Drug Criteria & Outcomes-Pneumococcal 7-Valent Conjugate Vaccine for infants and toddlers
By Chandace Benton, PharmD candidate
Medical University of South Carolina
Charleston, SC
Indications:
Pneumococcal 7-Valent Conjugate Vaccine (PCV), manufactured by Wyeth Lederle Vaccines, is indicated for active immunization of infants and toddlers against invasive disease caused by Streptococcus pneumoniae due to capsular serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F).1-2
Description:
PCV contains 2 mcg of the following serotypes: 4, 9v, 14, 18c, 19f, and 23f. PCV contains 4 mcg of the 6B serotype.1,2
Pharmacology:
PCV is a nontoxic form of the diphtheria toxin obtained from the Corynebacterium diphtheriae strain C7 (B197). It is grown in casamino acids and a yeast extract-based medium.1,3 It is formulated to target the seven strains of S. pneumoniae that are responsible for 80% of pneumococcal disease in children under age 6.1-3 Infections caused by S. pneumoniae include bacteremia, meningitis, pneumonia, and upper respiratory tract infections such as otitis media and sinusitis.1,4
Coupling polysaccharides to protein carriers induces a T-cell-dependent response and increases the immunogenicity of the vaccine, particularly in infants.4 PCV consists of saccharides from capsular antigens. These antigens are obtained from seven serotypes of S. pneumoniae and have been conjugated with the diphtheria CRM197 protein. PCV is chemically activated to make saccharides that are then conjugated to the protein carrier CRM197 to form the glycoconjugate.1-2 PCV is not live; it is a killed vaccine.5 Because the vaccine is inactivated, vaccine recipients cannot develop meningitis or any pneumococcal infection from the vaccine.5
Pharmacokinetics:
PCV increases the production of antibodies by the end of a three-part series of vaccinations. The immunologic response and duration are dependent on the serotypes involved and whether the saccharides are conjugated to the carrier proteins.6
Selected clinical trials:
Shinefield and associates conducted a randomized, double-blind study that evaluated the safety and immunogenicity of PCV.7 The investigators also evaluated the effect of using PCV concomitantly with an immunization vaccine series that included the diphtheria, tetanus, and acellular vaccine (DTaP); the hepatitis B vaccine (hepatitis B); the oral poliovirus vaccine (OPV); and the haemophilus influenzae Type B conjugate vaccine (Hib PRP).
The investigators randomized 302 healthy children from the Northern California Kaiser Permanente Health Plan. Specific exclusion criteria were not defined. Patients were randomized (2:1) to receive either PCV (n = 202) or the meningococcal vaccine (n = 100), which served as the control. The vaccine was given at 2, 4, and 6 months of age. A booster dose was given between 12 and 15 months of age. The PCV group was further divided for half to receive a concomitant hepatitis B vaccine, while the other half received PCV alone. When the patients were 12 to 15 months of age, they were even further randomized (3:3:2) to receive either a last dose of PCV with DTaP, or PCV and DTaP separately.
Safety was assessed by providing each child's parent or caretaker with a diary and a thermometer. They were asked to observe the child for 14 days following immunization. Temperature (> 38°C) was to be recorded for two days, along with any indication of an inflammatory reaction at the injection site. Follow-up was conducted by telephone interview 48 to 72 hours and 10 to 14 days after injection.
In order to evaluate safety, emergency room visits 30 days post-vaccination and hospitalizations 60 days post-vaccination were evaluated. Immunogenicity was assessed by measuring serum concentrations at the following intervals: before vaccination, one month after the third dose (6 months old), and one month after the booster dose (12 to 15 months old). Serotype comparison was determined for the concurrent hepatitis B group and the nonconcurrent hepatitis B group using the two-sample t-test. Geometric mean concentrations of the seven serotypes were not significantly different between the PCV and PCV with hepatitis B vaccine groups.
Results with PCV
There were no differences between the study groups when protective antibody titers for the seven antigens were measured. Concentrations of PCV serotypes were increased when PCV was used separately. A statistically significant lower antibody titer concentration was observed for Hib PRP, diphtheria toxoid, and pertussis when given concomitantly with the PCV vaccine. However, these concentrations were still well above those thought to be necessary for protection; therefore, they were not clinically significant.
Injection site reactions were less prevalent with the PCV vaccine. Both fever and irritability were adverse events reported by the PCV groups and the control. Serious adverse events were not reported due to vaccine administration. The data from this study support that PCV is both safe and effective when administered alone or in an immunization series.
Rennels and colleagues conducted a double-blind, multicenter, randomized trial in healthy infants (n = 212) to evaluate the immunogenicity and safety of PCV.8 In order to be enrolled in the trial, patients had to be healthy 2-month-old infants (+ 10 days). Exclusion criteria were not defined. A group receiving the meningococcal group C conjugate vaccine served as the control population (n = 106). Study vaccines were given at 2, 4, and 6 months of age into the left thigh along with routine pediatric immunizations (OPV, DTaP, and Hib). Booster shots were given between 12 and 15 months of age.
Safety was evaluated by temperature, injection site reactions, and changes in mood for 72 hours post-vaccination. Serologic response was evaluated using a standard enzyme-linked immunosorbent assay at baseline, before the third dose (6 months old), after the third dose (7 to 8 months old), and before and after the booster dose (12 to 15 months old).
Control group results
Injection site reactions were reported less frequently in the PCV groups compared with the control. Drug fever was seen more frequently in the PCV study group; however, a statistically significant difference was not shown. Due to concurrent administration of routine vaccines, adverse events could not be definitively attributed to the PCV or meningococcal C vaccine groups. After the third dose, concentrations of PCV were significantly higher (p < 0.001) for all serotypes. There was a 2- to 5-unit increase in the concentration of PCV after the third dose than before in all serotypes except serotype 4.
Although concentrations were decreased in the time period between the third dose and the booster dose, there was a noted rise in the antibody response one month following the booster dose. The data from this trial support that, when given in four subsequent doses, PCV appears to provoke a protective immune response for all serotypes.
Kaiser study
The Northern California Kaiser Permanente Study Center group conducted a randomized, double-blind, multicenter trial to evaluate the efficacy, safety, and immunogenicity of PCV.9 The primary endpoint was invasive disease caused by vaccine serotypes. A secondary endpoint of this trial was to assess efficacy of PCV against otitis media. Safety was assessed conducting telephone interviews at 48 to 72 hours and 14 days after each dose and by determining rates of 30- and 60-day emergency room and hospitalization visits.
Reported cases of invasive disease in the study population were assessed by automated clinical and laboratory databases. Invasive disease was defined by a positive culture. Several outcomes measures were assessed for otitis media, including the number of episodes, placement of ventilatory tympanostomy tubes, and the number of cases with spontaneously draining ruptured tympanic membranes. The study randomized 37,868 children to get either PCV (n = 18,927) or meningococcus type C CRM197 conjugate (n = 18,941) at 2, 4, 6, and between 12 and 15 months of age.
Patients were allowed to participate if the child had an infection that was caused by one of the seven serotypes, had an infection >14 days after the third dose of vaccine, and had routine vaccinations. Patients were excluded from the study if they had sickle cell disease, known immunodeficiency, serious chronic or progressive disease, a history of seizures, or a history of either pneumococcal or meningococcal disease. Children were given their usual recommended vaccines at the appropriate times along with either the PCV or the matching meningococcal vaccine.
Children and PVC
An advisory committee conducted intermittent evaluations. The follow-up period was dependent on when the child reached the endpoint of pneumococcal infection, death, or end of the study. Mild injection-site reactions were more common in the PCV group. A fever (> 38° C) was reported more often in the PCV groups than in the control. There was a significant decrease in the amount of pneumococcal cases in children who had received the vaccine when compared to the control group. No increase in disease was seen in the serotypes not contained in the vaccine.
In regard to the episodes of otitis media, a clinically significant reduction was seen in the PCV treatment group. Children who received PCV had a 20.1% decrease in the requirement of ventilatory tympanostomy tube placements. Review of emergency room visits showed statistically insignificant results between the groups (p < 0.679). The data from this study support that the PCV vaccine is both safe and effective for invasive disease in children and is additionally effective in decreasing occurrences of otitis media.
Adverse reactions:
To date, PCV has been studied in 18,927 patients. Of those patients, eight experienced seizures within three days of receiving the vaccine. Those patients also were receiving the DTaP vaccine and, therefore, it is difficult to determine which vaccine was responsible for the increased risk of seizures.1,6,9
Injection-site reactions occurred often with PCV and included edema, pain, redness, inflammation, and local hypersensitivity reactions.1-2 Fever, irritability, drowsiness, insomnia, mild nausea and vomiting, and decreased appetite were the most common adverse effects experienced by patients receiving PCV.1,2,6 Of note, stabilized patients with idiopathic thrombocytopenic purpura have been known to relapse when given PCV.
Pregnancy and lactation:
PCV is classified as a pregnancy category C agent by the Food and Drug Administration.1-2 This means either that studies in animals have revealed adverse effects in the fetus (teratogenic or embryocidal effects or other) and there are no controlled studies in women, or studies in women and animals are not available.10 An association between PCV and fetal harm has not been demonstrated. Further studies need to be performed to evaluate the effects of PCV on fertility and lactation. Use of this vaccine is not recommended in pregnant women or nursing mothers.1-2
Contraindications:
Use of this vaccine is contraindicated in patients with known allergies to any component of the vaccine.1-2 Delaying vaccination should be considered in the instances of severe illness and fever. If the patient is experiencing an active infection, this vaccine should not be given. This vaccine is intended for intramuscular use only and is absolutely contraindicated intravenously.1,6 PCV is not intended for adults and should not preclude the pneumococcal polysaccharide vaccine in elderly patients.1-2
Warnings/precautions:
The vaccine only confers protection against S. pneumoniae disease caused by the seven serotypes.1 PCV is not a substitute for regular diphtheria immunization and does not preclude use of the 23-valent pneumococcal vaccine in children with long-term diseases or decreased immune function.11 Administration should be avoided in pediatric patients with blood dyscrasias or any other type of hematological abnormalities due to its intramuscular route of injection.1-2 Caution should be used and the potential benefits must outweigh the potential risks if the PCV vaccine is administered to a patient with hematological abnormalities. PCV is packaged in rubber containers and may cause problems in patients who have latex hypersensitivity.1-2
Dosage and administration:
The recommended dose of PCV is 0.5 mL administered intramuscularly at 2, 4, and 6 months of age, and again between 12 and 15 months of age.1,2,11 The first dose should be given at 2 months of age; however, it has been studied in infants as young as 6 weeks.1,2 PCV should never be injected directly into a vein.1,2 The product should be shaken well before it is used and should appear as a homogenous, white suspension. The preferred site of injection is the thigh for infants and the upper arm for toddlers.1
| Dosing for Older Children1 | |
| Age at first dose | Total # doses |
| 7 to 11 months of age | 3 |
| 12 to 23 months of age | 2 |
| 24 months through 9 years | 1 |
Drug interactions:
PCV, when administered concomitantly with other routine immunizations, does not appear to have a significant effect on the immunogenicity. Response in children taking immune-altering agents (e.g., steroids, antimetabolites, alkylating agents, or cytotoxic agents) may be inadequate.1,6 As with other intramuscular injections, PCV should be given with caution to children receiving anticoagulant therapy.1,2
Potential for medication errors:
Medication names that sound similar to Prevnar include Prevacid, Prevpak, and Prinivil.
Discussion:
Streptococcus pneumoniae is one of the most common causes of invasive bacterial infection in children. The majority of cases occur before age 2 or after age 65. PCV is for active immunization of infants and toddlers against S. pneumoniae serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F).1,2 These serotypes are responsible for 80% of pneumococcal disease, including otitis media. PCV increases antibody production through stimulation of helper T-cells and is a killed vaccine. In clinical trials, injection-site reactions were the most common reported adverse events. Other adverse events included fever, irritability, drowsiness, insomnia, mild nausea and vomiting, and decreased appetite.1-2
Studies with expecting mothers and lactating women are not available.1-2 PCV may interact with anticoagulants and immune altering agents.1-2,6 This vaccine is not intended to replace the current pneumococcal vaccine that is given to elderly patients. Additionally, PCV will not be effective for pneumococcal infections other than those caused by the seven serotypes. The recommended dose is PCV 0.5 mL IM at 2, 4, and 6 months of age.
Additionally, a booster dose should be given between 12 and 15 months of age.1-2 Data from clinical trials support that PCV vaccine is safe and effective against pneumococcal disease and is additionally effective in decreasing occurrences of otitis media.7,8,9
PCV uses for children
The new AAP guidelines state that PCV is recommended for use in all children 23 months of age and younger.12 Although other pneumococcal vaccines are available, PCV represents the first pneumococcal vaccine approved for use in children younger than age 2. The policy recommends that PCV be given concurrently with other recommended childhood vaccines at 2, 4, 6, and 12 to 15 months. The number of PCV doses required depends upon the age at which vaccination is initiated. The vaccine is also recommended for all children 24 to 59 months of age who are at especially high risk of invasive pneumococcal infection.12,13 This includes children with sickle cell disease, human immunodeficiency virus (HIV) infection, and other children who are immunocompromised.
References
1. Prevnar package insert. Philadelphia: Wyeth Lederle vaccines; February 2000.
2. Tatro DS, ed. Drug Information Facts. Missouri: Drug Facts and Comparisons; 1997.
3. Abromowiez Mark, ed. A pneumococcal conjugate vaccine for infants and children. The Medical Letter 2000; March 20:25-27.
4. Prevnar Vaccine Effective Against Invasive Pneumococcal Disease and Ear Infections. March 16, 2000. Doctor's Guide to the Internet, May 3, 2000. Web site: http://www.docguide. com.
5. Strikas, Ray. "Pneumococcal conjugate vaccine gp; prevnar." E-mail communication, May 10, 2000.
6. Pneumococcal Vaccine, Polyvalent, Feb. 23, 2000. Clinical Pharmacology 2000-Monograph, May 8, 2000. Web site: http://cp.gsm.com.
7. Shinefield HR, Black S, Ray P, et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatr Infect Dis J 1999; 18:757-763.
8. Rennels MB, Edwards KM, Keyserling HL, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics 1998; 101:604-611.
9. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000; 19:187-195.
10. Lacy C, Armstrong LL, Ingram NB, Lance LL. Drug Information Handbook. Ohio: Lexi-Comp Inc.; 2000.
11. Drug Facts Q&A: Prevnar (diphtheria CRM197 protein), March 13, 2000. Pharmaceutical Information Network, May 3, 2000. Web site: http://pharminfo.com/drugfaq/prevnar_faq.html.
12. American Academy of Pediatrics. AAP Recommends Pneumococcal Vaccine for Cohildren Under Age 2. June 6, 2000; July 10, 2000. Web site: http://www.aap.org/advocacy/releases/junpcv7.htm.
13. Flu Season 2000-01: Pneumococcal Vaccine. June 20, 2000. Centers for Disease Control and Prevention. July 10, 2000. Web site: http://www.cdc.gov/od/oc/media/pressrel/r2k0622d.htm.
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