Pneumococcal conjugate vaccine
|Target disease||Streptococcus pneumoniae|
|Legal status||℞-only (US)|
|(what is this?)|
Pneumococcal conjugate vaccine (PCV) is a pneumococcal vaccine used to protect infants and young children against disease caused by the bacteria Streptococcus pneumoniae (pneumococcus). There are currently three PCV vaccines available on the global market: Prevnar (called Prevenar in some countries), Synflorix and Prevnar 13.
Prevnar is a heptavalent vaccine, meaning that it contains the cell membrane sugars of seven serotypes of pneumococcus, conjugated with Diphtheria proteins. It was manufactured by Wyeth. In the United States, vaccination with Prevnar is recommended for all children younger than 2 years, and for unvaccinated children between 24 and 59 months old who are at high risk for pneumococcal infections.
Synflorix is produced by GlaxoSmithKline. It is a decavalent vaccine, meaning that it contains ten serotypes of pneumococcus (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F) which are conjugated to a carrier protein. Synflorix received a positive opinion from the European Medicines Agency for use in the European Union in January 2009  and GSK received European Commission authorization to market Synflorix in March 2009.
Prevnar 13 is produced by Pfizer. It is a tridecavalent vaccine, meaning that it contains thirteen serotypes of pneumococcus (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) which are conjugated to a carrier protein. Prevnar 13 was approved by the U.S. Food and Drug Administration on February 24, 2010. However, the Centers for Disease Control and Prevention (CDC) has since stated that it will await the outcome of a trial under way in the Netherlands before deciding whether to recommend the drug for all adults aged 50 or older.
- 1 Production technique
- 2 Schedule of vaccination
- 3 Efficacy
- 4 Evidence supporting addition to routine vaccination schedules
- 5 Clinical study
- 6 Vaccination in Low-Income Countries
- 7 Sales
- 8 Controversy
- 9 See also
- 10 References
- 11 External links
The original Prevnar was produced from the seven most prevalent strains of Streptococcus pneumoniae bacteria in the US. The bacterial capsule sugars, a characteristic of these pathogens, are linked to CRM197, a nontoxic recombinant variant of diphtheria toxin (Corynebacterium diphtheriae).
The vaccine's polysaccharide sugars are grown separately in soy peptone broths. Through reductive amination, the sugars are directly conjugated to the protein carrier CRM197 to form the glycoconjugate. CRM197 is grown in Corynebacterium diphtheriae strain C7 in a medium of casamino acids and yeast extracts.
The original 7-valent formulation contains serotypes 4,6B,9V,14,18C,19F, and 23F, and results in a 98% probability of protection against these strains, which caused 80% of the pneumococcal disease in infants in the US. In 2010, Pfizer introduced Prevnar 13 which contains six additional strains (i.e., 1, 3, 5, 6A, 19A and 7F), which protect against the majority of the remaining pneumococcal infections.
Synflorix contains antigen from ten pneumococcal serotypes: the seven that are contained in Prevnar, plus serotypes 1, 5, and 7F. Eight of the ten serotypes are linked to a protein carrier derived from non-typeable Haemophilus influenzae strains.
Schedule of vaccination
As with all immunizations, whether it is available or required, and under what circumstances, varies according to the decisions made by local public health agencies.
Children under the age of two years fail to mount an adequate response to the 23-valent adult vaccine, and so the 7-valent Pneumococcal Conjugated Vaccine (PCV) (e.g. Prevnar) is used. Whilst this covers only seven strains out of more than ninety strains, these seven strains cause 80% to 90% of cases of severe pneumococcal disease, and it is considered to be nearly 100% effective against these strains.
Children at special risk (e.g., sickle cell disease and asplenia) require as full protection as can be achieved using the 7-valent congugated vaccine, with the more extensive 23-valent vaccine given after the second year of life:
|Age||2–6 months||7–11 months||12–23 months|
|Conjugated vaccine||3 x monthly dose||2 x monthly dose||Further dose in second year of life|
|23-valent vaccine||Then after 2nd birthday single dose of 23-valent|
In 2001, the Centers for Disease Control (CDC), upon advice from its Advisory Committee on Immunization Practices, recommended the vaccine be administered to every infant and young child in the US. The resulting demand outstripped production, creating shortages not resolved until 2004. All children, according to current US vaccination schedules, should receive four doses, at two months, four months, six months, and again between one year and fifteen months of age.
Prevnar is designed to stop seven of about ninety pneumococcal serotypes which have the potential to cause invasive pneumococcal disease (IPD). Each year, IPD kills approximately one million children worldwide. Since approval, Prevnar's efficacy in preventing IPD has been documented by a number of epidemiologic studies. There is evidence that other people in the same household as a vaccinee also become relatively protected. In fact, there is evidence that routine childhood vaccination reduces the burden of pneumococcal disease in adults and especially high-risk adults, such as those living with HIV/AIDS.
The vaccine is, however, primarily developed for the U.S. and European epidemiological situation, and therefore it has only a limited coverage of serotypes causing serious pneumococcal infections in most developing countries.
Evidence supporting addition to routine vaccination schedules
After introduction of the pneumococcal conjugate vaccine in 2000, several studies described a decrease in invasive pneumococcal disease in the United States. One year after its introduction, a group of investigators found a 69% drop in the rate of invasive disease in those age less than 2 years of age. By 2004, all-cause pneumonia admission rates had declined by 39% (95% CI 22–52) and rates of hospitalizations for pneumococcal meningitis decreased by 66% (95% CI 56.3-73.5) in children younger than 2.
Interestingly, rates of invasive pneumococcal disease among adults has also declined since the introduction of the vaccine. However, it is more difficult to specifically attribute this decline in adults to the childhood pneumococcal conjugate vaccine since the adult pneumococcal 23-valent polysaccharide vaccine is also available.
While an overall decline in invasive pneumococcal disease is well documented, concerns have been raised regarding a potential increase in the rate of infections caused by serotypes not covered in the vaccine. Recent data suggest that serotype replacement is increasing (1.61- and 1.28-fold increase in children and adults) but remains minimal when compared to the significant reduction observed in the burden of this vaccine-preventable disease.
Prevnar was administered to nearly 20,000 children prior to licensure, and the side effects were evaluated. Rashes at the site of injection were noted in about one percent of children.
Vaccination in Low-Income Countries
Pneumococcal disease is the leading vaccine-preventable killer of young children worldwide, according to the World Health Organization (WHO). It killed more than 500,000 children younger than five years of age in 2008 alone. Approximately ninety percent of these deaths occur in the developing world. Historically 15–20 years pass before a new vaccine reaches one quarter of the population of the developing world.
Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP) was a GAVI Alliance (GAVI) funded project to accelerate the introduction of pneumococcal vaccinations into low-income countries through partnerships between countries, donors, academia, international organizations and industry. GAVI continues this work and as of March 2013, 25 GAVI-eligible and supported countries have introduced the pneumococcal conjugate vaccine. Further, 15 additional GAVI countries have plans to introduce the vaccine into their national immunization program and 23 additional countries have approved GAVI support to introduce the vaccine.
Prevnar was among Wyeth's top revenue producers, with sales in 2005 of $1.5 billion, up 43 percent from 2004.
Controversy surrounded pneumococcal vaccine advertisements aired by Wyeth in Poland and Saudi Arabia. A television commercial for Prevnar, showing a dying child and its mother, was banned in Poland by the main pharmaceutical inspector (GIF), Zofia Ulz, on April 3, 2007. According to Ulz, the ad was designed to provoke fear to attract customers. Wyeth responded by asserting the tactic was used to increase awareness of the potential danger represented by pneumococcal infections.
In addition, Wyeth was accused of conflict of interest in economic evaluations of Prevnar.
The selling price of conjugate vaccines is clearly very high. The WHO, pneumo ADIP and other associations are taking steps to make cheaper, more effective vaccines available with partners in countries such as India, South Africa and Brazil.
Authorities in the Netherlands banned use of one batch of Pfizer's Prevenar after three infants died within two weeks of receiving the anti-infection vaccination. A Pfizer spokeswoman said that the three infants also received two unrelated other vaccines as part of routine immunizations. The Netherlands National Institute for Public Health and the Environment was investigating the cause of the infants' deaths. Other batches of Prevenar will continue to be used. The Pfizer spokeswoman said preliminary investigations by the company and health authorities had found no link between the vaccinations and the deaths and that the company initiated the "quarantine" of the batch which contained 110,000 doses of Prevenar.
Concerns about serotype replacement have been circulating since the CDC published a study in 2006 More recently, it was confirmed that children vaccinated with 7-valent PCV pneumococcal conjugate vaccine showed an increased rate of carriage of serotype 19A, a reasonably common disease-causing strain not included in the PCV7 vaccine. The study showed that the increased carriage rates were dose-dependent. Healthy infants were vaccinated with three doses, two doses, or were unvaccinated for PCV.
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- "American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis". Pediatrics 106 (2 Pt 1): 362–6. 2000. doi:10.1542/peds.106.2.362. PMID 10920169.
- EMEA Document
- GSK Release
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm201758.htm[full citation needed]
- Beasley, Deena; Dobbyn, Tim (February 22, 2012). "Prevnar trial results needed for CDC recommendation". Reuters.
- Centers for Disease Control and Prevention (CDC) (March 2010). "Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children — Advisory Committee on Immunization Practices (ACIP), 2010". MMWR Morb. Mortal. Wkly. Rep. 59 (9): 258–61. PMID 20224542.
- Childhood Pneumococcal Disease - information on the disease and the Prevnar vaccine, from the Victoria State (Australia) government. Includes possible side effects.
- "Chapter 25: Pneumococcal". Immunisation against infectious disease - 'The Green Book' (PDF). Department of Heath (UK). 2006.
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- Siemieniuk, Reed A.C.; Gregson, Dan B.; Gill, M. John (Nov 2011). "The persisting burden of invasive pneumococcal disease in HIV patients: an observational cohort study". BMC Infectious Diseases 11: 314. doi:10.1186/1471-2334-11-314. PMC 3226630. PMID 22078162.
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- PneumoADIP | Need for PneumoADIP
- Johns Hopkins Bloomberg School of Public Health, International Vaccine Access Center (2013). VIMS Report: Global vaccine introduction.
- http://phx.corporate-ir.net/phoenix.zhtml?c=78193&p=irol-sec Wyeth Annual report]
- "Controversial pneumococcal vaccine ad - Polish Market News". Retrieved 2008-02-20.
- Beutels P (2004). "Potential conflicts of interest in vaccine economics research: a commentary with a case study of pneumococcal conjugate vaccination". Vaccine 22 (25–26): 3312–22. doi:10.1016/j.vaccine.2004.03.001. PMID 15308354.
- Beall B (June 2007). "Vaccination with the pneumococcal 7-valent conjugate: a successful experiment but the species is adapting". Expert review of vaccines 6 (3): 297–300. doi:10.1586/147605184.108.40.2067. PMID 17542743.
- http://web.archive.org/web/20091109191848/http://www.msnbc.msn.com/id/33671008/ns/health-infectious_diseases/[full citation needed]
- Pai, R; Moore, MR; Pilishvili, T; Gertz, RE; Whitney, CG; Beall, B; Active Bacterial Core Surveillance Team (2005). "Postvaccine genetic structure of Streptococcus pneumoniae serotype 19A from children in the United States". The Journal of infectious diseases 192 (11): 1988–95. doi:10.1086/498043. PMID 16267772.
- Van Gils, EJ; Veenhoven, RH; Hak, E; Rodenburg, GD; Keijzers, WC; Bogaert, D; Trzcinski, K; Bruin, JP et al. (2010). "Pneumococcal conjugate vaccination and nasopharyngeal acquisition of pneumococcal serotype 19A strains". JAMA : the journal of the American Medical Association 304 (10): 1099–106. doi:10.1001/jama.2010.1290. PMID 20823436.