Vaccine/Sanofi
Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine - Menactra; MCV-4
Status: marketed; now the primary meningococcal vaccine
Organizations involved:
Sanofi Pasteur Inc. – Manuf.; R&D; Tech.; USA mark.
Sanofi Aventis S.A. – Intl mark.; Parent
Cross ref: See the entries above for Meningococcal Vaccines (#497); the upcoming competing product, Menveo, from Novartis (entry above); and the conventional unconjugated polysaccharide vaccines (Menomune-A/C/Y/W-13; also from Sanofi Pasteur). See also another conjugate vaccine, Menjugate (#501), from Chiron/Novartis.
Description: Meningococcal (Groups A, C, Y and W-135) Poly-saccharide Diphtheria Toxoid Conjugate Vaccine or Menactra is a quadravalent vaccine containing a combination of individually cultured, inactivated, and purified Neisseria meningitidis strain types A, C, Y and W-135 capsular polysaccharides chemically conjugated to diphtheria toxoid (formaldehyde-inactivated Corynebacterium diphtheriae toxin) carrier to increase the immunogenicity of the polysaccharides.
Menactra is packaged in single-dose vials, and single-dose syringes. Each 0.5 mL dose of vaccine is formulated in sodium phosphate buffered isotonic sodium chloride solution to contain 4 µg each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 µg of diphtheria toxoid protein carrier. The vaccine is stored at 2-8°C (refrigerated). The vaccine has an expiration dating period of 18 months when stored at 2-8°C (refrigerated).
Menactra vaccine is the world’s first quadrivalent conjugate vaccine. Menactra is the first quadravalent meningococcal vaccine shown effective to prevent meningococcal meningitis (the most deadly type of meningococcal meningitis), and the vaccine provides longer protection than prior unconjugated polysaccharide vaccines, attributed to induction of T cell-dependent immune responses due to antigen conjugation.
Nomenclature: Meningococcal Conjugates Vaccine/Sanofi [BIO]; Menactra [TR]; Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine [FDA]; NDC 49281-589-01 and NDC 49281-589-05 [NDC]; MCV-4 [SY]; MCv4 [SY]
Biological.: See the entries for Prevnar (#513) and HibTITER (#457) for further general information about polysaccharide conjugate vaccines. As with Haemophilus influenzae and Streptococcus pneumoniae bacterial toxoid conjugate vaccines, attachment (conjugation) of an inactivated bacterial toxin (toxoid), e.g., diphtheria toxoid, to bacterial polysaccharides substantially increases immune responses to the polysaccharides (N. meningitidis capsular polysaccharides, in the case of Menactra), particularly longer-term immune responses.
Companies.: The vaccine was developed and is manufactured and marketed in the U.S. by Sanofi Pasteur Inc., CBER/FDA est. no. 1279, formerly Aventis Pasteur Inc. Aventis merged into Sanofi Aventis S.A. in late 2004.
Manufacture: Aventis Pasteur Inc. constructed a new production plant at its facilities in Swiftwater, PA, CBER/FDA est. no. 1277, to manufacture the vaccine. The facility is intended to ensure the company’s ability to meet increased demand for the product (compared to polysaccharide vaccines, which are often in short supply due to manufacturing problems). The plant was constructed by Pharmadule AB (Sweden), involving construction of 52 modular units which were shipped to the U.S. for installation. The facility has the capacity to produce 5 million doses in the first year on the market. A new production facility, expected to come online in 2008, will further increase capacity.
Neisseria meningitidis A, C, Y and W-135 strains are cultured on Mueller Hinton agar and grown in Watson Scherp media. The polysaccharides are extracted from the N meningitidis cells and purified by centrifugation, detergent precipitation, alcohol precipitation, solvent extraction, and diafiltration. To prepare the polysaccharides for conjugation, they are depolymerized, derivatized, and purified by diafiltration.
Corynebacterium diphtheriae cultures are grown in a modified Mueller and Miller medium3 and detoxified with formaldehyde. The diphtheria toxoid protein is purified by ammonium sulfate fractionation and diafiltration.
The derivatized polysaccharides are covalently linked to diphtheria toxoid and purified by serial diafiltration. The four meningococcal components, present as individual serogroup-specific glycoconjugates, compose the final formulated vaccine. No preservative or adjuvant is added during manufacture. Potency of Menactra is determined by quantifying the amount of each polysaccharide antigen that is conjugated to diphtheria toxoid protein and the amount of unconjugated polysaccharide present.
FDA class: Biologics BLA
Approvals: Date = 20050114; BLA, original approval; Indication = Active immunization of adolescents and adults 11-55 years of age for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135
Date = 20051021; BLA supplement; Indication = package insert/labeling revision
Date = 20070330; BLA supplement; Indication = approval of a single dose syringe
Date = 20071018; BLA supplement; Indication = expand indications: to include children between ages 2-10
Date = 20081008; BLA supplement; Indication = include changes to the package insert to incorporate post-marketing safety information regarding anaphylaxis
Date = 20081018; BLA supplement; Indication =e xpanded age indication for subjects 2-10 years of age
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 12/31/2008]:
Menactra vaccine is indicated for active immunization of individuals 2 through 55 years of age for the prevention of invasive meningococcal disease caused by N meningitidis serogroups A, C, Y and W-135.
Menactra vaccine is not indicated for the prevention of meningitis caused by other microorganisms or for the prevention of invasive meningococcal disease caused by N meningitidis serogroup B.
Menactra vaccine is not indicated for treatment of meningococcal infections.
Menactra vaccine is not indicated for immunization against diphtheria.
Menactra vaccine may not protect 100% of individuals.
Status: Aventis Pasteur (now Sanofi Pasteur) submitted a BLA on Dec. 18, 2003, seeking FDA approval for use in adolescents and adults 11 to 55 years of age. The BLA was filed electronically (in digital format), the first such BLA filed by Aventis Pasteur. A hard copy of the application would have been >120,000 pages. On Sept. 22, 2004, the Vaccines and Related Biological Products Advisory Committee, FDA, voted unanimously to recommend licensure of Menactra. The BLA was approved on Jan. 14, 2005 (approval time = <13 months).
On Feb. 10, 2005 the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention’s (CDC), recommended immunization with Menactra vaccine for young adolescents at the pre-adolescent visit (11-12 year old), adolescents at high school entry (15 year old) and college freshmen living in dormitories. The committee recognized the need to reduce the threat of this potentially fatal bacterial infection among segments of the population found to be at increased risk of infection relative to the general population.
On March 17, 2005, Aventis Pasteur, now Sanofi Aventis, filed a BLA supplement seeking approval of Menactra for use in children aged 2 through 10 years. With serogroups C, Y and W-135 accounting for about 48% of meningococcal disease in 2 through 5 year-olds and 65% in 5 through 11 year-olds, and with children these ages already receiving other vaccines, approval and use in this population will further decrease the incidence and risk from meningitis.
In May 2005, the Advisory Committee for Immu-nization Practices (ACIP), Centers for Disease Control and Prevention (CDC), recommended pre-teens (11-12 years of age), adolescents of high school entry or age 15 years, and college freshmen living in dormitories receive Menactra. The vaccine is also recommended for use in persons at high risk of bacterial meningitis, such as those with underlying medical conditions and travelers to areas with high rates of meningococcal disease. Once supplies are adequate, the CDC plans to recommend routine vaccination for all adolescents beginning at 11 years of age.
In Aug. 2005, the CDC reported that Menactra was temporarily in short supply, owing to a high volume of demand after its U.S. launch. During the shortage, vaccine was allocated in the public and private sectors based on estimates of monthly needs and on available supply. The shortage was particularly severe in Fall 2006. FDA set the “Date of onset” of Menactra vaccine shortage as May 2006. FDA and CDC reported the shortage as resolved in Nov. 2006; and ACIP, CDC, reinstated the normal recommendations for Menactra use. During the shortage, CDC had recommended that vaccination be deferred for persons 11 to 12 years old, with priority given to adolescents entering high school and college freshmen living in dorms.
In Oct. 2005, FDA and the Centers for Disease Control and Prevention (CDC) issued an alert reporting five cases of Guillain-Barre Syndrome (GBS) in patients ages 17-18 given Menactra. GBS is a serious neurological disorder that can occur either spontaneously or after certain infections and vaccinations. It is not known whether the cases were caused by the vaccine or are coincidental. The rate of GBS in Menactra patients has been similar to that in the general population. All patients were reported to be recovering or have recovered. This did not affect recommendations for use of Menactra (i.e., cost- and risk-benefit ratios still favor vaccination to prevent meningititis). Since its U.S. launch in March 2005, over 2.5 million doses had been distributed in the U.S. No cases of GBS appeared in Sanofi Pasteur studies, involving more than 7,000 Menactra recipients, before the vaccine was licensed.
In Oct. 2006, FDA and CDC updated their alert concerning GBS associated with Menactra after further cases were reported. A total of 17 confirmed cases of patients developing GBS within six weeks of receiving Menactra had been reported through the Vaccine Adverse Event Reporting System (VAERS). Fifteen of the cases occurred in individuals between 11-19 years of age, and two in people over the age of 30. FDA and the CDC reiterated that they cannot determine whether the Menactra vaccine increases the risk of GBS. The agencies have not changed any recommendations (and the risks of not receiving the vaccine are still, presumably, significantly greater than the risks of vaccine-associated GBS, with a link between the vaccine and GBS not yet formally recognized).
In Dec. 2007, the Advisory Committee on Immunization Practices (ACIP), CDC, recommended routine vaccination with meningococcal polysaccharide vaccine (MPSV4; Menactra) in children aged 2-10 years who are at increased risk for meningococcal disease. These children include travelers to or residents of countries in which meningococcal disease is hyperendemic or epidemic, children who have terminal complement component deficiencies, and children who have anatomic or functional asplenia. ACIP revised its recommendations to state that Menactra 5 is preferable to Menomune-A/C/Y/W-135 for vaccination of children aged 2-10 years who are at increased risk for meningococcal disease. Also, Menactra is preferred to MPSV4 for use among children aged 2-10 years for control of meningococcal disease outbreaks..
In Jan 2008, the Childhood and Adolescent Immunization Schedules were released jointly by the Centers for Disease Control and Prevention, the American Academy of Pediatrics, and the American Academy of Family Physicians. Meningococcal Conjugate Vaccine (MCV4) is now recommended for children 11 to 12 years of age and teens 13 to 18 years of age who have not been previously vaccinated and other people at heightened risk of meningococcal disease, including college freshmen living in dorms, as well as military recruits. The goal is routine vaccination of all children beginning at age 11 years, with college freshmen living in dormitories vaccinated with MCV4 before college entry, if not previously.
Menactra is approved for use in infants and adults in over 25 countries worldwide, but has not received centralized European Union approval.
Tech. transfer: The same technologies involved in culture, purification, and formulation of unconjugated polysaccharide vaccines are used for manufacture of Menactra. Similarly, Sanofi Pasteur is also, presumably, using toxoid-conjugate technology it uses (or has used) with its other conjugate vaccines.
Trials: Six pivotal clinical trials with Menactra enrolled more than 7,500 participants supported its original BLA approval. Menactra vaccine induced the production of functional antibodies specific to the capsular polysaccharides of the four serogroups (A, C, Y and W-135) found in the vaccine. All vaccine immunogenicity measurements demonstrated strong immune responses to a single dose of Menactra vaccine that were equivalent to a single dose of Sanofi Pasteur’s Menomune-A/C/Y/W-135. Also, 98-100% of seronegative adolescents had four-fold increases in antibody titers to all four meningococcal serogroups. In seronegative adults, this range was 91-100%.
As stated by an Aventis Pasteur spokesperson, “At this point in time, we can’t say conclusively what duration of protection [Menactra] will offer because it hasn’t been studied long enough. However, we do know that Menactra induces a T cell-dependent immune response, which has been associated with long-term protection in other conjugate vaccines, so we believe it will provide longer duration of immunity.”
The BLA supplement approved in Oct. 2007 for use in 2-10 year olds was supported by three clinical studies. Two were randomized, multi-center, active-controlled, modified double-blind clinical studies of children aged 2-10 years comparing the safety and immunogenicity of Menactra vaccine to Menomune-A/C/Y/W-135, Sanofi Pasteur’s earlier polysaccharide meningococcal vaccine. The third was a controlled, multi-center, open-label Phase II study of children aged 3-5 years who had been vaccinated previously with Menactra vaccine ~2 years earlier. The objective of this study was to evaluate the antibody memory response to the vaccine. Overall, the studies demonstrated that for children aged 2-10 years Menactra vaccine is safe and immunogenic. Compared to Menomune, Menactra vaccine resulted in longer-term persistence of bactericidal antibodies, improved production of high avidity antibodies, and the establishment of immune memory. No clinically significant adverse events were identified after a 6-month controlled follow-up. The benefits of Menactra include longer-lasting immune responses and boostable memory responses.
With its U.S. approval for use in children (2--10 years old), its was predicted that about half of the meningitis cases in U.S. children 2 years through 5 years, and two-thirds in those 6 years through 11 years can potentially be prevented through vaccination.
Medical: Menactra vaccine is administered as a single 0.5 mL intramuscular injection, preferably in the deltoid region. It is currently assumed that Menectra is effective for more than eight years, while the older vaccine, Menomune-A/C/Y/W-135, lasted for just 3-5 years, and didn’t prevent people from being carriers of the bacteria. Menactra provides protection against people becoming asymptomatic carriers.
Experience in the U.K. (with Menjugate for sero-group C from Chiron) indicates that conjugate vaccines can provide significant benefits over traditional unconjugated polysaccharide vaccines, particularly longer-lasting immunity. The current primary FDA-licensed meningococcal disease vaccine, Menomune-A/C/Y/W-135 (Meningococcal Polysaccharide Vaccine, Groups A, C, Y and W-135 Combined) from Sanofi Pasteur, contains unconjugated meningococcal poly-sac-charides, and provides only a limited duration of immunity, approximately three to five years, with poor responses in the youngest infants/children. From 1999 to 2000, the U.K. ran a national campaign to immunize 15 million children under age 17 with Menjugate serogroup C conjugate vaccine. This resulted in an 85% overall decline in cases and 90% reduction in deaths from meningococcal serogroup C disease one year later. Disease rates declined among unvaccinated children as well as among those who were vaccinated, suggesting that the vaccine suppressed transmission of the infection to the unvaccinated population, offering the benefits of herd immunity. Similarly, about one million children in Quebec have been vaccinated with Menjugate C, with deaths from meningococcal C disease reduced by approximately 80%. However, obtaining similar public health benefits from a polyvalent meningococcal conjugates vaccine in the U.S. would require a vaccine that protects against multiple sero-groups of meningococcal bacteria. Four serogroups of the N. meningitidis (C, Y, W-135, and B) are predominant in the U.S. Menac--tra vaccine contains only three of these four serogroups, which cause approximately two-thirds of meningococcal disease overall and 79% in the adolescent U.S. population. In the U.K., by contrast, two serogroups (C and B) predominate, with the C serogroup causing 38% of meningococcal disease prior to vaccination. There is currently no vaccine available for meningococcal serogroup B.
Market: Total sales were $735 million in 2012; $557 million in 2011; $626 million in 2010; $620 in 2009 and $620 in 2008. Total 2007 sales were reported to be $570 million. Total 2006 estimated were $320 million. Total reported 2005 (first partial year) sales were $225 million. With the vaccine only on the market in the U.S. for about a half year in 2005 and with a shortage encountered in 2006, the author roughly estimates (guesses) 2006 sales to be on the order of $230 million.
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 $89.43 for single dose vials and packages of 5 vials ($82.00 in 2006). The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $73.09 for single dose vials and packages of 5 vials ($68.00 in 2006). These prices include the $0.75/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. Sanofi Pasteur’s contract with NIP, CDC, expires on March 31, 2008.
The 2007 Average Wholesale Price (AWP) is $535.85/5 prefilled syringes, with a Direct Price (Manufacturer’s discount price) of $447.17 (Red Book, 2007).
The Sanofi Pasteur list price (Jan. 2006) is $82.00/single-dose vial; $410.00 for five vials; and $410.00 for 5 single-dose syringes
With the approval of this new quadravelent vaccine in 2005, Menactra will quickly dominate the U.S. market. The market will be further driven by CDC and other recommendations for universal vaccination of adolescents with Menactra. However, at >$80 a dose, vaccinating all 40 million people from age 11-20 would cost $3.5 billion next year. This translates to >$1 million per life spared, far more than public health officials have usually been willing to spend for vaccines. Thus, despite government recommendations and regulations for universal or widespread vaccination, in most cases, this will be left up to individuals/families, insurers and public health programs. Menactra is covered by health insurance programs.
Aventis Pasteur (Sanofi Pasteur) has reported, “Potential sales of this vaccine group could eventually approach one billion Euros” or over $1 billion. As discussed in the Meningococcal Vaccines entry (#497), Sanofi Aventis is currently the only manufacturer and marketer of meningococcal vaccines in the U.S. market, and the introduction of Menactra is expected to significantly increase its meningococcal vaccine sales and be a major driver for corporate growth in coming years. Menactra may provide long-lasting protection, e.g., allowing vaccination at age 11, with protection against disease lasting into early adulthood, e.g., into early 20’s or longer.
Use of meningitis vaccines has grown rapidly in recent years, particularly among college students and military personnel. The market is expected to grow further as use is expanded to infants under the age of two, e.g., with U.S. approval of Menactra for this indication. College freshmen who live in dormitories are prime targets for marketing, to them and/or to their parents. These students are six times more likely than other people to be infected with meningitis; and have the highest rate of meningitis in the U.S. – 5.1 cases per 100,000. Many colleges, even before Menactra (with Menomune the only vaccine available), had been sending letters to parent urging meningococcal vaccination of students.
Menactra is among upcoming vaccines intended for 11-year-olds or early teens. The others include booster vaccines against tetanus, diphtheria and pertussis, and vaccines against human papillomavirus (cervical cancer) and, eventually, herpes simplex virus (genital herpes).
Competition: Menveo from Novartis is a comparable vaccine that will compete directly against Menactra, which lacks competition in major markets. Novartis is bravely conducting a head-to-head trial comparing Menveo to Menactra, and could capture significant market share quickly, if its vaccine is shown superior. If Novartis can prove its product also works in infants down to 2 months, it will also outflank Menactra by going to a younger patient group.
Ongoing: In Aug. 2006, Emergent BioSolutions Inc. licensed its Neisseria meningitidis serogroup B vaccine to Sanofi Pasteur, and the companies are collaborating on development of a group B conjugate vaccine for addition to Menactra.
Companies involvement:
Full monograph
503 Meningococcal Conjugates
Nomenclature:
Meningococcal Conjugates Vaccine/Sanofi [BIO]
Menactra [TR]
Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine [FDA]
MCV-4 [SY]
MCV4 [SY]
NDC 49281-589-01 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 2005
Date of 1st FDA approval = 20050114
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
conjugates
vaccines, bacterial
vaccines, combination
vaccines, subunit
bacterial culture <!-- bacterialculture -->
Corynebacterium diphtheriae
Neisseria catarrhalis
Bacillus anthracis prophylaxis
diphtheria toxin
Diphtheria Toxoid
formaldehyde
Neisseria meningitidis capsular polysaccharides
polysaccharides
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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