Vaccine Information: ProQuad (Page 4 of 6)
8.2 Lactation
Risk Summary
It is not known whether varicella, measles, or mumps vaccine virus is excreted in human milk. Studies have shown that lactating postpartum women vaccinated with live rubella vaccine may secrete the virus in breast milk and transmit it to breastfed infants [see Warnings and Precautions (5.6)] {16,17}.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ProQuad, and any potential adverse effects on the breastfed child from ProQuad or from the underlying maternal condition. For preventive vaccines, the underlying maternal condition is susceptibility to disease prevented by the vaccine.
8.4 Pediatric Use
Do not administer ProQuad to infants younger than 12 months of age or to children 13 years and older. Safety and effectiveness of ProQuad in infants younger than 12 months of age and in children 13 years and older have not been established [see Clinical Studies (14)].
8.5 Geriatric Use
ProQuad is not indicated for use in the geriatric population (≥age 65).
11 DESCRIPTION
ProQuad (Measles, Mumps, Rubella and Varicella Virus Vaccine Live) is a combined, attenuated, live virus vaccine containing measles, mumps, rubella, and varicella viruses. ProQuad is a sterile lyophilized preparation of (1) the components of M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live): Measles Virus Vaccine Live, a more attenuated line of measles virus, derived from Enders’ attenuated Edmonston strain and propagated in chick embryo cell culture; Mumps Virus Vaccine Live, the Jeryl Lynn™ (B level) strain of mumps virus propagated in chick embryo cell culture; Rubella Virus Vaccine Live, the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts; and (2) Varicella Virus Vaccine Live (Oka/Merck), the Oka/Merck strain of varicella-zoster virus propagated in MRC-5 cells. The cells, virus pools, bovine serum, and recombinant human albumin used in manufacturing are all tested to provide assurance that the final product is free of potential adventitious agents.
ProQuad, when reconstituted as directed, is a sterile suspension for intramuscular or subcutaneous administration. Each approximately 0.5 mL dose contains not less than 3.00 log10 TCID50 of measles virus; 4.30 log10 TCID50 of mumps virus; 3.00 log10 TCID50 of rubella virus; and not less than 3.99 log10 PFU of Oka/Merck varicella virus.
After reconstitution, each 0.5 mL dose of the vaccine also contains 21 mg of sucrose, 11 mg of hydrolyzed gelatin, 2.4 mg of sodium chloride, 1.8 mg of sorbitol, 0.40 mg of monosodium L-glutamate, 0.34 mg of sodium phosphate dibasic, 0.31 mg of recombinant human albumin, 0.17 mg of sodium bicarbonate, 72 mcg of potassium phosphate monobasic, 60 mcg of potassium chloride; 36 mcg of potassium phosphate dibasic; and residual components from the manufacturing process: MRC-5 cells including DNA and protein; <16 mcg of neomycin, ≤0.5 mcg of bovine calf serum, and other buffer and media ingredients. The product contains no preservative.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ProQuad has been shown to induce measles-, mumps-, rubella-, and varicella-specific immunity, which is thought to be the mechanism by which it protects against these four childhood diseases.
The efficacy of ProQuad was established through the use of immunological correlates for protection against measles, mumps, rubella, and varicella. Results from efficacy studies or field effectiveness studies that were previously conducted for the component vaccines were used to define levels of serum antibodies that correlated with protection against measles, mumps, and rubella. Also, in previous studies with varicella vaccine, antibody responses against varicella virus ≥5 gpELISA units/mL in a glycoprotein enzyme-linked immunosorbent assay (gpELISA) (not commercially available) similarly correlated with long-term protection. In these efficacy studies, the clinical endpoint for measles and mumps was a clinical diagnosis of either disease confirmed by a 4-fold or greater rise in serum antibody titers between either postvaccination or acute and convalescent titers; for rubella, a 4-fold or greater rise in antibody titers with or without clinical symptoms of rubella; and for varicella, varicella-like rash that occurred >42 days postvaccination and for which varicella was not excluded by either viral cultures of the lesion or serological tests. Specific laboratory evidence of varicella either by serology or culture was not required to confirm the diagnosis of varicella. Clinical studies with a single dose of ProQuad have shown that vaccination elicited rates of antibody responses against measles, mumps, and rubella that were similar to those observed after vaccination with a single dose of M-M-R II [see Clinical Studies (14)] and seroresponse rates for varicella virus were similar to those observed after vaccination with a single dose of VARIVAX [see Clinical Studies (14)]. The duration of protection from measles, mumps, rubella, and varicella infections after vaccination with ProQuad is unknown.
12.6 Persistence of Antibody Responses after Vaccination
The persistence of antibody at 1 year after vaccination was evaluated in a subset of 2107 children enrolled in the clinical trials. Antibody was detected in 98.9% (1722/1741) for measles, 96.7% (1676/1733) for mumps, 99.6% (1796/1804) for rubella, and 97.5% (1512/1550) for varicella (≥5 gpELISA units/mL) of vaccinees following a single dose of ProQuad.
Experience with M-M-R II demonstrates that neutralizing and ELISA antibodies to measles, mumps, and rubella viruses are still detectable in 95-100%, 74-91%, and 90-100% of individuals respectively, 11 to 13 years after primary vaccination series {18–24}. Varicella antibodies were present for up to ten years postvaccination in most of the individuals tested who received 1 dose of VARIVAX.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
ProQuad has not been evaluated for its carcinogenic, mutagenic, or teratogenic potential, or its potential to impair fertility.
14 CLINICAL STUDIES
Formal studies to evaluate the clinical efficacy of ProQuad have not been performed.
Efficacy of the measles, mumps, rubella, and varicella components of ProQuad was previously established in a series of clinical studies with the monovalent vaccines. A high degree of protection from infection was demonstrated in these studies {25–32}.
Immunogenicity in Children 12 Months to 6 Years of Age
Prior to licensure, immunogenicity was studied in 5845 healthy children 12 months to 6 years of age with a negative clinical history of measles, mumps, rubella, and varicella who participated in 5 randomized clinical trials. The immunogenicity of ProQuad administered subcutaneously was similar to that of its individual component vaccines (M-M-R II and VARIVAX), which are currently used in routine vaccination.
The presence of detectable antibody was assessed by an appropriately sensitive enzyme-linked immunosorbent assay (ELISA) for measles, mumps (wild-type and vaccine-type strains), and rubella, and by gpELISA for varicella. For evaluation of vaccine response rates, a positive result in the measles ELISA corresponded to measles antibody concentrations of ≥255 mIU/mL when compared to the WHO II (66/202) Reference Immunoglobulin for Measles.
Children were positive for mumps antibody if the antibody level was ≥10 ELISA units/mL. A positive result in the rubella ELISA corresponded to concentrations of ≥10 IU rubella antibody/mL when compared to the WHO International Reference Serum for Rubella; children with varicella antibody levels ≥5 gpELISA units/mL were considered to be seropositive since a response rate based on ≥5 gpELISA units/mL has been shown to be highly correlated with long-term protection.
Immunogenicity in Children 12 to 23 Months of Age After a Single Dose
In 4 randomized clinical trials, 5446 healthy children 12 to 23 months of age were administered ProQuad subcutaneously, and 2038 children were vaccinated with M-M-R II and VARIVAX given concomitantly at separate injection sites. Subjects enrolled in each of these trials had a negative clinical history, no known recent exposure, and no vaccination history for varicella, measles, mumps, and rubella. Children were excluded from study participation if they had an immune impairment or had a history of allergy to components of the vaccine(s). Except for in 1 trial [see ProQuad Administered with Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) and Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine below] , no concomitant vaccines were permitted during study participation. The race distribution of the study subjects across these studies following a first dose of ProQuad was as follows: 66.3% White; 12.7% African-American; 9.9% Hispanic; 6.7% Asian/Pacific; 4.2% other; and 0.2% American Indian. The gender distribution of the study subjects across these studies following a first dose of ProQuad was 52.6% male and 47.4% female. A summary of combined immunogenicity results 6 weeks following administration of a single dose of ProQuad or M-M-R II and VARIVAX is shown in Table 12. These results were similar to the immune response rates induced by concomitant administration of single doses of M-M-R II and VARIVAX at separate injection sites (lower bound of the 95% CI for the risk difference in measles, mumps, and rubella seroconversion rates were >-5.0 percentage points and the lower bound of the 95% CI for the risk difference in varicella seroprotection rates was either >-15 percentage points [one study] or >-10.0 percentage points [three studies]).
Group | Antigen | n | Observed Response Rate (95% CI) | Observed GMT(95% CI) |
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n = Number of per-protocol subjects with evaluable serology.CI = Confidence interval.GMT = Geometric mean titer.ELISA = Enzyme-linked immunosorbent assay.PFU = Plaque-forming units.OD = Optical density. | ||||
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ProQuad(N=5446*) | Varicella | 4381 | 91.2%(90.3%, 92.0%) | 15.5(15.0, 15.9) |
Measles | 4733 | 97.4%(96.9%, 97.9%) | 3124.9(3038.9, 3213.3) | |
Mumps(OD cutoff)† | 973 | 98.8%(97.9%, 99.4%) | 105.3(98.0, 113.1) | |
Mumps (wild-type ELISA)† | 3735 | 95.8%(95.1%, 96.4%) | 93.1(90.2, 96.0) | |
Rubella | 4773 | 98.5%(98.1%, 98.8%) | 91.8(89.6, 94.1) | |
M-M-R II + VARIVAX(N=2038*) | Varicella | 1417 | 94.1%(92.8%, 95.3%) | 16.6(15.9, 17.4) |
Measles | 1516 | 98.2%(97.4%, 98.8%) | 2239.6(2138.3, 2345.6) | |
Mumps(OD cutoff)† | 501 | 99.4%(98.3%, 99.9%) | 87.5(79.7, 96.0) | |
Mumps (wild-type ELISA)† | 1017 | 98.0%(97.0%, 98.8%) | 90.8(86.2, 95.7) | |
Rubella | 1528 | 98.5%(97.7%, 99.0%) | 102.2(97.8, 106.7) |
Immunogenicity in Children 15 to 31 Months of Age After a Second Dose of ProQuad
In 2 of the 4 randomized clinical trials described above, a subgroup (N=1035) of the 5446 children administered a single dose of ProQuad subcutaneously were administered a second dose of ProQuad subcutaneously, approximately 3 to 9 months after the first dose. Children were excluded from receiving a second dose of ProQuad if they were recently exposed to or developed varicella, measles, mumps, and/or rubella prior to receipt of the second dose. No concomitant vaccines were administered to these children. The race distribution across these studies following a second dose of ProQuad was as follows: 67.3% White; 14.3% African-American; 8.3% Hispanic; 5.4% Asian/Pacific; 4.4% other; 0.2% American Indian; and 0.10% mixed. The gender distribution of the study subjects across these studies following a second dose of ProQuad was 50.4% male and 49.6% female. A summary of immune responses following a second dose of ProQuad is presented in Table 13. Results from this study showed that 2 doses of ProQuad administered at least 3 months apart elicited a positive antibody response to all four antigens in greater than 98% of subjects. The geometric mean titers (GMTs) following the second dose of ProQuad increased approximately 2-fold each for measles, mumps, and rubella, and approximately 41-fold for varicella.
Dose 1N=1097 | Dose 2N=1097 | ||||||
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Serostatus Cutoff/ | Observed Response Rate | Observed GMT | Observed Response Rate | Observed GMT | |||
Antigen | Response Criteria | n | (95% CI) | (95% CI) | n | (95% CI) | (95% CI) |
ProQuad (Middle Dose) = ProQuad containing a varicella virus dose of 3.97 log10 PFU.ProQuad (High Dose) = ProQuad containing a varicella virus dose of 4.25 log10 PFU.ELISA = Enzyme-linked immunosorbent assay.gpELISA = Glycoprotein enzyme-linked immunosorbent assay.N = Number vaccinated at baseline.n = Number of subjects who were per-protocol Postdose 1 and Postdose 2 and satisfied the given prevaccination serostatus cutoff.CI = Confidence interval.GMT = Geometric mean titer.PFU = Plaque-forming units. | |||||||
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Measles | ≥120 mIU/mL † | 915 | 98.1% (97.0%, 98.9%) | 2956.8 (2786.3, 3137.7) | 915 | 99.5% (98.7%, 99.8%) | 5958.0 (5518.9, 6432.1) |
≥255 mIU/mL | 943 | 97.8% (96.6%, 98.6%) | 2966.0 (2793.4, 3149.2) | 943 | 99.4% (98.6%, 99.8%) | 5919.3 (5486.2, 6386.6) | |
Mumps | ≥OD Cutoff (ELISA antibody units) | 920 | 98.7% (97.7%, 99.3%) | 106.7 (99.1, 114.8) | 920 | 99.9% (99.4%, 100%) | 253.1 (237.9, 269.2) |
Rubella | ≥10 IU/mL | 937 | 97.7% (96.5%, 98.5%) | 91.1 (85.9, 96.6) | 937 | 98.3% (97.2%, 99.0%) | 158.8 (149.1, 169.2) |
Varicella | <1.25 to ≥5 gpELISA units | 864 | 86.6% (84.1%, 88.8%) | 11.6 (10.9, 12.3) | 864 | 99.4% (98.7%, 99.8%) | 477.5 (437.8, 520.7) |
≥OD Cutoff (gpELISA units) | 695 | 87.2% (84.5%, 89.6%) | 11.6 (10.9, 12.4) | 695 | 99.4% (98.5%, 99.8%) | 478.7 (434.8, 527.1) |
Immunogenicity in Children 4 to 6 Years of Age Who Received a First Dose of ProQuad After Primary Vaccination With M-M-R II and VARIVAX
In a clinical trial, 799 healthy 4- to 6-year-old children who had received M-M-R II and VARIVAX at least 1 month prior to study entry were randomized to receive ProQuad subcutaneously and placebo (N=399), M-M-R II and placebo concomitantly at separate injection sites (N=205), or M-M-R II and VARIVAX concomitantly at separate injection sites (N=195). Children were eligible if they were previously administered primary doses of M-M-R II and VARIVAX, either concomitantly or non-concomitantly, at 12 months of age or older. Children were excluded if they were recently exposed to measles, mumps, rubella, and/or varicella, had an immune impairment, or had a history of allergy to components of the vaccine(s). No concomitant vaccines were permitted during study participation [see Adverse Reactions (6.1) for ethnicity and gender information].
A summary of antibody responses to measles, mumps, rubella, and varicella at 6 weeks postvaccination in subjects who had previously received M-M-R II and VARIVAX is shown in Table 14. Results from this study showed that a first dose of ProQuad after primary vaccination with M-M-R II and VARIVAX elicited a positive antibody response to all four antigens in greater than 98% of subjects. Postvaccination GMTs for recipients of ProQuad were similar to those following a second dose of M-M-R II and VARIVAX administered concomitantly at separate injection sites (the lower bound of the 95% CI around the fold difference in measles, mumps, rubella, and varicella GMTs excluded 0.5). Additionally, GMTs for measles, mumps, and rubella were similar to those following a second dose of M-M-R II given concomitantly with placebo (the lower bound of the 95% CI around the fold difference for the comparison of measles, mumps, and rubella GMTs excluded 0.5).
Group Number | GMT(95% CI) | Seropositivity Rate(95% CI) | % ≥4-Fold Rise in Titer(95% CI) | Geometric Mean Fold Rise(95% CI) | |
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(Description) | n | Measles * | |||
gpELISA = Glycoprotein enzyme-linked immunosorbent assay; ELISA = Enzyme-linked immunosorbent assay; CI = Confidence interval; GMT = Geometric mean titer; N/A = Not applicable; N = Number of subjects vaccinated; n = number of subjects in the per-protocol analysis. | |||||
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Group 1 (N=399) | 367 | 1985.9 | 100% | 4.9% | 1.21 |
(ProQuad + placebo) | (1817.6, 2169.9) | (99.0%, 100%) | (2.9%, 7.6%) | (1.13, 1.30) | |
Group 2 (N=205) | 185 | 2046.9 | 100% | 4.3% | 1.28 |
(M-M-R II + placebo) | (1815.2, 2308.2) | (98.0%, 100%) | (1.9%, 8.3%) | (1.17, 1.40) | |
Group 3 (N=195) | 171 | 2084.3 | 99.4% | 4.7% | 1.31 |
(M-M-R II + VARIVAX) | (1852.3, 2345.5) | (96.8%, 100%) | (2.0%, 9.0%) | (1.17, 1.46) | |
Mumps † | |||||
Group 1 (N=399) | 367 | 206.0 | 99.5% | 27.2% | 2.43 |
(ProQuad + placebo) | (188.2, 225.4) | (98.0%, 99.9%) | (22.8%, 32.1%) | (2.19, 2.69) | |
Group 2 (N=205) | 185 | 308.5 | 100% | 41.1% | 3.69 |
(M-M-R II + placebo) | (269.6, 352.9) | (98.0%, 100%) | (33.9%, 48.5%) | (3.14, 4.32) | |
Group 3 (N=195) | 171 | 295.9 | 100% | 41.5% | 3.36 |
(M-M-R II + VARIVAX) | (262.5, 333.5) | (97.9%, 100%) | (34.0%, 49.3%) | (2.84, 3.97) | |
Rubella ‡ | |||||
Group 1 (N=399) | 367 | 217.3 | 100% | 32.7% | 3.00 |
(ProQuad + placebo) | (200.1, 236.0) | (99.0%, 100%) | (27.9%, 37.8%) | (2.72, 3.31) | |
Group 2 (N=205) | 185 | 174.0 | 100% | 31.9% | 2.81 |
(M-M-R II + placebo) | (157.3, 192.6) | (98.0%, 100%) | (25.2%, 39.1%) | (2.41, 3.27) | |
Group 3 (N=195) | 171 | 154.1 | 99.4% | 26.9% | 2.47 |
(M-M-R II + VARIVAX) | (138.9, 170.9) | (96.8%, 100%) | (20.4%, 34.2%) | (2.17, 2.81) | |
Varicella § | |||||
Group 1 (N=399) | 367 | 322.2 | 98.9% | 80.7% | 12.43 |
(ProQuad + placebo) | (278.9, 372.2) | (97.2%, 99.7%) | (76.2%, 84.6%) | (10.63, 14.53) | |
Group 2 (N=205)(M-M-R II + placebo) | 185 | N/A | N/A | N/A | N/A |
Group 3 (N=195) | 171 | 209.3 | 99.4% | 71.9% | 8.50 |
(M-M-R II + VARIVAX) | (171.2, 255.9) | (96.8%, 100%) | (64.6%, 78.5%) | (6.69, 10.81) |
Immunogenicity Following 2 Doses of ProQuad Administered Intramuscularly or Subcutaneously
In an open label clinical trial (NCT00402831) 405 children 12 through 18 months of age received two doses of ProQuad, administered 30 days apart (a non-US licensed interval), either intramuscularly (n=202) or subcutaneously (n=203). Antibody responses to measles, mumps, rubella and varicella viruses were measured by ELISAs using sera obtained 30 days post-dose 1, and 6-weeks post-dose 2. For anti-measles virus, anti-mumps virus, anti-rubella virus and anti-varicella virus, seroresponse rates were defined as the percentage of children seronegative at baseline who achieved antibody titers above the respective seroresponse threshold for each assay 30 days post-dose 1 and 6 weeks post-dose 2. Seroresponse thresholds were defined as 255 mIU/mL, 10 EU/mL, 10 IU/mL and 5 gpELISA units for anti-measles virus, anti-mumps virus, anti-rubella virus and anti-varicella virus antibodies, respectively after each dose. For each vaccine antigen at least 87% of enrolled children were seronegative at baseline.
The seroresponse rates to measles, mumps, and varicella viruses after dose 1 were noninferior in the intramuscular group compared to the subcutaneous group in a post hoc analysis (lower bound of the 95% confidence interval for the difference in seroresponse rates [intramuscular group minus subcutaneous group] ≥-5%). The seroresponse rate to rubella virus narrowly missed meeting the criterion for noninferiority (lower bounds of the 95% CI for the difference in seroresponse rate -5.5%). For measles, mumps, rubella, and varicella antigens, the lower bound of the 95% CI of the seroresponse rate was ˃90% after intramuscular administration. The proportions of children achieving antibody titers above the seroresponse thresholds for measles, mumps, rubella and varicella viruses after dose 1 were as follows: 100%, 97.4%, 98.4%, and 98.6%, respectively, in the intramuscular group and 97.3%, 91.3%, 100%, and 98.5%, respectively, in the subcutaneous group.
Immunogenicity Following Concomitant Use with Other Vaccines
ProQuad with Pneumococcal 7-valent Conjugate Vaccine and/or VAQTA
In a clinical trial, 1027 healthy children 12 to 15 months of age were randomized to receive ProQuad subcutaneously and pneumococcal 7-valent conjugate vaccine concomitantly (N=510) at separate injection sites or ProQuad administered subcutaneously and pneumococcal 7-valent conjugate vaccine non-concomitantly (N=517) at separate clinic visits [see Adverse Reactions (6.1) for ethnicity and gender information]. The statistical analysis of non-inferiority in antibody response rates to measles, mumps, rubella, and varicella at 6 weeks postvaccination for subjects are shown in Table 15. In the per-protocol population, seroconversion rates were not inferior in children given ProQuad and pneumococcal 7-valent conjugate vaccine concomitantly when compared to seroconversion rates seen in children given these vaccines non-concomitantly for measles, mumps, and rubella. In children with baseline varicella antibody titers <1.25 gpELISA units/mL, the varicella seroprotection rates were not inferior when rates after concomitant and non-concomitant vaccination were compared 6 weeks postvaccination. Statistical analysis of non-inferiority in GMTs to S. pneumoniae serotypes at 6 weeks postvaccination are shown in Table 16. Geometric mean antibody titers (GMTs) for S. pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F were not inferior when antibody titers in the concomitant and non-concomitant groups were compared 6 weeks postvaccination.
ProQuad + PCV7(N=510) | ProQuad followed by PCV7(N=259) | Difference | |||
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Assay Parameter | n | Estimated Response † | n | Estimated Response † | (percentage points)†, ‡ (95% CI) |
N = Number of subjects vaccinated in each treatment group.n = Number of subjects with measles antibody titer <255 mIU/mL, mumps antibody titer <10 ELISA Ab units/mL, rubella antibody titer <10 IU/mL, or varicella antibody titer <1.25 gpELISA units/mL at baseline and with postvaccination serology contributing to the per-protocol analysis.Ab = antibody; ELISA = Enzyme-linked immunosorbent assay; gpELISA = Glycoprotein enzyme-linked immunosorbent assay; CI = Confidence interval. | |||||
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Measles % ≥255 mIU/mL | 406 | 97.3% | 204 | 99.5% | -2.2 (-4.6, 0.2) |
Mumps % ≥10 Ab units/mL | 403 | 96.6% | 208 | 98.6% | -1.9 (-4.5, 1.0) |
Rubella % ≥10 IU/mL | 377 | 98.7% | 195 | 97.9% | 0.9 (-1.3, 4.1) |
Varicella % ≥5 gpELISA units/mL | 379 | 92.5% | 192 | 87.9% | 4.5 (-0.4, 10.4) |
Group 1ProQuad + PCV7 (N=510) | Group 2PCV7 followed by ProQuad (N=258) | |||||
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Serotype | Parameter | n | Estimated Response † | n | Estimated Response † | Fold-Difference *, ‡ (95% CI) |
N = Number of subjects vaccinated in each treatment group; n = Number of subjects contributing to the per-protocol analysis for the given serotype; GMT = geometric mean titer; CI = Confidence interval. | ||||||
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4 | GMT | 410 | 1.5 | 193 | 1.3 | 1.2 (1.0, 1.4) |
6B | GMT | 410 | 8.9 | 192 | 8.4 | 1.1 (0.9, 1.2) |
9V | GMT | 409 | 2.9 | 193 | 2.5 | 1.2 (1.0, 1.3) |
14 | GMT | 408 | 6.5 | 193 | 5.7 | 1.1 (1.0, 1.3) |
18C | GMT | 408 | 2.3 | 193 | 2.0 | 1.2 (1.0, 1.3) |
19F | GMT | 408 | 3.5 | 192 | 3.1 | 1.1 (1.0, 1.3) |
23F | GMT | 413 | 4.1 | 197 | 3.7 | 1.1 (1.0, 1.3) |
In a clinical trial, 653 healthy children 12 to 15 months of age were randomized to receive VAQTA, ProQuad subcutaneously, and pneumococcal 7-valent conjugate vaccine concomitantly (N=330) or ProQuad subcutaneously, and pneumococcal 7-valent conjugate vaccine concomitantly followed by VAQTA 6 weeks later (N=323) [see Adverse Reactions (6.1) for ethnicity and gender information]. Statistical analysis of non-inferiority of the response rate for varicella antibody at 6 weeks postvaccination among subjects who received VAQTA concomitantly or non-concomitantly with ProQuad and pneumococcal 7-valent conjugate vaccine is shown in Table 17. For the varicella component of ProQuad, in subjects with baseline antibody titers <1.25 gpELISA units/mL, the proportion with a titer ≥5 gpELISA units/mL 6 weeks after their first dose of ProQuad was non-inferior when ProQuad was administered with VAQTA and pneumococcal 7-valent conjugate vaccine as compared to the proportion with a titer ≥5 gpELISA units/mL when ProQuad was administered with pneumococcal 7-valent conjugate vaccine alone. Statistical analysis of non-inferiority of the seropositivity rate for hepatitis A antibody at 4 weeks postdose 2 of VAQTA among subjects who received VAQTA concomitantly or non-concomitantly with ProQuad and pneumococcal 7-valent conjugate vaccine is shown in Table 18. The seropositivity rate to hepatitis A 4 weeks after a second dose of VAQTA given concomitantly with ProQuad and pneumococcal 7-valent conjugate vaccine (defined as the percent of subjects with a titer ≥10 mIU/mL) was non-inferior to the seropositivity rate observed when VAQTA was administered separately from ProQuad and pneumococcal 7-valent conjugate vaccine. Statistical analysis of non-inferiority in GMT to S. pneumoniae serotypes at 6 weeks postvaccination among subjects who received VAQTA concomitantly or non-concomitantly with ProQuad and pneumococcal 7-valent conjugate vaccine is shown in Table 19. Additionally, the GMTs for S. pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F 6 weeks after vaccination with pneumococcal 7-valent conjugate vaccine administered concomitantly with ProQuad and VAQTA were non-inferior as compared to GMTs observed in the group given pneumococcal 7-valent conjugate vaccine with ProQuad alone. An earlier clinical study involving 617 healthy children provided data that indicated that the seroresponse rates 6 weeks post vaccination for measles, mumps, and rubella in those given M-M-R II and VAQTA concomitantly (N=309) were non-inferior as compared to historical controls.
Group 1: Concomitant VAQTA with ProQuad + PCV7 (N=330) | Group 2: Non-concomitant VAQTA separate from ProQuad + PCV7 (N=323) | Difference † (percentage points): Group 1 – Group 2 (95% CI) | |||
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Parameter | n | Estimated Response † | n | Estimated Response † | |
N = Number of subjects enrolled/randomized; n = Number of subjects contributing to the per-protocol analysis for varicella; CI = Confidence interval. | |||||
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% ≥5 gpELISA units/mL ‡ | 225§ | 93.2% | 232§ | 98.3% | -5.1 (-9.3, -1.4) |
Group 1: Concomitant VAQTA with ProQuad + PCV7(N=330) | Group 2: Non-concomitant VAQTA separate from ProQuad + PCV7 (N=323) | Difference † (percentage points): Group 1 — Group 2 (95% CI) | |||
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Parameter | n | Estimated Response † | n | Estimated Response † | |
CI = Confidence interval; N = Number of subjects enrolled/randomized; n = Number of subjects contributing to the per-protocol analysis for hepatitis A. | |||||
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% ≥10 mIU/mL ‡ | 182§ | 100.0% | 159§ | 99.3% | 0.7 (-1.4, 3.8) |
Group 1: Concomitant VAQTA with ProQuad + PCV7 (N=330) | Group 2: Non-concomitant VAQTA separate from ProQuad + PCV7 (N=323) | ||||
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Serotype | n | Estimated Response † | n | Estimated Response † | Fold-Difference †(95% CI) |
CI = Confidence interval; GMT = Geometric mean titer; N = Number of subjects enrolled/randomized; n = Number of subjects contributing to the per-protocol analysis for S. pneumoniae serotypes. | |||||
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4 | 246 | 1.9 | 247 | 1.7 | 1.1 (0.9, 1.3) |
6B | 246 | 9.9 | 246 | 9.9 | 1.0 (0.8, 1.2) |
9V | 247 | 3.7 | 247 | 4.2 | 0.9 (0.8, 1.0) |
14 | 248 | 7.8 | 247 | 7.6 | 1.0 (0.9, 1.2) |
18C | 247 | 2.9 | 247 | 2.7 | 1.1 (0.9, 1.3) |
19F | 248 | 4.0 | 248 | 3.8 | 1.1 (0.9, 1.2) |
23F | 247 | 5.1 | 247 | 4.4 | 1.1 (1.0, 1.3) |
ProQuad Administered with Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) and Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine
In a clinical trial, 1913 healthy children 12 to 15 months of age were randomized to receive ProQuad subcutaneously plus diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP) and Haemophilus influenzae type b conjugate (meningococcal protein conjugate) and hepatitis B (recombinant) vaccine concomitantly at separate injection sites (N=949), ProQuad at the initial visit followed by DTaP and Haemophilus b conjugate and hepatitis B (recombinant) vaccine given concomitantly 6 weeks later (N=485), or M-M-R II and VARIVAX given concomitantly at separate injection sites (N=479) at the first visit [see Adverse Reactions (6.1) for ethnicity and gender information]. Seroconversion rates and antibody titers for measles, mumps, rubella, varicella, anti-PRP, and hepatitis B were comparable between the 2 groups given ProQuad at approximately 6 weeks postvaccination indicating that ProQuad and Haemophilus b conjugate (meningococcal protein conjugate) and hepatitis B (recombinant) vaccine may be administered concomitantly at separate injection sites (see Table 20 below). Response rates for measles, mumps, rubella, varicella, Haemophilus influenzae type b, and hepatitis B were not inferior in children given ProQuad plus Haemophilus influenzae type b conjugate (meningococcal protein conjugate) and hepatitis B (recombinant) vaccines concomitantly when compared to ProQuad at the initial visit and Haemophilus influenzae type b conjugate (meningococcal protein conjugate) and hepatitis B (recombinant) vaccines given concomitantly 6 weeks later. There are insufficient data to support concomitant vaccination with diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (data not shown).
Concomitant Group | Non-Concomitant Group | ||||
---|---|---|---|---|---|
N=949 | N=485 | ||||
Vaccine Antigen | Parameter | Response | Response | Risk Difference(95% CI) | Criterion for Non-inferiority |
HiB-PRP = Haemophilus influenzae type b, polyribosyl phosphate; HepB = hepatitis B; LB = lower bound, limit for non-inferiority comparison. | |||||
Measles | % ≥120 mIU/mL | 97.8% | 98.7% | -0.9(-2.3, 0.6) | LB >-5.0 |
Mumps | % ≥10 ELISA Ab units/mL | 95.4% | 95.1% | 0.3(-1.7, 2.6) | LB >-5.0 |
Rubella | % ≥10 IU/mL | 98.6% | 99.3% | -0.7(-1.8, 0.5) | LB >-5.0 |
Varicella | % ≥5 gpELISA units/mL | 89.6% | 90.8% | -1.2(-4.1, 2.0) | LB >-10.0 |
HiB-PRP | % ≥1.0 mcg/mL | 94.6% | 96.5% | -1.9(-4.1, 0.8) | LB >-10.0 |
HepB | % ≥10 mIU/mL | 95.9% | 98.8% | -2.8(-4.8, -0.8) | LB >10.0 |
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