Pneumococcal conjugate vaccine

Pneumococcal polysaccharide vaccine

Vaccine description
Target disease	Streptococcus pneumoniae
Type	Conjugate vaccine
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
MedlinePlus	a607021
Pregnancy cat.	?
Legal status	?
Identifiers
ATC code	J07AL02 J07AL52
N(what is this?)  conjugate vaccine (verify)

Pneumococcal conjugate vaccine (PCV) is a vaccine used to protect infants and young children against disease caused by the bacterium 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.^[1] 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.^[2]

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 ^[3] and GSK received European Commission authorization to market Synflorix in March 2009.^[4]

Prevnar 13 is produced by Pfizer. It is a triskaivalent 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 for immediate release to the public on February 24, 2010. It is to be given on the same schedule as was Prevnar.^[5]

Production technique

Prevnar

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.[1]

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.^[6]

Synflorix

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

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) must be 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.^[7]

United Kingdom

The UK childhood vaccination schedule consists of a primary course of two doses at 2 and 4 months of age with a final third dose aged 13 months.^[8]

Special risk-group

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 then more extensive 23-valent vaccine given after the second year of life:

Vaccination schedule for children at special risk^[8]

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

United States

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.

Efficacy

Prevnar is designed to stop seven of about ninety pneumococcal serotypes which have the potential to cause invasive pneumococcal disease. Each year, IPD kills approximately one million children worldwide.[2] Since approval, Prevnar's efficacy in preventing invasive pneumococcal disease has been documented by a number of epidemiologic studies.^[9][10][11] There is evidence that other people in the same household as a vaccinee also become relatively protected.^[12] 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.^[13]

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.^[14]

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.^[9] 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.^[15][16]

Interestingly, rates of invasive pneumococcal disease among adults has also declined since the introduction of the vaccine.^[9][16] Although, 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.^[17]

Clinical study

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), killing over 800,000 and up to a million children a year. Ninety percent of these deaths occur in the developing world.^[18] Historically 15–20 years pass before a new vaccine reaches one quarter of the population of the developing world.^[19] Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP) is 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. With action now, a projected 5.4 million child deaths can be prevented by 2030. In May 2007, 30 of the 72 GAVI countries expressed interest in introducing pneumococcal conjugate vaccine between 2008 and 2010. These countries are Benin, Burundi, the Republic of Congo, Rep. of Côte d'Ivoire, Djibouti, the Democratic Republic of Congo, Ethiopia, Ghana, Guyana, Honduras, Indonesia, Kenya, Madagascar, Malawi, Mali, Mongolia, Nicaragua, Pakistan, Rwanda, São Tomé and Príncipe, Senegal, Solomon Islands, Sri Lanka, Sudan, The Gambia, Timor Leste, Togo, Uganda, Yemen, and Zambia.^[20] In April 2009 the first of these countries, Rwanda, introduced Prevnar into its routine vaccination schedule. The use of this vaccine in Rwanda is expected to save thousands of children each year and dramatically reduce the economic burden of this disease. It is expected that GAVI will help to fund many other low-income introductions in the coming years.^[21]

Sales

Prevnar is among Wyeth's top revenue producers, with sales in 2005 of $1.5 billion, up 43 percent from 2004.Wyeth Annual report

Controversy

Controversy has arisen regarding 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.^[22]

In addition, Wyeth has been accused of conflict of interest in economic evaluations of Prevnar.^[23]

The selling price of conjugate vaccines is clearly very high.^[14][24] The WHO, pneumo ADIP and other associations are taking steps to make cheaper, more effective vaccines available with partners in countries such as India, and Brazil.^{[citation needed]}

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.[3]

Concerns about serotype replacement have been circulating since the CDC published a study in 2006 [4] 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 new, more virulent and less treatable (antibiotic resistant) strain. 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. Journal of the American Medical Association (JAMA), Sept. 2010. [5]

See also

• Streptococcus pneumoniae
• Pneumonia
• PneumoADIP
• Pneumococcal polysaccharide vaccine

References

1. ^ "Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM₁₉₇ Protein)". Wyeth. 2006. http://www.wyeth.com/content/ShowLabeling.asp?id=134. 
2. ^ "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. PMID 10920169. 
3. ^ EMEA Document
4. ^ GSK Release
5. ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm201758.htm
6. ^ Morbidity and Mortality Weekly Report (MMWR)March 12, 2010 / 59(09);258-261 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5909a2.htm
7. ^ Childhood Pneumococcal Disease - information on the disease and the Prevnar vaccine, from the Victoria State (Australia) government. Includes possible side effects.
8. ^ ^{a b} "Chapter 25: Pneumococcal" (PDF). Immunisation against infectious disease - 'The Green Book'. Department of Heath (UK). 2006. http://www.dh.gov.uk/dr_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/dh_063655.pdf. 
9. ^ ^{a b c} Whitney CG, Farley MM, Hadler J, et al. (May 2003). "Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine". The New England journal of medicine 348 (18): 1737–46. doi:10.1056/NEJMoa022823. PMID 12724479. 
10. ^ Poehling KA, Talbot TR, Griffin MR, et al. (April 2006). "Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine". JAMA : the journal of the American Medical Association 295 (14): 1668–74. doi:10.1001/jama.295.14.1668. PMID 16609088. 
11. ^ Whitney CG, Pilishvili T, Farley MM, et al. (October 2006). "Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study". Lancet 368 (9546): 1495–502. doi:10.1016/S0140-6736(06)69637-2. PMID 17071283. 
12. ^ Millar EV, Watt JP, Bronsdon MA, et al. (2008). "Indirect effect of 7‐valent pneumococcal conjugate vaccine on pneumococcal colonization among unvaccinated household members". Clin Infect Dis 47 (8): 989–996. doi:10.1086/591966. PMID 18781875. 
13. ^ 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. http://www.biomedcentral.com/content/pdf/1471-2334-11-314.pdf. 
14. ^ ^{a b} Barocchi MA, Censini S, Rappuoli R (2007). "Vaccines in the era of genomics: the pneumococcal challenge". Vaccine 25 (16): 2963–73. doi:10.1016/j.vaccine.2007.01.065. PMID 17324490. 
15. ^ Grijalva CG, Nuorti JP, Arbogast PG, Martin SW, Edwards KM, Griffin MR (April 2007). "Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis". Lancet 369 (9568): 1179–86. doi:10.1016/S0140-6736(07)60564-9. PMID 17416262. 
16. ^ ^{a b} Tsai CJ, Griffin MR, Nuorti JP, Grijalva CG (June 2008). "Changing epidemiology of pneumococcal meningitis after the introduction of pneumococcal conjugate vaccine in the United States". Clinical Infectious Diseases 46 (11): 1664–72. doi:10.1086/587897. PMID 18433334. 
17. ^ Albrich WC, Baughman W, Schmotzer B, Farley MM (June 2007). "Changing characteristics of invasive pneumococcal disease in Metropolitan Atlanta, Georgia, after introduction of a 7-valent pneumococcal conjugate vaccine". Clinical Infectious Diseases 44 (12): 1569–76. doi:10.1086/518149. PMID 17516400. 
18. ^ "Pneumococcal vaccines. WHO position paper". Relevé épidémiologique hebdomadaire / Section d'hygiène du Secrétariat de la Société des Nations = Weekly epidemiological record / Health Section of the Secretariat of the League of Nations 74 (23): 177–83. June 1999. PMID 10437429. 
19. ^ PneumoADIP | Need for PneumoADIP
20. ^ PneumoADIP | Vaccine Introduction
21. ^ Rwanda Becomes First Developing Nation to Introduce Vaccine for World's Leading Infectious Child Killer
22. ^ "Controversial pneumococcal vaccine ad - Polish Market News". http://www.polishmarket.com/next.php?id=48543. Retrieved 2008-02-20. 
23. ^ 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. 
24. ^ 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:10.1586/14760584.6.3.297. PMID 17542743. 

External links

• World Health Organization: Pneumococcal vaccines
• Pneumococcal conjugate vaccine at the Open Directory Project