the tolerability and immunogenicity of a quadrivalent meningococcal glycoconjugate vaccine in healthy adolescents. Pediatr Infect Dis J. 2009;28:86–91.
19. Black S, Klein NP, Shah J, et al.. Immunogenicity and tolerability of a quadrivalent meningococcal glycoconjugate vaccine in children 2–10 years of age. Vaccine. 2010;28:657–663.
20. Menactra (Meningococcal [groups A, C, Y and W-135] polysaccharide diphtheria toxoid conjugate vaccine) for intramuscular injection [Prescribing Information, v0.33]. Philadelphia, PA: Sanofi Pasteur; , 2011.
21. Macneil JR, Cohn AC, Zell ER, et al.. Early estimate of the effectiveness of quadrivalent meningococcal conjugate vaccine. Pediatr Infect Dis J. 2011;30:451–455.
22. De Wals P, Deceuninck G, Lefebvre B, et al.. Effectiveness of serogroup C meningococcal conjugate vaccine: a 7-year follow-up in Quebec, Canada. Pediatr Infect Dis J. 2011;30:566–569.
23. Halperin SA, Diaz-Mitoma F, Dull P, et al.. Safety and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine after one or two doses given to infants and toddlers. Eur J Clin Microbiol Infect Dis. 2010;29:259–267.
24. Perrett KP, Snape MD, Ford KJ, et al.. Immunogenicity and immune memory of a nonadjuvanted quadrivalent meningococcal glycoconjugate vaccine in infants. Pediatr Infect Dis J. 2009;28:186–193.
25. Knuf M, Kieninger-Baum D, Habermehl P, et al.. A dose-range study assessing immunogenicity and safety of one dose of a new candidate meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate (MenACWY-TT) vaccine administered in the second year of life and in young children. Vaccine. 2010;28:744–753.
26. Vesikari T, Karvonen A, Bianco V, et al.. Tetravalent meningococcal serogroups A, C, W-135 and Y conjugate vaccine is well tolerated and immunogenic when co-administered with measles-mumps-rubella-varicella vaccine during the second year of life: An open, randomized controlled trial. Vaccine. 2011;29:4274–4284.
27. Knuf M, Pantazi-Chatzikonstantinou A, Pfletschinger U, et al.. An investigational tetravalent meningococcal serogroups A, C, W-135 and Y-tetanus toxoid conjugate vaccine co-administered with Infanrix hexa is immunogenic, with an acceptable safety profile in 12–23-month-old children. Vaccine. 2011;29:4264–4273.
28. Richmond P, Borrow R, Goldblatt D, et al.. Ability of 3 different meningococcal C conjugate vaccines to induce immunologic memory after a single dose in UK toddlers. J Infect Dis. 2001;183:160–163.
vaccines; meningococcal; tetravalent meningococcal vaccine; randomized controlled trial; infant
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