Secondary Logo

Journal Logo

Safety and Immunogenicity of a Quadrivalent Meningococcal Conjugate Vaccine and Commonly Administered Vaccines After Coadministration

Gasparini, Roberto MD*; Tregnaghi, Miguel MD; Keshavan, Pavitra PhD; Ypma, Ellen MSc; Han, Linda MD§; Smolenov, Igor MD, PhD

The Pediatric Infectious Disease Journal: January 2016 - Volume 35 - Issue 1 - p 81–93
doi: 10.1097/INF.0000000000000930
Vaccine Reports
Free

Background: Given the broad age range across which the quadrivalent meningococcal conjugate vaccine MenACWY-CRM is used, coadministration with routine vaccines should be evaluated across age groups for possible immunologic interference and impact on vaccine reactogenicity and safety.

Methods: We summarize data from a large population of infants, adolescents and international travelers from 10 phase 3 or 4 clinical studies to evaluate coadministration of MenACWY-CRM with commonly administered vaccines. Noninferiority analyses of immune responses were performed across studies and age groups for each vaccine. Reactogenicity and safety were also assessed.

Results: In infants, MenACWY-CRM coadministered with routine vaccines did not reduce immune responses to diphtheria, tetanus, poliovirus, hepatitis B, Haemophilus influenzae type b, pneumococcal conjugate, measles–mumps–rubella, varicella or pertussis antigens. Noninferiority criteria were not met for some pneumococcal conjugate serotypes at 7 months of age, but no consistent trends were observed. In adolescents, coadministration did not reduce immune responses to tetanus, diphtheria and human papilloma virus vaccine antigens. Noninferiority criteria for pertussis antigens were not uniformly met in infant and adolescent studies, although the clinical relevance is unclear. In adults, coadministration did not reduce immune responses to hepatitis A/B, typhoid fever, yellow fever, Japanese encephalitis and rabies antigens. Immune responses to MenACWY-CRM were not impacted by coadministration of commonly administered vaccines. Coadministration did not increase frequencies of postvaccination adverse events in any age group.

Conclusions: With no clinically relevant vaccine interactions or impact on vaccine reactogenicity or safety, these results support the coadministration of MenACWY-CRM with routine vaccines in all age groups.

From the *Department of Health Sciences, University of Genoa, Genoa, Italy; Department of Clinical Research Center Developing Advanced Projects (CEDEPAP), Córdoba, Argentina; Global Clusters, Research and Development, Novartis Pharma BV, Amsterdam, The Netherlands; §Biostatistics and Statistical Reporting, Novartis Pharma BV, Amsterdam, The Netherlands; and Global Clusters, Research and Development, Novartis Vaccines and Diagnostics, Inc., Cambridge, Massachusetts.

Accepted for publication August 4, 2015.

The institutions of R.G. and M.T. received funding from Novartis Vaccines and Diagnostics, Inc. for study conduct. R.G. has no other interests to declare. P.K., L.H., I.S. and E.Y. are employees of Novartis Pharmaceuticals. L.H., I.S. and E.Y. owns stock in the company. All studies were funded by Novartis Vaccines and Diagnostics, Inc. Medical Writing support for the finalization of this manuscript was provided by Zoetic Science, an Ashfield company. Funding for this support was provided by Novartis Vaccines and Diagnostics, Inc.

Address for correspondence: Igor Smolenov, MD, PhD, Novartis Pharma BV, Hullenbergweg 83–85, P.O. Box 23023, NL-1100 DM, Amsterdam, The Netherlands. E-mail: igor.smolenov@novartis.com.

Disease caused by Neisseria meningitidis remains a global public health problem, with rapid onset, fulminant course and epidemic potential. Morbidity and mortality rates are high, and long-term sequelae are common among survivors,1 in spite of appropriate treatment. All age groups can be affected, with infants in the first year of life being at highest risk for meningococcal disease,2,3 followed by adolescents and young adults, in whom transmission is facilitated by close living conditions and sociobehavioral factors.3–6 The incidence of meningococcal disease also varies by geographical location, time of year and serogroup, with most cases of invasive disease being caused by serogroups A, B, C, W and Y.7

Given the clinical and epidemiologic characteristics of meningococcal disease, vaccination has a major role in its prevention and control in all age groups and across multiple serogroups. Quadrivalent polysaccharide–protein conjugate vaccines against serogroups A, C, W and Y are currently licensed worldwide. Recommendations for use vary by country but include routine vaccination of healthy infants, adolescents and young adults and vaccination of specific individuals at high risk for disease, including infants and travelers to hyperendemic or epidemic regions such as Africa and the Middle East.8

The quadrivalent meningococcal CRM197-conjugate vaccine MenACWY-CRM (Menveo, Novartis Vaccines and Diagnostics, Inc., Cambridge, MA) is licensed in more than 60 countries worldwide for use. In the US, Canada, Argentina, Korea and Saudi Arabia, MenACWY-CRM has been approved for use in infants from 2 months of age. In clinical studies, MenACWY-CRM has been found to have a good tolerability profile and to be immunogenic in all indicated age groups.9–20

Given the wide age range across which MenACWY-CRM may be administered and the number of other licensed vaccines commonly administered in these age groups, it is essential to evaluate MenACWY-CRM coadministration with routinely used vaccines for possible immunologic interference and impact on vaccine reactogenicity and safety.21–24 Immunologic interference is of particular concern when concomitantly administered vaccines contain similar antigens, which can occur, for example, when concomitantly administered conjugate vaccines contain the same carrier protein.25,26

In this article, we present a summary of completed clinical studies in which MenACWY-CRM was administered concomitantly with a variety of commonly administered vaccinations given in different age groups and populations known to be at risk for meningococcal disease, including infants, adolescents and adult travelers.

Back to Top | Article Outline

MATERIALS AND METHODS

Coadministration Study Designs

This report includes 10 phase 3 and 4, open-label, randomized, multicenter studies assessing immune response and safety of routine vaccines coadministered with MenACWY-CRM.9–20 Overall, 5825 infants, 2292 children 6–23 months of age and 3493 adolescents were enrolled in these studies. The design and methodology of these studies are summarized in Table 1 and are described briefly below.

TABLE 1

TABLE 1

Back to Top | Article Outline

Infants

In studies 1, 2 and 3, infants received routine vaccines with or without MenACWY-CRM at 2, 4, 6 and 12 months of age.15,17–19 Immune responses to diphtheria, tetanus and pertussis (DTaP); Haemophilus influenzae type b (Hib); 7-valent pneumococcal conjugate (PCV7); polio [inactivated poliovirus vaccine (IPV)] and hepatitis B virus (HBV) vaccines were evaluated in studies 1 and 2,15,17,18 and immune responses to 13-valent PCV (PCV13) were evaluated in study 3.19 Study 1 included data from 2 distinct study settings (US and Latin America), which were analyzed separately. In study 4, older infants received measles–mumps–rubella (MMR) and varicella vaccines at 12 months of age, with or without a 2-dose series of MenACWY-CRM given at 7–9 and 12 months of age.16 Study 4 also assessed noninferiority of immune response to MenACWY-CRM at 13.5 months of age, among subjects who received coadministered MMR and varicella vaccines versus those who did not. In study 5, older infants received DTaP–HBV–IPV–Hib and PCV7 at 12 months of age, with either a single dose of Menjugate (MenC-CRM) or the second of a 2-dose series of MenACWY-CRM.20

Back to Top | Article Outline

Adolescents

Immune responses to Tdap were evaluated 1 month after receipt of (a) Tdap alone versus Tdap with MenACWY-CRM in subjects aged 11–25 years (study 6),13 (b) Tdap alone versus Tdap with human papilloma virus (HPV) vaccine and MenACWY-CRM in subjects aged 11–18 years (study 7)12 and (c) Tdap with HPV versus Tdap with HPV and MenACWY-CRM in subjects aged 11–18 years (study 8).14 Study 6 included descriptive analyses comparing immune responses to MenACWY-CRM when administered with and without Tdap. Immune responses 1 month after a 3-dose series of HPV vaccine were evaluated in study 7 in subjects who received MenACWY-CRM and Tdap concomitantly with the first dose of HPV vaccine versus subjects who received the 3-dose HPV series beginning 1 month after sequential administration of MenACWY-CRM and Tdap. Noninferiority of immune response to MenACWY-CRM when MenACWY-CRM was coadministered with Tdap and HPV versus when it was given alone was also evaluated in study 7.

Back to Top | Article Outline

Adults

Studies 9 and 10 evaluated immune responses to 3 pairs of “traveler” vaccines (typhoid fever and yellow fever vaccines, rabies and Japanese encephalitis (JE) vaccines, hepatitis A virus (HAV) and HBV vaccines) given with and without MenACWY-CRM.9–11 MenACWY-CRM, yellow fever vaccine and typhoid fever vaccine were given as a single dose on study day 1. Rabies vaccine was given on study days 1, 8 and 29, and JE vaccine was given on days 1 and 29. Hepatitis vaccines were given as a combined HAV/HBV vaccine on study day 1 and were given as a combined HAV/HBV vaccine or as monovalent HAV or HBV vaccines on study days 8 and 29 according to each subject’s history of hepatitis vaccinations. Immune responses to each vaccine antigen were measured 1 month after receipt of the last vaccination in the series. Both studies also included a descriptive evaluation of immune responses to MenACWY-CRM, when administered with and without each pair of concomitant vaccines.

All studies were conducted in accordance with good clinical practice and International Conference on Harmonisation of Techniques for Requirements for Registration of Pharmaceuticals for Human Use guidelines, and thus, each study complied with guidelines for the collection, analysis and presentation of vaccine safety data.27

Back to Top | Article Outline

Vaccines

MenACWY-CRM was supplied in 2 vials: 1 vial of lyophilized powder containing 10 μg of MenA oligosaccharide conjugated to CRM197 and a second liquid conjugate vaccine component containing 5 μg each of the Men C, W and Y oligosaccharides conjugated to CRM197. The vaccine was prepared by dissolving the MenA component with the liquid MenCWY component, with the reconstituted vaccine (0.5 mL) being administered by intramuscular injection in the deltoid of the nondominant arm (or in the anterolateral aspect of the thigh in infants).

Routine and traveler vaccines administered concomitantly with MenACWY-CRM were as follows.

Back to Top | Article Outline

Infants

Pediarix (DTaP–HBV–IPV; GlaxoSmithKline, Rixensart, Belgium), Pentacel (DTaP–IPV–Hib; Sanofi Pasteur, Swiftwater, PA), Infanrix-hexa (DTaP–HBV–IPV–Hib; GlaxoSmithKline), ActHIB (Hib; Sanofi Pasteur), Engerix-B (HBV; GlaxoSmithKline), Prevnar or Prevnar-13 (PCV7 or PCV13; Pfizer, Inc., New York City, NY), ProQuad (MMRV; Merck & Co., Inc., White House Station, NJ), M-M-R II (MMR; Merck & Co., Inc.), Varivax (varicella; Merck & Co., Inc.).

Back to Top | Article Outline

Adolescents

Boostrix (Tdap; GlaxoSmithKline) and Gardasil (HPV; Merck & Co., Inc.).

Back to Top | Article Outline

Adults

Typhim Vi (typhoid Vi polysaccharide; Sanofi Pasteur), Stamaril (yellow fever vaccine; Sanofi Pasteur), Ixiaro (JE vaccine; Novartis Vaccines and Diagnostics, Inc.), Rabipur (rabies vaccine; Novartis Vaccines and Diagnostics, Inc.), Twinrix (HAV/HBV; GlaxoSmithKline), Engerix-B (HBV; GlaxoSmithKline) and Havrix (HAV; GlaxoSmithKline).

All vaccines were administered in accordance with manufacturers’ instructions.

Back to Top | Article Outline

Serologic Assays

Immunogenicity was assessed by serologic assays, including enzyme-linked immunosorbent assay (ELISA) for the measurement of antibodies against diphtheria toxoid, tetanus toxoid, pertussis toxoid (PT), pertussis filamentous hemagglutinin (FHA), pertactin (PRN) and fimbriae (FIM), HBV, PCV7 and PCV13 serotypes, Hib, MMR, varicella and typhoid fever; neutralization test for antibodies against poliovirus types 1, 2 and 3, JE virus, rabies virus and yellow fever virus; competitive Luminex immunoassay for HPV antibodies and human serum bactericidal assay (hSBA) for bactericidal antibodies against meningococcal serogroups A, C, W and Y.

Back to Top | Article Outline

Immunogenicity Endpoints

The selection of immunogenicity endpoints for coadministration studies was based on clinical, regulatory and statistical considerations.

A simple and commonly used immunogenicity endpoint is the percentage of subjects achieving a level of postvaccination immune response that has been shown to correlate with disease protection.28 Use of this endpoint is generally most appropriate when robust and well-established antibody assays are available, such that the potential for inconsistencies in assay performance within and between laboratories is minimal. Accordingly, this endpoint was used for measuring immune responses to diphtheria, tetanus, HBV, Hib, poliovirus and pneumococcus (after infant series) antigens.

The percentage of initially seronegative subjects who seroconverted after vaccination was used as the primary immunogenicity endpoint for MMR, varicella and HPV. For some of these antigens (eg, measles, rubella and varicella), seroconversion was defined as a postvaccination antibody level similar to or greater than an established “protective” level (Table 2).

TABLE 2

TABLE 2

The geometric mean concentration (GMC) or the geometric mean titer (GMT) of vaccine-induced antibodies was used to measure immune response to those vaccine antigens for which a serocorrelate of protection is not well established (ie, typhoid fever), or for which a high postvaccination antibody concentration is important for sustained protection [ie, pneumococcus (after completion of the 4-dose vaccination series in infants), HBV (in adults), HAV, yellow fever, rabies and JE antigens]. For pertussis, GMCs and the percentage of subjects with at least a 4-fold rise in antibody concentration were used as endpoints, given the absence of an established serocorrelate of protection.

Finally, percentages of subjects with hSBA ≥1:8 or with seroresponse to serogroups A, C, W and Y were used as the primary immunogenicity endpoints for the MenACWY-CRM vaccine (Table 2). For a subject with baseline hSBA <1:4, seroresponse was defined as a postvaccination hSBA ≥1:8. For a subject with baseline hSBA ≥1:4, seroresponse was defined as a postvaccination hSBA titer of at least 4 times the baseline.

Back to Top | Article Outline

Safety

Solicited systemic reactions were routinely monitored as indicators of reactogenicity for at least 7 days after each vaccination in most infant/toddler and adolescent studies. Injection-site reactions were also monitored but are not described in this report because they are not useful indicators of possible effects of vaccine coadministration. Unsolicited adverse events (AEs) were collected for at least 1 month after each vaccination, and serious AEs were collected throughout each study.

Back to Top | Article Outline

Statistical Analyses

Noninterference with immune response was inferred by the results of noninferiority analyses, which tested the hypothesis that differences in immune response to routine vaccines coadministered with MenACWY-CRM and routine vaccines administered alone would be less than a prespecified noninferiority margin.

The selection of the noninferiority margin is based on a combination of statistical reasoning and clinical judgment.30 For vaccine immunogenicity, the noninferiority margin depends on factors such as immune response and vaccine efficacy correlation, immune response variability, the type of vaccine being tested and the relative importance of the immunogenicity endpoints in the given study.29 In practice, for vaccine trials, a difference of 10% between study groups in the percentage of subjects who achieve a “protective level” of antibodies is considered to be a clinically acceptable noninferiority margin.29 For vaccines with high postvaccination immune responses (eg, 98%–100%), a narrower margin (eg, 5%) is often used.31 For comparison of GMCs and GMTs, a difference of log (0.67) or log (0.5), corresponding to a 1.5-fold or 2-fold difference, respectively, is commonly used as a noninferiority margin.29

The key immunogenicity endpoints used for noninferiority testing are summarized in Table 2, along with prespecified noninferiority margins.

Immune responses to any of the tested routine vaccine antigen, when given concomitantly with MenACWY-CRM, were considered noninferior to those of the routine vaccine given alone, if the lower limit (LL) of the 2-sided 95% confidence interval (CI) for the group difference in the percentage of subjects with antibody response greater than or equal to the “protective” threshold level for that antigen (%routine vaccines + MenACWY-CRM minus %routine vaccines only) was greater than –5% for poliovirus, measles, mumps, rubella and HPV antigens, or greater than –10% for other antigens. In studies 4 and 7, immune responses to meningococcal serogroups were considered noninferior when MenACWY-CRM was given with routine vaccines versus when MenACWY-CRM was given alone, if the LL of the 2-sided 95% CI around the difference of the percentage of subjects with seroresponse hSBA ≥1:8 (%MenACWY-CRM + routine vaccines minus %MenACWY-CRM alone) was greater than –10%.

For analyses of GMCs (or GMTs), noninferiority was demonstrated if the LL of the 2-sided 95% CI for the ratio of GMCs (GMCroutine vaccine + MenACWY-CRM/GMCroutine vaccine alone) was >0.67 for pertussis antigens in infant studies and in study 6, or >0.50 for all other antigens (including pertussis antigens in study 8).

Noninferiority testing for concomitant vaccines was done without adjustment for multiplicity in both cohorts in study 1 and in study 5. In studies 2, 3, 4, 7, 8, 9 and 10, several approaches were applied to minimize inflation of potential type I error because of multiple noninferiority testing, by (hierarchically) ordering the families of hypotheses and sometimes also the hypotheses within each family. Some studies hierarchically tested the family of primary endpoints and the family of secondary endpoints. This means that rejections or nonrejections of null hypotheses of secondary endpoints depend on the outcomes of test results of primary endpoints. Another approach applied was to a priori order endpoints, for example, in terms of their importance. A fixed-sequence method then tests the ordered endpoints sequentially at level α as long as the test is significant and stops testing when a nonsignificant result is encountered. To facilitate examination of immune responses to specific vaccine antigens across studies, noninferiority of immune responses to individual antigens only will be considered in this report.

Studies were not always adequately powered for the noninferiority analyses of immune responses to coadministered vaccines, particularly in infant studies, where the studies were powered to demonstrate immunogenicity of MenACWY-CRM as the primary study objective.

No statistical testing was performed for safety assessments.

Back to Top | Article Outline

RESULTS

Infants: Concomitant Administration of MenACWY-CRM with DTaP, IPV, HBV and Hib

Infants Receiving a 4-Dose Series of MenACWY-CRM at 2, 4, 6 and 12 Months of Age

At 7 months of age, noninferiority criteria for diphtheria, tetanus, all 3 types of poliovirus, HBV and Hib antigens were consistently met in all 3 infant study settings (US and Latin America cohorts in study 1 and study 2; Fig. 1), with seroprotective antibody levels being achieved for each antigen in all studies and study groups in 95–100% of subjects (with the exception of 89% of subjects with anti-polyribosyl ribitol phosphate Hib antibodies ≥0.15 μg/mL in the routine vaccines group in study 2). Noninferiority of immune responses to pertussis antigens, as measured by GMC ratios, was demonstrated for all 3 antigens tested in US subjects in study 1 and for 2 of 3 antigens (except PRN) in Latin American subjects in the same study (Fig. 2). In study 2, immune responses to all 4 pertussis antigens, when DTaP was coadministered with MenACWY-CRM, were noninferior to those observed when DTaP was given without MenACWY-CRM.

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

When noninferiority of immune responses to pertussis antigens was assessed in terms of percentages of subjects with at least a 4-fold increase in antibody concentrations at 7 months of age, noninferiority criteria were met for 2 of 3 antigens in US subjects in study 1 (except PRN), for all 3 pertussis antigens in Latin American subjects in study 1 and for 2 of 4 antigens in study 2 (except PT and FIM; data not shown). For the pertussis antigens failing to meet noninferiority criteria, the percentages of subjects with a 4-fold increase in antibodies were 76% and 78% (in the MenACWY + routine group and the routine vaccines only group, respectively) for PRN in study 1, 77% and 81% for PT in study 2 and 74% and 76% for FIM in study 2.

At 13 months of age, noninferiority criteria were met for immune responses to all DTaP and Hib antigens (Latin America cohort, study 1; Fig. 3), with seroprotective antibody levels against diphtheria, tetanus and Hib antigens in 98%– 100% of subjects across groups, and a 4-fold rise in antibodies against PT, FHA and PRN in 84%– 89% of subjects. Immune responses to DTaP and Hib antigens were not tested in any other infant study settings.

FIGURE 3

FIGURE 3

Back to Top | Article Outline

Infants Receiving a 2-dose Series of MenACWY-CRM at 6–8 and 12 Months of Age

In study 5, infants received the first vaccination of MenACWY-CRM at 6–8 months of age and received the second vaccination at 12 months of age, along with a DTaP–HBV–IPV–Hib vaccine. All enrolled subjects had previously received 3 doses of DTaP, HBV, polio and Hib antigens, with the last vaccination occurring at least 30 days before study entry.

At 13 months of age, immune responses to diphtheria, tetanus, pertussis, HBV, poliovirus and Hib antigens, when DTaP–HBV–IPV–Hib was coadministered with MenACWY-CRM, were similar to those observed when DTaP–HBV–IPV–Hib was coadministered with Menjugate (study 5; data not shown). Seroprotective levels were achieved for diphtheria, tetanus, HBV, IPV and Hib antigens in 99%– 100% of subjects across groups, and serological response to PT, FHA and PRN was seen in 96%– 99% of subjects.

Back to Top | Article Outline

Infants: Concomitant Administration of MenACWY-CRM With PCV7/13

Infants Receiving a 4-Dose Series of MenACWY-CRM at 2, 4, 6 and 12 Months of Age

Figure 4 presents the intergroup differences in the percentages of subjects with antipneumococcal antibodies ≥0.35 μg/mL at 7 months of age (1 month after the third infant vaccination at 6 months of age), for each vaccine serotype. Overall, the prespecified criteria for noninferiority (Table 2) were consistently met for most serotypes, with the following exceptions: noninferiority criteria were not met for serotype 6B in the US arm of study 1, serotypes 6B and 23F in study 2 and serotype 19A in study 3 (Fig. 4). For the PCV antigens failing to meet noninferiority criteria, the percentages of subjects with antibodies ≥0.35 μg/mL were 88% and 96% (in the MenACWY + routine group and the routine vaccines only group, respectively) for serotype 6B in study 1, 86% and 90% for serotype 6B in study 2, 89% and 94% for serotype 23F in study 2 and 93% and 98% for serotype 19A in study 3. At 13 months of age, 1 month after completion of the full MenACWY-CRM vaccination series, immune responses against all 13 PCV serotypes met noninferiority criteria in each clinical study (Fig. 5). In study 5, immune responses to 7 PCV serotypes at 13 months of age were evaluated in subjects who received the fourth PCV dose at 12 months of age, along with the second of 2 MenACWY-CRM doses or a single dose of MenC vaccine. For all 7 PCV serotypes, GMCs were comparable between both vaccine groups (data not shown).

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

Back to Top | Article Outline

Infants: Concomitant Administration of MenACWY-CRM With MMR and Varicella Vaccines

Concomitant administration of MenACWY-CRM with MMR and varicella vaccines [given either as individual MMR plus varicella vaccines (MMR + V) or as a single combination MMRV vaccine (MMRV)] was assessed in study 4. Two doses of MenACWY-CRM were administered at 7–9 and 12 months of age, where the second dose was coadministered with MMR and varicella vaccines. One control group of subjects received 2 doses of MenACWY-CRM only, and a second control group received MMR and varicella vaccines only.

At age 13.5 months, the immune responses to MMR and varicella antigens, when MMR and varicella vaccines were coadministered with MenACWY-CRM, were noninferior to those observed when MMR and varicella vaccines were given alone, for all 4 antigens tested (Fig. 6). Seroprotective levels against each of the 4 antigens were achieved in 95%–99% of subjects in both study groups. Subgroup analyses, conducted for subjects who received individual MMR and varicella vaccines and subjects who received a single combination MMRV vaccine, also demonstrated noninferiority of immune response to all 4 vaccine antigens.

FIGURE 6

FIGURE 6

Immune responses to MenACWY-CRM when coadministered with MMR and varicella vaccines were noninferior to immune responses when MenACWY-CRM was given alone, as assessed by the percentage of subjects with hSBA ≥1:8 for serogroups A (88% in both groups) and C, W and Y (96%–100% in both groups) (Fig. 6).

Back to Top | Article Outline

Adolescents: Concomitant Administration of MenACWY-CRM With Tdap and HPV

Immune Responses to Routine Vaccines

In all 3 adolescent studies, immune response to diphtheria, measured as the percentage of subjects with antidiphtheria toxoid antibodies ≥1.0 IU/mL at 1 month after a booster dose of Tdap, was statistically higher when Tdap was coadministered with MenACWY-CRM compared with when Tdap was administered alone (94% and 85% of subjects in study 6 in the MenACWY + routine group and the routine vaccine group, respectively; 100% and 98% in study 7 and 95% and 82% in study 8, with the LL of the 95% CI for each between group differences being greater than 0).

Immune response to tetanus antigen, with 98%–100% of subjects with antitetanus toxoid antibodies ≥1.0 IU/mL in both groups, was noninferior among subjects who received a single dose of Tdap concomitantly with a single dose of MenACWY-CRM when compared with subjects who received Tdap alone, in all 3 studies (Fig. 7).

FIGURE 7

FIGURE 7

Noninferiority of immune responses to pertussis antigens was tested in study 6 in terms of percentages of subjects with at least a 4-fold increase in antibody concentration against PT, FHA and PRN and in studies 7 and 8, in terms of GMC ratios. In study 6, noninferiority was demonstrated for FHA but not for PT (for which 76% and 81% of subjects had a 4-fold increase in the MenACWY + Routine group and the routine vaccines only group, respectively) or PRN (84% and 91%, respectively) (Fig. 7). In study 7, noninferiority was demonstrated for PT but not for FHA or PRN; the LL of the 2-sided 95% CI for the vaccine group ratio of the GMCs for FHA and PRN were both 0.58, less than the prespecified noninferiority margin of 0.67 (Fig. 8). Finally, in study 8, noninferiority criteria were met for all 3 pertussis antigens, with the LL of the 2-sided 95% CI for the vaccine group ratios of the GMCs being 0.72–0.89, well above the prespecified margin of 0.5 (Fig. 8).

FIGURE 8

FIGURE 8

In study 7, immune responses to HPV antigens, when the first dose of HPV was given concomitantly with MenACWY-CRM and Tdap, were noninferior to those observed when HPV was given alone, for all 4 HPV types (Fig. 7), with 99%– 100% of subjects in both groups having HPV seroconversion. A similar analysis is planned for study 8, but results are not yet available.

Back to Top | Article Outline

Immune Responses to MenACWY-CRM

When MenACWY-CRM was administered concomitantly with Tdap and HPV, immune responses to all 4 MenACWY-CRM serogroups were noninferior to those observed when MenACWY-CRM was administered alone (study 7; Fig. 7), with 81%– 82% of subjects in both groups having hSBA ≥8 against serogroup A and 90%– 99% against serogroups C, W and Y. These findings are corroborated by descriptive analyses in study 6, in which immune responses against all 4 meningococcal serogroups were not influenced by concomitant administration with Tdap.

Back to Top | Article Outline

Adults: Concomitant Administration of MenACWY-CRM with Commonly Administered Traveler Vaccinations

Immune Responses to Routine Vaccines

Immune responses to yellow fever and typhoid fever vaccine, when these vaccines were coadministered with MenACWY-CRM, were noninferior to those observed when yellow fever and typhoid fever vaccines were given together without MenACWY-CRM (Fig. 9). Immune responses to rabies and JE virus vaccines when coadministered with MenACWY-CRM were similarly noninferior to those when given alone (Fig. 9).

FIGURE 9

FIGURE 9

Immune responses to 3 doses of HAV and HBV, where the first dose was coadministered with MenACWY-CRM, were noninferior to those observed when the hepatitis vaccines were given alone (Fig. 9).

Back to Top | Article Outline

Immune Responses to MenACWY-CRM

In study 9, no reductions in GMTs or percentages of subjects with seroresponse against meningococcal serogroups A, C, W and Y were observed when MenACWY-CRM was administered with TF, YF, JE or rabies vaccines, except for a higher GMT against serogroup A in the MenACWY group compared with the JE + Rab + MenACWY group. However, this difference could be because of the differing intervals between MenACWY-CRM vaccination and blood draw between the 2 groups (1 month for the MenACWY group vs. 2 months for the JE + Rab + MenACWY group). No differences between groups were observed in the percentage of subjects with hSBA titers ≥1:8 against meningococcal serogroups A, C, W and Y.

In study 10, immune responses to meningococcal serogroups A, C, W and Y were similar when MenACWY-CRM was administered alone or with HAV/HBV vaccines, as evidenced by vaccine group GMT ratios, and vaccine group differences in percentages of subjects with seroresponse or hSBA ≥1:8.

Back to Top | Article Outline

Safety

In all studies in which MenACWY-CRM was concomitantly administered with other vaccines, reactogenicity and safety of routine vaccines were not affected by MenACWY-CRM coadministration, as evidenced by similar frequencies of systemic reactions and rates of unsolicited AEs among subjects receiving MenACWY-CRM with routine vaccines and those receiving routine vaccines alone.

In the largest infant coadministration study (study 1), individual systemic reactions after each vaccination at 2, 4 and 6 months of age occurred with similar frequencies in study groups that received MenACWY-CRM with routine vaccines and those that received routine vaccines only. For example, in the US cohort 62% and 61% of infants in the 2 study groups, respectively, had irritability after the first set of vaccinations at 2 months of age, 55% and 50% had sleepiness, 37% and 35% had persistent crying and 26% in both groups had a change in eating habits. Likewise, the overall frequencies of any AEs were similar for the 2 groups, between 2 and 7 months of age (75% and 76% of US infants and 59% and 55% of Latin American infants, respectively) and between 7 and 12 months of age (32% and 35% of US infants and 20% and 23% of Latin American infants, respectively), with the most commonly reported unsolicited AEs throughout the study being upper respiratory tract infection, nasopharyngitis and otitis media. The most common AEs that were judged to be possibly (or probably) related to vaccination were irritability and malaise. Serious AEs were reported for 3% of US infants and 4% of Latin American infants, irrespective of MenACWY-CRM coadministration.

In infants receiving a 2-dose MenACWY-CRM series at 7–9 and 12 months of age (study 4), the frequencies of systemic reactions were generally highest among infants who received MMR and varicella vaccine alone at 12 months of age, followed by those who received MenACWY-CRM with MMR and varicella vaccines and those who received MenACWY-CRM alone.16 For example, 50%, 40% and 29% of subjects in the 3 groups, respectively, had irritability within 7 days after vaccination; 33%, 29% and 17% had sleepiness and 20%, 18% and 12% had persistent crying. The frequencies of fever ≥38°C (evaluated for 7 days starting from 5 days after the 12-month vaccinations) were 20%, 21% and 8%, for the 3 groups, respectively. The frequencies of AEs occurring within 1 month after the 12-month vaccinations were similar for infants who received MenACWY-CRM with MMR and varicella vaccines (47%) and for those who received MMR and varicella vaccines alone (45%) and were lower among infants who received MenACWY-CRM alone (37%). Serious AEs were reported throughout the study by 2% of subjects in the MMR and varicella group, compared with 4% in the other groups, a difference that likely reflects the shorter enrolment period for the MMR and varicella group (6 vs. 9–11 months for other groups).

Among adolescents, MenACWY-CRM was well tolerated when given alone or concomitantly with Tdap and HPV antigens (study 8),14 although the reported frequencies of any systemic solicited reactions were somewhat higher in the MenACWY-CRM + Tdap + HPV group than the Tdap + HPV group after the initial set of vaccinations (53% and 46%, respectively). The most commonly reported solicited systemic reaction within 7 days of the initial set of vaccinations was myalgia (30% and 26% in MenACWY-CRM + Tdap + HPV and Placebo + Tdap + HPV, respectively), followed by headache (29% and 25%), chills (15% and 13%) and malaise (15% and 11%), with no statistically significant differences between groups in the frequencies of any solicited systemic reaction. Unsolicited AEs were reported by similar percentages of subjects in the MenACWY-CRM + Tdap + HPV and Tdap + HPV groups (51% vs. 50%, respectively), as were serious AEs (1% in both groups).

Back to Top | Article Outline

DISCUSSION

The concomitant administration of multiple vaccines at a single clinic visit reduces the number of required visits to healthcare providers and can improve compliance with vaccine recommendations and coverage in at-risk groups. For travelers, concomitant administration of vaccines maximizes protection against multiple diseases within the often narrow timeframe available between vaccination and the start of travel. However, potential interactions between vaccines need to be assessed before concomitant administration.

In this report, we summarize the findings of 10 phase 3 and 4 clinical studies evaluating coadministration of the quadrivalent meningococcal conjugate vaccine MenACWY-CRM with a number of vaccines that are commonly given to infants, adolescents and adults. Immune responses to most of the vaccine antigens assessed in these studies, including diphtheria, tetanus, Hib, polio and HBV, were consistently found not to be impacted by MenACWY-CRM coadministration across multiple study settings and, for some vaccine antigens, in more than 1 age group. Robust data also support the absence of interference of MenACWY-CRM coadministration with immune responses to MMR, varicella, HPV, typhoid fever, yellow fever, JE, rabies and HAV.

For other vaccine antigens, namely, certain PCV and pertussis vaccine antigens, noninferiority was not uniformly demonstrated with coadministration with MenACWY-CRM. These exceptions are discussed further as follows.

In 3 study settings in which immune responses to PCV antigens were evaluated at 7 months of age, noninferiority criteria for individual serotypes were not met for serotype 6B in the US arm of study 1, serotypes 6B and 23F in study 2 and serotype 19A in study 3, although the percentages of subjects with seroprotective antibody levels ≥0.35 μg/mL were at least 86% for each of these serotypes in each group across studies. No serotype failed to meet noninferiority criteria consistently across studies, suggesting that these are chance findings that inevitably arise in the setting of multiple comparisons. In fact, in study 2, in which a strong study center effect was identified, all PCV7 serotypes, including serotypes 6B and 23F, met noninferiority criteria when the analyses were repeated with an adjustment for study center.

Failure to meet noninferiority criteria for certain PCV serotypes in some studies could also reflect limited sample sizes and insufficient power to demonstrate noninferiority of immune response with MenACWY-CRM coadministration. Study 3, for example, was recognized during planning stages to be underpowered for demonstration of noninferiority of immune response to PCV13. Furthermore, the retention rate of subjects during this study was lower than anticipated. When noninferiority analyses in study 3 were repeated with a larger study group (composed of infants who received a 4-dose MenACWY-CRM series as described earlier and infants who received a 3-dose MenACWY-CRM series at 2, 4 and 12 months of age), noninferiority criteria were met for all 13 serotypes at 7 months of age, suggesting that initial failure to meet criteria for serotype 19A could be attributable to low subject numbers, rather than being due to actual immune interference.

Evaluating noninferiority after the completion of the full MenACWY-CRM vaccination series is also of importance. At 13 months, 1 month after the vaccination series was completed, and all 13 PCV serotypes in the studies in infants met the noninferiority criteria.

Evaluation of the impact of MenACWY-CRM coadministration on immune responses to pertussis vaccine antigens in infants also yielded inconsistent results between study settings with respect to the pertussis antigens for which noninferiority criteria were not met.

At 7 months of age, the LL of 95% CIs for GMC ratios for pertussis antigens was >0.67 for all antigens in all 3 study cohorts (except PRN in Latin American subjects in study 1). Noninferiority criteria for the difference in percentage of subjects with a 4-fold increase in antibody concentration were met for all antigens except PRN in the US cohort in study 1 and PT and FIM in study 2. After adjustment for center differences in study 2, response to PT met noninferiority criteria. In these instances, the percentages of subjects with a 4-fold increase in antibodies differed between groups by 2%– 4%, with the majority of subjects in both studies having 4-fold increase. As such, the clinical relevance of failing to meet noninferiority criteria for certain pertussis antigens in certain studies is uncertain, particularly given the absence of an established serocorrelate of protection for pertussis disease.

Importantly, those noninferiority criteria were met for immune responses to all pertussis antigens at 13 months of age. In 3 adolescent studies evaluating MenACWY-CRM coadministration with Tdap, noninferiority criteria were missed for PT in study 6, FHA in study 7 and PRN in studies 6 and 7. Noninferiority criteria were met for all 3 pertussis antigens tested in study 8.

Although no single pertussis antigen failed to meet the noninferiority criteria for immune response across studies, 1 or more pertussis antigens failed to meet noninferiority criteria in each infant study and in 2 of 3 adolescent studies. Some degree of vaccine interaction cannot be excluded on the basis of available data and might be considered in certain epidemiological situations. However, in both age groups, the selected immunogenicity endpoint (GMC vs. proportion of subjects with 4-fold rise in antibody concentration), noninferiority margin (0.5 vs. 0.67 for GMC ratio) and timing of noninferiority testing (postinfant series vs. posttoddler dose) could all have significant impact on outcomes of statistical hypothesis testing for pertussis antigens. In a study by Storsaeter et al,32 it was demonstrated that clinical protection after household exposure to Bordetella pertussis was related to antibody levels, specifically anti-PRN and anti-FIM. This study demonstrated a tetanus, diphtheria, and acellular pertussis (TDaP) vaccine efficacy of 85% when both anti-PRN and anti-FIM antibody levels exceeded the authors’ analytical level of 5 U/mL.32 Furthermore, vaccine efficacy was still high (>70%) when antibody concentrations against only 1 of the 2 antigens exceeded >5 U/mL. Interestingly, in study 6, nearly all subjects given TDaP either with or without concomitant MenACWY-CRM had antibodies to all 3 pertussis antigens >5 EU/mL (Fig. 5),13 the level associated with high TDaP vaccine efficacy (~85%) in the study by Storsaeter et al.32 Similar antibody levels were also seen in the infant studies (studies 1 and 2) and the other adolescent studies (7 and 8) (data not shown). Although pertussis antibody results are known to differ between laboratories, these data, taken together, may suggest that concomitant administration of MenACWY-CRM with TDaP may not influence the effectiveness of the TDaP vaccine despite any putative vaccine interaction, and that failure to meet noninferiority criteria for 1 or more antigens across studies may not preclude a clinically meaningful level of protection against pertussis.32

Of interest, in all 3 adolescent studies evaluating impact of MenACWY-CRM on immune responses to Tdap, we found that antibody concentrations to the diphtheria toxoid 1 month after a booster vaccination were substantially higher when Tdap was coadministered with ACWY, compared with when Tdap was administered alone or with HPV. This increase in antidiphtheria responses in adolescents when MenACWY-CRM is coadministered with Tdap is likely attributable to the presence in MenACWY-CRM of CRM197, a nontoxic, natural mutant of the diphtheria toxoid. However, the clinical relevance of this augmented response is not known.

An important challenge associated with vaccine coadministration studies is the need to test multiple hypotheses associated with individual antigens (up to 25 for routine childhood vaccines during the first year of life) and assessment of multiple endpoints and time points for certain antigens (eg, percentage of subjects with antipneumococcal antibodies ≥0.35 μg/mL at 7 months of age and GMC at 13 months of age). Combinations of different sources of multiplicity may dramatically increase the complexity of coadministration studies. Several approaches have been proposed to control the potential type I error in coadministration studies,33 but a consensus regarding an optimal approach to address multiplicity has not been reached between researchers and health authorities.

One limitation of this report is that the clinical studies presented vary in terms of study populations, settings, key immunogenicity endpoints and prespecified success criteria for noninferiority testing. However, this limitation is outweighed by the benefit of being able to assess the consistency of results across multiple study settings and age groups and of being able to demonstrate robustness of results that are consistently found across studies in spite of recognized differences between studies. The fact that immune responses to most vaccine antigens were not impacted by MenACWY-CRM coadministration and that, for the few vaccine antigens that appeared to have been impacted in certain instances, immune interference was not consistently demonstrated across all studies suggests that MenACWY-CRM does not generally interfere with immune response to other vaccines.

A second limitation of this report is the lack of infant data demonstrating noninferiority of immune response to MenACWY-CRM when administered concomitantly with routine vaccines. These data are difficult to generate in infant studies because such studies would require that a group receives MenACWY-CRM only, without routine vaccines. However, vaccination with a 4-dose MenACWY-CRM series in infants and a 2-dose series in older infants, with coadministration of routine vaccines, generated protective antibody titers at clinically significant levels in almost all subjects, indicating the absence of any clinically relevant vaccine interactions. Furthermore, 5 studies (2 in adults, 2 in adolescents and 1 in older infants) collectively did not show a reduction in immune response to MenACWY-CRM when coadministered with MMR, varicella, Tdap or HPV vaccines, or with HAV, HBV or other traveler vaccines.

A third limitation is the lack of data on MenACWY-CRM coadministration with rotavirus and influenza vaccines. Coadministration with rotavirus vaccine was not studied because immunologic interactions between oral and injectable vaccines are thought to be highly unlikely. Furthermore, no indication of immunologic interference was found when a MenC conjugate vaccine (NeisVac and MenC-TT) was coadministered with Rotateq34 or when a quadrivalent meningococcal conjugate vaccine (MenACWY-TT) was coadministered with an inactivated influenza vaccine.35

In summary, results from 10 coadministration studies do not suggest any clinically relevant vaccine interactions between MenACWY-CRM and routine vaccines in any age group. Furthermore, coadministration of MenACWY-CRM with routine vaccines did not affect the reactogenicity or safety profile of any of the routine vaccines assessed. These findings support the concomitant administration of MenACWY-CRM with routine vaccines in all age groups, allowing MenACWY-CRM to be readily incorporated as recommended into existing infant and adolescent vaccination schedules and to be administered with other vaccines as needed in advance of international travel.

Back to Top | Article Outline

REFERENCES

1. Rosenstein NE, Perkins BA, Stephens DS, et al. Meningococcal disease. N Engl J Med. 2001;344:1378–1388
2. Goldschneider I, Gotschlich EC, Artenstein MS.. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med. 1969;129:1307–1326
3. Pollard AJ, Frasch C.. Development of natural immunity to Neisseria meningitidis. Vaccine. 2001;19:1327–1346
4. Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998-2007: implications for prevention of meningococcal disease. Clin Infect Dis. 2010;50:184–191
5. Cohn AC, MacNeil JR, Clark TA, et al.Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-2):1–28
6. Pace D, Pollard AJ.. Meningococcal disease: clinical presentation and sequelae. Vaccine. 2012;30(Suppl 2):B3–B9
7. ECDC. Surveillance of Invasive Bacterial Diseases in Europe 2008//2009. 2011 Available at: http://www.ecdc.europa.eu/en/publications/Publications/1107_SUR_IBD_2008-09.pdf. Accessed February 5, 2015
8. Ali A, Jafri RZ, Messonnier N, et al. Global practices of meningococcal vaccine use and impact on invasive disease. Pathog Glob Health. 2014;108:11–20
9. Alberer M, Burchard G, Jelinek T, et al. Co-administration of a meningococcal glycoconjugate ACWY vaccine with travel vaccines: a randomized, open-label, multi-center study. Travel Med Infect Dis. 2014;12:485–493
10. Alberer M, Burchard G, Jelinek T, et al. Immunogenicity and safety of concomitant administration of a combined hepatitis A/B vaccine and a quadrivalent meningococcal conjugate vaccine in healthy adults. J Travel Med. 2015;22:105–114
11. Alberer M, Burchard G, Jelinek T, et al. Safety and immunogenicity of typhoid fever and yellow fever vaccines when administered concomitantly with quadrivalent meningococcal ACWY glycoconjugate vaccine in healthy adults. J Travel Med. 2015;22:48–56
12. Arguedas A, Soley C, Loaiza C, et al. Safety and immunogenicity of one dose of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, when administered to adolescents concomitantly or sequentially with Tdap and HPV vaccines. Vaccine. 2010;28:3171–3179
13. Gasparini R, Conversano M, Bona G, et al. Randomized trial on the safety, tolerability, and immunogenicity of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis vaccine in adolescents and young adults. Clin Vaccine Immunol. 2010;17:537–544
14. Gasparini R, Johnston W, Conversano M, et al. Immunogenicity and safety of combined tetanus, reduced diphtheria, acellular pertussis vaccine when co-administered with quadrivalent meningococcal conjugate and human papillomavirus vaccines in healthy adolescents. J Vaccines Vaccin. 2014;5:231–240
15. Klein NP, Reisinger KS, Johnston W, et al. Safety and immunogenicity of a novel quadrivalent meningococcal CRM-conjugate vaccine given concomitantly with routine vaccinations in infants. Pediatr Infect Dis J. 2012;31:64–71
16. Klein NP, Shepard J, Bedell L, et al. Immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine administered concomitantly with measles, mumps, rubella, varicella vaccine in healthy toddlers. Vaccine. 2012;30:3929–3936
17. Nolan TM, Nissen MD, Naz A, et al. Immunogenicity and safety of a CRM-conjugated meningococcal ACWY vaccine administered concomitantly with routine vaccines starting at 2 months of age. Hum Vaccin Immunother. 2014;10:280–289
18. Tregnaghi M, Lopez P, Stamboulian D, et al. Immunogenicity and safety of a quadrivalent meningococcal polysaccharide CRM conjugate vaccine in infants and toddlers. Int J Infect Dis. 2014;26:22–30
19. Block SL, Shepard S, Garfield H, et al. Comparison of the safety and immunogenicity of 3- and 4-dose schedules of a meningococcal MenACWY conjugate vaccine in healthy infants. International Pathogenic Neisseria Conference. 2014 Asheville, NC October 12–17
20. Clinicaltrials.gov. NCT00667602 Study Results. Available at: https://clinicaltrials.gov/ct2/show/results/NCT00667602?term=NCT00667602.&rank=1. Accessed February 5, 2015
21. Broderick MP, Oberste MS, Moore D, et al. Effect of multiple, simultaneous vaccines on polio seroresponse and associated health outcomes. Vaccine. 2015;33:2842–2848
22. Cassidy WM, Jones G, Williams K, et al. Safety and immunogenicity of concomitant versus nonconcomitant administration of hepatitis B, tetanus-diphtheria, and measles-mumps-rubella vaccines in healthy eleven- to twelve-year-olds. J Adolesc Health. 2005;36:187–192
23. Dagan R, Poolman JT, Zepp F.. Combination vaccines containing DTPa-Hib: impact of IPV and coadministration of CRM197 conjugates. Expert Rev Vaccines. 2008;7:97–115
24. Saenger R, Maechler G, Potreck M, et al. Booster vaccination with hexavalent DTPa-HBV-IPV/Hib vaccine in the second year of life is as safe as concomitant DTPa-IPV/Hib + HBV administered separately. Vaccine. 2005;23:1135–1143
25. Shinefield HR.. Overview of the development and current use of CRM(197) conjugate vaccines for pediatric use. Vaccine. 2010;28:4335–4339
26. Pöllabauer EM, Petermann R, Ehrlich HJ.. The influence of carrier protein on the immunogenicity of simultaneously administered conjugate vaccines in infants. Vaccine. 2009;27:1674–1679
27. Bonhoeffer J, Bentsi-Enchill A, Chen RT, et al.Brighton Collaboration Methods Working Group. Guidelines for collection, analysis and presentation of vaccine safety data in pre- and post-licensure clinical studies. Vaccine. 2009;27:2282–2288
28. Plotkin SA.. Correlates of protection induced by vaccination. Clin Vaccine Immunol. 2010;17:1055–1065
29. Wang WW, Mehrotra DV, Chan IS, et al. Statistical considerations for noninferiority/equivalence trials in vaccine development. J Biopharm Stat. 2006;16:429–441
30. EMEA 2005. Committee for Medicinal Products for Human Use (CHMP). Guideline on the Choice of the Non-inferiority Margin. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003636.pdf. Accessed February 5, 2015
31. Vesikari T, Silfverdal SA, Boisnard F, et al. Randomized, controlled, multicenter study of the immunogenicity and safety of a fully liquid combination diphtheria-tetanus toxoid-five-component acellular pertussis (DTaP5), inactivated poliovirus (IPV), and haemophilus influenzae type b (Hib) vaccine compared with a DTaP3-IPV/Hib vaccine administered at 3, 5, and 12 months of age. Clin Vaccine Immunol. 2013;20:1647–1653
32. Storsaeter J, Hallander HO, Gustafsson L, et al. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine. 1998;16:1907–1916
33. Dmitrienko A, Tamhane A, Bretz F Multiple Testing Problems in Pharmaceutical Statistics. 2009 London Chapman & Hall/CRC
34. Vesikari T, Karvonen A, Borrow R, et al. Results from a randomized clinical trial of coadministration of RotaTeq, a pentavalent rotavirus vaccine, and NeisVac-C, a meningococcal serogroup C conjugate vaccine. Clin Vaccine Immunol. 2011;18:878–884
35. Aplasca-De Los Reyes MR, Dimaano E, Macalalad N, et al. The investigational meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine (ACWY-TT) and the seasonal influenza virus vaccine are immunogenic and well-tolerated when co-administered in adults. Hum Vaccin Immunother. 2012;8:881–887
    Keywords:

    Meningococcal; MenACWY-CRM; coadministration; immunogenicity; safety

    Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.