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

Disclosures

Pediatr Infect Dis J. 2016;35(1):81-93. 

In This Article

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.

Intergroup differences (95% CI) in percentages of subjects with antibody titers to diphtheria, tetanus, HBV, Hib and poliovirus types 1, 2 and 3 antigens greater than or equal to a prespecified threshold (Table 2) at 7 months of age between subjects who received a 3-dose series of routine infant vaccines with MenACWY-CRM versus those who received routine vaccines alone—studies 1 and 2. Noninferiority margins (–10% for diphtheria, tetanus, HBV and Hib; –5% for poliovirus) are represented by dotted lines. Vertical lines represent 95% CI limits. Three-dose vaccine series were given at 2, 4 and 6 months of age.

Figure 2.

Intergroup ratios (95% CI) of GMCs of antipertussis antibodies at 7 months of age, for subjects who received a 3-dose series of routine infant vaccines with MenACWY-CRM versus those who received routine vaccines alone—studies 1 and 2. The noninferiority margin (0.67) is represented by a dotted line. Vertical lines represent 95% CI limits. Three-dose vaccine series were given at 2, 4 and 6 months of age.

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.

Intergroup ratios (95% CI) of GMCs of antibodies against diphtheria, tetanus, Hib and pertussis antigens at 13 months of age, after administration of routine vaccinations at 12 months of age with or without MenACWY-CRM—study 1. Noninferiority margins (0.5 for diphtheria, tetanus and Hib; 0.67 for pertussis antigens) are represented by dotted lines. Vertical lines represent 95% CI limits. Vaccinations were given at 2, 4, 6 and 12 months of age.

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.

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.

Intergroup differences (95% CI) in percentages of subjects with antipneumococcal IgG concentrations ≥0.35 μg/mL against PCV vaccine antigens at 7 months of age between subjects who received 3 doses of routine infant vaccines with MenACWY-CRM versus those who received routine vaccines alone—studies 1, 2 and 3. The noninferiority margin (–10%) is represented by a dotted line. Vertical lines represent 95% CI limits. PCV7 was used in studies 1 and 2; PCV13 was used in study 3. Three doses were given at 2, 4 and 6 months of age.

Figure 5.

Intergroup ratios (95% CI) of GMCs of antipneumococcal IgG antibodies against PCV vaccine antigens at 13 months of age, for subjects who received a 4-dose series of routine infant vaccines with MenACWY-CRM versus those who received a 4-dose series of routine vaccines alone—studies 1, 2 and 3. The noninferiority margin (0.5) is represented by a dotted line. Vertical lines represent 95% CI limits.

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.

Intergroup differences (95% CI) in percentages of subjects with antibodies greater than or equal to a prespecified threshold (prespecified thresholds given in Table 1) against measles, mumps, rubella and varicella antigens (between infants who received MMR and varicella vaccines with MenACWY-CRM at 12 months of age and those who received MMR and varicella vaccines alone) and meningococcal serogroups A, C, W and Y (in infants given MMRV and MenACWY-CRM (second dose) either concomitantly or individually at 12 months of age)—study 4. Noninferiority margins (–5% for measles, mumps and rubella; –10% for varicella and meningococcal serogroups A, C, W and Y) are represented by dotted lines. Vertical lines represent 95% CI limits.

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).

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.

Intergroup differences (95% CI) in percentages of subjects with antibodies greater than or equal to a prespecified threshold (prespecified thresholds given in Table 1) against diphtheria, tetanus, pertussis and HPV vaccine antigens [between adolescents who received Tdap (or Tdap with HPV) with MenACWY-CRM and those who received Tdap (or Tdap with HPV) alone] and meninogococcal serogroups A, C, W and Y in adolescents [who received MenACWY-CRM with Tdap (or Tdap and HPV) versus those who received MenACWY-CRM alone]—studies 6, 7 and 8. Noninferiority margins (–10% for diphtheria, tetanus, pertussis and meningococcal serogroups A, C, W and Y; –5% for HPV antigens) are represented by dotted lines. Vertical lines represent 95% CI limits.

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.

Intergroup ratios (95% CI) of GMCs of antipertussis antibodies at 1 month after a booster dose of Tdap in adolescents and young adults who received Tdap (or Tdap with HPV) with MenACWY-CRM versus those who received Tdap (or Tdap with HPV) alone—studies 6, 7 and 8. Noninferiority margins of 0.67 (study 7) and 0.5 (study 8) were used. Vertical lines represent 95% CI limits. No margin was prespecified in study 6.

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.

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.

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.

Intergroup ratios (95% CI) of GMCs of antibodies against typhoid fever, yellow fever, JE, rabies, HAV and HBV vaccine antigens for adults who received commonly used traveler vaccines with MenACWY-CRM versus those who received traveler vaccines alone—studies 9 and 10. The noninferiority margin of 0.5 is represented by a dotted line. Vertical lines represent 95% CI limits.

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).

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.

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).

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