Status: U.S. approved in 2005

Organizations involved:

Merck & Co., Inc. – Manuf.; R&D; Tech.; USA mark.; Intl. mark.

Sanofi Pasteur MSD – Europe mark.

Cross ref.: See the entries for the four components of this combination vaccine – Measles Virus Vaccine (Attenuvax); Mumps Virus Vaccine Live (Mumpsvax); Rubella Virus Vaccine Live (Meruvax II); and Varicella Virus Vaccine Live (Oka/Merck) (Varivax). See also the entry for Measles, Mumps and Rubella Virus Vaccine Live (M-M-R II), the triple combination to which Varivax has been added to form ProQuad.

Description: ProQuad is a lyophilized (freeze-dried) quadravalent (four component) live vaccine combining Measles Virus Vaccine (Attenuvax); Mumps Virus Vaccine Live (Mumpsvax); Rubella Virus Vaccine Live (Meruvax II), with these three components the same as in Merck’s M-M-R II vaccine; and Varicella Virus Vaccine Live (Oka/Merck) (Varivax). The titer of Oka/Merck varicella-zoster virus (VZV) is higher in ProQuad than in single antigen varicella vaccine, Varivax, a minimum of 3.13 log10 plaque-forming units (pfu) vs. 1,350 pfu (~1.13 log10), respectively. ProQuad may also be viewed as the combination of M-M-R II and Varivax. See the individual component vaccines for information about their contents.

ProQuad is supplied in packages of 10 single-dose vials of lyophilized vaccine, with separate packages of 10 vials of sterile water diluent. Each 0.5 mL dose contains not less than 3.00 log10 TCID50 (50% tissue culture infectious dose) of live measles virus; 4.30 log10 TCID50 of live mumps virus; 3.00 log10 TCID50 of live rubella virus; and a minimum of 3.99 log10 PFU (plaque-forming units) of live Oka/Merck varicella virus. ProQuad contained five times more chickenpox antigen compared to the separate chickenpox vaccine (Varivax).

Each 0.5 mL dose of the vaccine also contains no more than 21 mg of sucrose, 11 mg of hydrolyzed gelatin (presumably animal, probably bovine, origin), 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 human albumin, 0.17 mg of sodium bicarbonate, 72 µg of potassium phosphate monobasic, 60 µg of potassium chloride; 36 µg 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. ProQuad is stored frozen and has a shelf life of up to 18 months. ProQuad, when reconstituted as directed, is a sterile preparation for subcutaneous administration.

Nomenclature: Measles Mumps Rubella & Varicella Vaccine [BIO]; ProQuad [TR]; , Mumps, Rubella and Varicella (Oka/Merck) Virus Vaccine Live [FDA]; M-M-R II plus Varivax [SY]; MMRV [SY]; NDC 0006-4999-00 [NDC]

CBER class: Vaccines

FDA class: Biologic BLA

Approvals: Date = 20050906; original BLA

Date = 20080227; BLA supplement; Indications: = changes in product insert/labeling; included information in the Post-Marketing Surveillance section on the possible risk of febrile seizures after ProQuad vaccination

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:

ProQuad is indicated for simultaneous vaccination against measles, mumps, rubella, and varicella in children 12 months to 12 years of age. ProQuad may be used in children 12 months to 12 years of age if a second dose of measles, mumps and rubella vaccine is to be administered.

Status: Merck filed a BLA on Aug. 31, 2004, and it was accepted for filing in early Nov. 2004. The application received standard (10-12 month) FDA review. Approval was granted on Sept. 6, 2005 (approval time = ~1.02 years).

In Feb. 2007, Merck reported that because of lower than expected VZV titers in its recently manufactured bulk varicella vaccine, Merck was prioritizing production of Varivax) and Zostavax over production of MMR-V vaccine (ProQuad), i.e., there would be a shortage of ProQuad. In May 2007, Merck reported that current projections of orders indicated ProQuad would be unavailable starting in July 2007, and after depletion of the existing supply, ProQuad was not expected to be available for the remainder of 2007. Merck noted that customers should begin transitioning from ProQuad to M-M-R II and Varivax at their earliest convenience. Merck expected to continue to meet demands for Varivax, M-M-R II and Zostavax. ProQuad continued in short supply in the U.S. in 2008, with the supply improving in 2009.

ProQuad has centralized European Union approval.

Trials: In April 2003, results were reported from a study comparing the immunogenicity of three different lots of ProQuad (to prove to FDA that the vaccine can be manufactured consistently). A single injection was administered to 3,928 healthy children between 12 and 23 months of age, with 75% receiving ProQuad and the others receiving M-M-R-II vaccine. Seroconversions (development of antibodies) of the children receiving different lots of ProQuad were similar and, in turn, were similar to seroconversions in children receiving M-M-R II and Varivax. For measles, 97.6% of ProQuad recipients seroconverted vs. 97.9% receiving M-M-R II and Varivax; for mumps, this was comparably 96% vs. 97.9%; for rubella, 98.8% vs. 99.2%; and for varicella, 93.5% vs. 95%. Those receiving ProQuad appeared to suffer more fevers in the 6 weeks following the inoculations, but this was not clinically relevant (39.1% versus 33.1%, p = 0.001). The rate of febrile seizure-related incidents was the same, 0.3%, for each group. ProQuad was concluded to be safe and well-tolerated.

Other trials have demonstrated that ProQuad can be administered in place of a second dose of M-M-R II or in place of both M-M-R II and Varivax at 4-6 years of age. The BLA included results from studies that evaluated the immunogenicity, antibody persistence and safety of ProQuad compared to its component vaccines. Clinical studies of 7,484 healthy children aged 12—23 months (of whom 5,446 received MMRV vaccine) have indicated that those who receive one dose of MMRV vaccine develope levels of antibody to measles, mumps, rubella, and varicella similar to those of children who receive one dose of M-M-R II and one dose of varicella vaccine (Varivax) concomitantly at separate injection sites.

Immunogenicity was studied in 5,835 healthy children 12 months to six years of age with a negative clinical history of measles, mumps, rubella and varicella who participated in five randomized trials. The immunogenicity of ProQuad was similar to that of its individual component vaccines, M-M-R II and Varivax.

In four randomized trials in which 5,446 healthy children aged 12 to 23 months received ProQuad, vaccine response rates were similar to the rates induced by the concomitant administration of single doses of M-M-R II and Varivax at separate injection sites in 2,038 children. Following a single dose of ProQuad, the immune response rates were 97.4% for measles, 95.8-98.8% for mumps, 98.5% for rubella and 91.2% for chickenpox. The duration of protection from measles, mumps, rubella and chickenpox infections after vaccination with ProQuad is unknown.

The immunogenicity of ProQuad was evaluated in a clinical trial of 799 healthy children four to six years of age who had received M-M-R II and VARIVAX as primary vaccination against measles, mumps, rubella and chickenpox at least one month prior to study entry. In this study, 399 children received ProQuad and placebo, 205 received M-M-R II and placebo concomitantly at separate injection sites, and 195 children received M-M-R II and Varivax concomitantly at separate injection sites. Following the dose of ProQuad, seropositivity rates were 99.2% for measles, 99.5% for mumps, 100% for rubella and 98.9% for varicella. The rates of adverse experiences, including the most commonly reported adverse experiences of injection site reactions, nasopharyngitis and cough, were generally similar among the three treatment groups.      

Formal studies to evaluate the clinical efficacy of ProQuad have not been performed. Efficacy of the measles, mumps, rubella and chickenpox components has been established in a series of clinical studies with the monovalent vaccines.

Medical: ProQuad is used for simultaneous vaccination against measles, mumps, rubella and varicella in children 12 months to 12 years of age. The first dose is recommended at age 12–15 months, and the second dose is recommended at ages 4–6 years.

In Feb. 2008, FDA instituted a labeling change for ProQuad, including statements information in the Post-Marketing Surveillance section on the possible risk of febrile seizures after ProQuad vaccination. Increased rate of fever was previously identified as a safety signal in the ProQuad prelicensure studies. To better understand the risk of febrile seizures that might be associated with ProQuad vaccination, Merck committed to conduct a large, postmarketing study at the time of licensure. In Jan. 2006, Merck initiated a large Phase IV observational study to evaluate the risk of febrile seizures in 25,000 children receiving their first dose of ProQuad. Interim results of the study were reflected in this labeling revision. Febrile seizures occurred more frequently 5 to 12 days following vaccination of ~14,000 children with ProQuad (0.5 per 1,000) when compared with a historical, age and sex-matched control group vaccinated with M-M-R and varicella vaccines administered separately at the same visit (0.2 per 1,000). The Centers for Disease Control and Prevention (CDC) also supported a post-licensure observational study to assess the risk of febrile seizures following vaccination with ProQuad compared to vaccination with MMR and varicella vaccines, given separately at the same visit. Preliminary results from the CDC study showed an increased risk of febrile seizure 7-10 days after vaccination with ProQuad versus MMR and varicella vaccines (9 per 10,000 vaccinations versus 4 per 10,000 vaccinations).

Market: The 2007 Average Wholesale Price (AWP) is $155.91/prefilled single-dose syringe, with and Direct Price (Manufacturer’s discount) of $130.34; and $1,486.43/package of 10, with a Direct Price of $1,243.69 (Red Book, 2007).

As reported by the National Immunization Program (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the Private Sector Cost/Dose (average cost) per dose is $124.47 for packages of 10 vials. The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $77.75 for packages of 10 vials. These prices include the $3.00/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. Merck’s contract with NIP, CDC, expires on March 31, 2008.

The Merck catalog (2006 list) price of ProQuad is $114.61 per dose purchased as a pack of 10 single-dose vials of lyophilized vaccine with sterile diluent water; or $120.25 if purchased as an individual single-dose vial of lyophilized vaccine with sterile diluent water.

Like other combination vaccines, ProQuad reduces the number of injections children must receive, which is expected to increase compliance with pediatric vaccination requirements and may result in reduced costs. By combining varicella with the other vaccines, it is hoped that ProQuad will result in higher, i.e., over 90%, vaccination rates for varicella (while U.S. vaccination rates for the other components are already high, since measles, mumps and rubella are among the universally required pediatric vaccinations in the U.S. and some other developed countries)