Vaccination is the cornerstone of pediatric preventive health care. Immunizations have changed pediatric practice in the United States. Pediatric residents now infrequently encounter varicella or Haemophilus influenzae type b meningitis, diseases which were routinely seen prior to the introduction of immunizations. This articie higfiiights the new vaccines and recommendations that have been added to the childhood immunization schedule in 2007.
The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), the American Academy of Family Physicians, and the American Academy of Pediatrics (AAP) annually publish a childhood and adolescent immunization schedule.1 The format of the 2007 schedule has changed from previous versions. Recommendations have been divided into two schedules: one for those aged 0 to 6 years (see Table, page 320) and another for those 7 to 18 years (see article by Domachowske et al, page 327). This review concentrates on the childhood schedule for 0 to 6 years.
Ten vaccines are routinely recommended for children prior to their seventh birthday: hepatitis B, rotavirus, diphtheria-tetanus-pertussis (DTaP), Haemophilus influenza type b (Hib), pneumococcal conjugate (PCV), inactivated poliovirus (IPV), influenza, measles-mumps-rubella (MMR), varicella, and hepatitis A. Changes in vaccine recommendations from the 2006 schedule include 1) the addition of rotavirus vaccine for infants, 2) the broadening of the recommended ages for influenza vaccine to all children 6 to 59 months from the previous 6 to 23 months' recommendation, and 3) the addition of a second dose of varicella vaccine at 4 to 6 years.
Rotavirus is the most common cause of severe diarrhea in infants and young children in the United States and worldwide. In the United States, by 5 years, 1 in 14 children will be hospitalized or will visit an emergency department because of rotavirus gastroenteritis. In infants, natural rotavirus infection confers some protection against subsequent infection. A study reported by Velazquez and colleagues showed that following two rotavirus infections, the risk for subsequent rotavirus-associated moderate to severe diarrhea is eliminated; however, three infections are required to nearly eliminate the risk for mild diarrhea.2
Vaccination is the primary public heath intervention to prevent rotavirus gastroenteritis. The goal of the vaccination program is to duplicate the degree of protection provided by natural infection. Rotavirus gastroenteritis is preventable with live oral rotavirus vaccines. The first product approved in the United States was RotaShield (Wyeth), a live, oral, tetravalent rhesus-based vaccine. This vaccine was withdrawn from the market in 1999, one year after licensure, because of an association with intussusception.3 In February 2006, a live, oral, pentavalent vaccine called RotaTeq (Merck) was licensed and shortly thereafter recommended for universal use in infants by ACIP.4 The AAP has also issued a policy statement recommending routine immunization of infants at 2, 4, and 6 months.5
The licensed pentavalent rotavirus vaccine (PRV) is a live, orally administered vaccine that aims to mimic the protection given by naturally occurring rotavirus infection.2 The vaccine is intended to prevent moderate-to-severe rotavirus diarrhea and dehydration but not necessarily mild rotavirus disease. PRV is designed to protect against each of the most prevalent rotavirus serotypes in the United States, including G1, G2, G3, G4, and P1A.
PRV is based on a bovine strain of rotavirus, which is naturally attenuated for humans. Each of the five viruses in the vaccine is essentially the parental bovine strain into which one human gene has been inserted through a process called reassortment. Four of the reassortants each express one of the outer capsid proteins (G1 , G2, G3, or G4) from a human rotavirus strain along with the attachment protein (P7) from the bovine strain. The fifth reassortant expresses the attachment protein (P1A) from a human strain and the outer capsid protein (G6) from the bovine virus. The bovine backbone is responsible for the attenuation of the vaccine. The human proteins are responsible for the immunogenicity. The bovine surface proteins (P7 and G6) play a minor role.
PRV was approved based on a very large double-blind, placebo-controlled, randomized trial (REST, Rotavirus Efficacy and Safety Trial), which was conducted from 2001 to 2004 in the United States, Mexico, and Taiwan and eight countries throughout Europe and Central America.6 Although primarily designed to evaluate safety with respect to intussusception, REST also looked at vaccine efficacy, including severity of illness, hospitalizations, and emergency department visits for rotavirus gastroenteritis.
Safety of PRV
Safety information for PRV includes data from REST6 and two other phase 3 trials.78 The risk of intussusception and other serious adverse events was evaluated among 71,799 infants vaccinated in the phase-3 program. In the 42 days postimmunization, six cases of intussusception were observed in the PRV group compared with five cases of intussusception in the placebo group. The data did not suggest an increased risk of intussusception relative to placebo. Among vaccine recipients, there were no confirmed cases of intussusception within the 42day period after the first dose, which was the period of highest risk for the previously licensed rhesus-human rotavirus reassortant-tetravalent vaccine (RRVTV) vaccine.3 In addition, no evidence of clustering of cases of intussusception was observed within a 7- or 14-day window after immunization for any dose. For the 1-year follow-up period after administration of the first dose, 13 cases of intussusception were observed in the pentavalent rotavirus vaccine group and IS cases of intussusception in the placebo group. The incidence of intussusception among infants in REST was 1 in 2,253 infants overall and 1 in 2,101 among placebo recipients. The overall rate of intussusception in REST is consistent with the expected background rate of intussusception.9 Hie age at diagnosis of intussusception in REST also appears to mirror the background rate of intussusception. The peak age of intussusception for both REST and the New York State data was 5 months. Among PRV and placebo recipients, the incidence of serious adverse events, including deaths, was similar.8
In clinical studies of RRV-TV (RotaShield), the vaccine was associated with statistically and clinically significant adverse events during the first 5 days following the first dose, including fever, irritability, and decreased appetite and activity. I0 In contrast to RRVTV, there were no significant increases in fever following the first dose of PRV when data from the phase-3 studies were combined.8
A subset of 11,722 children was studied in detail to assess potential adverse experiences such as fever, diarrhea, and vomiting.8 Among these children, the rates of vomiting and diarrhea within the week after the first dose were significantly increased among vaccine recipients. The difference between the PRV and placebo groups for each of these events was 1 .3%. However, the majority of episodes of diarrhea were reported as mild. Irritability and the rates of fever within the first week after each dose among infants were comparable between PRV and placebo recipients.
PRV or placebo was administered to 2,070 preterm infants in the phase3 trials. No cases of intussusception were reported among preterm infants. Among preterm infants given PRV and placebo, the incidence of serious adverse events was similar.
Results from the phase-3 trials showed that overall the incidence of shedding with PRV was <9%, shedding primarily occurred after the first dose, and the quantity of virus shed was relatively low.8 Shedding of vaccine-virus strains occurred in up to 50% of people during the 3- to 5 -day period after vaccination with RRV-TV (RotaShield), and low level transmission of vaccine strains was detected in one study conducted in Venezuela.10 Thus, the rate of fecal shedding among vaccine recipients with PRV (RotaTeq) was substantially lower than seen with RRV-TV. With the low rate of fecal shedding and the relatively low amount of virus shed, transmission appears unlikely.
Efficacy of PRV
The efficacy of PRV was evaluated in REST.6 The clinical efficacy of the vaccine against rotavirus gastroenteritis of any severity was 74%; however, against severe rotavirus gastroenteritis, the vaccine demonstrated efficacy of 98%. The efficacy of PRV in the second rotavirus season after immunization was 63% against rotavirus gastroenteritis of any severity and 88% against severe rotavirus gastroenteritis.
PRV also proved strongly efficacious in preventing rotavirus gastroenteritis of any severity caused by the predominant Gl serotype (75% efficacy) and the G2 serotype (63% efficacy). There was a trend toward efficacy for the remaining serotypes, but patient numbers were too small to show statistical significance (G3 83% efficacy, G4 48% efficacy, and G9 65% efficacy).
In REST, the efficacy of PRV in reducing the number of office visits for rotavirus gastroenteritis was evaluated among a subset of infants and in reducing the number of emergency department visits and hospitalizations for rotavirus gastroenteritis among all children throughout the first 2 years of life. PRV reduced the incidence of office visits by 86%; emergency department visits by 94%, and hospitalizations for rotavirus gastroenteritis by 96%.
Data on the efficacy of fewer than 3 doses of PRV are limited. In the REST study, the efficacy of PRV in reducing the number of emergency department visits and hospitalizations for rotavirus gastroenteritis was evaluated in children receiving fewer than three doses of vaccine.11 The results of REST show that PRV substantially reduced the rate of hospitalizations and ED visits after the first and second dose; however, optimal protection against G1-4 rotavirus acute gastroenteritis of any severity, and in particular milder disease, appears to require all three doses. PRV reduced the combined rate of rotavirus-associated hospitalizations and ED visits by 83% after the first dose, 81% after the second dose, and 95% after the third dose of vaccine. The rate reduction following each dose was statistically significant compared to placebo. However, it is important to note that the post-hoc analysis was limited to a short window of follow-up after each dose and does not imply longer-term efficacy in children who receive fewer than three doses. Efficacy against G 1-4 rotavirus acute gastroenteritis cases of any severity was 38% following the first dose, 39% following the second dose, and 74% following the third dose. These results are not unexpected and are similar to the level of protection conferred by natural infection against milder disease.2
Neither breastfeeding nor concurrent administration of other childhood vaccines appears to diminish the efficacy of a three-dose series of PRV (Merck, unpublished data, 2005). Among 204 immunized infants born preterm (<37 weeks' gestation), the point estimate of vaccine efficacy against G1-G4 rotavirus gastroenteritis of any severity was comparable to that among nonpreterm full-term infants (70%), but the confidence bounds included zero because of the small sample size (Merck, unpublished data, 2005).
The efficacy of PRV is similar to the protection observed after natural rotavirus infection. Thus, immunization early in life, which mimics a child's first natural infection, will not prevent all subsequent disease but should prevent most cases of severe rotavirus disease and their sequelae (eg, dehydration, physician visits, hospitalizations, and deaths).
Influenza viruses cause more illness, hospitalizations, and deaths in the United States than any other vaccine-preventable disease. Hospitalization rates among children under 24 months are comparable to those among adults older than 65 years.12 Depending on the degree of match between vaccine strains and circulating strains, annual immunization of children according to schedule reduces the risk of infection by as much as 80%.13 Implementation of current vaccine recommendations is essential to reduce the burden of disease in children.
Vaccination rates among children at an increased risk of complications from influenza are unacceptably low. Studies show that influenza-vaccine coverage levels among children with moderate to severe asthma range from 9% to 25%. 14,15 Data obtained in February 2005 estimated 48% vaccine coverage for one or more doses of influenza vaccine among children 6 to 23 months and 35% coverage among high-risk children 2 to 17 years.16 These data indicate low vaccine utilization among high-risk groups and form the basis for expanding the indication for routine annual vaccination.
Beginning with the 2004-2005 season, the CDC and the AAP recommended universal influenza vaccination with the trivalent inactivated vaccine (TIV) for children 6 to 23 months. Starting with the 2006-2007 season, influenza vaccine recommendations were expanded to all children 6 to 59 months.12 The rationale for the expansion from 24 to 59 months is that influenza-associated morbidity in healthy children 2 to 5 years approximates that of older children with high-risk conditions. This preschool-age cohort is also a potential source of transmission of influenza to household members and others in the community. Vaccination of household contacts and out-of-home caregivers of healthy children younger than 59 months is also recommended to reduce the risk of exposure to influenza. Immunization of close contacts of infants younger than 6 months is especially important because influenza vaccine is not licensed for use in these infants.
Both the ACIP and AAP currently recommend that children between 6 months and 9 years who are vaccinated for the first time should receive two doses, preferably before the start of the influenza season.1 Children in this age group who receive trivalent inactivated influenza vaccine (TIV) for the first time should receive the second dose at least one month after the initial dose. Children of 5 to 9 years who receive live, attenuated influenza vaccine (LAIV) as their first vaccine should receive a second dose of LATV 6 to 10 weeks after the initial dose. Children who receive two doses in the initial year the influenza vaccine was given should receive one dose in the second and subsequent years that they are vaccinated.
Many children who had not previously been vaccinated receive only one dose during the first influenza vaccination year. Available data suggest that children younger than 9 years who did not receive the second dose of influenza vaccine in the initial year influenza vaccine was given may not be adequately protected with only one dose of vaccine the next influenza season, especially if antigenic changes have occurred in the predominant strains from the previous year.17 When the vaccine antigen composition is not changed, current data indicate that antibody responses of children who received only a single dose during their first and second seasons are similar to those of children who received the recommended two doses during the first season then a single dose during the second season.18·19 However, when the influenza B antigen composition was changed for the second season, protective levels of antibody after a single vaccination in the second season against the influenza B antigen were observed in 27% of children who received only one dose the previous season. In contrast, 86% of children who received the recommended two doses in the first year of vaccination developed protective levels of antibody against the influenza B antigen.17 Children who have these low antibody responses might remain susceptible to influenza B virus infection. For this reason, the AAP recommends that two doses be given to these children the following influenza season. (The AAP policy statement is available online at: http://www.cispimmunize.org/ pro/pdf/Influenza%20Recommendatio ns-l-10-07.pdf.) This recommendation applies only to the influenza season that follows the first year that a child younger than 9 years receives influenza vaccine. Serologic data suggest that more children would potentially be protected by giving two doses the following year, especially because the formulation of influenza vaccine routinely changes to match the circulating strains of virus. Also, it would be easier for the practitioner to implement this strategy if the recommendation were to give two doses the second year whenever only one dose was given in the first year, rather than if a different recommendation was made annually on the basis of whether the formulation of the vaccine had changed from the previous year.
The AAP recommendation for children <9 years old who only received one vaccine dose during their first year of vaccination currently differs from that of the ACIP. For children who receive only one dose during the first year, the ACIP recommends a single dose in the second year.12 Harmonization of these recommendations is expected to occur before the 2007-2008 season.
The importance of a two-dose immunization policy for children younger than 9 years was confirmed by results from a retrospective study of 5,000 children conducted during the 20032004 influenza season.20 Despite some degree of mismatch between the circulating influenza strains and the vaccine strains, two doses of vaccine provided significant benefit. For children of 6 to 23 months who received two doses, vaccine efficacy against pneumonia and influenza requiring either an outpatient or emergency-department visit was 49%. No statistically significant reduction was observed for children who received one dose of vaccine.
Disruptions in vaccine supply have occurred in the past several years. Supply of influenza vaccine is uniquely susceptible to disruptions because of the need for yearly changes in vaccine composition and the short time interval for production, testing, and distribution of the vaccine once specific strains have been selected for inclusion in the vaccine. In the event of vaccine shortage or delays in production or distribution, tiered use of the vaccine is recommended. The highest priority groups include all healthy children younger than 5 years and their caregivers, as well as high-risk children who are 6 months to 18 years.
Varicella vaccine was licensed for use in the United States in 1995. The vaccine was recommended as a single dose for children 12 months to 12 years and two doses for nonimmune people older than 13 years. By 2000, the vaccine had 85% coverage levels resulting in a significant decrease in mortality, morbidity, and hospitalizations attributable to varicella.21 Vaccine effectiveness for prevention of moderate disease (>50 lesions) and complications requiring a visit to a clinician was 92%.22 However, 15% to 20% of children who receive one dose of vaccine are not fully protected and may develop mild chickenpox. These infections have been termed breakthrough varicella. Breakthrough infections are usually mild with <50 lesions, few complications, and are less contagious than moderate to severe cases of varicella.22
Since the introduction of varicella vaccine in 1995, the incidence of varicella has decreased as vaccination coverage has increased. Nevertheless, varicella outbreaks continue to occur, even among populations with high vaccination coverage.23 Although varicella typically is mild, the outbreaks can last for several months and can be challenging and costly for health departments to control. As outbreaks in schools and daycare centers continue to occur, confidence in the varicella vaccine has been eroding and public perception of vaccine "failure" has become important issue.24 Several studies have also raised concern about waning immunity, suggesting that one dose of varicella vaccine may not continue to provide protection into adulthood.25,26
In June 2005 and June 2006, the ACIP made policy changes to address these issues. These changes include routine twodose vaccination of children and second dose catch-up varicella vaccination for children, adolescents, and adults. The 2007 childhood immunization schedule now recommends that all children <13 years of age should be administered routinely two doses of varicella-containing vaccine, with the first dose administered at 12 to 15 months and the second dose at 4 to 6 years.1 A second catch-up dose is recommended for those children who previously had received one dose to improve individual protection against varicella and for more rapid impact on school outbreaks.
Field effectiveness studies of varicella vaccine conducted in the United States since the product was licensed in 1995 indicate that the effectiveness of a single dose of the vaccine against any varicella disease is generally 71% to 86%.21 Administration of a second dose of monovalent varicella vaccine increases the seroprotection rate from 87% to 99%.27 Although these data are insufficient to conclude whether two doses of varicella vaccine will prevent all varicella outbreaks, two doses are expected to decrease the susceptibility levels and increase herd immunity among school-aged children, the age group with the most cases, and thereby substantially decrease the number of varicella outbreaks.
The two-dose varicella vaccination schedule is similar to the measles, mumps, and rubella (MMR) vaccination schedule. Measles, mumps, rubella, and varicella vaccine (MMRV) was licensed in 2005 and is indicated for simultaneous vaccination against measles, mumps, rubella, and varicella among children ages 12 months to 12 years. For routine immunization, use of licensed combination vaccines, such as MMRV vaccine, is preferred over separate injection of the equivalent component vaccines.28
The ACIP and AAP annually review the recommended childhood immunization schedule to ensure that the schedule is current with changes in vaccine formulations and reflects revised recommendations for use of currently and newly licensed vaccines. In 2007, rotavirus vaccine was added to the childhood schedule and changes were made in the recommendations for influenza and varicella vaccines.
1. Recommended Immunization Schedules for Persons Aged 0-18 Years - United States, 2007. MMWR M orb Mortai WkIy Rep. 2007;55(5I):Q1-Q4.
2. Velazquez FR, Matson DO, Calva JJ, et al. Rotavirus infections in infants as protection against subsequent infections. N Engl J Med. 1996;335(14):1022-1028.
3. Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med. 2001;344(8):564-572.
4. Parashar UD, Alexander JP, Glass RI, Advisory Committee on Immunization Practices (ACIP), Centers for Deases Control and Prevention (CDC). Prevention of rotavirus gastroenteritis among infants and children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-12):1-13.
5. American Academy of Pediatrics Committee on Infectious Diseases. Prevention of rotavirus disease: guidelines for use of rotavirus vaccine. Pediatrics. 2007;119(1):171-182.
6. Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent humanbovine (WC3) reassortant rotavirus vaccine. N Engl J Med. 2006;354(1):23-33.
7. Block SL, Vesikari T, Goveia MG, et al. Efficacy, immunogenicity, and safety of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine at the end of shelf life. Pediatrics. 2007;1 19(1): 11-18.
8. Dennehy PH, Goveia MG, Dallas MJ, Heaton PM. The integrated phase III safety profile of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine. International Journal of Infectious Diseases. 2007 ;in press.
9. Rennels MB, Parashar UD, Holman RC, Le CT, Chang HG, Glass RI. Lack of an apparent association between intussusception and wild or vaccine rotavirus infection. Pediatr Infect Dis J. 1998;17(10):924-925.
10. Rotashield (rotavirus vaccine, live, oral, tetravalent) [package insert]. Marietta, PA: Wyeth-Ayerst.
11. Vesikari T, Matson D, Dennehy P, Dallas M, Itzler R, Dinubile M. Efficacy of the pentavalent rotavirus vaccine in subjects after 1 or 2 doses in the Rotavirus Efficacy & Safety Trial (REST). Presented at the 44th Annual Meeting of the Infectious Disease Society of America. Toronto, Canada; October 13, 2006.
12. Advisory Committee on Immunization Practices; Smith NM, Bresee JS, Shay DK, Uyeki TM, Cox NJ, Strikas RA. Prevention and Control of Influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-10):1-42.
13. Manzoli L, Schioppa F, Boccia A, Villari P. The Efficacy of Influenza Vaccine for Healthy Children: A Meta-Analysis Evaluating Potential Sources of Variation in Efficacy Estimates Including Study Quality. Pediatr Infect Dis J. 2007;26(2):97-106.
14. Kramarz P, DeStefano F, Gargiullo PM, et al. Influenza vaccination in children with asthma in health maintenance organizations. Vaccine Safety Datalink Team. Vaccine. 2000; 18(21):2288-2294.
15. Chung EK, Casey R, Pinto-Martin JA, Pawlowski NA, Bell LM. Routine and influenza vaccination rates in children with asthma. Ann Allergy Asthma Immunol. 1998;80(4):3 18-322.
16. Centers for Disease Control and Prevention (CDC). Estimated influenza vaccination coverage among adults and children - United States, September 1, 2004- January 31, 2005. MM WR Morb Mortal Wkly Rep. 2005;54(12):304-307.
17. Englund JA, Walter EB, Gbadebo A, Monto AS, Zhu Y, Neuzil KM. Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers. Pediatrics. 2006;118(3):e579-585.
18. Englund JA, Walter EB, Fairchok MP, Monto AS, Neuzil KM. A comparison of 2 influenza vaccine schedules in 6to 23-month-old children. Pediatrics. 2005;115(4):1039-1047.
19. Walter EB, Neuzil KM, Zhu Y, et al. Influenza vaccine immunogenicity in 6- to 23-month-old children: are identical antigens necessary for priming? Pediatrics. 2006;118(3):e570-578.
20. Ritzwoller DP, Bridges CB, Shetterly S, Yamasaki K, Kolczak M, France EK. Effectiveness of the 2003-2004 influenza vaccine among children 6 months to 8 years of age, with 1 vs 2 doses. Pediatrics. 2005;116(1):153-159.
21 . Seward J, Watson B, Peterson C, et al. Varicella disease after introduction of varicella vaccine in the United States, 1995-2000. JAMA. 2002;287(5):606-611.
22. Seward JF, Zhang JX, Maupin TJ, Mascola L, Jumaan AO. Contagiousness of varicella in vaccinated cases: a household contact study. JAMA. 2004;292(6):704-708.
23 . Public health response to varicella outbreaks - United States, 2003-2004. AfWWA Morb Mortal WkIy Rep. 2006;55(36):993-995. 24. Davis MM. Successes and remaining challenges after 10 years of varicella vaccination in the USA. Expert Rev Vaccines. 2006;5(2):295-302.
25. Galil K, Lee B, Strine T, et al. Outbreak of varicella at a day-care center despite vaccination. N Engl J Med 2002;347(24): 1909-1915.
26. Vazquez M, LaRussa PS, Gershon AA, et al. Effectiveness over time of varicella vaccine. JAMA. 2004:291 (7):85 1-855.
27. Kuter B, Matthews H, Shinefield H, et al. Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Pediatr Infect Dis J. 2004;23(2): 132-137.
28. Combination vaccines for childhood immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). Pediatrics. 1999;103(5 Pt 1):1064-1077.