Why Vaccination Timeliness Matters

Part 1 of 3

Despite the large number of recommended vaccinations, overall coverage is high for most vaccines in the primary series (the first 2 or 3 doses), exceeding 90% for diphtheria, tetanus, and acellular pertussis vaccine (DTaP); pneumo-coccal conjugate vaccine (PCV); Haemophilus influenzae type b (Hib) vaccine; and inactivated poliovirus vaccine (IPV).2 Coverage falls short of the Healthy People 2020 objectives (90%), however, when it comes to completing the full series of these vaccines as scheduled.2,3

The 2009 National Immunization Survey (NIS) showed a significant drop-off in coverage for DTaP and PCV between the third and fourth doses—from 95.0% to 83.9% for DTaP (Figure 1) and from 92.6% to 80.4% for PCV.2 The drop-off is even wider during times of vaccine shortage such as occurred with Hib vaccine in 2009—92.1% coverage for the primary series (2 or 3 doses depending on the product) compared with 54.8% for the full 3- or 4-dose series.2 This phenomenon—a drop-off in vaccination rates after the primary series—occurs to some extent in all ethnic groups and among children below, at, or above the poverty line.2

Improving immunization coverage and timeli-ness in infants and young children faces many—and varied—challenges. In addition to the complexity of the vaccination schedule, these include lack of understanding among parents and

clinicians of the rationale for on-time immuniza-tion, parental and clinician concerns about vaccine safety, failure to make the most of opportunities to vaccinate, lack of access to health care or a medical home, insurance issues, clinician eco-nomic barriers (eg, cost of vaccine, administration fees, reimbursement), and problems related to vaccine storage requirements and shortages.

Why The anTibody-reinforcing dose MaTTersThe antibody-reinforcing dosea of vaccine given between 12 and 18 months of age is a crucial component of protection. With each dose in the primary vaccine series, serum antibody concentrations rise, peaking after the third dose at about 7 months of age.4-6 Antibody concentrations then decline and may fall below protective levels, leaving some children vulner-able to disease.6 For premature infants, antibody concentrations may not reach protective levels until after the antibody-reinforcing dose.7

Re-exposure to the antigen in a reinforcing dose of vaccine not only increases the quantity of antibody but also the quality of the immune

ediTorial board

stephen i. Pelton, Md, Moderator

Pasquale g. bernardi, Md

stan l. block, Md

gary s. Marshall, Md

donald b. Middleton, Md

audrey M. stevenson, Phd, MPh, Msn, fnP-bc

In a series of 3 newsletters for

clinicians and their office staff, a

panel of experts offers practical

strategies for improving immuni-

zation coverage and timeliness in

infants and young children—and

explores what can happen when

patients are underimmunized.

Part 1 focuses on the importance

of staying on schedule and the

consequences of delayed vaccine

doses. Part 2 will discuss combi-

nation vaccines and their poten-

tial impact on the implementation

of immunization goals. Part 3 will

detail some of the barriers to vac-

cine timeliness and coverage, as

well as successful approaches to

overcoming those challenges.

K eeping infants and young children up to date on their vaccina-tions can be challenging. In the first 18 months of life, the 2011

recommended immunization schedule calls for up to 22 injections and 2 or 3 doses of an oral rotavirus vaccine to protect against 13 infectious diseases. In addition, 2 doses of seasonal influenza vaccine are recommended for first-time vaccinees 6 to 18 months of age, with an annual single dose in subsequent years.1

a This dose is also called the booster dose, toddler dose, and fourth dose. The panel of experts felt that—although no one term seems to characterize it perfectly— “antibody-reinforcing dose,” while not common terminology, is an appropriate and accurate alternative.

© Klaus Lahnstein/Stone/Getty Images

response. With each exposure, the immune response improves because the child’s immune system is maturing, so that the antibody reacts more strongly and specifically to the antigen (improved avidity).4

The implications of a missed antibody-reinforcing dose are greater for some patho-gens than others. For invasive disease caused by encapsulated pathogens such as Hib, maintain-ing protective circulating antibody concentra-tions is necessary because memory responses are not fast enough to protect exposed chil-dren.4,8 When a reinforcing dose isn’t given, antibody levels often fall below protective levels, vaccine effectiveness declines, and vac-cine failures occur.8-10

That is what happened in the United Kingdom in the 1990s. The country started routinely immunizing children with Hib vaccine at 2, 3, and 4 months of age (along with an initial catch-up program for children 6 months to 5 years of age), but didn’t give an antibody-reinforcing dose. Invasive Hib disease dropped precipitously, in part due to strong herd immunity effects and the robust catch-up program. However, once the catch-up program was discontinued and average antibody concentrations decreased to relatively low levels, disease re-emerged, especially in children 1 to 4 years of age. 8-10

A decline in pertussis antitoxin titers after primary immunization, with subsequent increase in disease, has also been observed.11-13 In Sweden, where children receive pertussis vaccinations at 3, 5, and 12 months of age, the age-specific incidence of pertussis began to rise during the toddler years in the absence of an antibody-reinforcing dose and increased sig-nificantly between about 5 and 8 years of age.13 A Canadian study found that children who received only 3 doses of pertussis-containing vaccine had a 2.5-fold greater risk of devel-oping pertussis than children who received 4 doses of vaccine.12

ouTbreaKs of Vaccine-PreVenTable disease sTill occurTimely immunization is key to breaking the cycle of transmission, lowering the incidence of disease, and protecting vulnerable infants, who are at highest risk of severe complications and death from some vaccine-preventable diseases, such as pertussis. As global travel increases, vac-cination plays an important role in protecting children against importation of diseases such as measles and polio that are no longer endemic in this country.

Periodic outbreaks of vaccine-preventable diseases such as pertussis, Hib, and measles provide stark reminders of the need for timely immunization. A pertussis epidemic in California throughout 2010 claimed the lives of 10 infants and led to more than 9400 cases of disease—the highest number of cases reported since 1945 and the highest statewide incidence since 1958.14 Most patients with reported pertussis (77%) in California were younger than 18 years of age. The highest inci-dence—346 cases per 100,000 population—occurred in infants younger than 6 months of age, followed by children 7 to 10 years of age (62 per 100,000). The youngest infants were probably incompletely protected because they had not yet completed the primary immu-nization series; the older children may have experienced primary vaccine failure or, more likely, waning immunity after immunization. Of 1215 affected children between 6 months and 18 years of age with available vaccina-tion history, 13% were unimmunized against pertussis, and 53% had missed 1 or more recommended doses of vaccine.15

Underimmunization also figured promi-nently in an outbreak of 345 cases of pertussis during 2004 and 2005 in an Amish community in Delaware, where children between 1 and 5 years of age accounted for 41% of cases. The age distribution of disease resembled that of

the prevaccine era. In 45% of 96 households interviewed that had a case of pertussis, none of the children had been vaccinated.16

Outbreaks of Hib and measles have also been reported in recent years. In 2008, 5 Minnesota children under 5 years of age con-tracted invasive Hib and 1 died; this was the largest Hib outbreak in Minnesota since 1992. Three of these children had not received Hib vaccination because their parents or guardians were concerned about the safety of vaccina-tion. The outbreak occurred during a nation-wide shortage of Hib vaccine.17 Also during 2008, 131 cases of measles were reported in 15 states and the District of Columbia, 76% in persons under 20 years of age. Ninety-one percent of measles cases were unvaccinated or of unknown vaccination status; 89% were imported from other countries or associated with imported cases.18

ProTecTing young infanTs Outbreaks are teachable moments for parents and health-care providers. They highlight the importance of timely vaccination not only for infants and children, but also for adolescents and adults—because for some diseases, adolescents and adults are often the source of infection for infants, who are especially likely to suffer severe or fatal consequences.

Pertussis provides a classic example. Unvaccinated and undervaccinated household members, especially adults between 19 and 39 years of age, are an important source of pertus-sis transmission to young infants.19,20 Pertussis during infancy is more closely linked to cases in adults than in adolescent siblings, but adults may contract disease from adolescents in the family, then pass it along to infants.21

A hospital-based, prospective, multicenter study in France, Germany, Canada, and the United States found that household mem-bers, most often the mother or father, were responsible for transmitting pertussis to infants 6 months of age or younger in 76%-83% of cases for which a source could be identified (Figure 2).22 Another study reported that of 264 pertussis cases in infants with a known or suspected source of infection, 75% came from a family member: 32% from the mother, 15% from the father, and 20% from a sibling.20

A 2009 study, which found that siblings were the sources for more cases of pertussis than parents (36% vs 24%) in infants less than 12 months of age, suggests that young children who have not yet received the antibody-reinforcing dose of DTaP may be important transmitters of household infection.23 The study, which was done in Australia where the

2 | Why Vaccination Timeliness Matters

Figure 1. In children 19-35 months of age, vaccination cover-age for DTaP drops off from the third to the fourth dose.

≥3 DTaP ≥4 DTaP

2005 2006 2007

Year

2008 20090

20

40

60

80

100

Per

cen

t va

ccin

ated

95.0%83.9%

Source: National Immu-nization Survey, United States, 2005-2009.2

12 to 18 month dose of DTaP is no longer required, found that 80% of the 20 siblings 3 or 4 years of age were sources of infection, compared with only 32% of the other 44 siblings less than 18 years of age (Figure 3).

The incidence of pertussis in adults and adolescents rose during the first part of the last decade, largely because of waning immunity from childhood vaccination (the estimated duration of immunity after immunization is 4 to 12 years24). Vaccinating adolescents and young adults may not only decrease disease in those age groups but also decrease dissemina-tion of pertussis in households, thereby reduc-ing the risk to young infants.19 Although it is estimated that a very high adult vaccination rate—85% or more—would be necessary to reduce pertussis cases in infants, immunization of adolescents and more targeted vaccination of household contacts (“cocooning”) may help decrease transmission.25

In October 2010, the CDC’s Advisory Committee on Immunization Practices (ACIP) approved expanded recommendations for use of Tdap in adolescents and adults.26 In addition to a single dose of Tdap for all persons between 11 and 64 years of age, the recommendations now call for a single dose for children 7 through 10 years of age who have not been fully immunized against pertussis.a Adults 65 years of age and older who have or anticipate having contact with an infant younger than 12 months of age and have not yet been given a dose of Tdap should be immunized.a Any adult 65 years of age and older who has not yet received Tdap and wants to be protected against per-tussis may receive a dose of Tdap in place of tetanus-diphtheria toxoids (Td) vaccine.a Tdap can be given regardless of the interval since the last diphtheria or tetanus toxoid-containing vaccine.a

A countywide outbreak of 261 cases of pertussis in Fond du Lac, Wisconsin in 2003-2004, before pertussis booster vaccination was available for adolescents and adults in the US, points to the potential benefits of vaccinating adolescents and adults with Tdap.27 Infection spread among teenagers who used a high school weight room and from there into the community. The outbreak affected primarily adolescents and adults—86% of patients were older than 10 years of age and 15% were older than 19 years of age—and caused significant morbidity among adults. In addition, 2 infants were hospitalized.27

Numerous hospital-based outbreaks of pertussis, many traced to infected staff, attest to the impor-tance of immunizing health-care workers.28-32 The need for more comprehensive vaccination extends to staff in physicians’ offices as well.

The introduction of 13-valent PCV provides another example of the importance of timely immunization. PCV13 was approved by the United States Food and Drug Administration in 2010 to prevent invasive pneumococcal dis-ease caused by the 13 pneumococcal sero-types included in the vaccine as well as otitis media caused by the serotypes included in the 7-valent PCV (PCV7). The recommendations for PCV13 are the same as for PCV7 for children under 59 months of age who haven’t received any previous doses of either vaccine.33

Giving the antibody-reinforcing dose of PCV13 on time—preferably at 12 months rather than 15 months of age—will be critical to building antibody levels to all 13 serotypes covered by the new vaccine and creating the protective herd immunity effects now seen with the serotypes covered by PCV7. Until such herd immunity develops, deferring the reinforcing dose of PCV13 to 15 months of

age prolongs the period of susceptibility to disease. Furthermore, because pediatric office visits tend to fall off after 12 months of age, postponing the dose also increases the risk that the child might not receive the dose at all.

iMPlicaTions of delayed dosesCoverage rates may mask underimmunization. For example, a study based on NIS data showed that among children who were “up-to-date” by 2 years of age, 74% were actually delayed for 1 or more immunizations (and therefore potentially vulnerable to disease).34 When do children fall behind in timeliness? NIS data for 2006-2007 suggest this occurs to a large extent between 7 months and 16 months of age.35 Each month that doses are delayed puts the child at increased risk of disease.

A study of 858 children with 2224 vaccina-tion visits from 2 to 8 months of age found that at least 1 scheduled vaccine dose was not given during 37% of visits. The deferral rate increased with the number of doses due: 26% for 3 or fewer doses due; 34% for 4 doses; and 48% for 5 doses.36 This suggests that 1 reason for deferral is the shot burden. Importantly, deferred-dose

Why Vaccination Timeliness Matters | 3

a These ACIP booster recommendations are inconsistent with the currently licensed indications for the vaccine.

Figure 2. Sources of transmission of pertussis to infants.22

Figure 3. Ages of siblings less than 18 years of age living in the households of infants with per-tussis.23 Siblings 3 and 4 years of age are particularly important sources of infection in infants.

Part-time Caretaker2%

Grandparent6%

Friend/Cousin10%

Aunt/Uncle10%

Sibling16%

Father18%

Mother37%

010 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

2

4

6

8

10

12

14

Age of siblings (years)

Non-source

Source of infection

Nu

mb

er o

f si

bli

ng

s in

all

ho

use

ho

lds

From Jardine A, et al. CDI. 2010;34(2):116-121. Used by permission of the Australian Government.

visits are a strong predictor of inadequate cov-erage: at 1 year of age, only 32% of children with 1 or more deferred-dose visits were fully covered, compared to 51% of children with no deferred-dose visits. At 2 years of age, 73% of children who had 1 or more deferred-dose visits were fully covered, compared to 80% of children with no deferred-dose visits.36

Some children are never fully up-to-date with recommended immunizations, or they don’t catch up until they need vaccinations to enter school. Excluding data for Hib, NIS data for 2009 show 70% compliance with the 4:3:1:3:3:1:4 (DTaP; IPV; measles, mumps, rubella; Hib; hepatitis B; varicella; PCV) immu-nization schedule among children between 19 and 35 months of age.2 Pediatricians cite the difficulty of tracking and recalling patients when a dose is deferred as a major barrier to vaccine timeliness and coverage.37

Failure to vaccinate a child on time not only puts the child and family at risk of disease but also increases the risk of exposure for others in the health-care setting, potentially leaving the medical practice open to disease spread or even legal liability. Unvaccinated or undervac-cinated children can spread disease to other children who have not been fully immunized as well as to office staff in the practice. When a dose is delayed, it is essential to document the reason(s) for the deferral and document that the parents have been informed of the risks of delaying vaccination.

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33. CDC.Preventionofpneumococcaldiseaseamonginfantsandchildren—useof13-valentpneumococcalconjugatevaccineand23-valentpneumococcalpolysaccharidevaccine—recommendationsoftheAdvisoryCommitteeonImmunizationPractices(ACIP).MMWR.2010;59(RR-11):1-18.

34. LumanET,BarkerLE,ShawKM,etal.Timelinessofchild-hoodvaccinationsintheUnitedStates:daysundervac-cinatedandnumberofvaccinesdelayed.JAMA.2005;293(10):1204-1211.

35. LumanET,ChuSY.Whenandwhychildrenfallbehindwithvaccinations:missedvisitsandmissedopportunitiesatmilestoneages.AmJPrevMed.2009:36(2):105-111.

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37. BroderKR,MacNeilA,MaloneS,etal.Who’scallingtheshots?Pediatricians’adherencetothe2001-2003pneu-mococcalconjugatevaccine-shortagerecommendations.Pediatrics.2005;115(6):1479-1487.

Improving immunization coverage and timeliness offers numerous advantag-es to children, parents, and health-care providers. Issues 2 and 3 of this news-letter series explore some of the chal-lenges involved in providing the best protection available against vaccine-preventable diseases—and strategies to meet those challenges.