Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein) - Prevnar; Prevenar; Strepto-coccus -pneu---moniae capsular antigen–Diphtheria CRM197 -protein conjugate vaccine; PCV7
Status: approved; marketed
Organizations involved:
Wyeth/Lederle Labs. – Manuf.; R&D; Tech.
Wyeth – World mark.; Parent
Cardinal Health, Inc. – Manuf. other
Praxis Biologics, Inc. – R&D; Tech.; Former
University of Rochester – Tech.
Cross ref: See the Pneumococcal Vaccines entry; and the entry for Prevnar 13, which is slated to replace this product. See also the entry (#457) for Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) or HibTITER also involving CRM197-conjugate bacterial polysaccharide.
Description: Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein) or Prevnar (PCV7) is a heptavalent (7-antigen-containing) aqueous formulation of partially hydrolyzed capsular (outer coat) polysaccharide and oligosaccharide antigens from seven Streptococcus pneumoniae bacteria serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) individually cultured, purified, chemically conjugated to diphtheria CRM197 carrier protein, and adsorbed on aluminum phosphate adjuvant.
CRM197 (CRM; cross-reactive material) protein is a nontoxic variant (mutant) form of diphtheria toxin isolated from Corynebacterium diphtheriae strain C7 (8197) cultured in cas-amino acids and yeast extract-based medium. The CRM197 protein is purified by ultrafiltration, ammonium sulfate precipitation, and ion-exchange chromatography. Conjugation of purified S. pneumoniae capsular polysaccharide to the CRM197 protein results in potent T-cell dependent immune responses, including antibody production, to the S. pneumoniae capsular polysaccharide in children less than 2 years of age (a group that does not normally respond to unconjugated pneumococcal vaccines). Although unconjugated pneumococcal vaccines had long been available, Prevnar was the first pneumococcal conjugate vaccine (PCV) and the first pneumococcal vaccine approved for children younger than age two.
About 90 serotypes of S. pneumoniae have been identified. Prevnar contains capsular antigens of serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, each conjugated to CRM197 carrier protein. These seven types (and potentially cross-reactive serotypes) account for about 80% of invasive pneumococcal disease in children less than 6 years of age; 74% of penicillin-nonsusceptible (resistant) S. pneumoniae (PNSP); and 100% of penicillin-resistant pneumococcal infection isolates from children less than 6 years of age with invasive disease (in 1993-1994, according to CDC).
Prevnar is supplied in packages containing five single-dose vials. Each 0.5 mL dose contains approximately 2 µg each of capsular polysaccharide from serotypes 4, 9V, 14, 19F, and 23F; 4 µg of serotype 6B; and oligosaccharide from 18C; plus 20 µg of the carrier protein CRM197, and 0.125 mg of aluminum (from the aluminum phosphate adjuvant). Prevnar contains no preservatives. The dating period when stored continuously at 2-8˚C (refrigerated) is 24 months from the date of manufacture, defined as the date of initiation of the last valid potency test on the final formulated bulk.
Note, as discussed in the following monograph, a new 13-antigen (13-valent) version of Prevnar containing 13 conjugate antigens is currently in late stages of development, with U.S., European Union and other international filings expected starting in early 2009, and with product launch expected in 2010. The vaccine includes serotype 19A, as well as serotypes 1, 3, 5, 6A and 7F, in addition to the seven serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) included in Prevnar. The 13-valent vaccine currently is in global Phase III trials and may offer broader coverage than the 7-valent vaccine. In May 2008, FDA granted fast-track designation to Wyeth’s planned BLA for its 13-valent, new version of Prevnar. This vaccine may well be needed to compete against GSK’s 10-valent Synflorix (see related entry), which uses a Haemophilus influenzae carrier/conjugate, and also provides some protection against otitis media (ear) and other infections caused by Haemophilus influenzae.
Nomenclature: Pneumococcal Vaccine(7)-CRM197 [BIO]; Prevnar [TR]; Prevenar [TR former; prior to approval]; Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein) [FDA]; PncCRM [SY]; PCV7 [SY]; PNUcn-7 [SY CDC]; NDC 0005-1970-67 [NDC]
Biological.: As discussed in the Pneumococcal Vaccines entry (#512), polysaccharides on the pneumococcal (S. pneu-moniae) outer capsule are T-independent antigens, that stimulate mature B-lymphocytes (antibodies) but not T-lym-phocytes (T-cell responses). This type of antigen induces an immune system response that is neither long-lasting nor characterized by an anamnestic (i.e., booster; memory) response upon subsequent challenge with native polysaccharides. Unconjugated polysaccharide vaccines fail to elicit a protective immune system response among infants and very young children, because these children respond poorly to T-independent antigens. Conjugation of polysaccharides to protein carriers changes the nature of the anti-polysaccharide response from T-independent to T-dependent. The antigen complex stimulates a T-helper cell response, leading to a substantial primary response in infants and a strong booster response upon reexposure.
Companies.: Diphtheria CRM197 protein conjugate vaccine technology was originally developed by Praxis Biologics, Inc. (West Henrietta, NY), which was acquired by Lederle Labs., then a subsidiary of American Cyanamid, and became Lederle-Praxis. Lederle was subsequently acquired by American Home Products Corp. (AHP), now Wyeth. Development started in the early 1980’s.
Prevnar is manufactured by Wyeth/Lederle Labs, FDA CBER est. no. 0017. The vaccine is manufactured at facilities in Sanford, NC, and Pearl River, NY. Wyeth has encountered repeated problems in the manufacture of Prevnar, which have resulted in recurring shortages. Prevnar is marketed in the U.S. and internationally by Wyeth and affiliates.
Cardinal Health, Inc. brought new fill and finish facilities online in April 2004, allowing an increase of the number of doses manufactured.
In March 2005, the Pharmaceutical Research and manufacturers of America (PhRMA) granted the Discoverers Award to three Wyeth researchers for their development of Prevnar.
In Sept. 2005, Wyeth completed a new $2 billion manufacturing facility in Grange Castle, South County Dublin, Ireland, as part of its BioNext Project Prevnar is among the products produced at Grange Castle.
Manufacture: Each of the seven S. pneumoniae strains is independently cultured in soy peptone broth (presumably including bovine- and/or other animal-derived materials). Starting with a single defrosted vial, the bacteria are serially cultured in larger bottles, and the production fermentor is inoculated with this material. The culture is inactivated/halted by addition of an unspecified cell lysis reagent, the culture is incubated overnight, and checked again to assure inactivation. During fermentation, in-process controls include S. pneumoniae serotypes purity and identity testing, pH, growth by optical density, and confirmation of inactivation. The poly-saccharides are purified by centrifugation and the supernatant recirculated through a depth filter assembly until optimum optical density is attained, the supernatant again passed through a depth filter assembly, through a membrane filter into a holding tank, and transferred to the purification area. The polysaccharides are purified by precipitation, diafil-tration, ultrafiltration, and column chromatography, then passed through a 0.22 µm filter into bulk containers. Release specifications for the polysaccharides apparently include dry weight, residual protein, nucleic acid content, immunological specificity and identity, molecular weight by SEC-MALLS, endotoxin quantification and sterility; with proton NMR used to document purity, identity and structure of the polysaccharides.
The CRM197 carrier protein is produced from C. diph-theriae strain C7 (beta197), which has a single point mutation in the diphtheria toxin gene. Three vials of frozen stock bacteria are used to inoculate soy peptone agar slants, with the contents of each then transferred to a series of larger fermenters containing CY medium Cultures are testing for purity (colony morphology, growth on enriched media) and identity (Gram stain, latex agglutination test). The contents are transferred to a harvest tank, cooled, and the cells separated by filtration. The permeate is passed through a 0.22 µm filter, and the culture broth diafiltered against phosphate buffer. The protein is precipitated, captured on a depth filter and stored at 5˚C. The protein is eluted from the filter using phosphate buffer, and again diafiltered, then further purified by column chromatography. The CRM197 fraction is concentrated by ultrafiltration, a cryoprotectant is added to the solution, which is filtered through a 0.22 µm filter, stored in polyethylene bottles at 65˚C, and lyophilized (freeze-dried). Batch testing includes SEC-HPLC for purity and tests for absence or reversion of the toxin to toxicity. Negligible toxicity, as indicated by toxin enzyme activity, is detectable.
The individual purified polysaccharides are partially hydrolyzed (broken down) by physical or chemical methods, providing polysaccharides with average molecular weights between about 100-1,000 kDa, depending on the particular pneumococcal subtype. The polysaccharides are chemically activated and covalently conjugated (no linker or spacer group) to the carrier diphtheria CRM197 protein by reductive animation to form the final polysaccharide-protein conjugate (glyco-conjugate). Two different reaction solvents are used, depending on the polysaccharide. The individual glycoconjugates are purified by ultrafiltration and column chromatography. The purified glycoconjugates are analyzed for saccharide/protein ratios, molecular size, free saccharide and free protein.
The final bulk for each constituent conjugate is prepared by mixing with saline. The glycoconjugates are mixed with aluminum phosphate adju-vant and pooled (mixed) to formulate Prevnar. Potency of the formulated vaccine is determined by quantification of each of the saccharide antigens and by the saccharide/protein ratios of the individual component glycoconjugates. Testing of the final product includes identity testing of CRM197 and individual polysaccharides; sterility; aluminum content by direct current plasma emission spectroscopy; total polysaccharide by anthrone assay; total protein content by the Lowry method; and endotoxin testing by the LAL gel clot method. Nephelometry is use as in in-process test in conjunction with final protein and polysaccharide assays to ensure that all conjugates are present.
During development, the vaccine adjuvant was changed from a commercial aluminum phosphate to steam-sterilized aluminum phosphate manufactured by Wyeth.
The entire manufacturing process takes about one year. Shortages of Prevnar have been attributed to insufficient capacity at the Pearl River facility for sterile vaccine filling and packaging. This was expected to be resolved in first half 2004.
The cell lines for manufacture of each of the seven poly--saccharides were derived from those used for manufacture of Pnu-Imune 23 (#514). Lyophilized seeds were reconstituted in soy peptone seed medium, and new Master and Working Cell Banks were developed. Animal-derived materials used during manufacture are sourced from countries with no reported BSE cases (reported upon approval).
The seven individual pneumococcal polysaccharides are manufactured at Wyeth’s Pearl River, NY, facilities, and shipped to Wyeth’s Sanford, NC, facilities in steel vessels where the CRM197 carrier protein is manufactured, the polysaccharides conjugated to CRM197, and the vaccine is formulated and finished. Final labeling and packaging for product for the European market are performed at Wyeth facilities in Havant, U.K.
See also the entry for Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) or HibTITER (#457). Much like Prevnar (also from Wyeth), HibTITER involves oligosaccharides (from Hae-mophilus influenzae type b) chemically conjugated to purified CRM197 protein.
FDA class: Biologic BLA
CBER class: Bacterial Antigens and Vaccines
Approvals: Date = 20000217; first approval; BLA ref. no. 99-0279 and 99-0724
Date = 20021001; BLA supplement; Indication = immunization of infants and toddlers against otitis media caused by vaccine serotypes
Date = 20080326; BLA supplement; Indication = include coadministration of Pneumococcal 7-valent Conjugate Vaccine (Prevnar) with Havrix for children in the second year of life
Indications: [full text of "Indications and USAGE” section of product insert/labeling; 1/5/2009]:
Prevnar is indicated for active immunization of infants and toddlers against invasive disease caused by S. pneumoniae due to capsular serotypes included in the vaccine (4, 6B, 9V, 18C, 19F, and 23F).
The decision to administer Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein), Prevnar should not be based primarily on its efficacy in preventing invasive pneumococcal disease. As with any vaccine, Prevnar may not protect all individuals receiving the vaccine from invasive pneumococcal disease.
Prevnar is also indicated for active immunization of infants and toddlers against otitis media caused by serotypes included in the vaccine. However, for vaccine serotypes, protection against otitis media is expected to be substantially lower than protection against invasive disease. Additionally, because otitis media is caused by many organisms other than serotypes of S. pneumoniae represented in the vaccine, protection against all causes of otitis media is expected to be low.
(See CLINICAL PHARMACOLOGY for estimates of efficacy against invasive disease and otitis media).
For additional information on usage, see DOSAGE AND ADMINISTRATION.
This vaccine is not intended to be used for treatment of active infection.
protect 100% of individuals receiving the vaccine.
Status: The BLA submission was completed on March 11, 1999, received priority review, and was approved on Feb. 17, 2000; approval time = ~11 months (~.92 years). This was the first priority review granted to a vaccine. Prevnar was launched in Feb. 2000.
In Oct. 2000, Wyeth paid a $30 million fine as part of a consent decree with FDA concerning GMP manufacturing method violations at its Pearl River, NY, facility and also Marietta, PA, facilities (not involved in Prevnar manufacture; being closed down)
The Oct. 2002 sBLA approved Prevnar for prevention of otitis media (ear ache) associated with Streptococcus pneumoniae in infants and toddlers. With pneumococcal disease now rare, this approval expanded indications: to include something parents are more familiar with.
European Union approval was granted on Feb. 2, 2003. However, European and other governments have been slow to adopt the vaccine due to its cost.
After recommendations for widespread use of this vaccine in 2000, a shortage developed. In Aug. 2001, CDC published interim recommendations for vaccination that called for withholding vaccine from healthy children aged 2 years and older and deferring some doses for healthy children aged less than 2 years. Reasons for this shortage included unexpectedly high demand, production difficulties, and the lengthy CBER/FDA release approval procedure required for each lot of vaccine. In July 2003, CDC announced an end to this shortage, with vaccine production and deliveries permitting a return to the routine vaccination schedule. A catch-up schedule was recommended for children who were incompletely vaccinated.
In Oct. 2003, a former Wyeth manufacturing manager, Mr. M. Livingston, filed a lawsuit in federal court against Wyeth and two employees alleging the company cut corners (violated GMP) in training employees and the manufacture of Prevnar at its Sanford, NC, manufacturing facility in its attempts to manufacture more vaccine, and claiming that Wyeth’s actions constitute fraud against shareholders by not revealing problems with Prevnar production (i.e., violated the Sarbanes-Oxley Act of 2002 concerning financial disclosures). Mr. Livingston first brought up his concerns at an FDA meeting in July 2003. The suit does not allege any health risks related to Wyeth’s actions.
In early Feb./March 2004, it was announced that production has been much less than had been expected and shipments have been delayed, resulting in another shortage of Prevnar, and that widespread shortages would likely continue beyond summer 2004. The possibility of a shortage was first announced by CDC in Dec. 2003. To further conserve vaccine, CDC, in consultation with the American Academy of Family Physicians (AAFP), the American Academy of Pediatrics (AAP), and the Advisory Committee on Immunization Practices (ACIP), recommended that health-care providers temporarily suspend routine use of both the third and fourth doses usually administered at 6 months and between 12-15 months for healthy children, with children at increased risk of severe disease continuing to receive the routine 4-dose series. These measures were expected to conserve more than 1 million doses by July 2004, by which time Wyeth expected the shortage to be resolved. Even with the dose schedule halved, 90% of children are expected to be protected against the worst infections, while the full four doses boosts the protective level to 97%. In July 2004, with shortage of Prevnar alleviating somewhat, the Centers for Disease Control and Prevention (CDC) issued a recommendation calling for resumption of use of Prevar for the third vaccination of all healthy children under 24 months of age.
In June 2004, the Australian government announced a $123 million (U.S.) contract with Wyeth to provide Prevnar for pediatric vaccination programs through 2008.
In Sept. 2004, the Centers for Disease Control and Prevention (CDC) issued new recommendations for Prevnar, reinstating the full, four-dose vaccination schedule. A “catch-up schedule” was made available for children who are incompletely vaccinated. This signalled the final end of the shortage of Prevnar. FDA formally designated the first shortage of Prevnar on Nov. 5, 2003, with this resolved on Nov. 14, 2004; and designated a second shortage on Feb. 10, 2004, with this resolved on Sept. 17, 2004.
In 2006, the U.K. adopted universal vaccination with Prevnar, and began major purchases from Wyeth. The vaccine was launched in India in July 2006. Mexico adopted use of the vaccine in late 2006.
In fall 2007, Prevnar was available in more than 80 countries worldwide and was part of the routine national childhood immunization schedule in 17 of these countries.This does not include some major markets, such as Japan, which were expected to adopt Prevnar for universal vaccination. Wyeth planned to launch Prevenar in China (PRC) in 2008.
In Feb. 2008, Wyeth disclosed in its annual report/SEC filings that two former employees were accusing the company of making false claims to FDA regarding manufacturing problems with Prevnar (which in early years had limited availability due to manufacturing problems). Two former staff filed a whistleblowers suit in Nov. 2006 in federal court in Virginia. Wyeth noted that the Dept. of Justice had declined to intervene in the case. One of the former employees, Mr. Livingston, had formerly filed a suit in 2003 charging Wyeth with not complying with training procedures. In 2007, a federal judge found in favor of Wyeth on the “substantive claims” of Livingston’s discrimination suit; Livingston appealed (with no resoluton at the time).
In March 2009, Prevenar (PCV7) received approval in Russia.
On Jan. 8, 2013, Prevenar received sMAA EU approval for use in older children and adolescents aged 6 to 17 years.
Tech. transfer: The University of Rochester receives royalties from sales of Prevnar, receiving total royalties of about $38 million in 2007 (also reported as $51 million) and $35 million in 2005, with about 90% of this from then Prevnar (and most of the rest from Gardasil as its sales ramp-up). Three university pediatric researchers, Drs. David Smith, Porter Anderson and Richard Insel, were among the first to develop and test “conjugate” vaccines. The university has received patents including U.S. 4,902,506 and 5,097,020, “Immunogenic conjugates,” with claims including bacterial polysaccharide antigens conjugated to diphtheria CRM197 carrier protein.
Trials: Nearly 38,000 children were involved in Phase III clinical trials, and Phase IV post licence studies are ongoing, with a study group of 60,000 children. Clinical efficacy was demonstrated in a large, randomized, double-blinded clinical trial which started in October 1995. A total of 37,816 infants received either Prevnar or a Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) (HibTITER) as control at 2, 4, 6 and 12-15 weeks of age. The efficacy rate for prevention of invasive pneumococcal disease (vaccine and non-vaccine serotypes) was 90.0%. Safety was determined in a study of 17,066 infants and children in a trial conducted by Northern California Kaiser Permanent, a large health maintenance organization (HMO), with a total of 55,352 doses administered. Overall, a significant antibody response, defined as the proportion of subjects reaching a given level of antibody concentration (generally ≥ 0.15 µg/mL, 0.5 µg/mL, and ≥ 1.0 µg/mL), was observed following the 3-dose primary series and the fourth booster dose. Response to all serotypes in the vaccine occurred, although the mean geometric antibody concentrations varied among serotypes. For all serotypes, Prevnar induced functional antibodies after the primary series.
A randomized, double-blind, efficacy trial in 1,662 Finnish infants reported in the Feb. 8, 2001 issue of the New England Journal of Medicine found Prevnar effective for prevention of certain childhood ear infections, particularly otitis media. Prevnar showed a 57% reduction in episodes of otitis media caused by the seven pneumococcal serotypes targeted by the vaccine; a 51% reduction in episodes of otitis media caused by serotypes closely related to those targeted by the vaccine; and a 34% reduction in the episodes of otitis media caused by any pneumococcal bacteria. The vaccine reduced recurrent otitis media by 16% and otitis media from any cause by 6%.
In 2003, one year after vaccine licensure, core surveillance sites of the Centers for Disease Control and Prevention (CDC) noted a 78% reduction in invasive pneumococcal disease cases in children younger than two years caused by vaccine serotypes. In 1998 and 1999, there was an average of 156.1 cases per 100,000 of invasive pneumococcal disease caused by vaccine serotypes among children younger than two years of age. In 2001, following routine use of the vaccine, the number of cases fell to 33.6 per 100,000.
In May 2004, the Kaiser Vaccine Study Center reported that pneumococcal infections were reduced 99% in a study of 150,000 vaccinated children; that since required pediatric vaccination began in 2000, the incidence of pneumococcal diseases have reduced by >50% in unvaccinated adults and other close contacts of immunized children; and the overall prevalence of penicillin-resistance pneumococcal infections reduced from 15% to 5% in 2003.
In Oct. 2004, a two-year post-licensing (Phase IV) study by FDA researchers published in the Journal of the American Medical Association (10/13/2004) showed that most adverse side effects associated with Prevnar are minor. However, a few reported cases of post-vaccination seizures in vaccinated children led the researchers to recommend additional studies on the safety of the vaccine. Among the first 98 reported seizures associated with the vaccine, the majority occurred in children who had either experienced a high fever or had a history of seizures.
In the March 26, 2005, issue of The Lancet, U.K. Medical Research Council investigators reported results from a 4-year trial in The Gambia, Africa, in 17,437 young children showing that a variation of Prevnar with 9 conjugate (9-valent) vaccine antigens was effective in the challenging environment of rural Africa. The vaccine had previously been shown effective in urban South Africa. The vaccine reduced childhood mortality by 16% and radiologically-diagnosed pneumonia by 37%, compared to placebo. The e vaccine was 77% effective against invasive pneumococcal. This was the first major randomised, controlled vaccine clinical trial in nearly twenty years to show a statistically significant reduction in overall child mortality. This may facilitate Prevnar-based vaccine use in lesser-developed countries.
In the Sept. 16, 2005, issue of Morbidity and Mortality Weekly Report, (MMWR), the Centers for Disease Control and Prevention (CDC) reported on the direct and indirect effects of routine vaccination of children with Prevnar on the incidence of invasive pneumococcal disease in the U.S., 1998-2003. Routine vaccination of young children with PCV7 continued to result in statistically significant declines in incidence of invasive pneumococcal disease (IPD) through 2003 in the age group targeted for vaccination and among older children and adults. The vaccine prevented more than twice as many IPD cases in 2003 through indirect effects on pneumococcal transmission (i.e., herd immunity) than through its direct effect of protecting vaccinated children. Increases in disease caused by pneumococcal serotypes not included in the vaccine (i.e., replacement disease) occurred in certain populations, but were small compared with overall declines in vaccine-serotype disease. From 1998-1999 to 2003, the incidence of vaccine-type (VT) (serotypes included in PCV7) IPD among children aged <5 years decreased from 80.0 cases per 100,000 population to 4.6, a decline of 94%.
In May 2006, investigators from the Centers for Disease Control and Preven-tion (CDC) reported in the New England Journal of Medicine that since the introduction of Prevnar in the U.S. in 2000, the rate of antibiotic-resistant invasive pneumococcal disease (IPD) has substantially decreased in infants and young children. The study found the rate of antibiotic-resistant IPD caused by penicillin-resistant strains has been reduced by 98% among children younger than two years of age, and by 79% among adults aged 65 years or older, implying an indirect effect in this non-vaccinated population.
In April 2007, investigators at Wake Forest University Medical Center reported the impact of the pneumococcal conjugate vaccination on cases of otitis media and the insertion of pressure-equalizing ear tubes among more than 175,000 children in Tennessee and upstate New York from 1998 to 2002. About 27,000 children in New York and 150,000 children in Tennessee from birth to two years old who were born after the Prevnar was approved were studied. Close to three-quarters of the children had received three doses of the vaccine by the later years of the study. Otitis media and the use of ear tubes plunged 17% in Tennessee and 28% in New York for children in the 1998-1999 cohort. Declines of 16% in Tennessee and 23% in New York were recorded for the 2000-2001 cohort. The declines matched or exceeded the results in Prevnar’s randomized controlled trials, suggesting direct and indirect benefits to children who were or were not fully vaccinated. Also, in April 2007, an investigator from Vanderbilt University School of Medicine reported that vaccinating infants with pneumococcal conjugate vaccine has resulted in a 39% drop in the number of children hospitalized for pneumonia in the U.S.
In Dec. 2007, U.K. government investigators reported that "over 300 children have avoided serious illness like
meningitis, septicaemia and severe pneumonia after being given the pneumococcal conjugate vaccine - just one year after its launch. Of these 300 cases, it is estimated that 17 would have died, and about 30 would have been left with a permanently disability."
These and other studies highlight a continuing trend, with it initially believed that the primary impact of Prevnar would be was on diseases such as meningitis and bacteremia, the vaccine also has shown considerable ability to protect against more common S. pneumonia infections, including pneumonia and otitis media. The vaccine apparently significantly contributes to herd immunity, with less disease among those vaccinated resulting in less transmission to unvaccinated persons. For example, among adults over age 50 in the U.S., there has been a 55% reduction in the number of reported infections due to the serotypes covered by the vaccine.
Medical: For infants, a course of immunization involves three doses of 0.5 mL each at two month intervals (generally 2, 4 and 6 months of age), followed by a fourth booster dose at 12-15 months of age. The customary age for the first dose is 2 months of age, but it may be given as early as 6 weeks of age. The recommended dosing interval is 4-6 weeks, with the fourth dose administered at least two months after the third dose. Prevnar reduces carriage of S. pneumoniae and transmission of pneumococcal disease, unlike the 23-valent vaccine that adults receive.
In June 2000, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Preven-tion (CDC), recommended Prevnar for use in all children under two, and for children between two and five who are at high risk of invasive pneumococcal infection (e.g., sickle cell disease, HIV-infection, immune compromised). Originally, ACIP had suggested that all children up to the age of five years receive the vaccine, but its high cost ($58/dose; over $200/full course) caused the panel to change its recommendation to just those under the age of two. Also in June 2000, the American Academy of Pediatrics (AAP) recommended Prevnar for use in all children 23 months of age or younger, and that the vaccine be given concurrently with other recommended pediatric vaccines at 2, 4, 6, and 12 to 15 months. AAP also recommended the vaccine for all children 24 to 59 months of age (2-12 years), with priority given to high risk groups: a) children aged 24-35 months, b) children who are of Alaskan Native, American Indian, and African-American descent, and c) children who attend group day care centers. The recommendations for use (or non-use) of Prevnar based on cost concerns and race/ethnic parameters set precedents and were controversial.
In May 2003, CDC reported that despite the persisting shortage of Prevnar, introduction of the vaccine has been associated with a 69% decline in invasive disease among children aged less than 2 years through 2001 (78% for vaccine serotypes and 50% for vaccine-related serotypes). It is presumed that vaccinated babies no longer carry the seven most prominent bacterial strains in their noses and throats, so they do not infect parents or other contacts.
An article reviewing the declines in invasive pneumococcal disease after introduction of Prevnar was published in the New England Journal of Medicine, 348, No. 18, p. 1737, May 1, 2003. A 59% overall decline in pneumococcal disease cases was seen in children under five years of age from 1998-2001. Disease rates for serotypes protected by the vaccine de-creased 50%, while there was a 27% increase in serotypes not covered by the vaccine. Rates of disease were also lower among all age populations of adults.
In October 2007, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC) updated the recommendation for use of Prevan in children aged 24-59 months who are either unvaccinated or who have a lapse in PCV7 administration. The new recommendations include: For all healthy children aged 24-59 months who have not completed any recommended schedule for PCV7, administer 1 dose
of PCV7; For all children with underlying medical conditions aged 24-59 months who have received 3 doses, administer 1 dose of PCV7; and For all children with underlying medical conditions aged 24-59 months who have received <3 doses, administer 2 doses of PCV7 at least 8 weeks apart. No changes were made to previously published recommendations regarding (1) the use of PCV7 in children aged 2-23 months, (2) the list of underlying medical or immunocompromising conditions, or (3) the use of 23-valent pneumococcal polysaccharide vaccine in children aged >=2 years who have previously received PCV7.
In March 2008, a CDC study reported, " This vaccine is continuing to provide a very substantial public health impact 6 years after its introduction.We estimate that between 2001 and 2006, 170,000 cases and 9,800 deaths were prevented as a result of this vaccine... The researchers found a significant decline in IPD rates for all age groups (-78%, under 5 years; -38%, 5-17 years; -39%, 18-49 years; -14%, 50-64 years; -32%, 65-79 years; and -42%, 80 years and older) with even greater declines in IPD caused by those strains included in the PCV7 vaccine.The incidence of IPD caused by strains not included in the vaccine rose by 40%.One of the non-vaccine strains, 19A showed an increase of 264%." but that is because these strains were relatively uncommon before the introduction of the vaccine, and the increase in actual numbers is still small."
Despite its high efficacy, Prevnar remains controversial. Some researchers point to a “replacement” effect, with infections by the seven vaccine-targeted strains of pneumococci being replaced by similar infections by the other 80+ strains, which have less competition to colonize the nose and throat. Prevnar vaccination is also associated with a slight increase in middle ear infections, particularly otitis media, caused by two unrelated Streptococci bacteria. These infections appear to spread, because the vaccine wipes out competing pneumococci. The reason other vaccines have not caused this replacement effect is because healthy people don’t normally harbor the bacteria those vaccines protect against, as they do with pneu-mococci.
Concerns persist about the bacterial strains not included in Prevnar. Strains not covered by Prevnar have been shown to multiply in infected children’s noses and throats after the vaccine reduces the amount of the other seven strains. However, the strains not covered by the vaccine are mostly less pathogenic, so this is not an immediate concern, although this poses a threat to high-risk patients with weakened immune systems, e.g., HIV/AIDS patients.
Although the seven pneumococcal serotypes covered by Prevnar are useful in the U.S., Prevnar is not effective against many strains that are prevalent in the developing world. Synflorix provides coverage for more than 80% of pediatric infectious pulmonary diseases worldwide, and could be a major step in reducing the impact of diseases caused by infection from S. pneumoniae and NTHI. Although a study in the NEJM (2001:344;403-409) attempted to address the potential benefit of Prevnar, the data showed that the vaccine only protected 6% of vaccinated children against AOM and resulted in increased infection rates from other pneumococcal serotypes not included in the vaccine. Also, in October 2007, University of Rochester researchers discovered that a serotype 19A pneumococcal strain was resistant to all U.S.-approved pediatric antibiotics was able to cause AOM in children already vaccinated with Prevnar.
Trials: In the Oct. 27, 2006, edition of the Lancet, investigators from the Centers for Disease Control and Prevention (CDC) reported that four inoculations may not be required for immunity. Comparing the effectiveness of different doses in 782 children at risk of pnuemococcal disease because of conditions such as chronic illnesses, and 2,512 other children, the effectiveness of two, three or four doses in preventing infection was very similar up to six months after vaccination. Even after more than six months, there was no significant difference in the impact of the doses. This suggests that alternative schedules may afford good protection and cost savings.
Disease: In Oct. 2007, it was reported that "Since the introduction of PREVNAR in the United States in 2000, the rate of antibiotic-resistant IPD [invasive pneumococcal disease] decreased through 2004 by 98 percent (95% CI: 97.6-98.4) for vaccine serotypes and 81 percent (95% CI: 80-82) for all serotypes in children younger than two years of age.
Market: Total 2012 sales are estimated at about $400 million. Total sales of Prevnar 7 were about $382 in 2011 (based on $82 million reported for the 4th quarter), with Prevnar 13 replacing Prevnar 7; about $892 in 2010; about 3 billion in 2009, $2.7 billion in 2008; $2.4 billion in 2007; $1.96 billion in 2006, ~$1.5 billion in 2005, $1.053 billion in 2004, achieving blockbuster status; and about $950 million in 2003. Over 26 million doses were sold globally in 2005. Total U.S. 2006 sales were $501.7 million. In 2007, about one-half of sales were in the U.S.
Note, for recent years where both Prevnar 13 and 7 are both on the market, sales/revenue data reported for one vs. the other are inconsistent and ambiguous.
Prevnar has been solidly established as the single largest-selling vaccine by a large margin, exceeding the total sales of the next four best-sellers combined, and accounting for about 20% of the worldwide vaccine market of ≤11 billion/year.
The British National Formulary reports Prevenar 13 costs £49.10 for a 0.5ml pre-filled syringe,, while Pneumovax costs £8.32 for a 0.5ml vial and protects against 23 types of pneumococcus, while Pfizer’s vaccine only protects against 13 types
In July 2012, the Joint Committee on Vaccination and Immunisation, U.K., recommending against a switch to Pfizer’s pneumococcal vaccine Prevenar 13 from Sanofi Pasteur’s Pneumovax for adult and other non-infant vaccination, citing costs.
Prevenar 13 is already used in the UK for its childhood immunity programs, but Pfizer was seeking to have this extended to include older adults and people at high-risk, with an EU approval for expanded use granted in Sept. 2011.
Wyeth believes there is a lot of as yet unrealized growth potential for Prevnar, with a potential market of over $3 billion by 2010, well above the market for any other single vaccine. Wyeth reports the vaccine has “virtually eliminated” invasive pneumococcal disease “wherever national immunization programs are undertaken.” Wyeth asserts the market could be expanded by $1.5 with introduction of an adult version of the vaccine. The market could expand even further, if non-profit public health organizations that support vaccination programs in many lesser-developed countries, e.g., GAVI, adopt the vaccine. These very optimistic projections apparently presume that lack of substantial resistance to the relatively high cost of Prevnar.
As reported in the Wall Street Journal, March 31, 2004, apparently referring to profit margins, “Prevnar is the most lucrative vaccine ever made,” then with $2.85 billion sales to date. This level of sales has been attained despite persistent manufacturing problems limiting supply. Sales could increase further, if supply constraints could be resolved. Total first year (2000) U.S. sales were $461 million, the most successful vaccine launch ever.
To attain its projected $3 billion market will require most of all of the world, particularly lesser-developed countries, to adopt Prevnar for universal infant vaccination. The vaccine’s own success limits growth. with the U.S. and other developed countries well on their way to adopting Prevnar for universal vaccination. In 2005, 83% of eligible infants in the U.S. received Prevar, very close to the “gold standard” of over 90% achieved for DTaP/DTP vaccines. Even capturing all of the remaining 17% of infants would result in less than $200 million in additional sales. Wyeth presumes that each 1% of infants in the U.S. accounts for about $10 million in U.S. sales.
As discussed in the Status section of the Pneumococcal Vaccine Products entry above, the World Health Organizations (WHO) has recommended use of Prevenar, facilitating access by Global Alliance for Vaccines and Immunisation (GAVI)-designated lesser-developed countries and public health programs which can purchase the vaccine at substantially subsidized prices (<$1/dose). Many countries and philanthropic organizations are participating in this effort, e.g., in Feb. 2007, Italy, Norway, Russia, the U.K., Canada and the Bill & Melinda Gates Foundation donated $1.5 billion to launch the first advance market commitment (AMC; involving GAVI purchasing vaccine in bulk and reselling it at substantial discount/loss) for pneumococcal vaccine (Prevnar, and vaccines targeted to lesser-developed countries, when they become available).
Wyeth projected manufacture of 20-23 million doses of Prevnar in 2004. A total of 20 million doses were manufactured/sold in 2003.
The 2007 Average Wholesale Price (AWP) is $414.75 ($369.15 in 2004) for 5 single-dose vials, with a Direct Price (manu-facturer’s discount price) of $342.50 ($326.00 in 2005; $304.50 in 2004) (Red Book, 2007). Prices include the $.75/dose ($.75/covered component vaccine) federal excise tax charged by the manufacturer for the federal vaccine injury compensation program.
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 $72.30 for packages of 10 prefilled single-dose syringes ($69.29 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 $62.14 for packages of 10 prefilled single-dose syringes ($57.59 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. Wyeth’s contract with NIP, CDC, expires on March 31, 2008.
In its March 30, 2004 price list, FFF Enterprises, a major biologics distributor, reported $342.50/package of five single-dose vials ($68.50/dose).
Upon launch in the U.S., the vaccine was reported to cost ~$58/dose or $232 for a four-dose series (at quantities ≥1,000 doses).
In the U.K., even with subsidy through the National Health Service (NHS), Prevenar costs £34.50 per initial course of three doses - as much as the other elements in the U.K. immunization programs put together. Other European countries have come under criticism for their slow adoption of Prevnar.
Competition: Prevnar has some advantages over earlier unconjugated pneumococcal vaccines – two older 23-valent pneumococcal polysaccharide vaccines (PNU-IMUNE 23 also from Wyeth, and Pneumovax 23 from Merck & Co.). These were not approved for use or effective in preventing invasive disease (as is Prevnar) in children aged less than two years old, a group at high risk for disease. These unconjugated vaccines also do not decrease nasopharyngeal carriage of S. pneu-mo-niae, a substantial source of transmission, while Prev-nar decreases colonization. Prevnar has also been approved to reduce otitis media.
Prevnar (and Prevenar) face direct competition from another pnuemococcal conjugates vaccine, Synflorix (see related entry) from GlaxoSmithKline. This vaccine contains 10 pneumococcal antigens, three more than Prevnar, with 8 of these conjugated an non-typeable Haemophilus influenzae protein D carrier that also confers immunity against disease from these strains. However, GSK has not yet even discussed introducing Synflorix in the U.S., so Prevnar will retain its dominance in this market at least until Synflorix enters the U.S. market. So, Wyeth appears likely to maintain its current near U.S. monopoly on pneumococcal conjugate vaccine. With international sales being the primary initial market for Synflorix, its impact on Prevenar sales will largely depend on how countries and organizations funding vaccination programs in lesser-developed countries perceive the relative cost-benefits of the two vaccines.
Because of its near 100% efficacy and good safety profile, proving clinical superiority or comparability to Prevnar could be very difficult, costly, and risky (unless approved as a follow-on biologic-type based largely on comparisons, rather than proving efficacy and safety in large placebo-controlled Phase III trials). New entrants would need to conduct large and expensive trials (comparable to those conducted by Wyeth). Prevnar has been so successful for Wyeth that its success is likely to have been a major factor in the company discontinuing its manufacture and marketing of most of its other vaccines.
Companies involvement:
Full monograph
513 Pneumococcal Vaccine(7)-CRM197
Nomenclature:
Pneumococcal Vaccine(7)-CRM197 [BIO]
Prevnar [TR current U.S.]
Prevenar [TR former; used prior to approval]
Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 Protein) [FDA]
PCV7 [SY]
PncCRM [SY]
Streptococcus pneumoniae capsular antigen-Diphtheria CRM197 protein conjugate vaccine [SY]
NDC 0005-1970-67 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 2000
Date of 1st FDA approval = 20000117
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
blepharospasm
bovine materials used<!-- bovinesource -->
conjugates
glycoconjugates
vaccines, bacterial
vaccines, subunit
vaccines, toxoids (inactivated toxins)
bacterial culture <!-- bacterialculture -->
Corynebacterium diphtheriae
CTH
peptone (medium)
soy peptone
Streptococcus pneumoniae
aluminum phosphate
ammonium sulfate
Bacillus anthracis prophylaxis
Corynebacterium diphtheriae CRM197 protein
CRM197 protein
polysaccharides
Streptococcus pneumoniae capsular polysaccharides
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
priority review status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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