- Email: [email protected]
Progress in adolescent immunization
Clinical Microbiology Newsletter Vol. 29, No. 19
www.cmnewsletter.com
October 1, 2007
Progress in Adolescent Immunization Erin M. Bennett, M.S. and Joseph B. Domachowske, M.D., Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York
Abstract The recent addition of three new vaccines to the routine adolescent immunization schedule opens new opportunities to provide preventative interventions for long-term health lasting well into adulthood. These newly approved vaccines, Tdap (adolescent tetanus, diphtheria, and pertussis) vaccine, conjugate meningococcal vaccine, and human papillomavirus vaccine, are now recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices to be administered routinely during the teenage years beginning at the11 to 12 year-old-health care visit and continuing through young adulthood. This approach not only allows for catch-up vaccination for those who did not receive earlier recommended childhood vaccines, but also provides protection at an age of increased risk for these infections. The specific recommendations for each of the three vaccines and the rationale for each of them are described. The U.S. Centers for Disease Control and Prevention and the Department of Health and Human Services released the new 2007 recommended pediatric immunization schedule in January. In this update, vaccine recommendations for older children and adolescents were listed separately from recommendations for infants and young children (Table 1). The new table for older children outlines immunization recommendations for ages 7 to 18 years, including routine immunization with Tdap (tetanus, diphtheria, and pertussis booster) vaccine, human papillomavirus vaccine, and conjugate meningococcal vaccine, with catch-up immunizations with hepatitis B, polio, measles, mumps, rubella, and varicella vaccines. Reminders that certain high-risk groups should be immunized with pneumococcal vaccine, annual influenza vaccine, and hepatitis
Mailing Address: Dr. Domachowske, Associate Professor of Pediatrics, Microbiology/Immunology, SUNY Upstate Medical University, 750 East Adams St., Syracuse, NY 13210. Tel.: 315-464-6331. Fax: 315-464-7564. E-mail: [email protected] Clinical Microbiology Newsletter 29:19,2007
A vaccine are also included. Three of the newly approved vaccines, Tdap vaccine, conjugate meningococcal vaccine, and human papillomavirus vaccine, are now recommended by the Advisory Committee on Immunization Practices (ACIP) to be administered to all adolescents. Administration of these new vaccines during the recommended adolescent health care visit at age 11 to 12 years reinforces the importance of preventative health care at this age. The timing of this recommendation also allows for catch-up vaccination for those who did not receive earlier recommended childhood vaccines.
Boosting Pertussis Immunity with Tdap Vaccine During Adolescence
account for more than half of reported cases, with both age groups representing important reservoirs of the disease.
Pertussis Infection Classic infant pertussis is characterized by three phases. The catarrhal phase lasts up to 2 weeks and is characterized by coryza and intermittent cough. This is followed by the paroxysmal phase, lasting several weeks. The paroxysmal stage is characterized by coughing fits, the characteristic inspiratory whooping, and post-tussive vomiting. Symptoms improve gradually during the convalescent phase, which can last for several months. In general, older patients tend to have fewer mani-
Despite universal immunization of infants and young children with combined diphtheria, tetanus, and acellular pertussis vaccine (DTaP), reported cases of pertussis have steadily increased in the United States since the late 1970s. A significant proportion of reported cases now occur in adolescents, in part because protective immunity from vaccination during young childhood has waned. Adolescents and adults now © 2007 Elsevier
0196-4399/00 (see frontmatter)
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Table 1. Recommended Immunization Schedule for persons aged 7 to 18 years — United States, 2007 age (yr) Vaccine
7-10
11-12
Tetanus, diphtheria, pertussis
13-14
Tdap
Human papillomavirus
HPV (3 doses)
Meningococcal MPSV4 Pneumococcal Influenza
MCV4 MCV4
Influenza (yearly)
Hepatitus B
HepB series
Varicella
HPV series
PPV
HepA series
Measles, mumps, rubella
16-18
Tdap
MCV4
Hepatitus A
Inactivated poliovirus
15
IPV series MMR series Varicella series
Source: www.cdc.gov/nip/recs/child-schedule.htm
Range of recommended ages Catch-up immunization Certain high-risk groups
festations of disease, but the prevailing symptom of persistent cough is commonplace. Epidemiologic evidence suggests that between 15 and 30% of adolescent and adult patients with prolonged cough illness (greater than 10 days) have pertussis infection, a diagnosis that is not always considered in these older individuals.
Pertussis Incidence Prior to 1943, approximately 200,000 pertussis cases were reported annually, with 4,034 deaths reported between 1934 and 1943. After the introduction of whole-cell DTP vaccine,
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reported cases fell dramatically, reaching a low in 1976 of only 1,010 reported cases. Since 1976, however, the number of reported cases in the U.S. has steadily risen. This observation can be explained, at least in part, by the increased recognition of non-classic disease in adolescents and adults, reinforcing the argument that childhood vaccination does not provide lifelong immunity. Prior to routine pertussis vaccination, more than 93% of pertussis cases occurred in children younger than 10 years (1). By 2004, 25,827 cases of pertussis were reported in the U.S., with 34% occurring in adolescents (2).
© 2007 Elsevier
Pertussis in Adolescents Outbreaks of pertussis are now commonplace in middle schools and high schools. In a 1996 study from Massachusetts, 20 distinct outbreaks of pertussis were identified, with 18 of those occurring in schools and 67% of all cases occurring in teenagers (3). During a 2003 to 2004 outbreak in Wisconsin, 70% of the 313 identified cases were diagnosed in adolescents, many traceable to a single high school weight room (4). Routine use of a pertussis booster vaccine in the adolescent population is expected to reduce disease
Clinical Microbiology Newsletter 29:19,2007
morbidity and to provide protection of unvaccinated or incompletely vaccinated infants via herd immunity. An enhanced pertussis surveillance study conducted between 1999 and 2002 found that 43 of 264 infant pertussis infections could be traced to an adolescent as the source (5). A study of risk factors for pertussisrelated hospitalizations in infants found that older siblings were the most common source of infection (53%), followed by parents (20%), other relatives (12%), neighbors (8%), and day care contacts (3%) (6). Infants, who are at high risk of infection-related complications, such as pneumonia, central nervous system manifestations, or death, are often infected by adolescents. While such severe complications are uncommon in older patients, pertussis morbidity remains significant at all ages. A Massachusetts study conducted between 1989 and 2004 found that of 7,000 adolescent pertussis infections, 41% required one clinic visit, 32% required two visits, and 24% needed three medical visits during the illness. Those teenagers also missed an average of 5.5 days of school. Most adolescents with pertussis experience a persistent cough, the majority of which last between 3 and 9 weeks. As adolescents often do not exhibit many of the more classic clinical symptoms of pertussis, such as paroxysmal coughing, whooping, or post-tussive vomiting, delays in diagnosis are frequent, and many cases still go unrecognized.
Boosting Pertussis Immunity in Adolescents Acellular pertussis booster vaccines are currently available as combined diphtheria, tetanus, and acellular pertussis vaccines (Tdap) (Adacel [Sanofi Pasteur] and Boostrix [Glaxo Smithkline]). These Tdap vaccines are highly immunogenic and well tolerated. In 2005, the FDA approved both formulations of Tdap vaccine for use in the U.S. as booster vaccines in patients beyond young childhood. Based on clinical-trial safety and immunogenicity data, Boostix was approved for use in patients between the ages of 10 and 18 years and Adacel was approved for use in patients 11 to 65 years old. The safety of both vaccines was evaluated by comparing adverse events following vaccination in persons receiving Tdap with Clinical Microbiology Newsletter 29:19,2007
those receiving tetnus and diphtheria (Td) vaccine alone. Tdap vaccination is currently recommended for all adolescents aged 11 to 18 years, preferably between the ages of 11 and 12. It is further advised that an interval of at least 5 years should elapse between any previous Td vaccination and the Tdap vaccine; however, a shorter interval is acceptable in high diseaseprevalence. Adolescents with a history of pertussis infection should also receive the Tdap vaccine, as the duration of protection induced by natural pertussis infection is not lifelong. The decision to recommend Tdap booster vaccines for all adolescents was based on the pertussis disease burden in the whole population, the disruption caused by pertussis outbreaks, the cost of postexposure prophylaxis, and the evidence that these vaccines are safe, effective, and economical. New ACIP recommendations now also advise providing a single dose of Tdap for all adults, with a special emphasis on adults living with children less than 1 year of age and all adults who are health care providers.
Vaccinating Adolescents Against Invasive Meningococcal Disease Neisseria meningitidis is a leading cause of meningitis in children and adults in the U.S. Among the identified capsular types of N. meningitidis, five (A, B, C, Y, and W-135) cause almost all cases of human infection. The proportion of each capsular type causing disease has shifted in recent years, with serogroup Y causing only 2% of cases in the U.S. between 1989 and 1991 but 37% of cases between 1997 and 2002. Together, serogroups B, C, and Y are now responsible for the majority of meningitis cases in the U.S., each accounting for approximately one-third of cases (7,8). Although colonization rates are high in the U.S. (between 8 and 20%), invasive-infection rates are comparatively low, with approximately 2,500 cases reported annually. For infected individuals, morbidity remains high, with nearly 20% developing serious sequelae. Approximately 10% of patients with invasive meningococcal infection do not survive (9). Although the highest incidence of meningococcal infection occurs in infants between 6 and 12 months of age, the majority of meningococcal disease occurs in those © 2007 Elsevier
over the age of 11 years. Groups considered at increased risk for invasive meningococcal disease include smokers and individuals exposed to second-hand smoke, those with upper respiratory tract infections, and those who live in crowded conditions, such as college dormitories. Freshman living in dormitories are five times more likely to develop meningococcal disease than other undergraduates. When adolescents are infected with meningococcus, they are more likely than infants to develop septic shock and more likely to die from the infection (10). In 2000, the ACIP formally recognized the increased risk of meningococcal disease among college freshmen living in dormitories compared to those of the same age in the general population and identified them for routine immunization with the then-available 4-valent polysaccharide vaccine, Menomune (Sanofi Pasteur).
Meningococcal Disease Outbreaks In recent years, the majority of meningococcal-disease outbreaks have occurred at colleges and in schools (11). These outbreaks are usually traced to closely related bacterial strains, with 75% of cases in adolescents caused by serogroup C,Y, or W-135. During outbreaks, bar patronage, combined with alcohol use, is associated with a higher risk for infection (12). The short incubation period and rapid onset of disease demand prompt antibiotic chemoprophylaxis of close contacts. Mass vaccination of the at-risk population is usually considered when the attack rate is greater than 10 cases per 100,000 patients during an outbreak. The recommendation that close contacts of invasive-meningococcal cases receive antibiotic prophylaxis remains important, even when vaccination campaigns are undertaken.
The Two Meningococcal Vaccines: Meningococcal Polysaccharide Vaccine 4-Valent and Meningococcal Conjugate Vaccine 4-Valent (MCV4) Immunization programs designed to vaccinate high-risk individuals against invasive meningococcal disease have been in place for many years, as the meningococcal polysaccharide A/C/Y/W135 (MPSV4) vaccine (Menomune; Sanofi Pasteur) has been available for use in patients 2 years old and older for more 0196-4399/00 (see frontmatter)
145
than 3 decades. This formulation of meningococcal vaccine offers 90 to 95% protection against infection caused by vaccine strains, but the protective antibody responses are relatively shortlived at only 3 to 5 years (13). Polysaccharide vaccines like MPSV4 are processed by the immune system in a T-cell-independent manner. Here, B lymphocytes produce antibodies to the vaccine antigens but do not retain immunologic memory in the absence of T-cell “help.” Another limitation of pure polysaccharide immunogens is that repeated doses can result in reduced antibody responses in some subjects, a phenomenon known as “immune tolerance.” Furthermore, polysaccharide vaccines like MPSV4 are not able to induce mucosal immunity and therefore do not contribute to the development of herd immunity by reducing nasopharyngeal carriage of the pathogen. Despite these limitations, the MPSV4 vaccine has proven effective in protecting populations who are at risk in the short term, such as travelers to areas of endemic disease, new military recruits, and college freshmen living in dormitories. To overcome the limitations seen with pure polysaccharide immunogens, conjugate meningococcal vaccines (MCV4) were developed. A conjugate vaccine is made by using the same polysaccharide antigens found in the pure polysaccharide vaccine but covalenly linking the antigens to simple peptides (such as diphtheria or tetanus toxoid). Unlike pure polysaccharide vaccines, conjugate vaccines are processed by the immune system in a Tcell-dependent manner, providing more durable antibody responses with efficient induction of immunologic memory. An MCV4 vaccine (Menactra; Sanofi Pasteur) was recently approved for use in the U.S. for patients 11 to 55 years of age. MCV4 contains the same polysaccharide antigens found in MPSV4 (A/C/Y/W135), but in this context, the antigens are conjugated to diphtheria toxoid. It is predicted that this vaccine will reduce nasopharyngeal carriage, allowing the disruption of transmission and the establishment of some degree of herd immunity. Further enthusiasm for conjugate meningococcal vaccine was recently generated in the United Kingdom, where the introduction of the monovalent, conjugated 146
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meningococcal C vaccine has been successful in curbing an ongoing group C meningococcal-disease epidemic (14).
Guillain-Barre´ Syndrome and MCV4 In October 2005, the Vaccine Adverse Event Reporting System received reports of Guillain-Barr´e syndrome (GBS) occurring in some patients within 6 weeks of receiving MCV4 vaccine, prompting warnings for its use and enhanced surveillance for additional cases. As of January 2007, 19 adolescents are reported to have developed GBS within 6 weeks of vaccination with MCV4. While it remains unclear whether this association is causal or simply temporally related, it is clear that the risk of developing GBS after vaccination with MCV4 (1.73 per 100,000) is much lower than the risk of developing invasive meningococcal infection. Moreover, population-based estimates of GBS in 11 to 18 year olds are 1.18 to 2.11 per 100,000, so to date, the incidence of GBS reported among MCV4 recipients has not been shown to be greater than that observed in the general population. Because of the ongoing public health risk of invasive meningococcal disease in the U.S., the ACIP continues to recommend routine immunization of all adolescents.
ACIP Recommendations ACIP recommendations for the use of meningococcal vaccines were updated in 2005. These recommendations stemmed, in part, from the U.K. data involving the conjugate serogroup C vaccine, where routine adolescent vaccination led to a corresponding drop in meningococcal disease in their entire population, demonstrating a herd immunity benefit of an adolescent vaccine public health program (15). Extrapolating the U.K. data to the U.S. population, immunizing adolescents would lead to an overall drop in invasive meningococcal disease of ~32% (16). Either MPSV4 or MCV4 can be used under the current guidelines, but the conjugate vaccine is preferred if it is available. Immunization with a single dose of meningococcal vaccine is recommended for all 11 to 12 year olds at the pre-adolescent visit or for those entering high school (15 years old) if they have not been previously vacci© 2007 Elsevier
nated. Eighteen year olds who have not received the vaccine should also be immunized. To date, adolescents are the only cohort for whom vaccine is recommended solely on the basis of age. Other recommendations are based on specific at-risk populations, such as travelers to areas of endemicity, college freshmen living in dormitories, individuals with immune deficiencies, and certain microbiology technologists.
Preventing Human Papillomavirus Infection During Adolescence and Beyond The most recent addition to the adolescent immunization schedule is the human papillomavirus (HPV) vaccine. Currently recommended for girls and young women, this vaccine is expected to dramatically reduce the incidence of cervical cancer. Among the more than 100 recognized HPV types, approximately 40 are known to infect the human genital tract. The HPV types that infect the genital tract are classified as lowor high-risk subgroups based on their potential to cause cancer. Among the high-risk virus types, HPV 16, 18, 31, and 45 cause ~80% of cervical cancers (17), while the low-risk virus types, especially types 6 and 11, are associated with anogenital warts (18). We already know that HPV infection is a leading cause of abnormal Pap smear results. Infection with HPV is seen on Pap smears as low, moderate, or advanced dysplasic changes. Moderate to advanced cervical dysplasia is most commonly caused by the persistence of the oncogenic strains of HPV. If these advanced dysplastic changes are left untreated, they will ultimately progress to invasive cervical cancer.
HPV Epidemiology The prevalence of HPV in the general population is between 14 and 35% (19), with the majority of those infected being young women. In the U.S., there are approximately 20 million people infected with HPV, with an additional 6.2 million newly acquiring infections each year (20). While this frequency of HPV infection is alarmingly high, the majority of infections are transient, with the average duration of infection in college-aged women being 8 months (21). Low-risk strains of HPV (especially types 6 and 11) cause genital warts in men and women, with 1% of people in Clinical Microbiology Newsletter 29:19,2007
the U.S. having visible warts present at any given time.
HPV Vaccination and Adolescents Population-based studies that include adolescent females have shown that the rate of Pap smear abnormalities among teenage girls is increasing. Studies that examined Pap test results in adolescent girls showed an increase from 1.9% to 4% between 1981 and 1999 (22,23). It is also clear that sexual debut is occurring in a majority of teenagers by the age of 17 years, with a smaller percentage engaging in penetrative sexual activity at younger ages. A study performed in 2002 discovered that 5.7% of females and 7.9% of males have sexual intercourse by the age of 14 years (24). In 2006, the first HPV vaccine was licensed for use in females between the ages of 9 and 26 years. This vaccine (Gardasil; Merck) targets HPV types 6, 11, 16, and 18 and is administered as a three-dose series (0, 2, and 6 months). The biologic license application for a second HPV vaccine, Cervarix (Glaxo Smithkline), that targets HPV 16 and 18 was submitted for consideration by the FDA in early 2007. Administration of HPV vaccine during adolescence is the most cost-effective approach, with cost per quality of life year saved due to vaccination against HPV types 16 and 18 estimated to be as high as $25,000 (25).
HPV Vaccine Recommendations The ACIP recommends that HPV vaccine be administered to all 11- to 12-year-old girls and to 13- to 26-yearold females who have not yet completed the vaccine series. Permissive wording allows the vaccine series to be started as early as age 9 years. Clinical trials of the available 4-valent HPV vaccine have demonstrated 100% efficacy in the prevention of cervical pre-cancers caused by vaccine-preventable strains and nearly 100% efficacy against genital warts caused by HPV types 6 and 11. It is important to note that vaccine efficacy was determined in the clinical trials in women who were documented to be seronegative and PCR negative for the four HPV types in the vaccine at study enrollment and who remained PCR negative during the vaccination phase. During the clinical trials, screening for pre-existing HPV infection was performed in order to document which Clinical Microbiology Newsletter 29:19,2007
study participants were infected before the vaccine series was initiated. Because these data were collected on all study participants, both efficacy and effectiveness data were available at the study conclusion. The so-called general-population effectiveness that was determined from all participants (modified intentto-treat study design) was lower than that seen in the “per-protocol” efficacy analysis, primarily because some vaccinated individuals were already infected with HPV before the vaccine series was completed. While the vaccine was shown to protect against newly acquired infection, there was no evidence to suggest it could impact the disease caused by an infection that had already been established. Longitudinal results from the HPV vaccine clinical trials indicate that protection will last for at least 5 years. Longer-term durability of the immune response, and more importantly, the long-term protection against HPV-associated malignancies and genital warts, will be determined as post-licensure experience is gained. The concept of herd immunity stipulates that we consider the potential impact of vaccinating all members at risk of transmitting the infection. While the currently available HPV vaccine is not yet licensed for use in boys or men, immunogenicity and safety studies in males are ongoing. References
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1. Matoo, S. and J.D. Cherry. 2005. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin. Microbiol. Rev. 18:326-382.
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2. De Serres, G. et al. 2000. Morbitity of pertussis in adolescents and adults. J. Infect. Dis. 182:174-179.
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3. Brennen, M. et al. 2000. Evidence for transmission of pertussis in schools, Massachusetts, 1996: epidemiologic data supported by pulsed-field gel electrophoresis studies. J. Infect. Dis. 181:210-215.
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4. Davis, J.P. 2005. Clinical and economic effects of pertussis outbreaks. Pediatr. Infect. Dis. J. 24(6 Suppl.):S109-S116.
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5. Bisgard, K.M. et al. 2004. Infant pertussis: who was the source? Pediatr. Infect. Dis. J. 23:985-989.
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6. Halperin, S.A. et al. 1999. Epidemiological features of pertussis in hospitalized patients in Canada, 1991-1997:
© 2007 Elsevier
21.
report of the Immunization Monitoring Program: Active (IMPACT). Clin. Infect. Dis. 28:1238-1243. Bilukha, O.O. and N. Rosenstein. 2005. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb. Mortal. Wkly. Rep. 54(RR):1-21. Rosenstein N.E. et al. 2001. Meningococcal disease. N. Engl. J. Med. 3441378. Edwards, M.S. and C.J. Baker. 1981. Complications and sequelae of meningococcal infections in children. J. Pediatr. 99:540. Harrison, LH. et al. 2001. Invasive meningococcal disease in adolescents and young adults. JAMA 286:694. Brooks, R.B., C.W. Woods, and N.E. Rosenstein. 2003. Neisseria meningitidis outbreaks in the United States, 1994-2002, abstr. 289, p. 81-82. Abstr. 41st Ann. Meet. Infect. Dis. Soc. Am. Imrey, P.B. et al. 1995. Meningococcal carriage, alcohol consumption, and campus bar patronage in a serogroup C meningococcal disease outbreak. J. Clin. Microbiol. 33:3133-3137. Musher, D.M., et al. 1993. Antibody to capsular polysaccharides of Streptococcus pneumoniae: prevalence, persistence, and response to revaccination. Clin. Infect. Dis. 17:66. Ramsay, M.E. et al. 2001. Efficacy of meningococcal serogroup C conjugate vaccine in teenagers and toddlers in England. Lancet 357:195. Ramsay M. et al. 2003. Herd immunity from meningococcal serogroup C conjugate vaccination in England: database analysis. BMJ 326:365-366. Shepard, C.W. et al. 2005. Cost-effectiveness of conjugate meningococcal vaccination strategies in the United States. Pediatrics 115:1220-1232. Munoz, N. et al. 2003. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N. Engl. J. Med. 348:518-527. Hildesheim, A. et al. 1994. Persistence of type-specific human papillomavirus infection among cytologically normal women. J. Infect. Dis. 169:235-240. American College of Obstetricians and Gynecologists. 2005. Human papillomavirus. ACOG Practice Bulletin No. 61. Weinstock, H., S. Berman, and W. Cates, Jr. 2004. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect. Sex. Reprod. Health 36:6-10. Ho, G.Y. et al. 1998. Natural history of
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cervicovaginal papillomavirus infection in young women. N. Eng. J. Med. 338:423-428. 22. Sadeghi, S.B., E.W. Hsieh, and S.W. Gunn. 1984. Prevalence of cervical intraepithelial neoplasia in sexually active teenagers and young adults. Results of data analysis of mass
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Papanicolaou screening of 796,337 women in the United States in 1981. Am. J. Obstet. Gynecol. 148:726-729. 23. Mount, S.L. and J.L. Papillo. 1999. A study of 10,296 pediatric and adolescent Papanicolaou smear diagnoses in northern New England. Pediatrics 103:539545.
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24. Abma, J.C. et al. 2004. Teenagers in the United States: sexual activity, contraceptive use, and childbearing, 2002. Vital Health Stat. 23:1-87. 25. Centers for Disease Control and Prevention. 2006. HPV and HPV vaccine: information for healthcare providers. http://www.cdc.gov/std/hpv.
Clinical Microbiology Newsletter 29:19,2007
www.cmnewsletter.com
October 1, 2007
Progress in Adolescent Immunization Erin M. Bennett, M.S. and Joseph B. Domachowske, M.D., Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York
Abstract The recent addition of three new vaccines to the routine adolescent immunization schedule opens new opportunities to provide preventative interventions for long-term health lasting well into adulthood. These newly approved vaccines, Tdap (adolescent tetanus, diphtheria, and pertussis) vaccine, conjugate meningococcal vaccine, and human papillomavirus vaccine, are now recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices to be administered routinely during the teenage years beginning at the11 to 12 year-old-health care visit and continuing through young adulthood. This approach not only allows for catch-up vaccination for those who did not receive earlier recommended childhood vaccines, but also provides protection at an age of increased risk for these infections. The specific recommendations for each of the three vaccines and the rationale for each of them are described. The U.S. Centers for Disease Control and Prevention and the Department of Health and Human Services released the new 2007 recommended pediatric immunization schedule in January. In this update, vaccine recommendations for older children and adolescents were listed separately from recommendations for infants and young children (Table 1). The new table for older children outlines immunization recommendations for ages 7 to 18 years, including routine immunization with Tdap (tetanus, diphtheria, and pertussis booster) vaccine, human papillomavirus vaccine, and conjugate meningococcal vaccine, with catch-up immunizations with hepatitis B, polio, measles, mumps, rubella, and varicella vaccines. Reminders that certain high-risk groups should be immunized with pneumococcal vaccine, annual influenza vaccine, and hepatitis
Mailing Address: Dr. Domachowske, Associate Professor of Pediatrics, Microbiology/Immunology, SUNY Upstate Medical University, 750 East Adams St., Syracuse, NY 13210. Tel.: 315-464-6331. Fax: 315-464-7564. E-mail: [email protected] Clinical Microbiology Newsletter 29:19,2007
A vaccine are also included. Three of the newly approved vaccines, Tdap vaccine, conjugate meningococcal vaccine, and human papillomavirus vaccine, are now recommended by the Advisory Committee on Immunization Practices (ACIP) to be administered to all adolescents. Administration of these new vaccines during the recommended adolescent health care visit at age 11 to 12 years reinforces the importance of preventative health care at this age. The timing of this recommendation also allows for catch-up vaccination for those who did not receive earlier recommended childhood vaccines.
Boosting Pertussis Immunity with Tdap Vaccine During Adolescence
account for more than half of reported cases, with both age groups representing important reservoirs of the disease.
Pertussis Infection Classic infant pertussis is characterized by three phases. The catarrhal phase lasts up to 2 weeks and is characterized by coryza and intermittent cough. This is followed by the paroxysmal phase, lasting several weeks. The paroxysmal stage is characterized by coughing fits, the characteristic inspiratory whooping, and post-tussive vomiting. Symptoms improve gradually during the convalescent phase, which can last for several months. In general, older patients tend to have fewer mani-
Despite universal immunization of infants and young children with combined diphtheria, tetanus, and acellular pertussis vaccine (DTaP), reported cases of pertussis have steadily increased in the United States since the late 1970s. A significant proportion of reported cases now occur in adolescents, in part because protective immunity from vaccination during young childhood has waned. Adolescents and adults now © 2007 Elsevier
0196-4399/00 (see frontmatter)
143
Table 1. Recommended Immunization Schedule for persons aged 7 to 18 years — United States, 2007 age (yr) Vaccine
7-10
11-12
Tetanus, diphtheria, pertussis
13-14
Tdap
Human papillomavirus
HPV (3 doses)
Meningococcal MPSV4 Pneumococcal Influenza
MCV4 MCV4
Influenza (yearly)
Hepatitus B
HepB series
Varicella
HPV series
PPV
HepA series
Measles, mumps, rubella
16-18
Tdap
MCV4
Hepatitus A
Inactivated poliovirus
15
IPV series MMR series Varicella series
Source: www.cdc.gov/nip/recs/child-schedule.htm
Range of recommended ages Catch-up immunization Certain high-risk groups
festations of disease, but the prevailing symptom of persistent cough is commonplace. Epidemiologic evidence suggests that between 15 and 30% of adolescent and adult patients with prolonged cough illness (greater than 10 days) have pertussis infection, a diagnosis that is not always considered in these older individuals.
Pertussis Incidence Prior to 1943, approximately 200,000 pertussis cases were reported annually, with 4,034 deaths reported between 1934 and 1943. After the introduction of whole-cell DTP vaccine,
144
0196-4399/00 (see frontmatter)
reported cases fell dramatically, reaching a low in 1976 of only 1,010 reported cases. Since 1976, however, the number of reported cases in the U.S. has steadily risen. This observation can be explained, at least in part, by the increased recognition of non-classic disease in adolescents and adults, reinforcing the argument that childhood vaccination does not provide lifelong immunity. Prior to routine pertussis vaccination, more than 93% of pertussis cases occurred in children younger than 10 years (1). By 2004, 25,827 cases of pertussis were reported in the U.S., with 34% occurring in adolescents (2).
© 2007 Elsevier
Pertussis in Adolescents Outbreaks of pertussis are now commonplace in middle schools and high schools. In a 1996 study from Massachusetts, 20 distinct outbreaks of pertussis were identified, with 18 of those occurring in schools and 67% of all cases occurring in teenagers (3). During a 2003 to 2004 outbreak in Wisconsin, 70% of the 313 identified cases were diagnosed in adolescents, many traceable to a single high school weight room (4). Routine use of a pertussis booster vaccine in the adolescent population is expected to reduce disease
Clinical Microbiology Newsletter 29:19,2007
morbidity and to provide protection of unvaccinated or incompletely vaccinated infants via herd immunity. An enhanced pertussis surveillance study conducted between 1999 and 2002 found that 43 of 264 infant pertussis infections could be traced to an adolescent as the source (5). A study of risk factors for pertussisrelated hospitalizations in infants found that older siblings were the most common source of infection (53%), followed by parents (20%), other relatives (12%), neighbors (8%), and day care contacts (3%) (6). Infants, who are at high risk of infection-related complications, such as pneumonia, central nervous system manifestations, or death, are often infected by adolescents. While such severe complications are uncommon in older patients, pertussis morbidity remains significant at all ages. A Massachusetts study conducted between 1989 and 2004 found that of 7,000 adolescent pertussis infections, 41% required one clinic visit, 32% required two visits, and 24% needed three medical visits during the illness. Those teenagers also missed an average of 5.5 days of school. Most adolescents with pertussis experience a persistent cough, the majority of which last between 3 and 9 weeks. As adolescents often do not exhibit many of the more classic clinical symptoms of pertussis, such as paroxysmal coughing, whooping, or post-tussive vomiting, delays in diagnosis are frequent, and many cases still go unrecognized.
Boosting Pertussis Immunity in Adolescents Acellular pertussis booster vaccines are currently available as combined diphtheria, tetanus, and acellular pertussis vaccines (Tdap) (Adacel [Sanofi Pasteur] and Boostrix [Glaxo Smithkline]). These Tdap vaccines are highly immunogenic and well tolerated. In 2005, the FDA approved both formulations of Tdap vaccine for use in the U.S. as booster vaccines in patients beyond young childhood. Based on clinical-trial safety and immunogenicity data, Boostix was approved for use in patients between the ages of 10 and 18 years and Adacel was approved for use in patients 11 to 65 years old. The safety of both vaccines was evaluated by comparing adverse events following vaccination in persons receiving Tdap with Clinical Microbiology Newsletter 29:19,2007
those receiving tetnus and diphtheria (Td) vaccine alone. Tdap vaccination is currently recommended for all adolescents aged 11 to 18 years, preferably between the ages of 11 and 12. It is further advised that an interval of at least 5 years should elapse between any previous Td vaccination and the Tdap vaccine; however, a shorter interval is acceptable in high diseaseprevalence. Adolescents with a history of pertussis infection should also receive the Tdap vaccine, as the duration of protection induced by natural pertussis infection is not lifelong. The decision to recommend Tdap booster vaccines for all adolescents was based on the pertussis disease burden in the whole population, the disruption caused by pertussis outbreaks, the cost of postexposure prophylaxis, and the evidence that these vaccines are safe, effective, and economical. New ACIP recommendations now also advise providing a single dose of Tdap for all adults, with a special emphasis on adults living with children less than 1 year of age and all adults who are health care providers.
Vaccinating Adolescents Against Invasive Meningococcal Disease Neisseria meningitidis is a leading cause of meningitis in children and adults in the U.S. Among the identified capsular types of N. meningitidis, five (A, B, C, Y, and W-135) cause almost all cases of human infection. The proportion of each capsular type causing disease has shifted in recent years, with serogroup Y causing only 2% of cases in the U.S. between 1989 and 1991 but 37% of cases between 1997 and 2002. Together, serogroups B, C, and Y are now responsible for the majority of meningitis cases in the U.S., each accounting for approximately one-third of cases (7,8). Although colonization rates are high in the U.S. (between 8 and 20%), invasive-infection rates are comparatively low, with approximately 2,500 cases reported annually. For infected individuals, morbidity remains high, with nearly 20% developing serious sequelae. Approximately 10% of patients with invasive meningococcal infection do not survive (9). Although the highest incidence of meningococcal infection occurs in infants between 6 and 12 months of age, the majority of meningococcal disease occurs in those © 2007 Elsevier
over the age of 11 years. Groups considered at increased risk for invasive meningococcal disease include smokers and individuals exposed to second-hand smoke, those with upper respiratory tract infections, and those who live in crowded conditions, such as college dormitories. Freshman living in dormitories are five times more likely to develop meningococcal disease than other undergraduates. When adolescents are infected with meningococcus, they are more likely than infants to develop septic shock and more likely to die from the infection (10). In 2000, the ACIP formally recognized the increased risk of meningococcal disease among college freshmen living in dormitories compared to those of the same age in the general population and identified them for routine immunization with the then-available 4-valent polysaccharide vaccine, Menomune (Sanofi Pasteur).
Meningococcal Disease Outbreaks In recent years, the majority of meningococcal-disease outbreaks have occurred at colleges and in schools (11). These outbreaks are usually traced to closely related bacterial strains, with 75% of cases in adolescents caused by serogroup C,Y, or W-135. During outbreaks, bar patronage, combined with alcohol use, is associated with a higher risk for infection (12). The short incubation period and rapid onset of disease demand prompt antibiotic chemoprophylaxis of close contacts. Mass vaccination of the at-risk population is usually considered when the attack rate is greater than 10 cases per 100,000 patients during an outbreak. The recommendation that close contacts of invasive-meningococcal cases receive antibiotic prophylaxis remains important, even when vaccination campaigns are undertaken.
The Two Meningococcal Vaccines: Meningococcal Polysaccharide Vaccine 4-Valent and Meningococcal Conjugate Vaccine 4-Valent (MCV4) Immunization programs designed to vaccinate high-risk individuals against invasive meningococcal disease have been in place for many years, as the meningococcal polysaccharide A/C/Y/W135 (MPSV4) vaccine (Menomune; Sanofi Pasteur) has been available for use in patients 2 years old and older for more 0196-4399/00 (see frontmatter)
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than 3 decades. This formulation of meningococcal vaccine offers 90 to 95% protection against infection caused by vaccine strains, but the protective antibody responses are relatively shortlived at only 3 to 5 years (13). Polysaccharide vaccines like MPSV4 are processed by the immune system in a T-cell-independent manner. Here, B lymphocytes produce antibodies to the vaccine antigens but do not retain immunologic memory in the absence of T-cell “help.” Another limitation of pure polysaccharide immunogens is that repeated doses can result in reduced antibody responses in some subjects, a phenomenon known as “immune tolerance.” Furthermore, polysaccharide vaccines like MPSV4 are not able to induce mucosal immunity and therefore do not contribute to the development of herd immunity by reducing nasopharyngeal carriage of the pathogen. Despite these limitations, the MPSV4 vaccine has proven effective in protecting populations who are at risk in the short term, such as travelers to areas of endemic disease, new military recruits, and college freshmen living in dormitories. To overcome the limitations seen with pure polysaccharide immunogens, conjugate meningococcal vaccines (MCV4) were developed. A conjugate vaccine is made by using the same polysaccharide antigens found in the pure polysaccharide vaccine but covalenly linking the antigens to simple peptides (such as diphtheria or tetanus toxoid). Unlike pure polysaccharide vaccines, conjugate vaccines are processed by the immune system in a Tcell-dependent manner, providing more durable antibody responses with efficient induction of immunologic memory. An MCV4 vaccine (Menactra; Sanofi Pasteur) was recently approved for use in the U.S. for patients 11 to 55 years of age. MCV4 contains the same polysaccharide antigens found in MPSV4 (A/C/Y/W135), but in this context, the antigens are conjugated to diphtheria toxoid. It is predicted that this vaccine will reduce nasopharyngeal carriage, allowing the disruption of transmission and the establishment of some degree of herd immunity. Further enthusiasm for conjugate meningococcal vaccine was recently generated in the United Kingdom, where the introduction of the monovalent, conjugated 146
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meningococcal C vaccine has been successful in curbing an ongoing group C meningococcal-disease epidemic (14).
Guillain-Barre´ Syndrome and MCV4 In October 2005, the Vaccine Adverse Event Reporting System received reports of Guillain-Barr´e syndrome (GBS) occurring in some patients within 6 weeks of receiving MCV4 vaccine, prompting warnings for its use and enhanced surveillance for additional cases. As of January 2007, 19 adolescents are reported to have developed GBS within 6 weeks of vaccination with MCV4. While it remains unclear whether this association is causal or simply temporally related, it is clear that the risk of developing GBS after vaccination with MCV4 (1.73 per 100,000) is much lower than the risk of developing invasive meningococcal infection. Moreover, population-based estimates of GBS in 11 to 18 year olds are 1.18 to 2.11 per 100,000, so to date, the incidence of GBS reported among MCV4 recipients has not been shown to be greater than that observed in the general population. Because of the ongoing public health risk of invasive meningococcal disease in the U.S., the ACIP continues to recommend routine immunization of all adolescents.
ACIP Recommendations ACIP recommendations for the use of meningococcal vaccines were updated in 2005. These recommendations stemmed, in part, from the U.K. data involving the conjugate serogroup C vaccine, where routine adolescent vaccination led to a corresponding drop in meningococcal disease in their entire population, demonstrating a herd immunity benefit of an adolescent vaccine public health program (15). Extrapolating the U.K. data to the U.S. population, immunizing adolescents would lead to an overall drop in invasive meningococcal disease of ~32% (16). Either MPSV4 or MCV4 can be used under the current guidelines, but the conjugate vaccine is preferred if it is available. Immunization with a single dose of meningococcal vaccine is recommended for all 11 to 12 year olds at the pre-adolescent visit or for those entering high school (15 years old) if they have not been previously vacci© 2007 Elsevier
nated. Eighteen year olds who have not received the vaccine should also be immunized. To date, adolescents are the only cohort for whom vaccine is recommended solely on the basis of age. Other recommendations are based on specific at-risk populations, such as travelers to areas of endemicity, college freshmen living in dormitories, individuals with immune deficiencies, and certain microbiology technologists.
Preventing Human Papillomavirus Infection During Adolescence and Beyond The most recent addition to the adolescent immunization schedule is the human papillomavirus (HPV) vaccine. Currently recommended for girls and young women, this vaccine is expected to dramatically reduce the incidence of cervical cancer. Among the more than 100 recognized HPV types, approximately 40 are known to infect the human genital tract. The HPV types that infect the genital tract are classified as lowor high-risk subgroups based on their potential to cause cancer. Among the high-risk virus types, HPV 16, 18, 31, and 45 cause ~80% of cervical cancers (17), while the low-risk virus types, especially types 6 and 11, are associated with anogenital warts (18). We already know that HPV infection is a leading cause of abnormal Pap smear results. Infection with HPV is seen on Pap smears as low, moderate, or advanced dysplasic changes. Moderate to advanced cervical dysplasia is most commonly caused by the persistence of the oncogenic strains of HPV. If these advanced dysplastic changes are left untreated, they will ultimately progress to invasive cervical cancer.
HPV Epidemiology The prevalence of HPV in the general population is between 14 and 35% (19), with the majority of those infected being young women. In the U.S., there are approximately 20 million people infected with HPV, with an additional 6.2 million newly acquiring infections each year (20). While this frequency of HPV infection is alarmingly high, the majority of infections are transient, with the average duration of infection in college-aged women being 8 months (21). Low-risk strains of HPV (especially types 6 and 11) cause genital warts in men and women, with 1% of people in Clinical Microbiology Newsletter 29:19,2007
the U.S. having visible warts present at any given time.
HPV Vaccination and Adolescents Population-based studies that include adolescent females have shown that the rate of Pap smear abnormalities among teenage girls is increasing. Studies that examined Pap test results in adolescent girls showed an increase from 1.9% to 4% between 1981 and 1999 (22,23). It is also clear that sexual debut is occurring in a majority of teenagers by the age of 17 years, with a smaller percentage engaging in penetrative sexual activity at younger ages. A study performed in 2002 discovered that 5.7% of females and 7.9% of males have sexual intercourse by the age of 14 years (24). In 2006, the first HPV vaccine was licensed for use in females between the ages of 9 and 26 years. This vaccine (Gardasil; Merck) targets HPV types 6, 11, 16, and 18 and is administered as a three-dose series (0, 2, and 6 months). The biologic license application for a second HPV vaccine, Cervarix (Glaxo Smithkline), that targets HPV 16 and 18 was submitted for consideration by the FDA in early 2007. Administration of HPV vaccine during adolescence is the most cost-effective approach, with cost per quality of life year saved due to vaccination against HPV types 16 and 18 estimated to be as high as $25,000 (25).
HPV Vaccine Recommendations The ACIP recommends that HPV vaccine be administered to all 11- to 12-year-old girls and to 13- to 26-yearold females who have not yet completed the vaccine series. Permissive wording allows the vaccine series to be started as early as age 9 years. Clinical trials of the available 4-valent HPV vaccine have demonstrated 100% efficacy in the prevention of cervical pre-cancers caused by vaccine-preventable strains and nearly 100% efficacy against genital warts caused by HPV types 6 and 11. It is important to note that vaccine efficacy was determined in the clinical trials in women who were documented to be seronegative and PCR negative for the four HPV types in the vaccine at study enrollment and who remained PCR negative during the vaccination phase. During the clinical trials, screening for pre-existing HPV infection was performed in order to document which Clinical Microbiology Newsletter 29:19,2007
study participants were infected before the vaccine series was initiated. Because these data were collected on all study participants, both efficacy and effectiveness data were available at the study conclusion. The so-called general-population effectiveness that was determined from all participants (modified intentto-treat study design) was lower than that seen in the “per-protocol” efficacy analysis, primarily because some vaccinated individuals were already infected with HPV before the vaccine series was completed. While the vaccine was shown to protect against newly acquired infection, there was no evidence to suggest it could impact the disease caused by an infection that had already been established. Longitudinal results from the HPV vaccine clinical trials indicate that protection will last for at least 5 years. Longer-term durability of the immune response, and more importantly, the long-term protection against HPV-associated malignancies and genital warts, will be determined as post-licensure experience is gained. The concept of herd immunity stipulates that we consider the potential impact of vaccinating all members at risk of transmitting the infection. While the currently available HPV vaccine is not yet licensed for use in boys or men, immunogenicity and safety studies in males are ongoing. References
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report of the Immunization Monitoring Program: Active (IMPACT). Clin. Infect. Dis. 28:1238-1243. Bilukha, O.O. and N. Rosenstein. 2005. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb. Mortal. Wkly. Rep. 54(RR):1-21. Rosenstein N.E. et al. 2001. Meningococcal disease. N. Engl. J. Med. 3441378. Edwards, M.S. and C.J. Baker. 1981. Complications and sequelae of meningococcal infections in children. J. Pediatr. 99:540. Harrison, LH. et al. 2001. Invasive meningococcal disease in adolescents and young adults. JAMA 286:694. Brooks, R.B., C.W. Woods, and N.E. Rosenstein. 2003. Neisseria meningitidis outbreaks in the United States, 1994-2002, abstr. 289, p. 81-82. Abstr. 41st Ann. Meet. Infect. Dis. Soc. Am. Imrey, P.B. et al. 1995. Meningococcal carriage, alcohol consumption, and campus bar patronage in a serogroup C meningococcal disease outbreak. J. Clin. Microbiol. 33:3133-3137. Musher, D.M., et al. 1993. Antibody to capsular polysaccharides of Streptococcus pneumoniae: prevalence, persistence, and response to revaccination. Clin. Infect. Dis. 17:66. Ramsay, M.E. et al. 2001. Efficacy of meningococcal serogroup C conjugate vaccine in teenagers and toddlers in England. Lancet 357:195. Ramsay M. et al. 2003. Herd immunity from meningococcal serogroup C conjugate vaccination in England: database analysis. BMJ 326:365-366. Shepard, C.W. et al. 2005. Cost-effectiveness of conjugate meningococcal vaccination strategies in the United States. Pediatrics 115:1220-1232. Munoz, N. et al. 2003. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N. Engl. J. Med. 348:518-527. Hildesheim, A. et al. 1994. Persistence of type-specific human papillomavirus infection among cytologically normal women. J. Infect. Dis. 169:235-240. American College of Obstetricians and Gynecologists. 2005. Human papillomavirus. ACOG Practice Bulletin No. 61. Weinstock, H., S. Berman, and W. Cates, Jr. 2004. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect. Sex. Reprod. Health 36:6-10. Ho, G.Y. et al. 1998. Natural history of
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cervicovaginal papillomavirus infection in young women. N. Eng. J. Med. 338:423-428. 22. Sadeghi, S.B., E.W. Hsieh, and S.W. Gunn. 1984. Prevalence of cervical intraepithelial neoplasia in sexually active teenagers and young adults. Results of data analysis of mass
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Papanicolaou screening of 796,337 women in the United States in 1981. Am. J. Obstet. Gynecol. 148:726-729. 23. Mount, S.L. and J.L. Papillo. 1999. A study of 10,296 pediatric and adolescent Papanicolaou smear diagnoses in northern New England. Pediatrics 103:539545.
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24. Abma, J.C. et al. 2004. Teenagers in the United States: sexual activity, contraceptive use, and childbearing, 2002. Vital Health Stat. 23:1-87. 25. Centers for Disease Control and Prevention. 2006. HPV and HPV vaccine: information for healthcare providers. http://www.cdc.gov/std/hpv.
Clinical Microbiology Newsletter 29:19,2007