Pediatric Annals

New Immunization Strategies for Preventing Infectious Diseases in Adolescents

Erin M Bennett, MSc; Joseph B Domachowske, MD

Abstract

1. Bilukha OO, Rosenstein N. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR-7): J -2 J .

2. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JMl. Meningococcal Disease. N Engl J Med. 200 1 ;344( 1 8): 1 378- 1 388.

3. Edwards MS, Baker CJ. Complications and sequelae of meningococcal infections in children. J Pediatr. 1981 ;99(44):540-545.

4. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 1969; 129(6): 1307- 1326.

5. Caugant DA, Hoiby EA, Magnus P, et al. Asymptomatic carriage of Neisseria meningitidis in a randomly sampled population. J Clin Microbiol. 1994;32(2):323-330.

6. Harrison LH, Pass MA, Mendelsohn AB, et al. Invasive meningococcal disease in adolescents and young adults. JAMA. 2001;286(6):694-699.

7. Brooks RB, Woods CW, Rosenstein NE. Neisseria meningitidis outbreaks in the United States, 1994-2002 [ Abstract 289]. In: Abstracts of the 41st Annual Meeting of the Infectious Diseases Society of America, San Diego, CA, October 9- 1 2;2003:8 1 -82.

8. Imrey PB, Jackson LA, Ludwinski PH, et al. Meningococcal carriage, alcohol consumption, and campus bar patronage in a serogroup C meningococcal disease outbreak. J Clin Microbiol. 1 995;33( 1 2):3 1 33-3 1 37.

9. Froeschle J. Meningococcal disease in college students. Clin Infect Dis. 1 999;29( 1 ):2 1 5-2 1 6.

10. Harrison LH, Dwyer DM, Maples CT, BiUmann L. Risk of meningococcal infection in college students. JAMA. 1999; 281(20): 1906-1910.

11. Control and prevention of meningococcal disease and Control and prevention of serogroup C meningococcal disease: evaluation and management of suspected outbreaks; recommendations of the Advisory Committee on Immunization Practices (ACJP). MMWR RecommRep. 1997;46(RR-5): 13-21.

12. Bruce MG, Rosenstein NE, Capparella JM, Shutt KA, Perkins BA, Collins M. Risk factors for meningococcal disease in college students. JAMA. 2001;286(6):688-693.

13. Neal KR, Nguyen- Van-Tarn J, Monk P, O'Brien SJ, Stuart J, Ramsay M. Invasive meningococcal disease among university undergraduates: association with universities providing relatively large amounts of catered hall accommodations. Epidemiol Infect. 1999; 1 22(3):35 1-357.

14. Musher DM, Groover JE, Rowland JM, et al. Antibody to capsular polysaccharides of Streptococcus pneumoniae: prevalence, persistence, and response to revaccination. Clin Infect Dis. 1993;17(l):66-73.

15. Ramsay ME, Andrews N, Kaczmarski EB, Miller E. Efficacy of meningococcal serogroup C conjugate vaccine in teenagers and toddlers in England. Lancet. 2001:357(9251): 195- 196.

16. Food and Drug Administration. Product approval information-licensing action. Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologies Evaluation and Research; 2005. Available at http://www.fda. gov/cber/products/mpdtaveOl 1405.htm.

17. Leino EV. ACHA college meningitis survey: results and analysis. Presented at the American College Health Association Annual Meeting, New Orleans, LA; June 10, 2004.

18. Ramsay M, Andrews NJ, Trotter CL, Kaczmarski EB, Miller E. Herd immunity from meningococcal serogroup C conjugate vaccination in England: database analysis. BMJ. 2003;326(7385):365-366.

19. Shepard CW, Ortega-Sanhez IR, Scott RD ?, Rosenstein NE; ABCs Team. Cost-effectiveness of conjugate meningococcal vaccination strategies in die United States. Pediatrics. 2005;115(5):1220-1232.

20. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348(6):518-527.

21. Hildesheim A, Schiffman MH, Gravitt PE, et al. Persistence of type-specific human papillomavirus infection among cytologically normal women. J Infect Dis. 1994;169(2):235-240.

22. American College of Obstetricians and Gynecologists. Human Papillomavirus. ACOG Practice Bulletin No. 61, April 2005.

23. Weinstock H, Berman S, Cates W. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Persped Sex Reprod Health. 2004;36( 1 ):6- 1 0.

24.…

The U.S. Department of Health and Human Services and the Centers for Disease Control and Prevention (CDC) released the 2007 recommended immunization schedule in January 2007. For the first time, vaccines recommended for infants and young children and vaccines recommended for older children and adolescents have been divided into separate tables. The table for older children (see Table 1, page 329) outlines the recommendations for ages 7 to 18 years, including routine immunization with human papillomavirus vaccine, conjugate meningococcal vaccine, and diphtheria, tetanus, and pertussis (DTaP) vaccine, with catch-up immunizations for hepatitis B, polio, measles, mumps, rubella, and varicella vaccines. In addition, reminders that certain high-risk groups should be immunized with pneumococcal vaccine, hepatitis A vaccine, and annual influenza vaccine are included.

The recent introduction of several new vaccines for use in adolescents gives healthcare providers new opportunities to provide a range of preventative interventions for long-term health lasting well into adulthood. Three of these newly approved vaccines - conjugate meningococcal vaccine, human papillomavirus vaccine, and adolescent DTaP vaccine - are now recommended by the Advisory Committee on Immunization Practices (ACIP) to be administered routinely for adolescents. Including these new vaccines in the well-child adolescent healthcare visits allows for the improvement of vaccine coverage in adolescents and further reinforces the importance of the routine healthcare visit at 11 to 12 years. This vaccine approach not only allows for catch-up vaccination for those who did not receive earlier recommended childhood vaccines but also provides protection during an age of increased risk for these infections.

VACCINATION AGAINST INVASIVE MENINGOCOCCAL DISEASE

Neisseria meningitidis is now the leading cause of meningitis in children and adults in the United States.1 Among the 13 identified capsular serogroups of N. meningitidis, five (A, B, C, Y, and W-135) cause nearly all cases of human disease.2 Infection rates among the various serogroups have changed in recent years, with serogroup Y causing only 2% of cases in the United States between 1989 and 1991 and 37% of cases between 1997 and 2002. ' Together, serogroups B, C, and Y are now responsible for the majority of meningitis cases in the United States, each accounting for approximately one third of cases.1,2 Transmission occurs through direct contact with large droplet respiratory secretions from either patients or asymptomatic carriers.1 Although colonization rates are high in the United States (between 8% and 20%), invasive infection rates are comparatively low, with only 2,500 cases reported annually (0.5 to 1.1 cases per 100,000). However, of these cases, 11% to 19% of patients suffer long-term effects and 10% die.3 Meningococcal disease is most often observed in previously seronegative non-carriers.4 Although the highest attack rate of meningococcal infection occurs in children younger than 12 months, the majority of meningococcal disease occurs in those older than 11 years,1 with current estimates of 62% of all cases seen in the United States occurring in this age range (unpublished data, CDC). The strains most commonly associated with invasive meningococcal disease in the United States are types B, C, and Y, with type B being most common in young infants and type Y most common in the elderly.1 Groups considered at increased risk for invasive meningococcal disease include those who smoke and those who have been exposed to second-hand smoke, those with upper respiratory infections, and those who live in crowded conditions such as college dormitories.1 Freshman living in dormitories are three times more likely to develop invasive meningococcal disease when compared with 18 to 23 year olds in the general population, and five times more likely to develop meningococcal disease when compared with other undergraduates. When adolescents are infected with meningococcus, they are more likely than infants to experience shock, septicemia, and death without meningitis at presentation.6 In 2000, the ACIP formally recognized the increased risk of meningococcal disease among college freshmen living in dormitories compared with those of the same age in the general population and identified them for routine immunization with the then-available 4-valent polysaccharide vaccine, Menomune.

Meningococcal Disease Outbreaks

Outbreaks of meningococcal disease have increased in recent years, with 65% occurring in colleges and schools.7 Such outbreaks are most often traced to closely related strains, with 75% of cases in adolescents caused by serogroups CY, or W-135 (CDC, unpublished data, 2004). During meningococcal outbreaks, bar or nightclub patronage, combined with alcohol use, are associated with higher risk for infection.8 With a short incubation period and rapid onset of disease, meningococcal outbreaks have traditionally been controlled via prompt antibiotic chemoprophylaxis of close contacts. The decision to implement a mass vaccination campaign to prevent further disease is based on whether the occurrence of more than one case in an area represents a true outbreak or an unusual clustering of endemic disease. 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. Because no vaccination can guarantee 100% protection, it is also recommended that close contacts who have previously been immunized should also receive antibiotic chemoprophylaxis.

Incidence of Meningococcal Disease in the University Community

A number of studies in recent years have been conducted in both the United States and the United Kingdom, attempting to delineate the specific risk of meningococcal disease in college students. A U.S. study conducted between 1990 and 1992 indicated that invasive meningococcal disease occurred 9 to 23 times more frequently in those students living in dormitories compared with those living in other housing.9 A study conducted in Maryland between 1992 to 1997 concluded that the incidence of meningococcal disease among college students was similar to the incidence observed in people of the same age in the general population, but the rate of disease was higher in those students living in dormitories compared with those living in off-campus housing.10 A 1998-1999 U.S. surveillance study found that the rate of meningococcal disease was lower among undergraduate students than the rate observed among persons 18 to 23 years of age who were not in college, although rates were somewhat higher in freshmen." Later, in a case-controlled study of 50 cases of invasive meningococcal disease detected among college students, a multivariate analysis determined that freshmen living in dormitories were specifically at higher risk for developing meningococcal disease when compared with other students.12 In a similar study conducted in the United Kingdom, it was determined that rates of meningococcal disease were higher in college students than in non-college students, with catered hall accommodation proving to be the primary risk factor.13

Meningococcal Polysaccharide Vaccine 4-valent (MPSV4) and Meningococcal Conjugate Vaccine 4-valent (MCV4)

Vaccination programs designed to immunize patients at high-risk for invasive meningococcal disease have been in effect for many years, but with notable limitations. The meningococcal polysaccharide A/C/Y/W135 (MPSV4) vaccine (Menomune, Sanofi Pasteur) has been available for use in patients 2 years and older for more than 20 years. This vaccine offers 90% to 95 % protection against infection caused by vaccine strains, although the protective antibody responses are relatively short lived at only 3 to 5 years.14 Polysaccharide vaccines including MPSV4 work through a T-cell independent mechanism in which mature B lymphocytes produce antibodies to the vaccine antigens but are not able to retain immunologic memory. Similarly, memory T-cells are not generated. Perhaps more importantly, repeated doses of polysaccharide vaccines (such as MPSV-4) results in reduced antibody responses in some patients, a phenomenon known as "immune tolerance." Furthermore, the MPSV4 vaccine does not provide mucosal immunity, and therefore is also unable to provide herd immunity through a reduction in nasopharyngeal carriage of meningococcus. Despite these limitations, the MPSV4 vaccine has proven to be effective in protecting populations who are at risk in the short term, such as travelers to areas of endemic disease and in college freshmen living in dormitories.

To overcome the limitations observed for MPSV4, conjugate vaccines were developed. Covalently linking the same meningococcal polysaccharide antigens to a carrier protein improves the efficiency of the immune response. This strategy of linking polysaccharide antigens to simple peptides has already been very successful for both Haemophilus influenzae B and Streptococcus pneumoniae vaccines. Unlike pure polysaccharide vaccines, conjugate vaccines are processed by the immune system in a T-cell dependent manner, providing more durable antibody responses with efficient induction of immunologic # memory. One of the available conjugate meningococcal vaccines, meningococcal conjugate vaccine (MCV4) (Menactra, sanofi pasteur), was approved for use in the United States in 2005 for patients 11 to 55 years. MCV4 contains the same polysaccharide antigens as 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 for the disruption of transmission and the establishment of some degree of herd immunity. Further enthusiasm for conjugate meningococcal vaccine was recently generated from the United Kingdom, where the introduction of the univalent, conjugated meningococcal C vaccine caused a very substantial reduction in epidemic group C disease in that country and demonstrated herd benefit.15

Safety of MPSV4 and MCV4

The safety of MPSV4 and MCV4 were compared among people 11 to 18 years in several randomized controlled trials, demonstrating that the percentage of patients reporting adverse events was similar for both vaccines. The data further showed that for both vaccines, roughly one half the participants experienced at least one systemic reaction, with fewer than 5% experiencing severe systemic reactions.16 It does appear, however, that those receiving MCV4 experience more local adverse reactions - 13% compared with only 3% of those receiving MPSV4. This is thought to be related to the amount of diphtheria toxoid contained in the conjugate formulation of the vaccine.

Guillain-Barre Syndrome and MCV4

In October 2005, the Vaccine Adverse Event Reporting System (VAERS) received reports of Guillain-Barre syndrome (GBS) occurring in some patients within six weeks of receiving MCV4 vaccine, prompting warnings for its use. Since then, 19 adolescents have been reported to have developed GBS within six weeks of vaccination with MCV4. Although it remains unclear whether this association is causal or simply temporally (coincidentally) related, it is clear that the risk of developing GBS after vaccination with MCV4 (1.25 per million) is much lower than the risk of developing invasive meningococcal disease (5 to 11 per million). Furthermore, 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 continuing public health risk of invasive meningococcal disease, the ACIP continues to recommend routine immunization of all adolescents with meningococcal vaccine.

ACIP Guidelines

Because college students are at increased risk for meningococcal disease, the ACIP and the American Academy of Pediatrics (AAP) have devised specific recommendations aimed at college students. It is recommended that colleges and healthcare providers supply information to prospective college students and their parents on the risks of infection and the potential benefits of vaccination. This includes the recommendation that university health services implement educational programs to educate students and families about meningococcal disease and to make the vaccine available to those who request it. A 2004 American College Health Association (ACHA) internet survey found that 60% of universities had implemented written policies on meningococcal vaccination, with 80% conducting awareness programs among students and/or their parents.17 These steps have led to increased vaccination rates among college students, with median vaccination rates of 20% in 2002-2003 and 35% in 2004-2005, with the majority of responding universities reporting increases in vaccination rates during the previous three years. Based on the number of vaccine doses sold during 2004-2005, it is estimated that 1.1 million U.S college students received the vaccine prior to matriculation, with an additional 50,000 to 100,000 students receiving the vaccine after arrival to college.

Formal recommendations concerning the administration of meningococcal vaccines were updated by the ACIP in 2005. These recommendations stemmed, in part, from U.K. data involving the conjugate serogroup C vaccine, where routine adolescent vaccination led to a corresponding drop in meningococcal disease in the entire population, demonstrating a "herd immunity" benefit of an adolescent vaccine public health program.18 Extrapolating the U.K. data to the U.S. population, immunizing adolescents would lead to an overall drop in invasive meningococcal disease of 32%.19 Although either MPSV4 or MCV4 can be used under the current guidelines, the conjugate vaccine is preferred and is also indicated for those who have been vaccinated previously with MPSV4 but still remain in a high-risk category. Although MPSV4 is considered a reasonable alternative when a shortage in MCV4 exists, the conjugate vaccine is expected ultimately to replace MPSV4 in all circumstances. 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), if they have not been previously vaccinated. To date, adolescents are the only cohort for which vaccine is recommended solely on the basis of age. Other recommendations are based on specific at-risk populations, such as college freshmen living in dormitories, people with specific immune deficiencies or asplenia, and for certain microbiology technologists.

HUMAN PAPILLOMAVIRUS VACCINATION

The newest addition to the adolescent immunization platform is the human papillomavirus (HPV) vaccine. Currently approved and recommended for girls and young women, this vaccine is expected to reduce the incidence of cervical cancer dramatically. Among the more than 100 recognized HPV types, approximately 40 are known to infect the human genital tract. The types are divided into low- and high-risk subgroups based on their oncogenic potential. Persistent infection with a high-risk HPV type causes cervical cancer. Among the high-risk virus types, HPV 16, 18, 31, and 45 cause about 80% of cervical cancers,20 while the low-risk virus types, especially types 6 and 11 are associated with anogenital condyloma.21 HPV infection is a leading cause of abnormal Pap smear results. Infection with HPV is seen on Pap smear as low, moderate, or advanced dysplasia. Moderate to advanced cervical dysplasia is most commonly caused by the persistence of the oncogenic strains of HPV and if left untreated will progress to cervical cancer.

HPV Epidemiology

The prevalence of HPV in the general population is between 14 and 35%,22 with the majority of those infected being young women. In the United States, there are approximately 20 million people infected with HPV, with an additional 6.2 million acquiring new infections each year.23 Longitudinal sampling studies have indicated that the prevalence of HPV in women between 15 and 19 years is 44%, with 60% of those still testing positive for HPV five years later.24 This rate is thought to be highly variable, however, with the demographics of the population under study being a major factor. Although the frequency of HPV infection is high, most infections are transient, with the average duration of infection in college-aged women being 8 months.25 Recent studies also indicate that 90% of women with HPV infections become HPV-negative within two years. Low oncogenic risk strains of HPV (especially types 6 and 11) cause genital warts in men and women, with 1% of people in the United States having visible warts present at any given time.23

HPV Vaccination and Adolescents

Population-based studies of cervical cancer incidence suggest that the rate of Pap smear cytologic abnormalities among adolescents is on the rise. In two comparable studies examining Pap test results in adolescents both in 1981 and in 1999, there was an increase in Pap smear abnormalities from 1.9% to 4% 26.27 sexuaj debut is occurring in a majority of teenagers by 17 years, with a smaller percentage engaging in penetrative sexual activity at significantly younger ages. In a 2002 study, it was found that 5.7% of girls and 7.9% of boys reported having sexual intercourse by 14 years.28

The Food and Drug Administration licensed the first HPV vaccine in 2006 for females between the ages of 9 and 26 years. This 4-valent vaccine (Gardasil, Merck) targets HPV types 6, 1 1, 16, and 18 and is administered as three doses (0, 2, and 6 months). It can be administered concomitantly with other adolescent vaccinations. Another HPV vaccine, Cervarix (Glaxo SmithKline), is a bivalent HPV 16/18 vaccine that is currently in phase-3 clinical trials and may become available for use in the United States in the next few years. It is important to note that HPV vaccines provide no therapeutic effect on HPV infection already present, therefore administering the vaccine prior to HPV infection is imperative. Administering the vaccine during adolescence will be most cost effective, with cost per quality of life year saved due to vaccination against HPV types 16 and 18 estimated to be between $15,000 to $25,000.29Any economic advantages will depend on vaccination age, duration of immunity, whether both males and females are vaccinated, and the predicted reduction in the number of recommended Pap smears following vaccination. Including vaccination against strains 6 and 11 is estimated to increase the cost effectiveness even further.

HPV Education in Adolescents

Despite the prevalence of HPV infection and the rise of cervical dysplasia in young women, there is still limited understanding of HPV by adolescents. In the United States, even though one study found that 67% of young women attending health clinics had heard of HPV,30 few women knew about the link between infection with HPV, abnormal Pap results, and cervical cancer. Other studies have indicated that many women do not know that the Pap test and pelvic examination are two separate procedures, or what a Pap test result indicates.31 Although these studies show an overall lack of education surrounding HPV and cervical cancer testing, other studies show that there appears to be an increased interest in learning more about HPV, with the healthcare provider being the preferred source of this information for most respondents. These findings highlight the need for increased efforts in educating young women and parents of adolescents about HPV-related diseases.

HPV Vaccine Recommendations

Shortly after approval of HPV vaccine 6, 11, 16, 18 (Gardasil) for females between 9 and 26 years, the ACIP recommended it be administered to all 11to 12-year-old girls, as well as to 13- to 26-year-old women who have not yet completed the vaccine series. Permissive wording allows the vaccine series to be started as early as 9 years. Clinical trials have demonstrated 100% efficacy in the prevention of cervical precancers 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 in the clinical trials was calculated in women who were documented to be seronegative or PCR negative to the four HPV types in the vaccine at study enrollment, remained PCR negative during the vaccination phase, and received all three doses of the vaccine without veering from the study protocol. During the prelicensure clinical trials, screening for pre-existing HPV infection was not performed to determine which women would be eligible for vaccine but rather to document which study participants were infected before the vaccine series so that robust efficacy and effectiveness data would be available at the study conclusion. As such, HPV vaccine effectiveness, as calculated from all clinical trial enrollees, even if significant violations in the study protocol were present was, as expected, lower than the efficacy seen in the "per protocol" efficacy analysis. The "so-called" general population effectiveness was lower, primarily because some people who were vaccinated were already infected with vaccine HPV before the vaccine series was begun. Although the vaccine was shown to protect against newly acquired infection, there was no evidence to suggest it could impact the disease cause 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, with little or no waning in antibody levels detected in 5-year follow-up studies. The long-term durability of the immune response, and more importantly the long-term protection against HPV-associated malignancies and genital warts, will be determined as postlicensure experience is gained. It is also obvious that to provide maximal benefits against a sexually transmitted infection, we must vaccinate both men and women. The concept of herd immunity dictates that, at the very least, we consider the potential impact of vaccinating all members at risk of transmitting the infection. Although the currently available HPV vaccine is not yet licensed for use in men, immunogenicity and safety studies in males are ongoing.

Like other vaccine programs, the success of any HPV vaccine is dependent on the support and recommendation of healthcare providers. Studies have shown that health care providers are more likely to recommend vaccination campaigns that are endorsed by professional organizations,32 and with specific recommendations now available from ACIP, vaccine uptake has been enthusiastic.

BOOSTING PERTUSSIS IMMUNITY DURING ADOLESCENCE AND BEYOND

Despite widespread successful universal immunization of infants and young children with multiple doses of combined DTaP vaccine, reported cases of pertussis have been on a steady upward trend in the United States since the early 1980s. As such, pertussis remains the least well-controlled vaccine-preventable disease in the United States. A significant proportion of cases now occurs in adolescents, as protective immunity from vaccination during young childhood wanes after 7 to 10 years. Adolescents and adults now make up more than half of cases reported,33 with both age groups representing important reservoirs of the disease.

Pertussis Disease

Pertussis is caused by the fastidious, gram-negative coccobacillus Bordetella pertussis. This acute respiratory infection is passed person to person via large respiratory droplets and is highly contagious, with attack rates in susceptible populations approaching 100%. Factors that influence clinical presentation include age, level of immunity from prior infection or vaccination, and whether antimicrobials are used very early in the course of the illness. Classic pertussis is characterized by three phases. The catarrhal phase lasts up to two weeks and is characterized by coryza and intermittent cough, followed by the paroxysmal phase, which lasts several weeks. The paroxysmal stage is characterized by spasmodic cough, post-tussive vomiting, and the characteristic inspiratory whoop. Symptoms improve gradually during the convalescent phase, which can last several months. A growing awareness of less classic disease manifestations, particularly among adolescents and adults, has led to a significant increase in the numbers of cases reported to occur in these age groups. 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 older people unless an exposed infant develops classic whooping cough.

Pertussis Incidence

Historically, it was thought that the early generation, whole cell pertussis vaccines developed in the 1940s would confer lifetime immunity to recipient young children, as reported pertussis infection rates among children and adults decreased dramatically following their use. Prior to 1943, an annual average of approximately 200,000 pertussis cases were reported in the United States, with 4,034 deaths reported from 1934-1943.34 After the introduction of whole cell DTP vaccine, reported cases fell dramatically, reaching a historic low in 1976 of only 1,010 reported cases nationwide. Since 1976, however, the number of reported cases in the United States has risen steadily. Although this observation is likely attributable, at least in part, to increased recognition and reporting of non-classic disease, the age-specific shift in cases also supports 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.35 In 2003, the majority of reported pertussis cases occurred in people older than 10 years. In 2004 alone, 25,827 cases of pertussis were reported in the United States, with 34% occurring in adolescents between the 18 years (incidence: 30 per 100,000).36 Furthermore, data from active surveillance studies suggest that reported cases represent only a small percentage of actual cases of pertussis. From these studies, Cherry estimates 800,000 to 3 million cases of pertussis occur annually in the United States.37

Pertussis in Adolescents

Adolescents often acquire pertussis infection during middle- and highschool outbreaks. Although the precise number of school outbreaks across the United States is unknown, descriptions of pertussis outbreaks in middle schools around the country suggest it is a common occurrence. In a 1996 study from Massachusetts, 20 distinct outbreaks of pertussis were identified, with 18 of those occurring in schools and 67% occurring in adolescents.38 In a 2003-2004 outbreak in Wisconsin, 70% of 313 cases were in adolescents, many traceable to a single high-school weight room.39 A 2002-2004 Massachusetts study found that approximately 90% of detected pertussis outbreaks occurred in schools, with the majority of those afflicted in the age range of 11 to 19 years (CDC, unpublished data 2005).

Regular and consistent use of an effective pertussis booster vaccine in the adolescent population is expected to reduce disease morbidity, as well as to provide protection of unvaccinated or incompletely vaccinated infants via herd immunity. An enhanced pertussis surveillance study conducted between 1999 and 2002 found that among 43 of 264 infant pertussis infections, an adolescent could be verified as the source.40 A study of risk factors for pertussis-related hospitalizations in infants found that siblings were the most common route of infection (53%), followed by parents (20%), other relatives (12%), neighbors (8%), and day-care contacts (3%).41 In another study that was case controlled, infants of mothers between 15 and 19 years were 6-fold more likely to contract pertussis compared with infants of mothers 20 to 29 years.42

Pertussis morbidity is significant in adolescents, with recent findings suggesting that complications of pertussis infection, such as hospitalizations for pneumonia, increase with age. Multiple studies have shown that most adolescents experience a sustained cough, with the majority lasting 3 to 9 weeks. As adolescents often do not exhibit many of the more classic clinical symptoms of pertussis, such as frequent and dramatic paroxysms, whooping, or post-tussive vomiting, many cases still go unrecognized and unreported. Even if pertussis infection is eventually diagnosed, treatment is delayed, allowing spread of the infection to susceptible contacts. A Massachusetts study conducted between 1989-2004 found that of 7,000 adolescents with pertussis, 41% had one clinic visit, 32% had two visits, and 24% had three medical visits during their illness, and 83% missed on average 5.5 days of school (Massachusetts Department of Public Health, unpublished data 2005). Enhanced surveillance data from this state also show that 62% of reported pertussis cases in adolescence occur before 14 years, suggesting that earlier boosting of pertussis vaccination is critical (CDC, unpublished data, 2005).

Vaccination against Pertussis

Acellular pertussis booster vaccines are currently available as combined diphtheria, tetanus, and acellular vaccines [Tdap, Adacel (sanofi pasteur), and Boostrix (Glaxo SmithKline)]. These DTaP vaccines are highly immunogenic and well tolerated. In 2005, the FDA approved both products for use in the United States as booster vaccines in patients beyond childhood. Based on clinical trial safety and immunogenicity data, Boostix was approved for use in patients between the ages of 10 and 18, and Adacel was approved for use in those 1 1 to 65 years. The safety of both vaccines was evaluated by comparison of adverse events following vaccination in persons receiving DTaP with those receiving the tetanus vaccine alone.

Adverse events, waning immunity, and cost have all been considered as potential barriers for the implementation of a standardized pertussis-boosting vaccination program for adolescents. Lee et al43 found that a one-time vaccination of adolescents would result in a significant net health benefit and be reasonably cost effective if the price per dose remained consistent with the current price in many other countries, taking into account incidence of pertussis, waning immunity, vaccine efficacy and coverage, and infant transmission. With a baseline incidence rate of 155 cases per 100,000, the one-time adolescent vaccination strategy would prevent 36% of pertussis cases, with the estimated societal cost at $37.6 million. These results were similar to a study conducted in Canada by Iskedjian et al,44 which predicted a reduction in both illness and hospitalizations associated with pertussis infection, even though the initial acquisition of the vaccine would cause a rise in costs of $2.2 million.

The decision to administer DTaP booster vaccines to adolescents is based on the pertussis disease burden in the whole population, the disruption caused by pertussis outbreaks in the community.

the expense of post-exposure management of contacts, and studies that demonstrate that the current vaccines are safe, effective, and economical. DTaP vaccination is currently recommended for all adolescents 11 to 18 years. New ACIP recommendations also advise providing a single dose of DTaP for all adults, with a special emphasis on adults living with children younger than 1 year and adults who are healthcare providers.

The preferred age to administer the adolescent dose of DTaP vaccine is 1 1 to 12 years, because this is predicted to reduce morbidity associated with pertussis infection in adolescents. It is further advised that an interval of at least 5 years should lapse between any previous tetanus vaccination and the DTaP vaccine; however, intervals as short as 1 8 to 24 months appear to be are acceptable. Adolescents with a history of pertussis infection should also receive the DTaP vaccine, as the duration of protection induced by natural pertussis infection is not life long.

CONCLUSIONS

Vaccinating adolescents against invasive meningococcal disease, human papillomavirus, and pertussis is considered to be the most effective method for reducing the risk, cost, and consequences posed by these infections for adolescents and for the general public. The benefits to the adolescent include not only the opportunity for vaccination catch up and protection against meningitis, HPV, and pertussis prior to increased risk for these infections but also the opportunity for further education of teens and parents about the importance of these vaccinations. The benefits to society include the establishment of a level of herd immunity to these infections, positively affecting both adults and young children, with an overall reduction in healthcare costs.

REFERENCES

1. Bilukha OO, Rosenstein N. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR-7): J -2 J .

2. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JMl. Meningococcal Disease. N Engl J Med. 200 1 ;344( 1 8): 1 378- 1 388.

3. Edwards MS, Baker CJ. Complications and sequelae of meningococcal infections in children. J Pediatr. 1981 ;99(44):540-545.

4. Goldschneider I, Gotschlich EC, Artenstein MS. Human immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 1969; 129(6): 1307- 1326.

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