- Email: [email protected]
Progress in infant immunization
Clinical Microbiology Newsletter Vol. 29, No. 6
www.cmnewsletter.com
March 15, 2007
Progress in Infant Immunization Joseph B. Domachowske, M.D., Associate Professor, Departments of Pediatrics and Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, New York Abstract The use of modern-day vacines has resulted in the marked reduction and, in some cases, elimination of a number of infectious diseases. The success of these vaccination programs has identified immunization as the number one public health achievement of the 20th century and among the most effective interventions in medicine. This article will consider the recent changes in the recommendations for use of influenza and hepatitis A vaccines during childhood and review clinical-trial results for the new infant vaccine licensed in 2006 for the prevention of rotavirus infection.
Introduction Modern-day vaccines have resulted in the eradication of smallpox, the elimination of polio in the Western hemisphere, and marked reductions in reported cases of diphtheria, pertussis, tetanus, measles, rubella, and invasive Haemophilus influenzae b infection (1,2) (Table 1). These accomplishments identify immunization programs as among the most effective interventions in medicine, and given the documented successes, it is not surprising that immunizations were named the number one public health achievement of the 20th century by the U.S. Centers for Disease Control and Prevention (CDC) (3). Despite these achievements, there is still work to be done. Millions of cases of vaccine preventable disease and thousands of vaccine-preventable deaths still occur annually in the United States (4) (Table 2). Existing vaccination programs must continue in order to control these diseases, protect the health of our
Mailing address: Joseph B. Domachowske, M.D., Associate Professor, Department of Pediatrics and Microbiology & Immunology, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY 13210. Tel.: 315-464-6331. Fax: 315-464-7564. E-mail: [email protected] Clinical Microbiology Newsletter 29:6,2007
communities, and limit disease outbreaks. This was illustrated most recently during the 2006 U.S. outbreak of nearly 6,000 cases of mumps infection. Adherence to the pediatric immunization schedule (Table 3) is arguably the single most important strategy behind the reduction in the number of cases of these preventable infections. Formal recommendations for the manner in which we use several of these vaccines have evolved over the last few years, with new vaccines being added to the schedule as they become available. An examination of national hospital discharge data for infants is one benchmark that can be used to identify the infections that are most logical to target next for vaccine development. After a brief review of those data, we will consider the recent changes in the recommendations for use of influenza and hepatitis A vaccines during early childhood. Finally, we will review clinicaltrial results for the new infant vaccine licensed in 2006 for the prevention of rotavirus infection.
(RSV) bronchiolitis remains the leading cause of infant hospitalization in the U.S. (5). The second leading reason for hospitalization is bronchiolitis, undefined. Many of these cases are due to RSV, although a significant number are also likely caused by other respiratory viral pathogens, including human metapneumovirus, influenza virus, parainfluenza virus, adenovirus, and bocavirus. The third most common reason for infant hospitalization is pneumonia. During infancy, most cases of pneumonia are caused by the same respiratory viruses that cause bronchiolitis. Among the respiratory viral infections already listed, currently only influenza is vaccine preventable. The fourth leading cause of infant hospitalization in the U.S. is jaundice, largely secondary to noninfectious causes. Finally, the fifth leading cause of infant hospitalization is dehydration. The majority of infants hospitalized for dehydration have acute viral gastroenteritis, most commonly
A Needs Assessment Based on national hospital discharge surveys done in the late 1990s, it is clear that respiratory syncytial virus © 2007 Elsevier
0196-4399/00 (see frontmatter)
41
from rotavirus infection. There has been significant progress in the development of safe and effective vaccines for use in infancy and in young children, including vaccines against influenza and rotavirus, but we desperately need an RSV vaccine. The development of safe and effective RSV vaccines for use in infants and young children has made only very slow progress in the last decades. The newly developed reverse genetics technology and the development of recombinant RSV strains should finally allow this field to advance. In the meantime, passive protection for the highest-risk infants has been more successful with the use of the anti-RSV-F monoclonal antibody, palivizumab. Newer generation anti-RSV-F monoclonal antibodies are undergoing phase 3 clinical trials and may offer additional improvements in clinical efficacy. An active vaccine against RSV is still at least a decade away. In 2006, three major changes were made to the universal immunization schedule for infants and young children. The first change is an expanded recommendation for use of influenza vaccine in all children 6 months to 5 years of age. The second change is a recommendation to use hepatitis A vaccine for all children starting at 1 year of age, and the third change was the introduction of the new live attenuated rotavirus vaccine to the universal schedule. The specific rationale for each of these recommended changes will be reviewed below.
Evolving Recommendations for the Use of Influenza Vaccine in Children Table 2 reminds us that influenza infection is very common, with average annual cases in the U.S. approximating 31 million, roughly 1 in 10 Americans! During a “usual” influenza season, about
42
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Table 1. Impact of vaccination on infectious disease eradication 20th century annual case reports (yr)
No. of 2004 case reports
% Decrease
Smallpox
48,164 (1900-04)
0
100
Paralytic polio
16,316 (1951-54)
0
100
175,885 (1920-1922)
0
100
Pertussis
147,271 (1922-25)
25,827
83
Haemophilus influenzae B
~20,000 (pre-1985)
19
99.9
Measles
503,282 (1958-62)
11 (indigenous)
>99.9
Rubella
47,745 (1966-68)
10
>99.9
Disease
Diphtheria
Table 2. Vaccine-preventable deaths Estimated annual no. of cases
Avg. annual no. of deaths
31,000,000
38,000
Hepatitis B
78,000
5,000
Hepatitis A
20,000
100
Varicella
26,660
9
Invasive pneumococcal infection
>40,000
5,500
Meningococcal disease
2,000-3,000
125
Human papillomavirusrelated disease
6,200,000
4,000 (cervical cancer)
5,783 during 2006 outbreak
0
Disease Influenza
Mumps
38,000 individuals die from influenza or influenza-related complications. It is recognized that young children shed larger amounts of influenza virus during infection than adults, making children more highly contagious and more likely to spread influenza. Influenza-related hospitalizations are common in both healthy and highrisk young children. Influenza disease surveillance indicates that previously healthy infants who are less than 6 months old have high influenza-related hospitalization rates (10.4 per 1,000). By comparison, healthy children
© 2007 Elsevier
between 1 and 4 years of age have influenza-related hospitalization rates of 1 to 2 per 1,000. Children identified as at high risk for influenza infection are nearly eight times more likely to be hospitalized than children without underlying medical conditions (6,7). Epidemiologic data have shown that, of all age groups, influenza infection is most prevalent in children between 3 and 10 years old. Glezen, et al. (8) demonstrated that 48% of all 6 to 10 year olds develop an influenza virus infection each year. Approximately 40% of this age group have an acute
Clinical Microbiology Newsletter 29:6,2007
respiratory infection secondary to influenza, and approximately 5% develop lower respiratory tract symptoms. We were reminded during the 2003-2004 influenza season that influenza A is also associated with significant mortality in children. In Bhat et al.’s description of 153 children who died from influenza-related causes during that influenza season (9), only 12% were less than 6 months of age. In their description, influenza-related mortality was not restricted to children with underlying health problems. Almost half of the children who died from influenza that season were previously healthy. In 2004, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that all infants and young children between the ages of 6 months and 23 months be immunized against influenza. During that influenza season, almost half of all 6 to 23 month olds in the U.S. were immunized. This is recognized as the single greatest percent uptake for any ACIP-recommended vaccine in history. In contrast, only 35% of individuals between the ages of 2 and 17 years of age with known high-risk factors for the development of influenza disease or complications thereof were immunized. Not surprisingly, 2-to-17year olds who were not identified as having specific risk factors were immunized much less frequently, with a rate of only 12% (10). Reported vaccination levels continue to be low among children at increased risk for influenza complications. One study conducted among patients in health maintenance organizations reported influenza vaccination percentages of only 10% among children with asthma (11). Twenty-five percent vaccination coverage was reported among children with moderate to severe asthma who attended an allergy and immunology clinic, and a study conducted in pediatric clinics demonstrated substantial increases in vaccine coverage for children with asthma (5% to 32%) after a reminder recall system was implemented (12). Another study reported an impressive 79% vaccination coverage among children attending a cystic fibrosis center (13). Improving vaccine coverage rates against influenza in children requires continued education. The three existing vaccine manufacturers of trivalent inacClinical Microbiology Newsletter 29:6,2007
tivated vaccine in the U.S. are Sanofi Pasteur, Novartis (formerly Chiron), and GlaxoSmithKline. In addition, MedImmune supplies live attenuated influenza vaccine for healthy individuals between the ages of 5 and 50 years. At the February 2006 ACIP meeting, there was a unanimous vote to expand the recommendation for influenza vaccine to include all children between 6 months and 5 years of age. It was further recommended that routine vaccination of household contacts and caregivers of children up to 5 years of age begin in the 2006-2007 influenza season. The benefits of expanding our influenza vaccine programs to include all children are very likely to extend to all age groups, including the elderly. There is already robust epidemiologic evidence from the Japanese experience that this is the case. In 1957, the Asian influenza epidemic claimed the largest recorded death toll from influenza in Japan. With widespread school closures and attack rates as high as 60% coinciding with school sessions, school attendance clearly played an important role in the spread of infection. In 1962, a nationwide program was launched to vaccinate schoolchildren against influenza in the attempt to prevent another deadly epidemic. By 1977, legislation made influenza vaccination mandatory for school attendance, and coverage rates approached 85%. The excess deaths attributed to pneumonia and influenza in Japan dropped from approximately 14 per 100,000 to less than 4 per 100,000 by the early 1980s. The benefit was seen in all age groups, despite the fact that the vaccine program focused on school-age children, suggesting that school-age children are a major reservoir for the transmission of influenza infection. In 1987, new legislation was passed allowing parents to refuse vaccination for their children. By 1990, vaccination rates sagged, and the excess deaths attributed to pneumonia and influenza crept back up close to 10 excess deaths per 100,000 population (14). This experience demonstrates the power of herd immunity in relationship to public health vaccination efforts against influenza and supports the argument that universal influenza vaccination for all U.S. children 6 months to 5 years of age will decrease the influenza disease burden in all age groups. © 2007 Elsevier
Evolving Recommendations for the Use of Hepatitis A Vaccine in Children The benefits of herd immunity are not restricted to vaccines against respiratory viral pathogens. In the U.S., we have witnessed a similar epidemiologic success story with the use of hepatitis A vaccine. The first ACIP recommendations for hepatitis A vaccine use in children were reported in 1999 (15). At that time, children who lived in states, counties, or communities where the average hepatitis A rate was ≥20 cases per 100,000 during a baseline period (Arizona, Alaska, Oregon, New Mexico, Utah, Washington, Oklahoma, South Dakota, Idaho, Nevada, and California) were recommended to get the vaccine routinely. In addition, children who lived in states, counties or communities where the average hepatitis A rates were between 10 and 20 cases per 100,000 should have been considered for the vaccine (at the time, these were Missouri, Texas, Colorado, Arkansas, Montana, and Wyoming). Hepatitis A vaccine has been available for use in the U.S. since 1995. In the pre-vaccine era, there were approximately 12 cases per 100,000 of hepatitis A in the U.S. per year. In the 3 years following implementation of routine vaccination of children in states with high hepatitis A rates, there was an 86% reduction in the incidence of infection (16). During the same period, states where the vaccine was to be considered for use enjoyed an 89% reduction in hepatitis A cases. The herd immunity effect of these vaccination programs was most evident in areas where no statewide recommendations were made for use of hepatitis A vaccine. In those states, despite a lack of intervention, there was a 50% reduction in hepatitis A disease incidence. Currently, nationwide, the overall incidence of hepatitis A infection has dropped from 12 to approximately 3 cases per 100,000. Because of the successful implementation of hepatitis A vaccine, highprevalence areas are no longer highprevalence areas, leading to evolving changes in the ACIP recommendations for using hepatitis A vaccine. The new recommendations now state that the vaccine should be used universally in children beginning at age 1 year (17). The need for universal childhood hepa0196-4399/00 (see frontmatter)
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Table 3. Recommended immunization schedule for ages 0 to 6 years, United States, 2007 Vaccine
Birth
Hepatitus B
HepB
1 month
2 4 months months
6 12 months months
HepB
15 months
18 months
19-23 months
HepB
Rotavirus
Rota
Rota
Rota
Diphtheria, tetanus, pertussis
DTaP
DTaP
DTaP
Haemophilus influenzae type b
Hib
Hib
Hib
Hib
Pneumococcal
PCV
PCV
PCV
PCV
Inactivated poliovirus
IPV
IPV
2-3 years
4-6 years
HepB Series
DTaP
DTaP Hib PCV PPV
IPV
IPV
Influenza
Influenza (yearly)
Measles, mumps, rubella Varicella
MMR
MMR
Varicella
Varicella
Hepatitis A
HepA (2 doses)
Meningococcal
HepA Series MPSV4
Range of recommended ages Catch-up immunization Certain high-risk groups
titis A vaccine has been questioned now that disease rates are at historic lows; however, mathematical models support the notion that cost efficacy for hepatitis A vaccine is similar to that for other existing vaccine programs. Moreover, the epidemiology of hepatitis A infection supports the contention that if vaccine coverage rates fall, herd immunity will wane and hepatitis outbreaks will return. The most effective public health measure to prevent such outbreaks is to maintain our current herd immunity status through routine vaccination during childhood.
The 2006 Rotavirus Vaccine Dehydration is a leading cause of infant hospitalization in the U.S., with most cases occurring secondary to viral gastroenteritis. The single most common infectious agent of infant gastroenteritis is rotavirus, with an estimated 2.7 million episodes of rotavirus gastroenteritis every year in the U.S. alone. This number is particularly impressive, since the annual birth cohort in the U.S. is 4 million. These nearly 3 million episodes of rotavirus gastroenteritis result in a quarter of a million emergency department visits, leading to between 55,000 and 70,000 hospitalizations annually. Rotavirus infects more than 95% of infants and children by their fifth birthday and is responsible for an estimated billion 44
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dollars in direct and indirect medical costs each year (18,19). The first rotavirus vaccine that was FDA approved for use in infants in the U.S. became available in 1998. This vaccine, marketed under the trade name RotaShield, was a tetravalent rhesus monkey-based rotavirus vaccine evaluated in prelicensure trials in approximately 18,000 patients. In 1998, the vaccine was licensed and recommended for the prevention of rotavirus gastroenteritis in infants in the U.S., but shortly after it’s licensure, a temporal association between receiving the vaccine and the development of a form of bowel obstruction called intussusception was observed. The number of excess cases of intussusception was found to be approximately 1 per 10,000 doses delivered, with the highest-risk period occurring in the 2 weeks following the first dose of the vaccine. The clustering of intussusception cases in the 2 weeks following receiving RotaShield vaccine lead to the suspicion that the vaccine itself was causing intussusception. The epidemiologic data supported this argument (20). Because of this rare but serious complication, Rotashield vaccine was voluntarily withdrawn from the market approximately 1 year after licensure. Despite this experience, the development of new-generation rotavirus © 2007 Elsevier
vaccines continued (21), but now with particular attention to the possibility that new vaccine candidates could share this potential complication. Following intense scrutiny and with safety data obtained from more than 70,000 infants, a new rotavirus vaccine was approved for use in infants by the Food and Drug Administration in 2006. This newgeneration rotavirus vaccine, manufactured by Merck under the trade name RotaTeq, is a live oral pentavalent bovine-based vaccine containing five different reassortant rotaviruses. It was approved as a three-dose series to be delivered to infants between the ages of 6 weeks and 32 weeks, with the first dose given sometime between 6 and 12 weeks of age. Overall, more than 70,000 infants were randomized in three different placebo-controlled phase III trials. The largest of these three trials was the rotavirus efficacy and safety trial, commonly referred to as the R.E.S.T. trial. This vaccine trial was double blinded, randomized, and placebo controlled, with a total enrollment of approximately 70,000 infants (22). About half of those infants received vaccine, and half received placebo. The first dose was given between 6 and 12 weeks of age, and two additional doses were given at approximately 4- to 10-week intervals. Serious adverse reactions were monitored in all subClinical Microbiology Newsletter 29:6,2007
jects, and all adverse events were monitored in a sub-study. Efficacy against rotavirus diarrhea and against rotavirusrelated hospitalization was evaluated. In the efficacy analysis, there were 82 cases of rotavirus diarrhea in vaccine recipients and 315 episodes of rotavirus diarrhea in placebo recipients, yielding a 74% efficacy against any grade severity of rotavirus gastroenteritis. Interestingly, there was only a single case of severe rotavirus gastroenteritis in vaccine recipients, while there were 51 episodes of severe rotavirus gastroenteritis in placebo recipients, so the vaccine was found to be 98% effective at preventing severe rotavirus diarrhea. Because the clinical trial was so large, there was also an ability to evaluate reduction in hospitalizations for rotavirus diarrhea. Hospitalization secondary to rotavirus infection occurred six times in the vaccine group (n = 34,035) and 144 times in the placebo group (n = 34,003), yielding a rate reduction of 95.8%. The single most important adverse reaction followed in the R.E.S.T. trial was cases of intussusception. In the 10 days following either vaccine or placebo, there were only two cases of intussusception documented. One case occurred in a placebo recipient, one in a vaccine recipient. When the total number of cases of intussusception over a 2-year period were evaluated, it was shown that there were 13 cases of intussusception in infants who had received vaccine and 15 cases of intussusception in infants who received placebo, indicating an absence of association of intussusception with this new-generation rotavirus vaccine. RotaTeq was FDA approved in 2006 as a three-dose series given at 2 months, 4 months, and 6 months of age. ACIP recommends routine delivery of this vaccine to all infants in the U.S. unless specific contraindications exist.
Conclusions The recent changes in the universal pediatric immunization schedule to include the new rotavirus vaccine, and to expand the use of influenza and hepatitis A vaccines open new opportunities for disease prevention. The herd immunity advantages of these and other
Clinical Microbiology Newsletter 29:6,2007
immunization efforts extend beyond the infants and children receiving the vaccines, because prevention of disease in this cohort also limits the spread of infection to older individuals. From a public health perspective, immunization efforts like these make sense in every instance. As new vaccines are developed, additional opportunities will emerge. Several of these opportunities are already materializing in the form of new vaccines for the prevention of meningococcal disease and human papillomavirus-associated diseases in adolescents and adults. References 1. Centers for Disease Control and Prevention. 1999. Impact of vaccines universally recommended for children — United States, 1900-1998. Morb. Mortal. Wkly. Rep. 48:243-248.
vaccination coverage among adults and children — United States, September 1, 2004-January 31, 2005. Morb. Mortal. Wkly. Rep. 54:304-307. 11. Kramarz, P. et al. 2000. Influenza vaccination in children with asthma in health maintenance organizations. Vaccine 18:2288-2294. 12. Gaglani, M. et al. 2001. Computerized reminder strategy is effective for annual influenza immunization of children with asthma or reactive airway disease. Pediatr. Infect. Dis. J. 20:1155-1160. 13. Marshall, B.C. et al. 2002. Influenza vaccination coverage level at a cystic fibrosis center. Pediatrics 109:e80. 14. Reichert, T.A. et al. 2001. The Japanese experience with vaccinating schoolchildren against influenza. N. Engl. J. Med. 344:889-896.
2. Centers for Disease Control and Prevention. 2005. Final 2004 reports of notifiable disease Morb. Mortal. Wkly. Rep. 54:770-780.
15. Centers for Disease Control and Prevention. 1999. Prevention of hepatitis A through active or passive immunization: recommendations of the advisory committee on immunization practices. Morb. Mortal. Wkly. Rep. 48:1-37.
3. Centers for Disease Control and Prevention. 1999. Achievements in public health, 1990-1999: changes in the public health system. Morb. Mortal. Wkly. Rep. 48:1141-1147.
16. Centers for Disease Control and Prevention. 2005. Hepatitis A vaccination coverage among children aged 24-35 months — United States, 2003. Morb. Mortal. Wkly. Rep. 54:141-144.
4. Atkinson, W. (ed.). 2006. Epidemiology and prevention of vaccine-preventable diseases, 9th ed. Centers for Disease Control and Prevention, Washington, D.C.
17. Centers for Disease Control and Prevention. 2006. Prevention of hepatitis A through active or passive immunization. Morb. Mortal. Wkly. Rep. 55:1-23.
5. Leader, S. and K. Kohlhase. 2002. Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 1999. Pediatr. Infect. Dis. J. 21:629-632. 6. Neuzil, K.M. et al. 2000. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N. Engl. J. Med. 342:225-231. 7. Neuzil, K.M. et al. 2000. The burden of influenza illness in children with asthma and other chronic medical conditions. J. Pediatr. 137:856-864. 8. Glezen, W.P. et al. 1997. Influenza virus infections in infants. Pediatr. Infect. Dis. J. 16:1065-1068. 9. Bhat, N. et al. for the Influenza Special Investigations Team. 2005. Influenza associated deaths among children in the United States, 2003-2004. N. Engl. J. Med. 353:2559-2567. 10. Centers for Disease Control and Prevention. 2005. Estimated influenza
© 2007 Elsevier
18. Tucker, A.W. et al. 1998. Cost-effectiveness analysis of a rotavirus immunization program for the United States. JAMA 279:1371-1376. 19. Parashar, U. et al., and the Centers for Disease Control and Prevention. 2005. Anticipating a new rotavirus vaccine in the United States — Surveillance and estimates of disease burden. Presented at the Infectious Diseases Society of America Conference, San Francisco, CA. 20. Centers for Disease Control and Prevention. 1999. Intussusception among recipients of rotavirus vaccine, United States, 1998-1999. Morb. Mortal. Wkly. Rep. 48:577-581. 21. Glass, R.I. and U.D. Parashar. 2006. The promise of new rotavirus vaccines. N. Engl. J. Med. 354:75-77. 22. Vesikari, T. et al. 2006. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N. Engl. J. Med. 354:23-33.
0196-4399/00 (see frontmatter)
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www.cmnewsletter.com
March 15, 2007
Progress in Infant Immunization Joseph B. Domachowske, M.D., Associate Professor, Departments of Pediatrics and Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, New York Abstract The use of modern-day vacines has resulted in the marked reduction and, in some cases, elimination of a number of infectious diseases. The success of these vaccination programs has identified immunization as the number one public health achievement of the 20th century and among the most effective interventions in medicine. This article will consider the recent changes in the recommendations for use of influenza and hepatitis A vaccines during childhood and review clinical-trial results for the new infant vaccine licensed in 2006 for the prevention of rotavirus infection.
Introduction Modern-day vaccines have resulted in the eradication of smallpox, the elimination of polio in the Western hemisphere, and marked reductions in reported cases of diphtheria, pertussis, tetanus, measles, rubella, and invasive Haemophilus influenzae b infection (1,2) (Table 1). These accomplishments identify immunization programs as among the most effective interventions in medicine, and given the documented successes, it is not surprising that immunizations were named the number one public health achievement of the 20th century by the U.S. Centers for Disease Control and Prevention (CDC) (3). Despite these achievements, there is still work to be done. Millions of cases of vaccine preventable disease and thousands of vaccine-preventable deaths still occur annually in the United States (4) (Table 2). Existing vaccination programs must continue in order to control these diseases, protect the health of our
Mailing address: Joseph B. Domachowske, M.D., Associate Professor, Department of Pediatrics and Microbiology & Immunology, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY 13210. Tel.: 315-464-6331. Fax: 315-464-7564. E-mail: [email protected] Clinical Microbiology Newsletter 29:6,2007
communities, and limit disease outbreaks. This was illustrated most recently during the 2006 U.S. outbreak of nearly 6,000 cases of mumps infection. Adherence to the pediatric immunization schedule (Table 3) is arguably the single most important strategy behind the reduction in the number of cases of these preventable infections. Formal recommendations for the manner in which we use several of these vaccines have evolved over the last few years, with new vaccines being added to the schedule as they become available. An examination of national hospital discharge data for infants is one benchmark that can be used to identify the infections that are most logical to target next for vaccine development. After a brief review of those data, we will consider the recent changes in the recommendations for use of influenza and hepatitis A vaccines during early childhood. Finally, we will review clinicaltrial results for the new infant vaccine licensed in 2006 for the prevention of rotavirus infection.
(RSV) bronchiolitis remains the leading cause of infant hospitalization in the U.S. (5). The second leading reason for hospitalization is bronchiolitis, undefined. Many of these cases are due to RSV, although a significant number are also likely caused by other respiratory viral pathogens, including human metapneumovirus, influenza virus, parainfluenza virus, adenovirus, and bocavirus. The third most common reason for infant hospitalization is pneumonia. During infancy, most cases of pneumonia are caused by the same respiratory viruses that cause bronchiolitis. Among the respiratory viral infections already listed, currently only influenza is vaccine preventable. The fourth leading cause of infant hospitalization in the U.S. is jaundice, largely secondary to noninfectious causes. Finally, the fifth leading cause of infant hospitalization is dehydration. The majority of infants hospitalized for dehydration have acute viral gastroenteritis, most commonly
A Needs Assessment Based on national hospital discharge surveys done in the late 1990s, it is clear that respiratory syncytial virus © 2007 Elsevier
0196-4399/00 (see frontmatter)
41
from rotavirus infection. There has been significant progress in the development of safe and effective vaccines for use in infancy and in young children, including vaccines against influenza and rotavirus, but we desperately need an RSV vaccine. The development of safe and effective RSV vaccines for use in infants and young children has made only very slow progress in the last decades. The newly developed reverse genetics technology and the development of recombinant RSV strains should finally allow this field to advance. In the meantime, passive protection for the highest-risk infants has been more successful with the use of the anti-RSV-F monoclonal antibody, palivizumab. Newer generation anti-RSV-F monoclonal antibodies are undergoing phase 3 clinical trials and may offer additional improvements in clinical efficacy. An active vaccine against RSV is still at least a decade away. In 2006, three major changes were made to the universal immunization schedule for infants and young children. The first change is an expanded recommendation for use of influenza vaccine in all children 6 months to 5 years of age. The second change is a recommendation to use hepatitis A vaccine for all children starting at 1 year of age, and the third change was the introduction of the new live attenuated rotavirus vaccine to the universal schedule. The specific rationale for each of these recommended changes will be reviewed below.
Evolving Recommendations for the Use of Influenza Vaccine in Children Table 2 reminds us that influenza infection is very common, with average annual cases in the U.S. approximating 31 million, roughly 1 in 10 Americans! During a “usual” influenza season, about
42
0196-4399/00 (see frontmatter)
Table 1. Impact of vaccination on infectious disease eradication 20th century annual case reports (yr)
No. of 2004 case reports
% Decrease
Smallpox
48,164 (1900-04)
0
100
Paralytic polio
16,316 (1951-54)
0
100
175,885 (1920-1922)
0
100
Pertussis
147,271 (1922-25)
25,827
83
Haemophilus influenzae B
~20,000 (pre-1985)
19
99.9
Measles
503,282 (1958-62)
11 (indigenous)
>99.9
Rubella
47,745 (1966-68)
10
>99.9
Disease
Diphtheria
Table 2. Vaccine-preventable deaths Estimated annual no. of cases
Avg. annual no. of deaths
31,000,000
38,000
Hepatitis B
78,000
5,000
Hepatitis A
20,000
100
Varicella
26,660
9
Invasive pneumococcal infection
>40,000
5,500
Meningococcal disease
2,000-3,000
125
Human papillomavirusrelated disease
6,200,000
4,000 (cervical cancer)
5,783 during 2006 outbreak
0
Disease Influenza
Mumps
38,000 individuals die from influenza or influenza-related complications. It is recognized that young children shed larger amounts of influenza virus during infection than adults, making children more highly contagious and more likely to spread influenza. Influenza-related hospitalizations are common in both healthy and highrisk young children. Influenza disease surveillance indicates that previously healthy infants who are less than 6 months old have high influenza-related hospitalization rates (10.4 per 1,000). By comparison, healthy children
© 2007 Elsevier
between 1 and 4 years of age have influenza-related hospitalization rates of 1 to 2 per 1,000. Children identified as at high risk for influenza infection are nearly eight times more likely to be hospitalized than children without underlying medical conditions (6,7). Epidemiologic data have shown that, of all age groups, influenza infection is most prevalent in children between 3 and 10 years old. Glezen, et al. (8) demonstrated that 48% of all 6 to 10 year olds develop an influenza virus infection each year. Approximately 40% of this age group have an acute
Clinical Microbiology Newsletter 29:6,2007
respiratory infection secondary to influenza, and approximately 5% develop lower respiratory tract symptoms. We were reminded during the 2003-2004 influenza season that influenza A is also associated with significant mortality in children. In Bhat et al.’s description of 153 children who died from influenza-related causes during that influenza season (9), only 12% were less than 6 months of age. In their description, influenza-related mortality was not restricted to children with underlying health problems. Almost half of the children who died from influenza that season were previously healthy. In 2004, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that all infants and young children between the ages of 6 months and 23 months be immunized against influenza. During that influenza season, almost half of all 6 to 23 month olds in the U.S. were immunized. This is recognized as the single greatest percent uptake for any ACIP-recommended vaccine in history. In contrast, only 35% of individuals between the ages of 2 and 17 years of age with known high-risk factors for the development of influenza disease or complications thereof were immunized. Not surprisingly, 2-to-17year olds who were not identified as having specific risk factors were immunized much less frequently, with a rate of only 12% (10). Reported vaccination levels continue to be low among children at increased risk for influenza complications. One study conducted among patients in health maintenance organizations reported influenza vaccination percentages of only 10% among children with asthma (11). Twenty-five percent vaccination coverage was reported among children with moderate to severe asthma who attended an allergy and immunology clinic, and a study conducted in pediatric clinics demonstrated substantial increases in vaccine coverage for children with asthma (5% to 32%) after a reminder recall system was implemented (12). Another study reported an impressive 79% vaccination coverage among children attending a cystic fibrosis center (13). Improving vaccine coverage rates against influenza in children requires continued education. The three existing vaccine manufacturers of trivalent inacClinical Microbiology Newsletter 29:6,2007
tivated vaccine in the U.S. are Sanofi Pasteur, Novartis (formerly Chiron), and GlaxoSmithKline. In addition, MedImmune supplies live attenuated influenza vaccine for healthy individuals between the ages of 5 and 50 years. At the February 2006 ACIP meeting, there was a unanimous vote to expand the recommendation for influenza vaccine to include all children between 6 months and 5 years of age. It was further recommended that routine vaccination of household contacts and caregivers of children up to 5 years of age begin in the 2006-2007 influenza season. The benefits of expanding our influenza vaccine programs to include all children are very likely to extend to all age groups, including the elderly. There is already robust epidemiologic evidence from the Japanese experience that this is the case. In 1957, the Asian influenza epidemic claimed the largest recorded death toll from influenza in Japan. With widespread school closures and attack rates as high as 60% coinciding with school sessions, school attendance clearly played an important role in the spread of infection. In 1962, a nationwide program was launched to vaccinate schoolchildren against influenza in the attempt to prevent another deadly epidemic. By 1977, legislation made influenza vaccination mandatory for school attendance, and coverage rates approached 85%. The excess deaths attributed to pneumonia and influenza in Japan dropped from approximately 14 per 100,000 to less than 4 per 100,000 by the early 1980s. The benefit was seen in all age groups, despite the fact that the vaccine program focused on school-age children, suggesting that school-age children are a major reservoir for the transmission of influenza infection. In 1987, new legislation was passed allowing parents to refuse vaccination for their children. By 1990, vaccination rates sagged, and the excess deaths attributed to pneumonia and influenza crept back up close to 10 excess deaths per 100,000 population (14). This experience demonstrates the power of herd immunity in relationship to public health vaccination efforts against influenza and supports the argument that universal influenza vaccination for all U.S. children 6 months to 5 years of age will decrease the influenza disease burden in all age groups. © 2007 Elsevier
Evolving Recommendations for the Use of Hepatitis A Vaccine in Children The benefits of herd immunity are not restricted to vaccines against respiratory viral pathogens. In the U.S., we have witnessed a similar epidemiologic success story with the use of hepatitis A vaccine. The first ACIP recommendations for hepatitis A vaccine use in children were reported in 1999 (15). At that time, children who lived in states, counties, or communities where the average hepatitis A rate was ≥20 cases per 100,000 during a baseline period (Arizona, Alaska, Oregon, New Mexico, Utah, Washington, Oklahoma, South Dakota, Idaho, Nevada, and California) were recommended to get the vaccine routinely. In addition, children who lived in states, counties or communities where the average hepatitis A rates were between 10 and 20 cases per 100,000 should have been considered for the vaccine (at the time, these were Missouri, Texas, Colorado, Arkansas, Montana, and Wyoming). Hepatitis A vaccine has been available for use in the U.S. since 1995. In the pre-vaccine era, there were approximately 12 cases per 100,000 of hepatitis A in the U.S. per year. In the 3 years following implementation of routine vaccination of children in states with high hepatitis A rates, there was an 86% reduction in the incidence of infection (16). During the same period, states where the vaccine was to be considered for use enjoyed an 89% reduction in hepatitis A cases. The herd immunity effect of these vaccination programs was most evident in areas where no statewide recommendations were made for use of hepatitis A vaccine. In those states, despite a lack of intervention, there was a 50% reduction in hepatitis A disease incidence. Currently, nationwide, the overall incidence of hepatitis A infection has dropped from 12 to approximately 3 cases per 100,000. Because of the successful implementation of hepatitis A vaccine, highprevalence areas are no longer highprevalence areas, leading to evolving changes in the ACIP recommendations for using hepatitis A vaccine. The new recommendations now state that the vaccine should be used universally in children beginning at age 1 year (17). The need for universal childhood hepa0196-4399/00 (see frontmatter)
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Table 3. Recommended immunization schedule for ages 0 to 6 years, United States, 2007 Vaccine
Birth
Hepatitus B
HepB
1 month
2 4 months months
6 12 months months
HepB
15 months
18 months
19-23 months
HepB
Rotavirus
Rota
Rota
Rota
Diphtheria, tetanus, pertussis
DTaP
DTaP
DTaP
Haemophilus influenzae type b
Hib
Hib
Hib
Hib
Pneumococcal
PCV
PCV
PCV
PCV
Inactivated poliovirus
IPV
IPV
2-3 years
4-6 years
HepB Series
DTaP
DTaP Hib PCV PPV
IPV
IPV
Influenza
Influenza (yearly)
Measles, mumps, rubella Varicella
MMR
MMR
Varicella
Varicella
Hepatitis A
HepA (2 doses)
Meningococcal
HepA Series MPSV4
Range of recommended ages Catch-up immunization Certain high-risk groups
titis A vaccine has been questioned now that disease rates are at historic lows; however, mathematical models support the notion that cost efficacy for hepatitis A vaccine is similar to that for other existing vaccine programs. Moreover, the epidemiology of hepatitis A infection supports the contention that if vaccine coverage rates fall, herd immunity will wane and hepatitis outbreaks will return. The most effective public health measure to prevent such outbreaks is to maintain our current herd immunity status through routine vaccination during childhood.
The 2006 Rotavirus Vaccine Dehydration is a leading cause of infant hospitalization in the U.S., with most cases occurring secondary to viral gastroenteritis. The single most common infectious agent of infant gastroenteritis is rotavirus, with an estimated 2.7 million episodes of rotavirus gastroenteritis every year in the U.S. alone. This number is particularly impressive, since the annual birth cohort in the U.S. is 4 million. These nearly 3 million episodes of rotavirus gastroenteritis result in a quarter of a million emergency department visits, leading to between 55,000 and 70,000 hospitalizations annually. Rotavirus infects more than 95% of infants and children by their fifth birthday and is responsible for an estimated billion 44
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dollars in direct and indirect medical costs each year (18,19). The first rotavirus vaccine that was FDA approved for use in infants in the U.S. became available in 1998. This vaccine, marketed under the trade name RotaShield, was a tetravalent rhesus monkey-based rotavirus vaccine evaluated in prelicensure trials in approximately 18,000 patients. In 1998, the vaccine was licensed and recommended for the prevention of rotavirus gastroenteritis in infants in the U.S., but shortly after it’s licensure, a temporal association between receiving the vaccine and the development of a form of bowel obstruction called intussusception was observed. The number of excess cases of intussusception was found to be approximately 1 per 10,000 doses delivered, with the highest-risk period occurring in the 2 weeks following the first dose of the vaccine. The clustering of intussusception cases in the 2 weeks following receiving RotaShield vaccine lead to the suspicion that the vaccine itself was causing intussusception. The epidemiologic data supported this argument (20). Because of this rare but serious complication, Rotashield vaccine was voluntarily withdrawn from the market approximately 1 year after licensure. Despite this experience, the development of new-generation rotavirus © 2007 Elsevier
vaccines continued (21), but now with particular attention to the possibility that new vaccine candidates could share this potential complication. Following intense scrutiny and with safety data obtained from more than 70,000 infants, a new rotavirus vaccine was approved for use in infants by the Food and Drug Administration in 2006. This newgeneration rotavirus vaccine, manufactured by Merck under the trade name RotaTeq, is a live oral pentavalent bovine-based vaccine containing five different reassortant rotaviruses. It was approved as a three-dose series to be delivered to infants between the ages of 6 weeks and 32 weeks, with the first dose given sometime between 6 and 12 weeks of age. Overall, more than 70,000 infants were randomized in three different placebo-controlled phase III trials. The largest of these three trials was the rotavirus efficacy and safety trial, commonly referred to as the R.E.S.T. trial. This vaccine trial was double blinded, randomized, and placebo controlled, with a total enrollment of approximately 70,000 infants (22). About half of those infants received vaccine, and half received placebo. The first dose was given between 6 and 12 weeks of age, and two additional doses were given at approximately 4- to 10-week intervals. Serious adverse reactions were monitored in all subClinical Microbiology Newsletter 29:6,2007
jects, and all adverse events were monitored in a sub-study. Efficacy against rotavirus diarrhea and against rotavirusrelated hospitalization was evaluated. In the efficacy analysis, there were 82 cases of rotavirus diarrhea in vaccine recipients and 315 episodes of rotavirus diarrhea in placebo recipients, yielding a 74% efficacy against any grade severity of rotavirus gastroenteritis. Interestingly, there was only a single case of severe rotavirus gastroenteritis in vaccine recipients, while there were 51 episodes of severe rotavirus gastroenteritis in placebo recipients, so the vaccine was found to be 98% effective at preventing severe rotavirus diarrhea. Because the clinical trial was so large, there was also an ability to evaluate reduction in hospitalizations for rotavirus diarrhea. Hospitalization secondary to rotavirus infection occurred six times in the vaccine group (n = 34,035) and 144 times in the placebo group (n = 34,003), yielding a rate reduction of 95.8%. The single most important adverse reaction followed in the R.E.S.T. trial was cases of intussusception. In the 10 days following either vaccine or placebo, there were only two cases of intussusception documented. One case occurred in a placebo recipient, one in a vaccine recipient. When the total number of cases of intussusception over a 2-year period were evaluated, it was shown that there were 13 cases of intussusception in infants who had received vaccine and 15 cases of intussusception in infants who received placebo, indicating an absence of association of intussusception with this new-generation rotavirus vaccine. RotaTeq was FDA approved in 2006 as a three-dose series given at 2 months, 4 months, and 6 months of age. ACIP recommends routine delivery of this vaccine to all infants in the U.S. unless specific contraindications exist.
Conclusions The recent changes in the universal pediatric immunization schedule to include the new rotavirus vaccine, and to expand the use of influenza and hepatitis A vaccines open new opportunities for disease prevention. The herd immunity advantages of these and other
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immunization efforts extend beyond the infants and children receiving the vaccines, because prevention of disease in this cohort also limits the spread of infection to older individuals. From a public health perspective, immunization efforts like these make sense in every instance. As new vaccines are developed, additional opportunities will emerge. Several of these opportunities are already materializing in the form of new vaccines for the prevention of meningococcal disease and human papillomavirus-associated diseases in adolescents and adults. References 1. Centers for Disease Control and Prevention. 1999. Impact of vaccines universally recommended for children — United States, 1900-1998. Morb. Mortal. Wkly. Rep. 48:243-248.
vaccination coverage among adults and children — United States, September 1, 2004-January 31, 2005. Morb. Mortal. Wkly. Rep. 54:304-307. 11. Kramarz, P. et al. 2000. Influenza vaccination in children with asthma in health maintenance organizations. Vaccine 18:2288-2294. 12. Gaglani, M. et al. 2001. Computerized reminder strategy is effective for annual influenza immunization of children with asthma or reactive airway disease. Pediatr. Infect. Dis. J. 20:1155-1160. 13. Marshall, B.C. et al. 2002. Influenza vaccination coverage level at a cystic fibrosis center. Pediatrics 109:e80. 14. Reichert, T.A. et al. 2001. The Japanese experience with vaccinating schoolchildren against influenza. N. Engl. J. Med. 344:889-896.
2. Centers for Disease Control and Prevention. 2005. Final 2004 reports of notifiable disease Morb. Mortal. Wkly. Rep. 54:770-780.
15. Centers for Disease Control and Prevention. 1999. Prevention of hepatitis A through active or passive immunization: recommendations of the advisory committee on immunization practices. Morb. Mortal. Wkly. Rep. 48:1-37.
3. Centers for Disease Control and Prevention. 1999. Achievements in public health, 1990-1999: changes in the public health system. Morb. Mortal. Wkly. Rep. 48:1141-1147.
16. Centers for Disease Control and Prevention. 2005. Hepatitis A vaccination coverage among children aged 24-35 months — United States, 2003. Morb. Mortal. Wkly. Rep. 54:141-144.
4. Atkinson, W. (ed.). 2006. Epidemiology and prevention of vaccine-preventable diseases, 9th ed. Centers for Disease Control and Prevention, Washington, D.C.
17. Centers for Disease Control and Prevention. 2006. Prevention of hepatitis A through active or passive immunization. Morb. Mortal. Wkly. Rep. 55:1-23.
5. Leader, S. and K. Kohlhase. 2002. Respiratory syncytial virus-coded pediatric hospitalizations, 1997 to 1999. Pediatr. Infect. Dis. J. 21:629-632. 6. Neuzil, K.M. et al. 2000. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N. Engl. J. Med. 342:225-231. 7. Neuzil, K.M. et al. 2000. The burden of influenza illness in children with asthma and other chronic medical conditions. J. Pediatr. 137:856-864. 8. Glezen, W.P. et al. 1997. Influenza virus infections in infants. Pediatr. Infect. Dis. J. 16:1065-1068. 9. Bhat, N. et al. for the Influenza Special Investigations Team. 2005. Influenza associated deaths among children in the United States, 2003-2004. N. Engl. J. Med. 353:2559-2567. 10. Centers for Disease Control and Prevention. 2005. Estimated influenza
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18. Tucker, A.W. et al. 1998. Cost-effectiveness analysis of a rotavirus immunization program for the United States. JAMA 279:1371-1376. 19. Parashar, U. et al., and the Centers for Disease Control and Prevention. 2005. Anticipating a new rotavirus vaccine in the United States — Surveillance and estimates of disease burden. Presented at the Infectious Diseases Society of America Conference, San Francisco, CA. 20. Centers for Disease Control and Prevention. 1999. Intussusception among recipients of rotavirus vaccine, United States, 1998-1999. Morb. Mortal. Wkly. Rep. 48:577-581. 21. Glass, R.I. and U.D. Parashar. 2006. The promise of new rotavirus vaccines. N. Engl. J. Med. 354:75-77. 22. Vesikari, T. et al. 2006. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N. Engl. J. Med. 354:23-33.
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