The United States Centers for Disease Control and Prevention (CDC) released the 2015 recommended immunization schedule for ages 0 to 18 years in January 2015 (Figure 1).1 The schedule lists 14 vaccines, with a schematic that indicates the number of doses in each series, and the age(s) when the children should receive them. Bars are used to illustrate whether the vaccine is recommended for all children, for catch-up immunization only, or for certain high-risk groups only. Extensive footnotes detail specific issues related to each of the vaccines listed.
The current US recommended immunization schedule for ages 0 to 18 years. From the Centers for Disease Control and Prevention (permission is not required).1
At age 11 or 12 years, it is recommended that children receive four vaccines: (1) a tetanus, diphtheria, pertussis (Tdap) booster, (2) the first of two doses of quadrivalent conjugate meningococcal vaccine (MCV4), (3) a three-dose series of human papillomavirus (HPV) vaccine, and (4) an annual influenza vaccine. Children who have had a delay in their immunization schedule should be caught up at the first opportunity. The catch-up schedule specifically recommends continuing or completing the hepatitis B, polio, measles, mumps, and rubella, and varicella vaccine series. Finally, pneumococcal vaccine and hepatitis A vaccine are identified for children and adolescents with certain risk factors that place them at high risk for these infections.
The process of tracking immunization coverage rates in an office setting has been simplified by the use of electronic medical records. Results of practice-initiated ‘internal audits’ can be surprising to the providers in the practice, as vaccine coverage is characteristically lower than predicted prior to the audit. Regional and statewide data are reported from immunization registries. The reporting of national data allows comparisons across states and regions to facilitate the identification of specific geographies that are unable to maintain high immunization rates. Tracking adolescent vaccine coverage across the US is one of the primary objectives of the National Immunization Survey (NIS).
NIS is a random digit-dial-telephone survey, conducted by the CDC. This tool has been used to collect provider-reported vaccination information in children ages 19 to 35 months since 1995, and began collecting data on 13- to 17-year-olds in 2005 (NIS-teen). During randomly generated telephone calls, demographic and socioeconomic data are collected, and parents are asked to list the vaccines that their adolescent has received. A questionnaire is then mailed to the adolescent’s provider to verify the vaccination history.2
In 2005, Tdap and MCV4 vaccines were added to the recommended immunization schedule as single doses to be administered at ages 11 or 12 years. HPV vaccine was added as a three-dose series for all 11- to 12-year-old girls in 2006, approved for use in boys beginning at age 9 years up to young men who are age 26 years in 2009 (with a permissive recommendation), and added as a formal recommendation for all boys at ages 11 or 12 years in 2011. The timing of the routine recommendations are important when reviewing the NIS-teen survey results, showing the rate of uptake for each of the vaccines (Figure 2). Note the steady uptake of both Tdap and MCV4 reaching approximately 50% of teenagers by 2009. After 2009, uptake of single-dose MCV4 slows compared to the more robust and sustained uptake of Tdap. By 2013, the percentage of teens that received at least one dose of Tdap was 86%, and the percentage of teens that had received at least one dose of MCV4 was 78%. The finding is counterintuitive because both vaccines have been recommended since 2005, and both should be given at the same time, during the same visit. One possibility for the difference relates to state immunization laws that require certain vaccines for school entry. Each state has its own immunization laws describing vaccines that are required for public school attendance, and the age at which the vaccine must be administered. In general, states that mandate Tdap and/or MCV4 vaccines require that the vaccine(s) be given either at age 11 years, or upon entry to grade 6 or 7. Twenty-one states and Washington, DC, require MCV4 vaccine for school entry, whereas 46 states and Washington, DC, require Tdap. Among the states that require both Tdap and MCV4 for school attendance, mean coverage rates were 85% and 82%, respectfully.3 Conversely, states without Tdap legislation had an average teen Tdap immunization rate of 79%, and among states without MCV4 legislation, rates were 68%.
Estimated vaccination coverage with selected vaccines and doses among adolescents ages 13 to 17 years. From the Centers for Disease Control and Prevention (permission is not required).2
As shown in Figure 2, HPV vaccine uptake has been slower than uptake for either Tdap or MCV4. Although it is tempting to conclude that rates are lower because the HPV series requires three doses of vaccine, the percentage of teens that have received at least one dose of HPV vaccine was only 57% (girls) and 35% (boys). Lower teen vaccination rates for even one dose of HPV vaccine compared with Tdap and MCV4 indicates that opportunities are being missed to immunize them.
Efforts to pass legislation mandating HPV vaccine for school entry have not met with the same success seen with either Tdap or MCV4 vaccines. The state of Michigan first introduced legislation in 2006 to require HPV vaccine for girls entering grade 6, but the bill was not enacted. In 2007, Texas became the first state to enact a mandate by executive order requiring HPV vaccine for girls entering grade 6. Legislators immediately passed a law to override the executive order and the governor withheld his veto. Currently, only Washington, DC, has enacted school-entry legislation for HPV vaccine; at least 10 states continue legislative efforts. In the meantime, developing strategies that effectively reduce HPV vaccine hesitancy and encourage improvements in vaccine uptake remain a focus of the CDC.
The CDCs Healthy People 2020 national targets for vaccination coverage among adolescents ages 13 to 15 years are 80% for Tdap, MCV4, and a three-dose series of the HPV vaccine (girls only for now).4 Forty-two states have already met the 2020 target for Tdap and 18 states have met the target for MCV4.2 Although no state has yet achieved the 80% goal for three-dose HPV vaccine coverage, Rhode Island led the country in 2013 with 57% of adolescent girls having completed the series.2
The Rationale for Tdap, MCV4, and HPV Vaccines During Adolescence
Tdap: Boosting Pertussis Immunity in Adolescents
Before pertussis vaccines were available, nearly 250,000 of 1 million cases of whooping cough were reported annually. The introduction of pediatric whole cell diphtheria, tetanus, whole cell pertussis (DTP) vaccine led to dramatic reductions in disease, but pertussis remains endemic to the US. Pediatric whole cell DTP vaccines were replaced with acellular diphtheria, tetanus, acellular pertussis (DTaP) vaccines in the 1990s. In an effort to further reduce the pertussis disease burden, an adolescent booster dose of Tdap vaccine was introduced in 2005. Despite this effort, outbreaks of disease have continued, with an overall trend showing increasing numbers of reported cases. The most logical explanation for this problem is that immunity afforded by acellular pertussis vaccines is not as durable as initially expected. Fortunately, in cases where vaccination does not prevent illness, patients who have previously been immunized are less contagious, have milder and less protracted symptoms, and are at reduced risk for severe outcomes, including hospitalization.5
The use of pertussis booster vaccines in the adolescent population is also an important aspect of reducing transmission to young infants where disease morbidity and mortality is highest. An enhanced surveillance study found that an adolescent was the source for 16% of infant pertussis infections.6
The Advisory Committee on Immunization Practices (ACIP) continues to recommend a single dose of Tdap vaccine for all adolescents at ages 11 to 12 years. At the present time, additional booster doses are not recommended. One exception where booster Tdap doses are recommended is for women during each pregnancy.7 The rationale for a booster Tdap vaccine in women during each pregnancy is two-fold: (1) the vaccine may prevent the mother from developing a pertussis infection and transmitting it to her newborn and (2) a booster during pregnancy allows for a transplacental endowment of protective maternal antibody to the newborn.7 Although this passive form of protection is expected to wane in the first months of life, it is important to note that most pertussis deaths occur prior to age 3 months. However, during the brief period of passive protection, infants will begin their routine DTaP vaccine series.
Despite excellent DTaP coverage rates in children and Tdap coverage rates in adolescents across the US, pertussis remains endemic, and outbreaks continue to be described. Vaccine effectiveness can most certainly be improved, perhaps using novel strategies currently under investigation.
Vaccinating Adolescents Against Invasive Meningococcal Disease
Neisseria meningitidis is a Gram-negative diploccoccus that causes life-threatening illness in all age groups. Among otherwise healthy children, disease incidence is highest in infants, with a secondary peak during the teenage years. Although unusual forms of illness can be encountered rarely, about one-half of cases present as meningitis, and the other half present as meningococcemia with septic shock, often with purpura fulminans. Among the 12 identified capsular types of N. meningitidis, 6 (A, B, C, X, Y, and W-135) cause almost all cases of human infection, although type A and X infections are not currently seen in the US. The proportion of each capsular–type-causing disease in the US varies from decade-to-decade. For example, serogroup Y caused 2% of cases in the US 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 cases in the US, each accounting for approximately one-third of cases.8 In 2013, only 564 cases of meningococcal disease were reported to the CDCs National Notifiable Disease Surveillance System for an incidence of 0.18 per 100,000 individuals. There are two notable and striking observations related to recent disease incidence. First, rates are the lowest since surveillance has been tracked, and have now been sustained below the CDCs Healthy People 2020 objective of 0.3 per 100,000 individuals or lower since 2009. Although invasive infection rates are uncommon in the US, overall mortality is approximately 10%, and nearly 20% of those who survive the illness develop serious sequelae.
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 (capsular types A, C, Y, W135) pure polysaccharide vaccine. In 2005, the first conjugate MCV4, which includes the same four capsular types as the polysaccharide vaccine, was licensed by the US Food and Drug Administration (FDA). Shortly thereafter, a routine recommendation was made by the ACIP to vaccinate all adolescents starting at ages 11 or 12 years. Postlicensure serologic data from adolescents immunized at ages 11 to 12 years indicated that the predicated duration of protection after a single dose of MCV4 was insufficient to sustain protection during the later teen years, a time when disease incidence increases and a time when many teens leave home to live in a residence hall with dining facilities at a university. In response to those serologic data, in 2010, ACIP recommended that all adolescents receive a two-dose series of vaccine with the booster dose recommended at age 16 years (or 5 years after the first dose). For adolescents who receive MCV4 on or after their 16th birthday, a booster dose is not routinely recommended.8
Recent Meningococcal Disease Outbreaks
Most cases of invasive meningococcal disease described in the US are sporadic; outbreaks have historically occurred at universities, schools, or military barracks. With a short incubation period and rapid onset of disease, meningococcal outbreaks have traditionally been controlled via prompt antibiotic chemoprophylaxis of close contacts. A decision to also implement a vaccination campaign to curb a cluster of disease is based on whether the occurrence of more than one case in an area represents a true outbreak or an unusual group of endemic infections. Mass vaccination of the at-risk population is usually considered when the attack rate is greater than 10 cases per 100,000 individuals. The recommendation that close contacts of invasive meningococcal cases receive antibiotic prophylaxis remains important even when mass vaccination campaigns are undertaken.
2012 Meningococcus C Outbreak
In September 2012, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) alerted health care providers about invasive serogroup C infections occurring since the summer of 2010 among men who have sex with men (MSM). A total of 18 cases were identified, 10 of whom were HIV infected. All were hospitalized, and five died. In October 2012, DOHMH recommended administration of MCV4 to men who lived in NYC and who were human immunodeficiency virus (HIV)-infected and had intimate contact with any man met online, via a smartphone application, or at a bar or party since September 1, 2012.9 Although HIV and MSM are not generally considered independent risk factors for invasive meningococcal infection, adolescent boys in these categories may be aware of the NYC outbreak and ask about being vaccinated.
2013 Meningococcal B Outbreaks
During 2013, two separate outbreaks of invasive meningococcal disease attributed to serogroup B infections occurred among US university students. In an effort to facilitate outbreak control, the CDC and FDA intervened through the use of an experimental meningococcal B vaccine.
Between March and November 2013, eight students at Princeton University were diagnosed with serogroup B meningococcal meningitis strain 409.10 Seven subsequent cases were identified throughout the following semester. A final related case, which was fatal, developed in a Drexel University student after spending time with a group of Princeton students. After the ninth-related case was identified, the FDA approved an Investigational New Drug (IND) application for a serogroup B meningococcal vaccine that had already been approved for use in Europe, Australia, and Canada. A university-wide vaccination campaign at Princeton University began in December 2013 for undergraduate students, those living in the undergraduate dormitories, and other members of the Princeton University community with specified medical conditions. More than 5,000 students (90%) and staff ultimately were immunized. The last case of serogroup B meningitis at Princeton University occurred in November 2013, but given the persistence of cases after the summer break in 2013 and the associated fatal case at Drexel University, there was a suggestion that a significant portion of the that population may still be acting as carriers. Thus, new and returning students were offered the same IND from the previous year in September 2014.
In a separate outbreak during November 2013, four cases of serogroup B infection occurred at the University of California Santa Barbara (UCSB) within a 2-week period. Because four cases occurred in such a short period of time, UCSB, working in collaboration with the local and state health departments and the CDC, petitioned the FDA to allow IND access to the same meningocoocal B vaccine used during the Princeton outbreak. It is notable that the outbreak strain at UCSB was strain 32, demonstrating that although the two outbreaks were temporally associated, they were not epidemiologically linked. UCSB’s vaccination campaign began in February 2014 with more than 8,000 individuals immunized. No further cases were reported.
The meningococcal B vaccine used under the IND approval at both Princeton and UCSB was approved by the FDA in early 2015 for use in patients ages 10 to 25 years as a two-dose series. In October 2014, a different meningococcal B vaccine was approved by the FDA for use in patients ages 10 to 25 years as a three-dose series. In October 2014, a different meningococcal B vaccine was approved by the FDA for use in patients ages 10 to 25 years as a three-dose series. Both of these meningococcal B vaccines are distinct from the currently recommended quadrivalent conjugate A, C, Y, W-135 vaccines because the immunogens are bacterial proteins rather than the bacterial capsular polysaccharides. Discussions on how best to incorporate the new meningococcal B vaccine into the immunization schedule have already begun at ACIP meetings.
Preventing HPV Infection During Adolescence
Among the more than 100 recognized HPV types, approximately 40 are known to infect the human genital tract. Among the oncogenic ‘high-risk’ virus types, HPV 16, 18, 31, and 45 cause approximately 80% of cervical cancers, whereas the low-risk virus types, especially types 6 and 11 are associated with anogenital warts.12 HPV vaccines were initially developed primarily to prevent HPV-related cervical cancer but data also support its role in the prevention of vulvar, vaginal, anal, and penile cancers. Moreover, the association of some cancers of the head and neck with oncogenic types of HPV (particularly type 16) suggests the potential for these vaccines to reduce the frequency of those malignancies as well.
HPV Vaccination and Adolescents: The Current Approach
ACIP recommends routine HPV vaccination, as a three-dose series, starting at ages 11 or 12 years for all girls and boys. For those who have not yet been immunized, “catch up” is recommended for all girls and women through age 26 years, and for all boys and men through age 21 years (or up to age 26 years). Girls and women can be vaccinated with bivalent (HVP 16, 18) or quadrivalent (HPV 6, 11, 16, 18) vaccine. Boys and men should receive the quadrivalent formulation.13 Although HPV-related cancers are very uncommon in this age group, HPV infection is not. The primary immediate goal of immunization is to reduce the incidence of HPV infections that occur commonly in adolescents and young adults so that HPV-related malignancies do not subsequently develop during adulthood.
HPV Vaccination and Adolescents: New Approaches Going Forward
Two major changes in the way in which HPV vaccines are being used in adolescents will emerge in 2015: (1) the approval of a new 9-valent HPV vaccine in December 2014 will require discussion on how it should be incorporated into the routine immunization schedule; and (2) emerging data appear to support consideration for a two-dose HPV vaccine series, rather than a three-dose series.
The new 9-valent HPV vaccine targets the same HPV types as the quadrivalent vaccine (6, 11, 16, 18) as well as five additional oncogenic HPV types (31, 33, 45, 52, 58). The clinical trials were conducted using a three-dose schedule, with results supporting its safety and immunogenicity. The vaccine was licensed by the FDA in December 2014 for use in girls and young women ages 9 to 26 years, and boys ages 9 to 15 years. Additional data have been collected for adolescent boys and young men in the 16- to 26-year-old group since the original submission. Because the clinical trials using the 9-valent HPV vaccine have been conducted using a three-dose series, no data are currently available for this new vaccine using a two-dose schedule. Trials to determine the immunogenicity of a two-dose series of the 9-valent vaccine are ongoing.
Data from clinical trials using quadrivalent HPV vaccine as a two-dose series were first discussed at the June 2014 ACIP meeting. Quadrivalent HPV vaccine has been in use and recommended as a three-dose series in the US since 2006. Antibody titers in 9- to 14-year-old girls who received a two-dose schedule (at 0 and 6 months) were noninferior to titers found in 16- to 26-year-old girls and women who received three doses (at 0, 1-2, and 6 months). However, effectiveness studies suggest that a two-dose series may negatively impact HPV prevalence, cervical pre-cancers, and genital warts. Globally, a two-dose schedule for HPV vaccines has already gained regulatory approval from the European Medicines Agency, and by several other countries. The World Health Organization changed its formal recommendation in 2014 to include a two-dose schedule if vaccination is initiated before age 15 years. Although addenda to the licensing applications for HPV vaccines have not been submitted to the FDA to consider two-dose schedules, the ACIP has begun to discuss the possibility of incorporating a two-dose schedule for children ages 9 to 14 years.
In the last decade, the approach to adolescent immunizations has evolved substantially. With the FDA approval of two new meningococcal B vaccines and the 9-valent HPV vaccine since 2014, and emerging data on using HPV vaccine as a two-dose series in some age groups, 2015 looks to be another year of evolving recommendations. As we learn more on how best to incorporate new vaccines into the adolescent immunization schedule, it is important to continue efforts on improving current vaccine coverage rates, particularly for HPV.
- Centers for Disease Control and Prevention. Recommended immunization schedule for persons aged 0 through 18 years. http://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html. Accessed March 30, 2015.
- Centers for Disease Control and Prevention. National, regional, state, and selected local area vaccination coverage among adolescents aged 13–17 years--United States, 2013. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6329a4.htm. Accessed April 1, 2015.
- Centers for Disease Control and Prevention. School and childcare vaccination surveys. http://www2a.cdc.gov/nip/schoolsurv/schImmRqmt.asp. Accessed March 19, 2015.
- HealthyPeople.gov. Immunization and infectious diseases. https://www.healthypeople.gov/2020/topics-objectives/topic/immunization-and-infectious-diseases/objectives. Accessed March 19, 2015.
- Centers for Disease Control and Prevention (CDC). Pertussis epidemic--Washington, 2012. MMWR Morb Mortal Wkly Rep. 2012;61(28):517–522.
- Bisgard KM, Pascual FB, Ehresmann KR, et al. Infant pertussis: who was the source?Pediatr Infect Dis J. 2004;23:985–989. doi:10.1097/01.inf.0000145263.37198.2b [CrossRef]
- Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women--Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep. 2013;62:131–135.
- Cohn AC, MacNeil JR, Clark TACenters for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-2):1–28.
- Centers for Disease Control and Prevention (CDC). Notes from the field: serogroup C invasive meningococcal disease among men who have sex with men - New York City, 2010-1012. MMWR Morb Mortal Wkly Rep. 2013;61(51–52):1048.
- Centers for Disease Control and Prevention. Serogroup B meningococcal vaccine & outbreaks. http://www.cdc.gov/meningococcal/outbreaks/vaccine-serogroupb.html. Accessed March 19, 2015.
- Centers for Disease Control and Prevention. About meningococcal outbreaks. http://www.cdc.gov/meningococcal/outbreaks/about.html. Accessed March 19, 2015.
- Munoz N, Bosch FX, de Sanjose S, et al. International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348(6):518–527. doi:10.1056/NEJMoa021641 [CrossRef]
- Markowitz LE, Dunne EF, Saraiya M, et al. Centers for Disease Control and Prevention (CDC). Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2014Aug29;63(RR-05):1–30.