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Mount Sinai Hospital is a University of Toronto patient care, teaching, and research centre.
Mount Sinai Hospital is a University of Toronto patient care, teaching, and research centre.

Frequently Asked Questions

FAQ: PREVNAR

 

PREVNAR
The World's First and Only Pneumococcal Conjugate Vaccine

The first vaccine to help prevent pneumococcal diseases, Prevnar™, a conjugated pneumococcal polysaccharide will be marketed by Wyeth-Ayerst Canada, on January 2001. It targets the seven serotypes (strains) of pneumococcus that cause more than 80% of serious pneumococcal disease in North American children.

Introduction

S. pneumoniae is an important cause of morbidity and mortality in persons of all ages worldwide. The organism causes invasive infections, such as bacteremia and meningitis, as well as pneumonia and upper respiratory tract infections including otitis media and sinusitis. In children older than 1 month, S. pneumoniae is the most common cause of bacteremic disease. It is estimated there are over one million annual deaths worldwide caused by this organism in children less than 5 years of age, mostly due to pneumonia. It is found as the causing organism in 50% of cases with bacterial meningitis, 85% of bacteremia, 66% of bacteremic pneumonia, and 40% of bacterial acute otitis media among children. In a population - based surveillance study conducted in Toronto and area from 1995 to 1998, in children < 16 years old, it was found that the incidence of S. pneumonia infections was 13.8 cases/100,000/year, and according to age groups of 0-6 months, and 6-23 months, the average annual incidence was respectively 23 and 70 per 100,000.

Children who are at increased risk in getting pneumococcal infections include children with anatomic or functional asplenia (including those with sickle cell disease), recipients of chemotherapy, those with congenital and acquired immunodeficiency, those with chronic renal disease (including nephrotic syndrome), those with diabetes, with cerebro-spinal fluid leak, and also children attending out of home care.

Every year in Canada, over half a million cases of pneumococcal disease are reported in infants and children, and thousands of Canadian children will undergo ear tube insertion to treat otitis media. The total annual treatment costs for pneumococcal disease amounts to nearly 200 million dollars a year. This includes unscheduled physician visits, surgical interventions and hospitalization. In addition, pneumococcal disease results in lost work time for parents due to at-home care for children who miss school or day care. Increased resistance to penicillin and other important classes of antimicrobials has complicated the management of S. pneumoniae infections in recent years. In the study conducted in Toronto, it was found that 28.5% of isolates were antimicrobial resistant S. pneumoniae (DRSP) and resistance to >2 antimicrobial classes ( penicillin and other antibiotics), increased from 10.3% to 25.3% from 1995 to 1998. Continued reductions in antimicrobial prescribing and vaccination may have the greatest impact to reduce infections caused by drug resistant S. pneumoniae.

Approximately 90 serotypes of S. pneumoniae have been identified based on antigenic differences in their capsular polysaccharides. The distribution of responsible for disease differs with age and geographic location. Serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F have been responsible for approximately 80% of invasive pneumococcal disease in children <6 years old. In the Toronto study 84.2% of all isolates are included in the heptavalent pneumococcal conjugate vaccine called Prevnar, which includes the serotypes previously mentioned.

The Vaccine

Bacterial polysaccharides, including those present on the pneumococcal capsule, are T-independent antigens. Infants and very young children respond poorly to T-independent antigens. Immune system response to T-independent antigens requires 2 or 3 years after birth to develop.

Conjugation of polysaccharides to proteins changes the response to polysaccharide from T-independent to T-dependent. This antigen complex stimulates a T-helper cell response, leading to a substantial primary response among infants and stronger booster response at reexposure.

The vaccine currently in use, licensed in 1983, contains purified capsular polysaccharide antigen of 23 serotypes of S. pneumoniae. Although this vaccine has been effective in reducing severe disease in the adult population, it cannot impact significantly on the frequency of disease in children <2 years of age because it does not elicit a significant antibody response in these children. This vaccine also has not been shown to be effective in protection against acute otitis media caused by S. pneumoniae. In contrast, the new conjugated heptavalent pneumococcal vaccine induces good antibody responses in 90% to 100% of children to all seven vaccine serotypes, after administration of 3 doses.

Vaccine Composition

The 7-valent pneumococcal conjugate vaccine (PCV7), Prevnar (Lederle Laboratories/Wyeth- Ayerst ) was licensed in US by US FDA on February 2000, and also is in market in Switzerland, Argentina and Peru. It is expected to be licensed in Canada early in 2001. It includes seven purified capsular polysaccharides of S. pneumoniae, each coupled with a nontoxic variant of diphtheria toxin, CRM197 (CRM, cross-reactive material). The vaccine contains capsular polysaccharides from serotypes 4, 9V, 14, 19F, and 23F, and oligosaccharide from 18C, 6B, the carrier protein CRM 197, and aluminum phosphate adjuvant. Prevnar contains no thimerosal or other preservative. Serotypes included in PCV7 accounted for 86% of bacteremia, 83% of meningitis, and 65% of AOM among children aged <6 years occurring in the United States during the period 1978-1994.

Efficacy

In a prospective double-blind study among patients of a health maintenance organization in northern California, a total of 37,830 healthy children were randomly assigned to receive either PCV7 or a control (meningococcal C conjugate) vaccine. Vaccinations were administered at ages 2, 4, 6 and 12-15 months concurrently with routine licensed vaccines. When all cases of invasive disease were evaluated during follow-up analysis in April 1999, PCV7 was 97.4% efficacious against vaccine serotypes among children who were fully or partially vaccinated respectively. No increase in invasive disease due to by nonvaccine serotypes occurred.(4)

Among children who received >1 doses of study vaccine, use of PCV7 resulted in 11.4% fewer episodes of clinical pneumonia. Cases of clinical pneumonia accompanied by an X-ray with any evidence of an infiltrate were reduced by 33.0%. among children who had clinically diagnosed pneumonia and X-ray evidence of an area of consolidation of >2.5 cm as read by both a pediatrician and a radiologist, efficacy of PCV7 was 73.1%.

Compared with who received control vaccine, children who received PCV7 had 6.4% fewer episodes of AOM, and they underwent 20.3 % fewer tympanostomy tube placements.

The ability of PCV7 to protect children against AOM was also evaluated in an efficacy trial conducted in Finland. In this trial the estimated efficacy was found to be 57% against culture-confirmed AOM caused by vaccine serotypes. (8)

Prevention of pneumococcal infections among young children after widespread use of PCV7 might result in decreased use of antibiotics, as reported in the Northern California Kaiser Permanente vaccine efficacy trial . A reduction in antibiotic use might slow or reverse the trend of increasing prevalence of antimicrobial resistance among pneumococci.

Duration of Protection

Duration of protection after vaccination with PCV7 is unknown. However, immunologic memory does occur. Among infants aged <20 months who received primary vaccination with two or three doses of PCv7, administration of PPV23 (Pneumococcal polysaccharide vaccine 23) <18 months later resulted in a booster response. A similar response was elicited among children aged 2-3 years when administered PPV23 <20 months after a bivalent CRm197 conjugate vaccine. Additional studies of PCV7 with longer follow-up periods are needed. Evaluation of duration of protection will be critical for older children at high risk for disease (e.g. those with SCD or HIV infection).

Recommendation for Use of PCV7

All children aged <23 months should be vaccinated with PCV7. Infant vaccination provides the earliest possible protection, and children aged <23 months have the highest rates of pneumococcal infection. PCV7 is safe and highly efficacious in preventing invasive disease, and it is effective in preventing a portion of AOM cases and pneumonia among healthy infants and young children. Children aged 24-59 months should receive PCV7 vaccination if they are at high risk for pneumococcal infection caused by an underlying medical condition. This recommendation applies to the following groups:

  • Children with sickle cell disease, and other sickle cell hemoglobinopathies, or children who are functionally or anatomically asplenic
  • Children with HIV infection
  • Children who have chronic disease, including chronic cardiac and pulmonary disease (excluding asthma), diabetes mellitus, or CSF leak
  • Children with immmunocompromising conditions, including a)malignancies (e.g. leukemia, lymphoma, Hodgkin's disease); b) chronic renal failure or nephrotic syndrome; c) those children receiving immunosuppressive chemotherapy, including long-term systemic corticosteroids; and d) those children who have received a solid organ transplant.

Vaccination Schedule

The recommended primary series is three doses given at 2, 4, and 6 months of age with 2 months between doses. A fourth (booster) dose is recommended at 12 to 15 months of age or at least 60 days after completion of the primary series. The proposed vaccination schedule is the same for all children aged <23 months, regardless of the presence of underlying medical conditions. Interruption of the vaccination schedule does not require reinstitution of the entire series or the addition of extra doses.

For children aged 24-59 months with underlying medical conditions it is recommended to give 2 doses of PCV7, administered 2 months apart, followed by one dose of PPV23 administered >2 months after the second dose of PCV7.

Contraindications

The vaccination can be delayed for children with moderate or severe illness until the child has recovered, although minor illnesses (e.g. mild upper-respiratory infection with or without low-grade fever) are not contraindications to vaccination. The vaccine should not be given to infants or children with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection.

Dosage and Administration

The dose is 0.5 ml and should be given intramuscularly. PCV7 can be administered at the same time as other routine childhood vaccinations in a separate syringe at a separate injection site. Manufacturers are, currently evaluating the combination of PCV7 with other vaccines in one product.

Adverse Effects

The PCV7 vaccine has been associated with an acceptable incidence of adverse effects when given at 2, 4, 6 , and 12 to 15 months of age with concurrent administration of recommended, age-appropriate vaccines(DtaP, HbOC, DTP, Hepatitis B, OPV, IPV, MMR). Available data, mostly from NCKP efficacy trial, suggest that PCV7 may prove to be among the most reactogenic (e.g., local reactions and incidence of fever) vaccine of those currently used. Local reaction like redness, swelling and tenderness occurred after fourth dose of the vaccine respectively in 10.9%, 12.1%, and 23.3% of children. Such local reactions are usually self-limited and require no therapy.

The incidence of fever (body temperature >38 C within 48 hours of vaccination) occurred in 21% of children vaccinated with PCV7 compared with 17% of children of the control vaccine group. Of 727 children who received PCV7 without any concurrent vaccine 45.8 % experienced irritability, 15.9% drowsiness, 21.2% restless sleep, 18.3% decreased appetite, 18.3% vomiting, 6.3% 12.8% diarrhea, and rush or hives 1.2%. Febrile seizures were more common in the PCV7 group than in controls( 7:1, P=0.039).

Conclusions and Future Areas for Research

Pneumococcal conjugate vaccine Prevnar™ is a significant new contribution to the potential control of pneumococcal disease in young children.. It is the first vaccine to help prevent pneumococcal diseases such as meningitis, bacteremia, pneumonia and otitis media, and also to help reduce the resistance to the antibiotics traditionally used to treat these infections in children <2 years of age.

With licensure and introduction of PCV7, close monitoring of disease trends and long-term vaccine safety will be high priorities for public health organizations and health-care providers. Postlicensure surveillance will be necessary to a) detect potential changes in serotype distribution, including any increase in disease caused by serotypes not contained in PCV7; b) follow trends in antimicrobial resistance ant antibiotic use; c) detect potential herd immunity induced by widespread use of PCV7; d) track vaccine related health events.

The following ongoing studies are necessary to determine the most effective use of PCV7: optimal vaccination schedule for older children at high risk; combined vaccines including PCv7 and other routine vaccines for infants to reduce the number of required separate injections; studies of safety, immunogenicity, and efficacy among adults at high risk for pneumococcal infection; duration of infection; identifying and defining immune system correlates of protection and development of alternative pneumococcal vaccines.

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