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Proquad

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Proquad

Proquad

CLINICAL PHARMACOLOGY

Background

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 ba 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's syndrome.

Mechanism of action

In clinical efficacy studies, seroconversion in response to vaccination against measles, mumps, and rubella paralleled protection from these diseases. Also, in previous studies with varicella vaccine, antibody responses against varicella virus ≥ 5 units/mL in a glycoprotein enzyme-linked immunosorbent assay (gpELISA) (not commercially available) similarly correlated with long-term protection. Clinical studies with a single dose of ProQuad (measles mumps rubella varicella vaccine live) 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) and seroresponse rates for varicella virus were similar to those observed after vaccination with a single dose of VARIVAX® (see Clinical Studies). The duration of protection from measles, mumps, rubella, and varicella infections after vaccination with ProQuad (measles mumps rubella varicella vaccine live) is unknown.

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 (measles mumps rubella varicella vaccine live) .

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.1 Varicella antibodies were present for up to ten years post-vaccination in most of the individuals tested who received 1 dose of VARIVAX.

Clinical Studies

Formal studies to evaluate the clinical efficacy of ProQuad (measles mumps rubella varicella vaccine live) have not been performed.

Efficacy of the measles, mumps, rubella and varicella components of ProQuad (measles mumps rubella varicella vaccine live) 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.2-9

Immunogenicity

Immunogenicity was studied in 5835 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 (measles mumps rubella varicella vaccine live) was similar to that of its individual component vaccines (M-M-R II and VARIVAX), which are currently used in routine immunization.

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 mlU/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.

Children who received a single dose of ProQuad (measles mumps rubella varicella vaccine live) at 12-23 months of age

In 4 randomized clinical trials, 5446 healthy children 12 to 23 months of age were administered ProQuad (measles mumps rubella varicella vaccine live) , 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 Studies With Other Vaccines), no concomitant vaccines were permitted during study participation. Following a single dose of ProQuad (measles mumps rubella varicella vaccine live) , the vaccine response rates were 97.4% (95% CI: 96.9, 97.9) for measles, 95.8 (95% CI: 95.1, 96.4) to 98.8% (95% CI: 97.9, 99.4) for mumps, and 98.5% (95% CI: 98.1, 98.8) for rubella. The vaccine response rate was 91.2% (95% CI: 90.3, 92.0) for varicella. 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. Fever and measles-like rashes were the only adverse experiences that occurred more frequently in recipients of a single dose of ProQuad (measles mumps rubella varicella vaccine live) compared with recipients of single doses of M-M-R II and VARIVAX (see ADVERSE REACTIONS).

Children Who Received a Second Dose of ProQuad (measles mumps rubella varicella vaccine live)

In 2 of the 4 randomized clinical trials described above, a subgroup (N=1035) of the 5446 children administered a single dose of ProQuad (measles mumps rubella varicella vaccine live) were administered a second dose of ProQuad (measles mumps rubella varicella vaccine live) approximately 3 months after the first dose. Children were excluded from receiving a second dose of ProQuad (measles mumps rubella varicella vaccine live) 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 proportion of initially seronegative vaccinees with positive serological responses following two doses were 99.4% (95% CI: 98.6, 99.8) for measles, 99.9% (95% CI: 99.4, 100) for mumps, 98.3% (95% CI: 97.2, 99.0) for rubella, and 99.4% (95% CI: 98.7, 99.8) for varicella ( ≥ 5 gpELISA units/mL). The geometric mean titers (GMTs) following the second dose of ProQuad (measles mumps rubella varicella vaccine live) increased approximately 2-fold each for measles, mumps, and rubella, and approximately 41-fold for varicella.

In these trials, the rates of adverse experiences after the second dose of ProQuad (measles mumps rubella varicella vaccine live) 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.

Children Who Received ProQuad (measles mumps rubella varicella vaccine live) at 4 to 6 Years of Age After Primary Vaccination With M-M-RII and VARIVAX

In a clinical trial involving 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, 399 received ProQuad (measles mumps rubella varicella vaccine live) and placebo while 205 received M-M-R II and placebo concomitantly at separate injection sites. Another 195 healthy children were administered M-M-R II and VARIVAX concomitantly at separate injection sites. 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.

Following the dose of ProQuad (measles mumps rubella varicella vaccine live) , seropositivity rates were 99.2% (95% CI: 97.6, 99.8) for measles, 99.5% (95% CI: 98.0, 99.9) for mumps, 100% (95% CI: 99.0, 100) for rubella, and 98.9% (95% CI: 97.2, 99.7) for varicella ( ≥ 5 gpELISA units/mL). Approximate geometric mean fold-rises in antibody titers (pre- vaccination to post-vaccination) for measles, mumps, rubella, and varicella were 1.2, 2.4, 3.0 and 12, respectively. Post-vaccination GMTs for recipients of ProQuad (measles mumps rubella varicella vaccine live) 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. The rates of adverse experiences, including the most commonly reported adverse experiences of injection site reactions, nasopharyngitis and cough were generally similar among the 3 treatment groups.

Studies With Other Vaccines

In a clinical trial involving 1913 healthy children 12 to 15 months of age, 949 received ProQuad (measles mumps rubella varicella vaccine live) 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. Another 485 healthy children received ProQuad (measles mumps rubella varicella vaccine live) at the initial visit followed by DTaP and Haemophilus b Conjugate and Hepatitis B (Recombinant) Vaccine given concomitantly 6 weeks later while 479 children were immunized with M-M-R II and VARIVAX given concomitantly at separate injection sites at the first visit. Seroconversion rates and antibody titers for measles, mumps, rubella, varicella, anti-PRP and hepatitis B were comparable between the 2 groups at approximately 6 weeks post-vaccination indicating the ProQuad (measles mumps rubella varicella vaccine live) and Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine may be administered concomitantly at separate injection sites. There are insufficient data to support concomitant immunization with diphtheria, tetanus and acellular pertussis vaccine. No clinically significant differences in adverse experiences were reported between treatment groups.

Herpes Zoster

2 cases of herpes zoster were reported in 2108 healthy subjects 12 to 23 months of age who were vaccinated with ProQuad (measles mumps rubella varicella vaccine live) in clinical trials and followed for 1 year. Both cases were unremarkable and no sequelae were reported (see ADVERSE REACTIONS, Other).

Reye's Syndrome

Reye's syndrome following wild-type varicella infection has occurred in children and adolescents, the majority of whom had received salicylates. In clinical studies of ProQuad (measles mumps rubella varicella vaccine live) or VARIVAX, the recommendation was made to avoid the use of salicylates for 6 weeks after vaccination. There were no reports of Reye's syndrome in recipients of ProQuad (measles mumps rubella varicella vaccine live) or VARIVAX during these studies.

REFERENCES

1. Weibel RE, et al. Clinical and laboratory studies of combined live measles, mumps, and rubella vaccines using the RA 27/3 rubella virus. Proc Soc Exp Biol Med. 165(2):323-326, 1980.

2. Hilleman MR, Stokes J, Jr., Buynak EB, Weibel R, Halenda R, Goldner H. Studies of live attenuated measles virus vaccine in man: II. appraisal of efficacy. Am J Public Health. 52(2):44-56, 1962.

3. Krugman S, Giles JP, Jacobs AM. Studies on an attenuated measles-virus vaccine: VI. clinical, antigenic and prophylactic effects of vaccine in institutionalized children. N EnglJ Med. 263(4):174-7,1960.

4. Hilleman MR, Weibel RE, Buynak EB, Stokes J, Jr., Whitman JE, Jr. Live, attenuated mumps-virus vaccine. 4. Protective efficacy as measured in a field evaluation. N Engl J Med. 276(5):252-8,1967.

5. Sugg WC, Finger JA, Levine RH, Pagano JS. Field evaluation of live virus mumps vaccine. J Pediatr. 72(4):461-6, 1968.

6. The Benevento and Compobasso Pediatricians Network for the Control of Vaccine-Preventable Diseases, D'Argenio P, Citarella A, Selvaggi MTM. Field evaluation of the clinical effectiveness of vaccines against pertussis, measles, rubella and mumps. Vaccine. 16(8):818-22,1998.

7. Furukawa T, Miyata T, Kondo K, Kuno K, Isomura S, Takekoshi T. Rubella vaccination during an epidemic. JAMA. 213(6):987-90, 1970.

8. Vazquez M, et al. The effectiveness of the varicella vaccine in clinical practice. N Engl J Med. 344(13):955-960, 2001.

9. Kuter B, et al. Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Pediatr Infect Dis J. 23(2): 132-137, 2004.

10. Levy O, et al. Disseminated varicella infection due to the vaccine strain of varicella-zoster virus, in a patient with a novel deficiency in natural killer T cells. J Infect Dis. 188(7):948-53, 2003.

Last reviewed on RxList: 2/14/2008
This monograph has been modified to include the generic and brand name in many instances.

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