Prevnar (heptavalent pneumococcal conjugate vaccine): Disease prevention in infants and children

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CLINICAL REPORT

EDITOR SECTION EDITORS e .SJo a gnrave rm LRionsdaal i K i d e ss,, BPSh,a R ND, , C FPC NCPP f etses oPrraacntdi cD l l eAglel eonf D Pu hm a romnat cy P rro iva e ewa int,h CDor. Thnen U i tiychoifgIalnl i n o i s a t C h i c a g o A A rnbive o r,r sM Chicago, Illinois C a ro l R u dy, M P H , A R N P, C P NA R o ck wo o d C l i n i c Pe d i a t r i c s S p o k a n e , Wa s h i n g t o n

PEDIATRIC PHARMACOLOGY

Prevnar (Heptavalent Pneumococcal Conjugate Vaccine): Disease Prevention in Infants and Children

CE ARTICLE

S a l ly Wa l s h , M S N , R N , C P N P Pe d i a t r i c A s s o c i a t e s o f N o r wo o d B o s t o n , M a s s a ch u s e t t s

Beth Shields, PharmD

OBJECTIVES Based on the content of the article, you will be able to: 1. identify the role of Streptococcus pneumonia (pneumococcus) as a bacterial pathogen in the pediatric population. 2. delineate the major differences between the pneumococcal polysaccharide and conjugate vaccines. 3. review the appropriate dosage schedule, administration technique, and adverse effect profile for the pneumococcal conjugate vaccine in healthy infants and children. 4. outline appropriate dosing schedules for the pneumococcal conjugate and polysaccharide vaccines in high-risk pediatric populations. 5. describe the potential role of pneumococcal conjugate vaccine in the prevention of invasive pneumococcal infections, including acute otitis media. See page 209 for instructions.

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treptococcus pneumoniae (pneumococcus) was first isolated as a pathogen more than 100 years ago. Currently, more than 90 serotypes cause disease in both adults and children worldwide. In the United States, fewer than 10 serotypes cause 83% of invasive disease in children younger than 5 years (Fiore, Levine, Elliott, Facklam, & Butler, 1999; Kaiser Permanente Vaccine Study Center Group, 2000). The World Health Organization estimates that every year, pneumococcal infections kill more than 1 million children younger than 5 years, with the vast majority of these deaths occurring in developing countries (Klein, 2000; Shinefield & Black, 2000; Shinefield, Black, Ray, Chang, &

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Lewis, 1999). In the United States, pneumococcus has been implicated in approximately 50,000 cases of bacteremia, 5000 cases of meningitis, 500,000 cases of pneumonia, and 7 million cases of otitis media in children younger than 5 years annually (American Academy of Pediatrics [AAP], 2000b; Eskola, 2000; Shinefield & Black, 2000). Chil-

dren at an increased risk for pneumococcal infections include specific racial and ethnic populations, children with functional or anatomic asplenia, HIVinfected children, and children in day care. Infection with pneumococcus varies from asymptomatic colonization to invasive disease. Pneumococcal coloniza-

Beth Shields, PharmD, is Clinical Pharmacy Specialist in Pediatrics, Department of Pharmacy, RushPresbyterian St. Luke’s Medical Center, Chicago. Reprint requests: Beth Shields, PharmD, Department of Pharmacy-Subasement Atrium, Rush-Presbyterian St. Luke’s Medical Center, 1653 W Congress Parkway, Chicago, IL 60612-3833. J Pediatr Health Care. (2001). 15, 203-210. Copyright © 2001 by the National Association of Pediatric Nurse Practitioners. 0891-5245/2001/$35.00 + 0 25/8/116249 doi:10.1067/mph.2001.116249

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TABLE 1 PCV7 dosing schedule: children ≤23 months Dosing schedule (primary series)

Age at first dose

2-6 mo 7-11 mo 12-23 mo

Dosing schedule (booster dose)*

3 doses, 6-8 wk apart 2 doses, 6-8 wk apart 2 doses, 6-8 wk apart

1 dose at 12-15 mo 1 dose at 12-15 mo No booster recommended

Modified from AAP, 2000a, 2000b, and CDC, 2000. *Administer booster dose at least 6-8 weeks after the final dose of the primary series.

tion may serve as a reservoir for local or invasive disease and for transmission of pneumococcus from person to person. Invasive disease is associated with increased morbidity and mortality in infants and young children, the elderly, immunocompromised patients, and patients with hematologic malignancies. Invasive diseases in pediatric patients include otitis media, sinusitis, bacteremia, pneumonia, and meningitis. With the licensure of the Haemophilus influenza b (Hib) conjugate vaccines in the 1990s, pneumococcus has become the most common cause of bacterial meningitis in young children (AAP, 2000b; Kaiser Permanente Vaccine Study Center Group, 2000).

TREATMENT For many years, invasive pneumococcal infections were successfully treated with systemic penicillin therapy. In the United States, approximately 25% to 40% of pneumococcal isolates have intermediate sensitivity or are now resistant to penicillin therapy (Peters & Edwards, 2000; Rubin, 2000). Risk factors associated with acquiring penicillinresistant pneumococci include young age, day care attendance, recent antibiotic use (≤3 months), and recurrent acute otitis media (Centers for Disease Control and Prevention [CDC], 2000). Penicillin-resistant pneumococcal strains are often resistant to multiple classes of antibiotics, including not only penicillin and closely related antibiotics but also cephalosporin and macrolide antibiotics and trimethoprim-sulfamethoxazole.

PREVENTION THROUGH VACCINATION Prevention of pneumococcal disease through vaccination is important because infections may not be promptly identified, are prevalent and often severe, and may be resistant to antibiotic therapy. The pathogenicity of S pneu-

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moniae is attributed to its polysaccharide capsule, which protects against phagocytosis by granulocytes and macrophages of the immune system. Because there are more than 90 distinct polysaccharide capsules or serotypes, vaccine production is complicated. Antibodies directed against the capsular polysaccharide protect against infection. Type-specific antibodies bind capsular antigens and facilitate phagocytosis of these antigens by the immune system. Therefore, effective antibody production against the most prevalent pneumococcal serotypes is the goal of vaccine production. The first whole-cell, heat-killed pneumococcal vaccine trials were initiated in 1911 in a large number of South African mine workers. Subsequent vaccine development began in the 1930s when type specificity and immunogenicity of the various pneumococcal capsules were identified. An epidemic of pneumonia among military men in World War II to the development of a tetravalent polysaccharide vaccine. The vaccine was 87% effective in decreasing disease, although 80% of invasive disease was caused by serotypes not present in the tetravalent vaccine. During the next 25 years, little development occurred on the pneumococcal vaccine front, in part because of the dramatic success of penicillin therapy. In 1977, Dr Robert Austin successfully developed a 14-valent polysaccharide pneumococcal vaccine, and subsequently in 1992 he developed a 23-valent polysaccharide pneumococcal vaccine.

PNEUMOCOCCAL POLYSACCHARIDE VACCINES (23PS) The 23-valent polysaccharide vaccines (23PS) Pneumovax 23 (Merck) and PnuImmune 23 (Wyeth-Ayerst) are mixtures of capsular polysaccharides from 23 pneumococcal serotypes that cause

C

hildren at an

increased risk for pneumococcal infections include specific racial and ethnic populations, children with functional or anatomic asplenia, HIVinfected children, and children in day care.

invasive disease. They are recommended for use in chronically ill children and adults ages 2 to 64 years, as well as all adults older than 65 years (CDC, 1997). In high-risk populations, revaccination is recommended after 3 to 5 years in children younger than 10 years of age and after 5 years in those older than 10 years of age. Polysaccharide vaccines such as 23PS provoke a B cell or T cell independent immune response. Polysaccharide vaccines do not elicit a protective immune system response among infants or children under 2 years of age, because this age group does not respond to T cell independent antigens. In addition, a T cell immune response is necessary for both optimal antibody production and the production of immunologic memory, a so-called anamnestic or booster response (Eskola, 2000; Peters & Edwards, 2000; Rubin, 2000). In addition to the lack of an anamnestic response, the 23PS vaccines exhibit several additional weaknesses. They do not affect the rate of pneumococcal otitis media or nasopharyngeal colonization. A lack of effect on colonization implies that 23PS does not protect against mucosal pneumococcal infections or the spread of resistant pneumococcal strains from person to person. In addition, 23PS elicits a nonuniform antibody response across the 23 serotypes contained in the vaccine and induces only limited protection in

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PH PEDIATRIC PHARMACOLOGY C patients with underlying immunodeficiencies or hematologic malignancies (Borowitz, 2000; Fedson, 2000; Kaiser Permanente Vaccine Study Center Group, 2000; Shinefield & Black, 2000).

HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV7) Conjugate vaccine technology in the pediatric population evolved with the production of Hib conjugate vaccines. Pneumococcal conjugate vaccines couple pneumococcal polysaccharide antigens to carrier proteins, and therefore change the nature of the immune response from T cell independent to T cell dependent. T cell based immunity is active in children by approximately 2 months of age and is capable of inducing an anamnestic response after subsequent doses of vaccine or exposure to the bacteria of interest (Blum, Dagan, Mendelman, Pinsk, & Giordani, 2000; Eskola, 2000; Shinefield & Black, 2000). A 7-valent pneumococcal conjugate vaccine, Prevnar (PCV7), was licensed for use in infants and children in February 2000. PCV7 consists of a highly immunogenic but inert diphtheria carrier protein (cross-reactive material [CRM197]) that is covalently coupled to the polysaccharide coat of 7 serotypes of pneumococci. The 7 polysaccharide serotypes that include 4, 6B, 9V, 14, 18C, 19F, and 23F are responsible for approximately 80% of pneumococcal disease in children younger than 6 years in the United States (Borowitz, 2000; CDC, 2000; Peters & Edwards, 2000; Wyeth-Lederle Vaccines, 2000).

CLINICAL EFFICACY OF PCV7 A number of trials have examined the immunogenicity, efficacy, and safety of PCV7 in healthy children (Fiore et al., 1999; Kaiser Permanente Vaccine Study Center Group, 2000; Rennels et al., 1998; Shinefield et al., 1999). The immunogenicity of PCV7 is based on the quantitative and qualitative measurement of serum antibody concentrations (Eskola, 2000). PCV7 results in a substantial increase in serum antibody concentration to all 7 serotypes, with a drop in antibody concentrations noted before booster doses. A significant anamnestic response to each serotype in the formulation has been noted after additional doses of both conjugate or polysaccharide vaccine at 12 to 15 months

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TABLE 2 PCV7 dosing schedule: children 24-59 months in high-risk* children No. of previous doses of PCV7 or 23PS

4 Doses of PCV7 1-3 Doses of PCV7 1 Dose of 23PS No previous doses of PCV or 23PS

Dosing schedule†,‡,§

2 Doses of 23PS (first dose at 24 months if at least 6-8 wk after last dose of PCV7) 1 Dose of PCV7 and 2 doses of 23PS 2 Doses of PCV7 (6-8 wk apart) and 2 Doses of 23PS 2 Doses of PCV7 (6-8 wk apart) and 2 doses of 23PS

Modified from AAP, 2000a, 2000b, and CDC, 2000. *Annual rate of invasive pneumococcus at least 150 cases/100,000 people; high-risk populations defined by AAP, ACIP, and AAFP include persons with: sickle cell disease or sickle cell hemoglobinopathies; congenital or acquired asplenia; functional or anatomic asplenia; human immunodeficiency virus (HIV) infection; primary immunodeficiencies; children receiving immunosuppressive therapy; and persons with chronic diseases (ie, heart disease, pulmonary disease, diabetes mellitus). †23PS doses given at least 6-8 weeks after last dose of PCV7. ‡If second dose of 23PS is recommended, administer 3-5 years after the first dose of 23PS. §As seen with previous data, repeat doses of 23PS may be associated with increased incidence of local reactions.

(Eskola, 2000; Kaiser Permanente Vaccine Study Center Group, 2000; Rennels et al., 1998; Rubin, 2000). The primary efficacy trial performed by the Kaiser Permanente Vaccine Study Center Group was a randomized, multicenter, double-blind study that included approximately 38,000 healthy infants and children without serious chronic disease or immune system disorders.

I

nfection with

pneumococcus varies from asymptomatic colonization to invasive disease. Infants were randomly assigned in a 1:1 fashion to receive either PCV7 or a control vaccine (meningococcal C conjugate vaccine) at 2, 4, 6, and 12 to 15 months of age. Pneumococcal conjugate vaccine was administered intramuscularly at a dose of 0.5 mL. Both groups received their routine immunizations according to the American Academy of Pediatrics schedule, and all children received follow-up for 3 years. The primary outcome measure was protection against invasive pneumococcal disease caused by the 7 vaccine serotypes. Invasive disease was defined as infection in a normally sterile body

site with pneumococcus, accompanied by clinical signs and symptoms of acute disease. Efficacy was evaluated in both fully vaccinated and partially vaccinated infants. Invasive pneumococcal disease (vaccine strains) occurred in 40 fully vaccinated children, 39 of whom were in the control group. The one case of invasive disease in the pneumococcal vaccine group was a case of bacteremic pneumonia caused by serotype 19F in a child who had received all 4 vaccine doses. Fifty-two cases of invasive disease (vaccine strains) were reported in both fully and partially vaccinated children. Furthermore, the study found that the vaccine was 89.1% effective in preventing invasive pneumococcal disease caused by all (vaccine and nonvaccine) serotypes, and 97.4% and 93.9% effective against preventing disease resulting from vaccine serotypes in fully and partially vaccinated subjects, respectively. No evidence of an increase in invasive disease caused by nonvaccine serotypes was found. Of note, pneumococcal nasopharyngeal carriage rates were decreased in vaccinated subjects, a finding not seen with the 23PS vaccine (Dagan, Melamed, Muallem, Piglansky, & Greenberg, 1996; Kaiser Permanente Vaccine Study Center Group, 2000; Rubin, 2000). O’Brien, Swift, and Winkelstea (2000) recently published a study examining the immune response to PCV7 in one high-risk population, people with sickle cell anemia. When infants with sickle cell disease were compared with matched control subjects, a similar an-

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PH PEDIATRIC PHARMACOLOGY C tibody response was noted. The authors concluded that PCV7 was immunogenic and safe in a small group of infants with sickle cell disease (O’Brien et al., 2000). Currently, data exist but are limited for using PCV7 in immunocompromised hosts, including HIV-infected children.

EFFICACY OF CONJUGATE VACCINE IN PNEUMONIA PREVENTION The effectiveness of PCV7 in preventing pneumonia of any cause was evaluated as a secondary outcome of the multicenter trial (Kaiser Permanente Vaccine Study Center Group, 2000). Outcomes included clinical diagnosis of pneumonia, clinical pneumonia with abnormal chest radiographs, and clinical pneumonia with consolidation seen on chest radiograph. Among children who received ≥1 dose of PCV7, an 11.4% reduction was noted in cases of clinical pneumonia. In addition, a reduction in clinical pneumonia with abnormal chest radiograph or chest radiograph with consolidation of 33% and 73.1%, respectively, was noted following PCV7 administration (CDC, 2000).

EFFICACY OF CONJUGATE VACCINES IN OTITIS MEDIA PREVENTION S pneumoniae is an important cause of acute otitis media (AOM), with up to 40% of cases caused by this organism. The vast majority of pneumococcal otitis media is caused by a small number of pneumococcal serotypes (Black & Shinefield, 2000). 23PS has been studied and found ineffective in the prevention of both acute and chronic recurrent otitis media in childhood (Makela, Leinonen, Pukander, & Karma, 1981). Although prevention of invasive disease was the primary outcome measure for the Kaiser Permanente Vaccine Study Center Group, the impact on clinical episodes (tympanocentesis not performed) of otitis media was also evaluated. In fully vaccinated children, the vaccine produced a significant reduction in all otitis episodes (7%) and in all otitis physician visits (8.9%). The vaccine also produced a significant reduction in tympanostomy tube placements (20.1%) and a significant decrease in chronic otitis media (22.8%) as defined by ≥3 episodes in 6 months or ≥4 episodes in a 1-year period. An evalua-

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tion of middle ear fluid in children with spontaneously ruptured tympanic membranes estimated a 65% reduction in AOM caused by vaccine-serotype pneumococci in children receiving PCV7 versus control vaccine (CDC, 2000: Dagan, Given-Lavi, Shkolnik, Yagupsky, & Fraser, 2000; Kaiser Permanente Vaccine Study Center Group, 2000).

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revention of

pneumococcal disease through vaccination is important because infections may not be promptly identified, are prevalent and often severe, and may be resistant to antibiotic therapy.

A randomized, double-blind trial enrolling approximately 1600 infants revealed similar otitis media outcomes. Infants received a seven-valent pneumococcal conjugate vaccine or a control vaccine (hepatitis B vaccine) at 2, 4, 6, and 12 months of age. The clinical diagnosis of AOM was based on predefined criteria. Middle ear fluid samples were obtained by myringotomy with each clinical episode of AOM. Pneumococcal conjugate vaccine recipients showed a 57% reduction in AOM episodes caused by vaccine serotypes, a 34% reduction in all pneumococcal AOM, and a 6% reduction in total AOM episodes when compared with control infants (Eskola, Kilpi, Palmu, Jokinen, & Haapakoski, 2001; Peters & Edwards, 2000; Rubin, 2000).

PRECAUTIONS AND CONTRAINDICATIONS PCV7 is contraindicated in subjects with a known hypersensitivity to any component of the vaccine. In addition, in patients with contraindications

to intramuscular injections, including thrombocytopenia or coagulation disorders, the risk-to-benefit ratio should be considered. In children with moderate or severe illness, vaccine dosing may be postponed, although a mild illness with or without a low-grade temperature is not considered a contraindication to vaccine administration. Concurrent administration of PCV7 and 23PS is not recommended, because safety and efficacy have not been studied (CDC, 2000; Wyeth-Lederle Vaccines, 2000).

ADVERSE EFFECT PROFILE The safety of PCV7 vaccine has been evaluated in 5 studies, with most of the safety data from children enrolled in the large multicenter trial (Kaiser Permanente Vaccine Study Center Group, 2000; Wyeth-Lederle Vaccines, 2000). Much of the safety data compares PVC7 with control vaccine (meningococcal conjugate vaccine) in children receiving other routine childhood immunizations concomitantly. Initially, children received diphtheria-tetanus toxoidwhole cell pertussis vaccine (DTwP) and oral polio vaccine, but later in the trial they received diphtheria-tetanus toxoid-acellular pertussis vaccine (DtaP) and inactivated poliovirus vaccine as the recommendations for universal immunization changed. Mild local reactions (redness, swelling, and tenderness) similar to those associated with other routine childhood immunizations were noted within 48 to 72 hours of PCV7 injection. Fewer children were noted to experience local reactions with PCV7 than with DTwP, whereas mild local reactions were more common in children receiving PCV7 than in children receiving DtaP. No statistically significant difference was noted for severe local reactions when PCV7 was compared with other routine childhood immunizations (Rennels et al., 1998; Shinefield et al., 1999; Wyeth-Lederle Vaccines, 2000). Fever (≥38°C) less than 48 hours following vaccination was more common with the primary series but not with booster doses when PCV7 was compared with the control vaccine. Of note, higher temperatures (39°C) were noted after the second dose of the primary series. With regard to more serious adverse events, three cases of a hypotonichyporesponsive episode were reported

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PH PEDIATRIC PHARMACOLOGY C in children who had received PCV7 vaccine. All three children had received concurrent DTwP vaccination. Eight recipients of PCV7 exhibited seizures within 3 days of vaccination. Seven of these eight recipients received concomitant DTwP vaccine, and one received DTaP vaccine. Four cases of sudden infant death syndrome (SIDS) were observed among PCV7 recipients, a rate less than expected based on historic statistics (CDC, 2000; Kaiser Permanente Vaccine Study Center Group, 2000; Wyeth-Lederle Vaccines, 2000).

VACCINE INDICATIONS (PCV7 AND 23PS) PCV7 (Prevnar) is administered at a dose of 0.5 mL intramuscularly in a separate syringe and at a separate site from other routine childhood immunizations. PCV7 has been tested and may be administered concurrently with other routine childhood immunizations. The preferred site of administration is anterolateral aspect of thigh in infants or the deltoid muscle of the upper arm in toddlers and young children. PCV7 is recommended for the universal immunization of all children younger than 24 months of age at 2, 4, and 6 months, with a booster required at 12 to 15 months (see Table 1). The first dose of PCV7 may be given as early as 6 weeks of age, and the fourth dose should be administered at least 6 to 8 weeks after the third dose. For infants with a birthweight <1500 g, doses should be administered according to the infant’s chronologic age regardless of his or her gestational age. Currently, insufficient safety, efficacy, and immunologic data exist for universal immunization of low- or moderate-risk children older than 24 months of age. The AAP, American Association of Family Physicians (AAFP), and Advisory Committee on Immunization Practices (ACIP) have made recommendations for immunization of highrisk children older than 24 months (Table 2). Recommendations for highrisk children from 24 to 59 months include both PCV7 to enhance the immune response and decrease nasopharyngeal carriage as well as 23PS to expand serotype coverage. In addition, recommendations have been made in low- or moderate-risk groups where PCV7 administration may be considered.

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Data are limited regarding the efficacy of PCV7 among children ≥5 years of age and adults. However, the administration of PCV7 to older children with high-risk conditions is not contraindicated (CDC, 2000).

needed to assess vaccine efficacy and safety in high-risk groups, including those infected with HIV and other immunocompromised patients.

CONCLUSIONS

American Academy of Pediatrics, Committee on Infectious Diseases. (2000a). 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, 362-366. American Academy of Pediatrics, Committee on Infectious Diseases. (2000b). Technical report: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate and polysaccharide vaccines and antibiotic prophylaxis. Pediatrics, 106, 367-376. Black, S., & Shinefield, H. (2000). Vaccines and otitis media. Pediatric Annals, 29, 648-651. Blum, M. D., Dagan, R., Mendelman, P. M., Pinsk, V., & Giordani, M. (2000). A comparison of multiple regimens of pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in toddlers. Vaccine, 18, 2359-2367. Borowitz, S. M. (2000). Pneumococcal conjugate vaccine. Pediatric Pharmacotherapy, 6, 6-10. Centers for Disease Control and Prevention, Advisory Committee on Immunization Practices. (2000). Preventing pneumococcal disease among infants and young children: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report, 49(RR-9), 1-35. Centers for Disease Control and Prevention. (1997). Prevention of pneumococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report, 46(RR-8), 1-24. Dagan, R., Melamed, R., Muallem, M., Piglansky, L., & Greenberg, D. (1996). Reduction in nasopharyngeal carriage of pneumococci during the second year of life by heptavalent conjugate pneumococcal vaccine. The Journal of Infectious Diseases, 174, 1271-1278. Dagan, R., Givon-Lavi, N., Shkolnik, L., Yagupsky, P., & Fraser, D. (2000). Acute otitis media caused by antibiotic–resistant Streptococcus pneumoniae in southern Israel: Implications for immunizing with conjugate vaccines. The Journal of Infectious Diseases, 181, 1322-1329. Eskola, J. (2000). Immunogenicity of pneumococcal conjugate vaccines. Pediatric Infectious Disease Journal, 19, 388-393. Eskola, J., Kilpi, T., Palmu, A., Jokinen, J., & Haapakoski, J., the Finnish Otitis Media Study Group. (2001). Efficacy of a pneumococcal conjugate vaccine against acute otitis media. The New England Journal of Medicine, 344, 403-408. Fedson, D.S. (2000). Pneumococcal conjugate vaccination for adults: Why it’s important for children. Pediatric Infectious Disease Journal, 19, 183-186. Fiore, A. E., Levine, O. S., Elliott, J. A., Facklam, R. R., & Butler, J. C. (1999). Effectiveness of pneumococcal polysaccharide vaccine for preschoolage children with chronic disease. Emerging Infectious Diseases, 5, 828-831. Kaiser Permanente Vaccine Study Center Group. (2000). Efficacy, safety, and immunogenicity of heptavalent pneumococcal conjugate vaccine in

The preventative efficacy and safety of PCV7 shows great promise for children younger than 2 years of age, a population in which 23PS is not effective or indicated. The direct costs of pneumococcal disease, including physician visits, hospital costs, and drug therapy costs, should all be decreased with the use of PCV7. However, the economic impact of large-scale immunization with PCV7 is yet to be seen. Pneumococcal conjugate vaccine currently costs approximately $58 per dose, a cost that has doubled the total current expenditure of all other routine childhood vaccines (Lieu, Ray, Black, Butler, & Klein, 2000).

T

he preventative

efficacy and safety of PCV7 shows great promise for children younger than 2 years of age, a population in which 23PS is not effective or indicated.

A number of unanswered questions still exist regarding the use of PCV7. Long-term follow-up is needed to assess the duration of immunity, the need for possible later booster doses, potential changes in pneumococcal serotype distribution, trends in antimicrobial resistance, and the potential herd immunity induced by widespread use of PCV7. In addition, more information is needed to assess exact target populations other than healthy infants and high-risk populations. More controlled studies are

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PH PEDIATRIC PHARMACOLOGY C children. Pediatric Infectious Disease Journal, 19, 187-195. Klein, J. O. (2000). The pneumococcal conjugate vaccine arrives: a big win for kids. Pediatric Infectious Disease Journal, 19, 181-182. Lieu, T. A., Ray, G. T., Black, S. B., Butler, J. C., & Klein, J. O. (2000). Projected cost-effectiveness of pneumococcal conjugate vaccination of healthy infants and young children. Journal of the American Medical Association, 283, 14601468. Marchant, C. D. (1999). Pneumococcal conjugate vaccines. Pediatric Annals, 28, 540-545. Makela, P. H., Leinonen, M., Pukander, J., & Karma, P. (1981). A study of the pneumococcal vaccine in prevention of clinically acute attacks

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of recurrent otitis media. Reviews of Infectious Diseases, 3, S124-S132. O’Brien, K. L., Swift, A. J., & Winkelstea, J. A. (2000). Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 among infants with sickle cell disease. Pediatrics, 106, 965-972. Peters, T. R., & Edwards, K. M. (2000). The pneumococcal protein conjugate vaccines. The Journal of Pediatrics, 137, 416-420. Rennels, M. B., Edwards, K. M., Keyserling, H. L., Reisinger, K. S., Hogerman, D. A., Madore, D. V., Chang, I., Paradiso, P. R., Malinoski, F. J., & Kimura, A. (1998). Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics, 101, 604-611.

Rubin, L. G. (2000). Pneumococcal vaccine. Pediatric Clinics of North America, 47, 269-285. Shinefield, H. R., & Black, S. (2000). Efficacy of pneumococcal conjugate vaccines in large scale field trials. Pediatric Infectious Disease Journal, 19, 394-397. Shinefield, H. R., Black, S., Ray, P., Chang, I., & Lewis, N. (1999). Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatric Infectious Disease Journal, 18, 757-763. Wyeth-Lederle Vaccines. (2000). Prevnar (pneumococcal 7-valent conjugate vaccine (diphtheria CRM197 protein) package insert. Philadelphia, PA: Author. Wyeth-Lederle Vaccines. (1998). Pneumococcal vaccine polyvalent (Pnu-immune 23) package insert. Pearl River, NY: Author.

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