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Pharmacotherapeutic group: Viral Vaccine. ATC code: J07BD54.
Pharmacology: Measles, mumps, rubella, and varicella are 4 common childhood diseases caused by measles virus, mumps virus, rubella virus, and varicella virus, respectively. These diseases may be associated with serious complications and/or death. For example, measles can be associated with pneumonia and encephalitis; mumps can be associated with aseptic meningitis, deafness, and orchitis; rubella occurring during pregnancy can cause congenital rubella syndrome in the infants of infected mothers; and wild-type varicella can be associated with bacterial superinfection, pneumonia, encephalitis, and Reye syndrome.
Efficacy: Formal studies to evaluate the efficacy of ProQuad have not been performed. However, the efficacy of M-M-R II and VARIVAX has been demonstrated in numerous studies.
Efficacy of the measles, mumps, and rubella components of ProQuad was previously established in a series of double-blind controlled field trials with the monovalent vaccines produced by Merck, which demonstrated a high degree of protective efficacy. In these studies seroconversion in response to vaccination against measles, mumps, and rubella paralleled protection from these diseases. ProQuad elicits rates of antibody responses against measles, mumps, and rubella similar to those observed after vaccination with M-M-R II.
More than 518 million doses of M-M-R II have been distributed worldwide (1978 to 2007). Widespread use of a 2-dose vaccination schedule in the United States and countries such as Finland and Sweden has led to a >99% reduction in the incidence of each of the 3 targeted diseases. Vaccination against measles, mumps, and rubella has led to a significant reduction in the incidence of these diseases.
In combined clinical trials of VARIVAX, the protective efficacy of the vaccine against all forms of varicella ranged from 81 to 100%. In a large case-control study, the vaccine was estimated to be 85% effective against all forms of varicella and 97% effective against moderately severe and severe disease. Long-term estimated efficacy for the vaccine against all forms of varicella over 10 years was 94%. Antibody responses against varicella virus ≥ 5 units/mL in the glycoprotein enzyme-linked immunosorbent assay (gpELISA, a highly sensitive assay which is not commercially available) have been shown to be highly correlated with long-term protection. Clinical studies have shown that vaccination with ProQuad elicits rates of antibody responses against varicella virus ≥ 5 units/mL in the gpELISA similar to those observed after vaccination with VARIVAX.
Immunogenicity: Immunogenicity was studied in children 12 through 23 months of age with a negative clinical history of measles, mumps, rubella, and varicella who participated in 5 randomized clinical trials. The immunogenicity of the current refrigerator-stable formulation was shown to be similar to the immunogenicity of the earlier formulation of ProQuad. Clinical trials also established that the earlier formulation of ProQuad is similar to the individual component vaccines (M-M-R II and VARIVAX), which are currently used in routine vaccination in some countries.
Clinical trials involving 6987 subjects who received ProQuad demonstrated detectable immune responses to measles, mumps, rubella, and varicella in a high proportion of individuals. 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. Following a single dose of ProQuad, the vaccine response rates were 97.7% for measles, 96.3 to 98.8% for mumps, and 98.8% for rubella. The vaccine response rate was 90.9% for varicella based on an antibody response rate ≥ 5 gpELISA units/mL (a response rate that has been shown to be highly correlated with long-term protection). These results were similar to the immune response rates induced by concomitant administration of M-M-R II and VARIVAX at separate injection sites.
Children who received ProQuad at 4 through 6 years of age after primary vaccination with M-M-R II and VARIVAX: The immunogenicity and safety of ProQuad were evaluated in a clinical trial involving 799 subjects 4 through 6 years of age who had received M-M-R II and VARIVAX at least 1 month prior to study entry. Following the dose of ProQuad, GMTs for measles, mumps, rubella, and varicella were similar to those following a second dose of M-M-R II and VARIVAX administered concomitantly at separate injection sites. Additionally, GMTs for measles, mumps, and rubella were similar to those following a second dose of M-M-R II given concomitantly with placebo. In this trial, the rates and types of adverse experiences seen in the group that received ProQuad were generally similar to those seen in the control groups.
Persistence of Immune Response: The persistence of antibody at 1 year after vaccination was evaluated in a subset of 2108 subjects who were involved in 1 clinical trial. The antibody persistence rates 1 year postvaccination in recipients of a single dose of ProQuad were 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).
Experience with M-M-R II demonstrates that antibodies to measles, mumps, and rubella viruses are still detectable in most individuals 11 to 13 years after primary vaccination. In clinical studies involving healthy subjects who received 1 dose of VARIVAX, detectable varicella antibodies were present in most individuals tested for up to 10 years postvaccination.
Herpes Zoster: In a clinical trial, 2 cases of herpes zoster were reported in 2108 healthy subjects 12 through 23 months of age who were vaccinated with ProQuad and followed for 1 year. Both cases were unremarkable and no sequelae were reported.
The reported rate of zoster in recipients of VARIVAX appears not to exceed that previously determined in a population-based study of healthy children who had experienced wild-type varicella. In clinical trials, 12 cases of herpes zoster were reported in 9543 vaccinated individuals 12 months through 12 years of age during 84,414 person-years of follow-up. This resulted in a calculated incidence of at least 0.14 cases per 1,000 person-years. The incidence of herpes zoster following naturally acquired infection in subjects >5 years of age and persons 5 to 9 years of age has been reported to be 1.1 and 0.51 per 1,000 person-years, respectively. All 12 cases reported after VARIVAX were mild and no sequelae were reported. The long-term effect of VARIVAX on the incidence of herpes zoster is unknown at present.
Post-Exposure Prophylaxis: The safety and efficacy of ProQuad for use after exposure to measles, mumps, rubella, or varicella have not been established. No clinical data are available for ProQuad administered after exposure to measles, mumps, rubella, or varicella.
Reye Syndrome: Reye syndrome following wild-type varicella infection has occurred in children and adolescents, the majority of whom had received salicylates. In clinical studies of ProQuad and in the clinical studies of VARIVAX, physicians advised subjects not to use salicylates for 6 weeks after vaccination. There were no reports of Reye syndrome in recipients of ProQuad or VARIVAX during these studies.
Studies with Other Vaccines: In a clinical trial involving 1913 healthy subjects 12 through 15 months of age, 949 received ProQuad, Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) and Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine concomitantly at separate injection sites. Another 485 healthy subjects received ProQuad at the initial visit followed by DTaP and Haemophilus b Conjugate and Hepatitis B (Recombinant) Vaccine given concomitantly 6 weeks later. In subjects 13.5 months of age or older, seroconversion rates and antibody titers were comparable between the 2 groups at approximately 6 weeks postvaccination. However, in subjects less than 13.5 months of age, seroconversion rates and antibody titers were comparable between the 2 groups for each of the vaccine components except pertussis FHA (see INTERACTIONS). No clinically significant differences in adverse experiences were reported between the 2 treatment groups.
In a clinical trial involving 1027 healthy children 12 to 15 months of age, 510 were randomized to receive ProQuad and Prevnar concomitantly at separate injection sites, and 517 were randomized to receive ProQuad and Prevnar non-concomitantly. Seroconversion rates and antibody titers for measles, mumps, rubella, varicella, and S. pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F were comparable in the concomitant and non-concomitant groups at 6 weeks post-vaccination indicating that ProQuad and Prevnar can be administered concomitantly at separate injection sites. No clinically significant differences in adverse events were reported between treatment groups.
In a clinical trial involving 1800 healthy children 12 to 23 months of age, 1453 were randomized to receive 2 doses of VAQTA, and 347 were randomized to receive 2 doses of VAQTA concomitantly with 2 doses ProQuad at least 6 months apart. Rates of adverse experiences were lower following a second dose than following the first dose of both vaccines given concomitantly.
In a clinical trial involving 653 healthy children 12 to 15 months of age, 330 were randomized to receive VAQTA, ProQuad, and Prevnar concomitantly, and 323 were randomized to receive ProQuad and Prevnar concomitantly followed by VAQTA 6 weeks later. Seroconversion rates and antibody titers for measles, mumps, rubella, varicella, and S. pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F were comparable between the 3 groups at 6 weeks post-vaccination indicating that ProQuad, VAQTA, and Prevnar can be administered concomitantly at separate injection sites. No clinically significant differences in adverse events were reported among treatment groups.
In the above 3 post-licensure clinical trials evaluating the concomitant use of ProQuad with other pediatric vaccines, a total of 1745 children 12 to 23 months of age received 2 doses of ProQuad, of which 1661 completed safety follow-up after both doses. Rates of adverse experiences after the second dose of ProQuad were generally similar to, or lower than, those seen with the first dose. The fever rate was lower after the second dose than after the first dose.
Toxicology: Animal Toxicology: Carcinogenesis, Mutagenesis, Reproduction: ProQuad has not been evaluated for its carcinogenic or mutagenic potential, or its potential to impair fertility.
