(13)-CRM197
Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) - Prevnar 13; Prevenar 13; Streptococcus pnuemoniae capsular antigen-Diphtheria CRM197 protein conjugate vaccine; PCV13
Status: Approved by FDA in 2010 and in the EU in Dec. 2011
Organizations involved:
Prizer – Manuf.; R&D; Tech.; World mark.
Wyeth – Former
Cardinal Health, Inc. – Manuf. other
1
Praxis Biologics, Inc. – Former
University of Rochester – Tech.
Cross ref.: See the Pneumococcal Vaccines entry (#512), and the entry for Prevar 7, which this product is slated to replace. See also the entry (#457) for Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) or HibTITER also involving CRM197-conjugate bacterial polysaccharide.
Description: Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) or Prevnar 13 (PCV13) is a 13-antigen-containing aqueous formulation of partially hydrolyzed capsular (outer coat) polysaccharide and oligosaccharide antigens from the seven Streptococcus pneumoniae bacteria serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) contained in prior Prevnar7, each individually cultured, purified, chemically conjugated to diphtheria CRM197 carrier protein (apparently, a recombinant protein), and adsorbed on aluminum phosphate adjuvant; plus six additional serotypes (1, 3, 5, 6A, 7F and 19A), each associated with the greatest remaining burden of invasive diseas and individually cultured, purified, chemically conjugated to diphtheria CRM197 carrier protein.
Prevnar 13 is packaged in a prefilled syring and is stored refrigerated at +2ºC to +8ºC (36ºF to 46ºF).
Coverage includes serotype 19A, which has has emerged as the predominant invasive pneumococcal serotype in the U.S. 19A is frequently resistant to antibiotics.
Nomenclature: Pneumococcal Vaccine(13)-CRM197 [BIO]; Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) [FDA, preliminary]; Prevnar 13 [TR]; Prevenar 13 [TR foreign, presumably]; PCV13 [SY]; Streptococcus pnuemoniae capsular antigen-Diphtheria CRM197 protein conjugate vaccine [SY]; NDC 0005-1971-02 [NDC]
Companies.: Prevnar 13 was developed and is manufactured and marketed by Wyeth, now merged into Pfizer
In March 2010, Pfizer signed a 10-year Provisional Supply Agreement to supply Prevenar 13 for infants and young children in the world’s poorest countries under the terms of the Advance Market Commitment (AMC) pilot project against pneumococcal disease, administered by the United Nations Children’s Fund (UNICEF) and supported by GAVI. The AMC is a novel public-private approach to public health funding designed to create a sustainable marketplace, ensure a stable supply of pneumococcal vaccines and stimulate the development and expansion of manufacturing capacity of vaccines specifically for the world’s poorest countries. Under the terms of the agreement, the price of the vaccine under the AMC framework is $7.00 for the first several years. The vaccine price will include a $3.50 subsidy to be paid by the AMC donor fund, and $3.50 to be paid by GAVI with a co-financing contribution paid by the developing country governments that introduce the vaccine. Participating vaccine manufacturers must make a binding commitment to supply vaccine for 10 years at a maximum “tail” price of $3.50 per dose to meet long-term demand and ensure affordability of the vaccine in developing countries even after the donor contributions are exhausted.
Manufacture:
Prevnar 13 is a
sterile suspension of saccharides of the capsular antigens of Streptococcus pneumoniae
serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, individually linked to nontoxic
diphtheria CRM197 protein. Each serotype is grown in soy peptone broth. The individual
polysaccharides are purified through centrifugation, precipitation, ultrafiltration, and column
chromatography. The polysaccharides are chemically activated to make saccharides, which are
directly conjugated by reductive amination to the protein carrier CRM197, to form the
glycoconjugate. CRM197 is a nontoxic variant of diphtheria toxin isolated from cultures of
Corynebacterium diphtheriae strain C7 (β197) grown in a casamino acids and yeast extract-based
medium. CRM197 is purified through ultrafiltration, ammonium sulfate precipitation, and
ion-exchange chromatography. The individual glycoconjugates are purified by ultrafiltration
and column chromatography and analyzed for saccharide to protein ratios, molecular size, free
saccharide, and free protein.
The individual glycoconjugates are compounded to formulate Prevnar 13. Potency of the
formulated vaccine is determined by quantification of each of the saccharide antigens and by
the saccharide to protein ratios in the individual glycoconjugates. Each 0.5 mL dose of the
vaccine is formulated to contain approximately 2.2 μg of each of Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F saccharides, 4.4 μg of 6B saccharides,
34 μg CRM197 carrier protein, 100 μg polysorbate 80, 295 μg succinate buffer and 125 μg
aluminum as aluminum phosphate adjuvant.
FDA class: Biologic BLA
Approvals: Date = 20100224, full BLA
Date = 20111230, supplemental accelerated BLA approval for adults 50 years of age and older for active immunization for the prevention of pneumonia and invasive disease caused by the 13 Streptococcus pneumoniae serotypes contained in the vaccine
Date = 20130125; BLA supplement; Indication = use in children and adolescents aged 6 years to 17 years.
Indications: [Full text of the "INDICATIONS AND USAGE" section of the product insert/labeling; not yet updated with Jan. 2013 approval];
In children 6 weeks through 5 years of age (prior to the 6th birthday),
Prevnar 13 is a vaccine indicated for:
Status: On Dec. 3, 2008, Wyeth filed a MAA seeking European Union (EU) approval of Prevnar 13, referring to it as PCV13.
Wyeth filed a BLA for Prevnar 13 on March 31, 2009. In May 2008, FDA had granted fast-track designation to Wyeth’s planned BLA for its 13-valent, new version of Prevnar. In March 2009, Wyeth submitted its BLA for Prevnar 13. The BLA submission included data from 13 Phase 3 studies, involving more than 7,000 infants and young children. The Company initiated its global pediatric filings in late 2008 and, to date, has submitted regulatory applications for the 13-valent candidate vaccine in more than 40 countries worldwide. Prevnar 13 is also being studied in global Phase 3 clinical trials in adults, with regulatory submissions expected in 2010.
In Dec. 2009, the EMA/EU granted approval of Prevnar 13.
In Oct. 2010, the EU granted supplemental MAA approval for the prevention of vaccine-type invasive disease caused by Streptococcus pneumoniae in adults aged 50 years and older. This indication covers the prevention of invasive pneumococcal disease caused by the 13 serotypes contained in the vaccine and is for a single dose of Prevnar 13 in adults aged 50 years and older. Regardless of prior pneumococcal vaccination status, if the use of 23-valent polysaccharide vaccine is considered appropriate, Prevenar 13 should be given first.
In Feb. 2012, the Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) recommended Prevnar 13 for all adults 50 years of age and older, given the current burden of pneumococcal disease in this age group.
Tech. transfer: The U.S. product insert cites 5,614,382, "Plasmid for production of CRM protein and diphtheria toxin."
Trials: The Prevnar 13 submission to the FDA included data from 13 Phase III studies, involving more than 7,000 infants and young children. Wyeth initiated its global pediatric filings in late 2008 and in March 2009 submitted regulatory applications for the 13-valent candidate vaccine in more than 40 countries worldwide. The PCV13 submission to EU regulators included data from 12 Phase 3 studies, involving more than 7,000 infants and young children.
Data from these studies have demonstrated that, for the pneumococcal serotypes common to both the new and older vaccines, the immunogenicity of PCV13 is comparable to that of PCV7 using a pre-determined set of immunological criteria. PCV13 elicits antibacterial functional antibodies to the six additional serotypes. These observations indicate that PCV13 may be as effective as PCV7 in preventing invasive pneumococcal disease (IPD) due to the seven shared serotypes in the vaccines and may also be effective in helping to prevent IPD due to the six additional serotypes. The results also showed that the safety and tolerability of PCV13 and PCV7 are comparable, and that PCV13 can be administered with other commonly used pediatric vaccines..
Safety was evaluated in 5,084 infants and young children who received Prevnar 13, compared with 2,760 who received Prevnar, the control vaccine. Common adverse reactions reported after administration of Prevnar 13 were pain, redness and swelling at the injection site, irritability, decreased appetite and fever. These reactions were similar to what has been observed with Prevnar, which has a good safety record in the United States.
Market: Prevnar 13 costs about $130/dose in the U.S.
This vaccine competes 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.
Total worldwide sales were $3.718 billion in 2012 and $3.657 in 2013. Note, Prevnar 7 was also marketed during this period.
In Nov. 2012, Pfizer in its 3rd quarter report noted that Prevnar 7 sales were down 17% and Prevnar 13 sales were down 14%. Also, Prevnar 13 use in adults--one of the company's strategies for expanding the franchise--"remains minimal at this time."
Companies involvement:
Full monograph
513.3 Pneumococcal Vaccine
active immunization for the prevention of invasive disease caused
by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F,
9V, 14, 18C, 19A, 19F and 23F.
active immunization for the prevention of otitis media caused by
Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F,
and 23F. No otitis media efficacy data are available for
serotypes 1, 3, 5, 6A, 7F, and 19A.
In adults 50 years of age and older, Prevnar 13 is a vaccine indicated for:
active immunization for the prevention of pneumonia and invasive
disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5,
6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. This indication is
based on immune responses elicited by Prevnar 13. There have
been no controlled trials in adults demonstrating a decrease in
pneumococcal pneumonia or invasive disease after vaccination
with Prevnar 13.
Limitations of Prevnar 13 Use and Effectiveness
Prevnar 13 will not protect against disease caused by
Streptococcus pneumoniae serotypes that are not in the vaccine.
The effectiveness of Prevnar 13 administered less than 5 years
after 23 valent pneumococcal polysaccharide vaccine is not
known.
Nomenclature:
Pneumococcal Vaccine(13)-CRM197 [BIO]
Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein) [FDA, preliminary]
Prevnar 13 [TR]
Prevenar 13 [TR foreign, presumably]
PCV13 [SY]
Streptococcus pnuemoniae capsular antigen-Diphtheria CRM197 protein conjugate vaccine [SY]
NDC 0005-1971-02. [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 2010
Date of 1st FDA approval = 20100224
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
conjugates
glycoconjugates
nonoxynol 101 (Triton N101)
vaccines, bacterial
bacterial culture <!-- bacterialculture -->
casamino acids
Corynebacterium diphtheriae
CTH
peptone (medium)
soy peptone
Streptococcus pneumoniae
yeast extract
aluminum phosphate
ammonium sulfate
Bacillus anthracis prophylaxis
Corynebacterium diphtheriae CRM197 protein
polysaccharides
Streptococcus pneumoniae capsular 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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