Vaccine Information: ProQuad (Page 3 of 4)

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 subcutaneous administration. Each 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 a minimum of 3.99 log10 PFU of Oka/Merck varicella virus.

After reconstitution, each 0.5-mL dose of the vaccine contains no more than 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; residual components of MRC-5 cells including DNA and protein; <16 mcg of neomycin, bovine calf serum (0.5 mcg), 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 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, 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 10. 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]).

Table 10: Summary of Combined Immunogenicity Results 6 Weeks Following the Administration of a Single Dose of ProQuad (Varicella Virus Potency ≥3.97 log10 PFU) or M-M-R II and VARIVAX (Per-Protocol Population)
Group Antigen n Observed Response Rate (95% CI) Observed GMT(95% CI)
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.
*
Includes ProQuad + Placebo followed by ProQuad (Visit 1) (Protocol 009), ProQuad Middle and High Doses (Visit 1) (Protocol 011), ProQuad (Lot 1, Lot 2, Lot 3) (Protocol 012), both the Concomitant and Non-concomitant groups (Protocol 013).
The mumps antibody response was assessed by a vaccine-strain ELISA in Protocols 009 and 011 and by a wild-type ELISA in Protocols 012 and 013. In the former assay, the serostatus was based on the OD cutoff of the assay. In the latter assay, 10 mumps ELISA units was used as the serostatus cutoff.
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 were administered a second dose of ProQuad 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 11. 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.

Table 11: Summary of Immune Response to a First and Second Dose of ProQuad in Subjects <3 Years of Age Who Received ProQuad with a Varicella Virus Dose ≥3.97 Log10 PFU *
Dose 1N=1097 Dose 2N=1097
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.
*
Includes the following treatment groups: ProQuad + Placebo followed by ProQuad (Visit 1) (Protocol 009) and ProQuad (Middle and High Dose) (Protocol 011).
Samples from Protocols 009 and 011 were assayed in the legacy format Measles ELISA, which reported antibody titers in Measles ELISA units. To convert titers from ELISA units to mIU/mL, titers for these 2 protocols were divided by 0.1025. The lowest measurable titer postvaccination is 207.5 mIU/mL. The response rate for measles in the legacy format is the percent of subjects with a negative baseline measles antibody titer, as defined by the optical density (OD) cutoff, with a postvaccination measles antibody titer ≥207.5 mIU/mL.Samples from Protocols 009 and 011 were assayed in the legacy format Rubella ELISA, which reported antibody titers in Rubella ELISA units. To convert titers from ELISA units to IU/mL, titers for these 2 protocols were divided by 1.28.
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 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 12. 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).

Table 12: Summary of Antibody Responses to Measles, Mumps, Rubella, and Varicella at 6 Weeks Postvaccination in Subjects 4 to 6 Years of Age Who Had Previously Received M-M-R II and VARIVAX (Per-Protocol Population)
Group Number GMT(95% CI) Seropositivity Rate(95% CI) % ≥4-Fold Rise in Titer(95% CI) Geometric Mean Fold Rise(95% CI)
(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.
*
Measles GMTs are reported in mIU/mL; seropositivity corresponds to ≥120 mIU/mL.
Mumps GMTs are reported in mumps Ab units/mL; seropositivity corresponds to ≥10 Ab units/mL.
Rubella titers obtained by the legacy format were converted to their corresponding titers in the modified format. Rubella serostatus was determined after the conversion to IU/mL: seropositivity corresponds to ≥10 IU/mL.
§
Varicella GMTs are reported in gpELISA units/mL; seropositivity rate is reported by % of subjects with postvaccination antibody titers ≥5 gpELISA units/mL. Percentages are calculated as the number of subjects who met the criterion divided by the number of subjects contributing to the per-protocol analysis.
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 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 and pneumococcal 7-valent conjugate vaccine concomitantly (N=510) at separate injection sites or ProQuad 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 13. 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 14. 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.

Table 13: Statistical Analysis of Non-Inferiority in Antibody Response Rates to Measles, Mumps, Rubella, and Varicella at 6 Weeks Postvaccination for Subjects Initially Seronegative to Measles, Mumps, or Rubella, or With Varicella Antibody Titer <1.25 gpELISA units at Baseline in the ProQuad + PCV7* Treatment Group and the ProQuad Followed by PCV7 Control Group (Per-Protocol Analysis)
ProQuad + PCV7(N=510) ProQuad followed by PCV7(N=259) Difference
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.
*
PCV7 = Pneumococcal 7-valent conjugate vaccine.Seronegative defined as baseline measles antibody titer <255 mIU/mL for measles, baseline mumps antibody titer <10 ELISA Ab units/mL for mumps, and baseline rubella antibody titer <10 IU/mL for rubella.
Estimated responses and their differences were based on statistical analysis models adjusting for study center.
ProQuad + PCV7 — ProQuad followed by PCV7.The conclusion of non-inferiority is based on the lower bound of the 2-sided 95% CI on the risk difference being greater than -10 percentage points (i.e. , excluding a decrease equal to or more than the prespecified criterion of 10.0 percentage points). This indicates that the difference is statistically significantly less than the prespecified clinically relevant decrease of 10.0 percentage points at the 1-sided alpha = 0.025 level.
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)
Table 14: Statistical Analysis of Non-Inferiority in GMTs to S. pneumoniae Serotypes at 6 Weeks Postvaccination in the ProQuad + PCV7* Treatment Group and the PCV7 Followed by ProQuad Control Group (Per-Protocol Analysis)
Group 1ProQuad + PCV7 (N=510) Group 2PCV7 followed by ProQuad (N=258)
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.
*
PCV7 = Pneumococcal 7-valent conjugate vaccine.
Estimated responses and their fold-difference were based on statistical analysis models adjusting for study center and prevaccination titer.
ProQuad + PCV7 / PCV7 followed by ProQuad.The conclusion of non-inferiority is based on the lower bound of the 2-sided 95% CI on the fold-difference being greater than 0.5, (i.e. , excluding a decrease of 2-fold or more). This indicates that the fold-difference is statistically significantly less than the pre-specified clinically relevant 2-fold difference at the 1-sided alpha = 0.025 level.
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, and pneumococcal 7-valent conjugate vaccine concomitantly (N=330) or ProQuad 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 15. 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 16. 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 17. 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.

Table 15: 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 PCV7* (Per-Protocol Analysis Set)
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)
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.
*
PCV7 = Pneumococcal 7-valent conjugate vaccine.
Estimated responses and their differences were based on a statistical analysis model adjusting for combined study center.
6 weeks following Dose 1.
§
Initial Serostatus <1.25 gpELISA units/ mL.The conclusion of similarity (non-inferiority) was based on the lower bound of the 2-sided 95% CI on the risk difference excluding a decrease of 10 percentage points or more (lower bound >-10.0). This indicated that the risk difference was statistically significantly greater than the pre-specified clinically relevant difference of -10 percentage points at the 1-sided alpha = 0.025 level.
% ≥5 gpELISA units/mL 225§ 93.2% 232§ 98.3% -5.1 (-9.3, -1.4)
Table 16: Statistical Analysis of Non-Inferiority of the Seropositivity Rate (SPR) for Hepatitis A Antibody at 4 Weeks Postdose 2 of VAQTA Among Subjects Who Received VAQTA Concomitantly or Non-Concomitantly With ProQuad and PCV7* (Per-Protocol Analysis Set)
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)
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.
*
PCV7 = Pneumococcal 7-valent conjugate vaccine.
Estimated responses and their differences were based on a statistical analysis model adjusting for combined study center.
4 weeks following receipt of 2 doses of VAQTA.
§
Regardless of initial serostatus.The conclusion of non-inferiority was based on the lower bound of the 2-sided 95% CI on the risk difference being greater than -10 percentage points (i.e. , excluding a decrease of 10 percentage points or more) (lower bound >-10.0). This indicated that the risk difference was statistically significantly greater than the pre-specified clinically relevant difference of -10 percentage points at the 1-sided alpha = 0.025 level.
% ≥10 mIU/mL 182§ 100.0% 159§ 99.3% 0.7 (-1.4, 3.8)
Table 17: Statistical Analysis of Non-Inferiority in Geometric Mean Titers (GMT) to S. pneumoniae Serotypes at 6 Weeks Postvaccination Among Subjects Who Received VAQTA Concomitantly or Non-Concomitantly With ProQuad and PCV7* (Per-Protocol Analysis Set)
Group 1: Concomitant VAQTA with ProQuad + PCV7 (N=330) Group 2: Non-concomitant VAQTA separate from ProQuad + PCV7 (N=323)
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.
*
PCV7 = Pneumococcal 7-valent conjugate vaccine.
Estimated responses and their fold-difference were based on statistical analysis models adjusting for combined study center and prevaccination titer.The conclusion of non-inferiority was based on the lower bound of the 2-sided 95% CI on the fold-difference being greater than 0.5 (i.e. , excluding a decrease of 2-fold or more). This indicates that the fold-difference was statistically significantly less than the prespecified clinically relevant 2-fold difference at the 1-sided alpha = 0.025 level.
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 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 18 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).

Table 18: Summary of the Comparison of the Immunogenicity Endpoints for Measles, Mumps, Rubella, Varicella, Haemophilus influenzae type b, and Hepatitis B Responses Following Vaccination with ProQuad, Haemophilus influenzae type b Conjugate (Meningococcal Protein Conjugate), and Hepatitis B (Recombinant) Vaccine and DTaP Administered Concomitantly Versus Non-Concomitant Vaccination with ProQuad Followed by These Vaccines
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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