Prevenar 13/ Prevnar 13 approval history in Europe and in the U.S

July 22 2013 | By Márcio Barra

Latest update – July 29, 2013

Prevenar 13, or Prevnar 13 as it is known in the U.S., is a 13-valent pneumococcal conjugate vaccine marketed by Pfizer inc. and manufactured by its Wyeth division, used to immunize and protect against Streptococcus pneumoniae infection. This vaccine is the direct successor of the vaccine Prevenar, and is currently the best-selling vaccine in the world (1). The first Prevenar was a 7-valent vaccine that contained 7 different outer sugar coating (polysaccharides) from 7 different Streptococcus pneumoniae serotypes: 4, 6B, 9V, 14, 18C, 19F, and 23F. Each serotype was conjugated to diphtheria toxoid CRM197 protein, which acts as an immunologic carrier (2) (3).

This first Prevenar vaccine was licensed in the United States in 2000 for the prevention of invasive pneumococcal disease caused by the 7 serotypes included in the vaccine. Within 1 year of routine use, incidence of vaccine-serotype invasive pneumococcal disease in the U.S. had fallen dramatically among children younger than 2 years, with indirect effects noted among other age groups as well (4).

In Europe, the vaccine was granted an approval in February 2001 from the European Commission after the European Medicines Agency’s evaluation (5), and the impact of the introduction of the vaccine in the European territory was noticeable. After implementation of routine immunization with Prevenar, the incidence of invasive and non-invasive pneumococcal infections due to vaccine serotypes decreased by 80% in children below 2 years of age (6).

Understandably, the success of the first Prevenar vaccine also led to an increase in disease caused by serotypes not included in the vaccine (e.g. 1, 7 F and 19A), due to antibiotic pressure (7). Prevenar’s successor, Prevenar 13, was developed with this in mind (8), adding  serotypes 1, 3, 5, 6A, 7F, and 19A to the formulation, for a total of 13 serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. The six additional polysaccharides added in Prevenar 13 are responsible for between 16 and 60% of infection cases, and the combination of these 13 serotypes provide coverage for 85% of epidemiologically important pneumococcal serotypes in the United States and throughout the world (9). 19A coverage is especially important seeing as it is the only serotype that is prevalent worldwide, clinically important, and highly multidrug-resistant (10).

Like the first Prevenar vaccine, each Serotype is individually conjugated to diphtheria toxoid CRM197 protein. Succinate buffer is also included in the Prevenar 13 formulation to improve process control and pH control following the addition of aluminum phosphate. 0.02% Polysorbate 80 (P80) is also included in the final vaccine formulation to improve the robustness of the manufacturing process (11).

About Streptoccocus pneumoniae

Pneumonia is one of the leading infectious causes of childhood morbidity and mortality in the world. The organism behind it, Streptoccocus pneumoniae, is a significant human pathogenenic bacterium and, despite its name, it can cause other types of pnemoccocal infections that are not pneumonia, like bacteremia and meningitis, otitis media and sinusitis (12).  In 2010-11, it is estimated that 120 million episodes of pneumonia occurred in children younger than 5 years. Of these 120 million episodes, 14 million progressed to a severe status and 1.3 million resulted in death (13).

There are 91 distinct Streptoccocus pneumoniae serotypes, which can be grouped by immunological similarity into 46 serogroups. However, only 10 to 15 serotypes are responsible for the vast majority of invasive disease worldwide (14).

Approval history of Prevenar 13 – Europe

The first approval for Prevenar 13 in Europe was issued by the European Medicines Agency on 24 September 2009, for the “Active immunisation for the prevention of invasive disease, pneumonia and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks to 5 years of age.” (15) The clinical trial information provided for the evaluation and approval of Prevenar 13 included immunogenicity results from a total of 14 clinical trials, including a formulation study in Poland, 2 pivotal non-inferiority trials in Germany and in US,with safety and immunogenicity data obtained from 4429 infants (16) (17).

Two years later, on 22 September 2011, the vaccine was approved for the “Active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae in adults aged 50 years and older”. This made the vaccine approved in two age groups:  infants and children from 6 weeks to 5 years of age and adults aged 50 years and older (18).

Afterwards, on 15 November 2012, the CHMP issued a positive opinion recommending a variation on the vaccine’s marketing authorization , extending the vaccine’s target pediatric population coverage: “Active immunization for the prevention of invasive disease, pneumonia and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks to 17 years of age” (19)

The last approval was on 30 May 2013, with an additional age group being approved for immunization with the vaccine, bridging the gap between the 6 week – 17 years and 50 or more years population. The approved indication is for the “Active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae in adults ≥18 years of age and the elderly”. The European Commission gave the final approval for this indication on July 10 2013 (20). This decision to approve this label expansion for Prevenar 13 followed the submission and review of data from an open-label Phase 3 trial of the vaccine in healthy adults aged 18 to 49 years (21).

Summing up, the current approved indications for Prevenar 13 in Europe are (22) (23):

  • Active immunization for the prevention of invasive disease, pneumonia and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks to 17 years of age.
  • Active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae in  adults aged 18 years and older.

Dosage schedule of Prevenar 13 in Europe

The vaccination schedule approved in Europe is different for each approved indication and target population (24):

  • Children aged between 6 weeks and 6 months are normally given four doses. The first three doses, each one 0.5 ml, are given within one month of each other, with the first administered as early as six weeks. The last dose is given between 11 and 15 months of age. If Prevenar 13 is given to children as part of an immunization programme, a similar regimen applies, but instead of four doses only three are given. The first dose is administered from the age of 2 months, and the second 2 months later. The third dose is given between 11 and 15 months of age.
  • Children aged 7-11 months are given two doses, each of 0.5 ml, with an interval of at least 1 month between doses. A third dose is recommended in the child’s second year.
  • Children aged 12-23 months are given solely two doses, with an interval of at least 2 months between doses.
  • Children aged 2-17 years are given a single dose of 0.5 ml.
  • Adults aged 18 years and older should receive a single dose of 0.5 ml.

Approval history of Prevenar 13 in the U.S.

In the U.S., the vaccine was first approved in February 2010 by the FDA for the prevention of invasive pneumococcal disease and otitis media caused by Streptococcus pneumoniae  in infants and young children ages 6 weeks through 5 years (25). Safety was evaluated in 5,084 infants and young children who received Prevnar 13, compared with 2,760 who received the first Prevnar vaccine.

Then, on 30 December 2011, Prevnar 13 won approval from the FDA for use in adults 50 and older. Like in Europe, the vaccine was later approved for a wider pediatric age group for prevention of invasive disease; children and adolescents aged 6 years through 17 years, on 25 January 2013(26) (27), This last approval followed the submission and review of a Phase 3, open-label trial of Prevnar 13 in 592 older children and adolescents, with the study hitting all safety and efficacy endpoints (28).

Thus, in the U.S., Prevnar 13 is approved for the following indications (29):

  • 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, and prevention of otitis media caused by S. pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F in children aged 6 weeks through 5 years of age.
  • 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 in children aged 6 years through 17 years of age.
  • 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 in adults 50 years of age and older.

Dosage schedule in the U.S.

As expected, the approved dosage regimen is similar as the one in Europe (30):

  • Children aged 6 weeks through 5 years go through a four-dose immunization series, each consisting of 0.5 mL administered at 2, 4, 6,  and the last one, the booster, given between12-15 months of age.
  • Children aged 6 through 17 years of age are given a single, 0.5 mL dose.
  • Similarly, adults aged 50 years and older take a single dose of 0.5 mL.

Safety Precautions

Like all medicines and vaccines, there are many safety considerations and precautions that a healthcare professional must be aware of when deciding to prescribe the vaccine to a patient. A small list follows (31) (32):

  • Prevenar 13 should not be given to anyone with a history of severe allergic reaction to any component of the vaccine or any diphtheria toxoid–containing vaccine (prevenar contains diphtheria toxoid CRM197 protein),
  • Children and adults with weakened immune systems (e.g., HIV infection, leukemia) may have a reduced immune response from the vaccine,
  • When administering the vaccine in some infants born prematurely, a temporary pause of breathing following vaccination has been observed,
  • The most typically reported serious adverse events in children were bronchiolitis (an infection of the lungs), gastroenteritis (inflammation of the stomach and small intestine), and pneumonia. Common side effects include tenderness, redness, or swelling at the injection site, irritability, decreased appetite, decreased or increased sleep, and fever,
  • In adults, immune responses to the vaccine are reduced when given with seasonal flu vaccine. Common side effects in this population include pain, redness, or swelling at the injection site, limitation of arm movement, fatigue, headache, muscle pain, joint pain, decreased appetite, chills, or rash.

Sales numbers

In the first 9 months that Prevnar 13 was approved in the US, the vaccine generated $2.82 billion in profits (33). More recently, the worldwide revenues for the vaccine increased 2% in 2012, compared to 2011, generating $3.7 billion in revenue for the company and making it Pfizer’s fourth best selling product in 2012 (34).

This makes Prevenar 13 one of the current pillars of the company for future growth, and its expected development hinges mostly on broader indications that the vaccine is currently expecting. While the U.S. Centers for Disease Control and Prevention (CDC) recently recommended it for adults aged 19 years or older with impaired immune system, Pfizer is still awaiting the CDC’s recommendation for adults aged 50 years and above. This is especially important when considering that health plans in the U.S. usually wait for the CDC recommendations to cover the use of a vaccine (35).While the FDA has approved the vaccine in 30 December 2011 for adults aged 50 years and above, the CDC is waiting for the efficacy results of an ongoing clinical study, the Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA trial), which is expected to be completed this year, before recommending the vaccine’s use in this population (36).

On 29 July 2013, Pfizer announced that it agreed to sell 260M shots of Prevnar 13 against pneumococcal disease in poor countries for just a few dollars a shot vs $130 in the U.S, making this the third agreement for Prevnar 13 under a program for companies to sell their drugs cheaply in poor nations. In total, Pfizer is selling 740M doses through 2025.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: