Pediatr Drugs 2007; 9 (3): 143-148CURRENT OPINION 1174-5878/07/0003-0143/$44.95/0 2007 Adis Data Information BV. All rights reserved.

Delays in Immunization Have Potentially SeriousHealth ConsequencesFernando A. Guerra1,2,3

1 Director of Health, San Antonio Metropolitan Health District, San Antonio, Texas, USA2 Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas, USA3 Department of Public Health, Air Force School of Aerospace Medicine, Brooks Air Force Base, San Antonio, Texas, USA

When children are not administered vaccinations according to the recommended schedule, they not only failAbstractto receive timely protection from preventable diseases at a time when they are most vulnerable, but also increasetheir risk of never fully completing the vaccination course. Both outcomes compromise a successful childhoodimmunization program. Although current data suggest that vaccination rates are near 95% for school-agedchildren in the US, the rate of timely vaccination is much lower. A number of large studies have found that themajority of children are not currently vaccinated on schedule. Moreover, immunization levels for 2- to 3-year-old children have reached a plateau.

It is essential to recognize that low overall rates of the targeted diseases mask the persistent threat they pose ifadherence to vaccination schedules declines. A delay in one vaccine will produce a domino effect if catch-upadjustments in scheduled visits are not implemented aggressively. Published reports have demonstrated thatfailure to adhere to scheduled booster immunizations, not just the initial inoculation, results in resurgence ofdisease. Children fall off the vaccination schedule for a variety of reasons. Although many studies suggest thatinadequate availability to healthcare is not a major determinant of delayed immunization, it still factors intoparental decisions. Parents should be reminded of available healthcare options. From the clinicians end,computerization of healthcare records should allow for the generation of reminders. It is vital for clinicians to beaware that there are few contraindications to vaccination. They should also be prepared to address parentalconcerns regarding the safety of vaccines and should not hesitate to use topical analgesics or distractiontechniques to facilitate inoculation.

With the anticipation of several novel vaccines being added to the childhood and adolescent immunizationschedule in the future, pediatricians face new challenges to not only provide every vaccination, but to do so in atimely manner. A lack of willingness on the part of the parent, or, occasionally, on the part of the clinician, tohave multiple vaccines administered to the child during a single visit has been shown to be a significant cause ofdelayed vaccination. Since combination vaccines reduce the number of shots that need to be administered, theuse of combination vaccines may provide the best opportunity to simplify the immunization schedule, increasingadherence in the process. Improved adherence to established schedules may present a major opportunity tofurther protect children from disease.

According to 20056 aggregate state estimates collected by the 20045 and 20034 and are the highest achieved to date for thoseNational Immunization Program, more than 95% of children enter- series of vaccines.[1,2] As vaccination rates have increased, manying kindergarten in the US were vaccinated for polio, measles, diseases, such as polio and smallpox, have been essentially elimi-mumps, rubella, diphtheria, tetanus, and pertussis.[1] These rates nated from the US.[3] Most recently, the director of the Centers fordemonstrate only an incremental climb over those reported in Disease Control and Prevention (CDC) declared that rubella, of

Marlee MorganText

144 Guerra

which only eight US cases were reported in 2006, can no longer beconsidered a major health threat in the US.[4,5]

Despite this progress, important challenges remain. In particu-lar, the cumulative rates of vaccination at school admission maskthe frequency with which delivery of one or more doses of thevaccine is delayed.[6-8] The risks posed by a significant delay,defined as 6 months, are not just theoretical. Published reports,most notably those evaluating outbreaks of pertussis, have demon-strated that failure to adhere to scheduled booster immunizations,not just the initial inoculation, results in resurgence of disease.[9-12]It is essential to recognize that low overall rates of the targeteddiseases mask the persistent threat they pose if adherence tovaccination schedules declines. Although the risks posed by spe-cific lengths of delay in vaccination are not well defined and maydiffer for different boosters in the series, improved adherence toestablished schedules may present a major opportunity to furtherprotect children from disease.

40

35

30

25

20

15

10

5

06

Under-vaccination period3 (mo)

Num

ber o

f chi

ldre

n un

der-v

accin

ated

(%)2

Total: 34.2%

Total: 28.6%

Total: 37.1%

Number of vaccines1 delayed01234

Fig. 1. Months under-vaccinated during first 24 months of life and numberof vaccines delayed. Delay begins after the end of a recommendationperiod and continues until the child is vaccinated or reaches 24 months ofage. Data from Luman et al.[17] 1 One or more doses of six vaccines:diphtheria, tetanus toxoids, and acellular pertussis; poliovirus; measles,mumps, and rubella; Haemophilus influenzae type b; hepatitis B; and vari-cella; 2 Based on weighted data; 3 During the first 24 months of life for oneor more doses of a recommended vaccine. 1. Timeliness of Vaccination: A Poor Record

The overall 2003 NIS results suggest children in the US areCumulative vaccination rates are a useful measure of the pene-under-vaccinated by a mean of 172 days for all vaccines during thetration of national immunization programs but they may be mis-first 24 months of life.[17] Among children with any delay, 52%leading for assessing protection from childhood diseases. Whetherwere under-vaccinated for at least 6 months, and 15% of all

rates are evaluated at school entry, when parents must produce anchildren were under-vaccinated for more than 12 of their first 24immunization record as part of the registration process, or atmonths.earlier timepoints, such as at age 2 years, when children are closer

to peak susceptibility for many of the infections vaccines are 2. Delayed Vaccination Poses a Major Threatdesigned to prevent, cumulative vaccination data can concealsignificant periods of no or inadequate protection. A number of There is good evidence that delays in vaccination are associatedlarge studies have found that the majority of children are not with risk. Some simulation models predict up to a 40% increase incurrently vaccinated on schedule.[13-16] cases of pertussis over 1 year when delays in delivery of the DTaP

In 2005, Luman et al.[17] published data from the 2003 National combination vaccine exceed 6 months.[19] This prediction has beenImmunization Survey (NIS), which collected information on supported by several studies of subsequent outbreaks. In one14 810 children between the ages of 24 and 35 months, and analysis of a series of pertussis outbreaks in the US in the 1990s,revealed that only 26% of children were vaccinated in a timely 54% of infants were under-vaccinated for their age.[19] In a signifi-fashion. While an additional 29% of children received all of their cant outbreak that occurred in 19934 in Chicago, 52% of casesvaccines 6 months in at least provide vaccination on time.[9] In Auckland, New Zealand, thefour of the six vaccines evaluated (hepatitis B, Haemophilus odds ratio for developing pertussis in an outbreak during 19957influenzae type b, poliovirus, varicella, the combination of diph- was increased 4.5-fold by delay in receiving any of the three dosestheria, tetanus, and acellular pertussis [DTaP], and the combina- of DTaP.[20] For a delay in the third dose alone, the odds ratio oftion of measles, mumps, and rubella), were found in 21% of those developing pertussis was increased by slightly more than 6-fold.surveyed (figure 1). While vaccination rates have been increasing Moreover, the focus on infection rates in under-vaccinated chil-in school-aged children, immunization levels for 2- to 3-year-old dren does not capture the full impact of missed or delayed immuni-children have reached a plateau at 7075%.[18] zation. For example, there is evidence that under-vaccinated older

2007 Adis Data Information BV. All rights reserved. Pediatr Drugs 2007; 9 (3)

Health Consequences of Delays in Immunization 145

siblings provide an important vector of transmission of pertussis to trated in school environments when there is a maximal opportunityinfants not yet old enough to receive the vaccine.[21] It is reasona- for disease transmission, the risks to preschool children fromble to predict that other susceptible individuals, such as those who serious sequelae of preventable diseases, including those who areare immunocompromised, are also at risk when children are under- not enrolled in daycare or another setting with close interpersonalvaccinated. contact, should not be underestimated.

In an analysis of an epidemic in measles in the US that began in The second threat from delayed immunization is supported by1989, the increase in measles cases was found to be concentrated several studies suggesting that failure to receive vaccinations onin preschool children predominantly from inner city populations schedule increases the risk of failing to ever achieve full immuni-who had not been vaccinated on schedule.[11] Failure to enforce zation.[25,28] In an evaluation of 4691 children who had missed atmeasles immunization laws for the school-aged children in this least one immunization between 15 and 24 months of age, 9%epidemic, which produced 25 000 cases and 60 deaths in 1990 went on to miss the remaining immunizations.[28] This rate ofalone, was identified as one of the contributing factors.[22] In missed immunization persisted despite subsequent opportunities20014, only 177 cases of measles were reported to the CDC, but to provide immunizations during urgent office visits, which were100 (56%) were considered preventable because they occurred in made by 53% of under-immunized children during the studycandidates for the vaccine who missed one or more doses.[23] A period. In almost 80% of cases, there was no contraindication forstudy evaluating children who received exemptions from measles immunization at the time of the urgent visit.immunizations not only demonstrated a steep increase in measles In a study evaluating why children were under-immunized at 3cases among those exempted but a substantial increase in cases months of age, defined as failure to receive DTaP, poliovirus,among non-exempted individuals.[24] H. influenzae type b, and hepatitis B vaccines on schedule, the

In a study of H. influenzae type b infections in Canada over a most significant factor was missed opportunities, such as a deci-3-year period (20013), 20 (69%) of the 29 cases occurred in sion to forego a scheduled immunization at a time when the childchildren without any vaccination or those with incomplete vacci- was ill.[29] Indeed, 85% of children had received at least one dosenation.[12] While 11 of the cases were in children too young to have of one of the vaccines, suggesting that access to appropriatecompleted the series, nine (i.e. almost half of the cases) occurred in healthcare was not a major obstacle. In an analysis of coverage forchildren with significant delays or whose parents had refused the the 4 : 3 : 1 : 3 vaccine series (four or more doses of DTaP, threeinitial or subsequent doses. or more doses of poliovirus vaccine, one or more doses of any

measles-containing vaccine, and three or more doses of H. influen-zae type b vaccine) in 1999 NIS data, missed opportunities, not3. Delayed versus Missed Vaccinationslack of access to care, was found to be the major factor for under-vaccination of non-Hispanic, African American preschoolers.[30]Vaccination schedules in childhood were developed to provide

protection over peak periods of risk and they serve as one basis forwell child check-ups. Delays in providing vaccine on schedule 4. Strict Adherence to Schedules is Criticalpose two major threats. The first is that children will not beprovided immunity when they are most vulnerable. The second is All of the currently recommended vaccines have demonstratedthat a delay in one vaccine will produce a domino effect if catch-up significant protection against the diseases at which they areadjustments in scheduled visits are not implemented aggressively, targeted, but no protection is absolute. Failure to strive for 100%extending the period at which children remain at risk for preventa- participation in recommended vaccination schedules risks exacer-ble diseases.[25,26] bating outbreaks due to both the risks of primary vaccine failure

The first threat is underscored by the fact that the peak inci- and diminished herd immunity (the indirect protection received bydences of many of the diseases for which vaccines are adminis- the un- or under-immunized segment of a population in which atered occur early in life. For example, the incidence of H. in- large proportion is immunized).[31] Achieving adequate herd im-fluenzae infection, although rare before the age of 3 months, rises munity is particularly important in a population of young childrensteeply over the first year of life, peaking between 6 and 12 who can spread disease quite easily. Both phenomena may explainmonths.[27] After 4 years, rates are relatively low. Substantial rates disease outbreaks where there have been good but suboptimalof pertussis, rubella, and varicella also occur in children under the rates of vaccination. A measles outbreak in one school in Texas,age of 3 years. Although the major risk of outbreaks is concen- USA, was documented even though only 4.2% were seronegative 2007 Adis Data Information BV. All rights reserved. Pediatr Drugs 2007; 9 (3)

146 Guerra

prior to the event.[22] It is possible that cases of disease in unvac- In a modeling study based on clinical data, it was calculated that ifcinated children overwhelmed suboptimal immunity to infection the proportion of exemptors doubled, the incidence of measlesin children who, despite seropositivity, received incomplete vacci- infection in non-exempted vaccinated individuals could increasenation. by as much as 60% depending on intergroup mixing ratios.[24]

The data suggesting that exemptors pose a health risk to chil-The risk of outbreaks from diminishing adherence to vaccina-dren compliant with immunization requirements raises thornytion schedules differs by disease. For example, the efficacy of theissues about individual rights. The same issues of responsibility tovaccine for measles, mumps, and rubella has been estimated tothe community may also be raised by failure to obtain timelyrange from 93% to 98%,[32,33] while the efficacy for the varicellavaccinations. Children who are not vaccinated on schedule notvaccine ranges from 70% to 90%.[34,35] Similarly, although onlyonly face the risks already enumerated but increase the health risksabout an 80% immunization rate is required to confer herd immu-of the community at large.nity to polio, the rate is estimated to be approximately 90% for

As diseases targeted by vaccines diminish in prevalence due tomeasles. Sophisticated mathematical models are not required tosuccessful prevention programs, it is easy to become complacentpredict that the lowest risk of disease outbreaks is achieved whenabout their potential threat. Some diseases, such as poliomyelitis,the maximum number of children receive full vaccination at thehave become sufficiently rare that clinicians know of them onlyscheduled doses. However, the number of parents who seek anthrough pictures. However, the pathogens persist in the communi-exemption from vaccination is increasing across the US.[36] Thesety, and vaccines are essential to prevent resurgence. In 2006, thechildren can serve as a reservoir for disease, and may contribute toWHO counted 1977 cases of poliomyelitis worldwide.[39] More-community outbreaks by spreading illness to those children whoover, not all of the health benefits of vaccines are adequatelyare under-vaccinated.captured in statistics. For example, children with respiratory syn-One approach to evaluating the risks posed by suboptimalcytial virus, for which there is not yet a vaccine, are likely to haveimmunization rates has been the series of studies evaluating dis-a worse outcome if simultaneously infected with another respirato-ease incidence among children exempted from immunization.[24]ry pathogen, such as H. influenzae.[40]Although all 50 states of the US require proof of immunizations

for school admission, 48 states allow religious exemptions, whichare granted for a variety of criteria.[37] These studies show that the 5. Measures to Increase On-Time Immunizationrisk of developing the diseases for which they have not been

The program of childhood immunization has already beenvaccinated increases dramatically even when exempted individu-adapted to maximize the likelihood of adherence. This includes aals form a small minority of the community in which they live. Inschedule of immunizations that coincides with well child visitsdata collected by the CDC from 1985 through 1992, those whoand the effort to use combination vaccines when possible to reducechose to be exempt from vaccination for religious or philosophicalthe number of inoculations required at each visit.[8,41] There are areasons were 35 times more likely to contract measles than vacci-variety of reasons that children fall off the vaccination schedule,nated persons.[24] Outbreaks of pertussis and rubella have alsobut it is imperative to consider both healthcare- and parent-relatedbeen recorded in religious communities opposing immuniza-obstacles to full and timely compliance.[42]tion.[37] Importantly, the risks of non-vaccination are not contained

among children who forego immunization but are passed to vacci- On the healthcare side of the equation, good methodology fornated children, another strong argument for uniform adherence to ensuring that children registered in a healthcare system, whetherrecommended vaccination schedules. A study undertaken in Colo- an office practice or managed care organization, are on schedulerado, USA, found exempted children to have a 22.2-fold increased for well child visits and scheduled immunizations is an essentialrisk of measles than vaccinated children; rates of disease were also first step.[29,43] Computerization of healthcare records may helphigher in vaccinated children than expected from national data.[38] with this task and in generating reminders when appropriate.Other studies have also projected an increased risk of preventable Clinicians should also be aware that there are few contraindica-infections in vaccinated children when exposed to unvaccinated tions to vaccination, most of which can be performed even at achildren.[24] The evidence that vaccinated children are put at risk sick visit. All office visits for children of vaccination age shouldby inadequately vaccinated children, whether due to missed oppor- be considered opportunities to review immunization records and totunities, refusal, or delays, is a critical issue for both public health provide vaccines when appropriate. Clinicians should also bepolicy and clinical decisions at the level of the individual patient. prepared to address parental concerns regarding the safety of

2007 Adis Data Information BV. All rights reserved. Pediatr Drugs 2007; 9 (3)

Health Consequences of Delays in Immunization 147

vaccines, which may encompass a broad range of issues. Clini- changing perceptions about the urgency of vaccination in a timecians should not hesitate to use topical analgesics or distraction when the incidence of many of these diseases is low. While currenttechniques to facilitate inoculation and reduce the potential psy- US data suggest that vaccination rates are near 95% for school-chologic burden of needle use for both parent and child. These aged children, the rate of timely administration of vaccines istechniques have proven to reduce the pain associated with vacci- much lower, posing its own threat to the optimal protection againstnation without affecting protective antibody levels.[44,45] The de- the morbidity and mortality of serious communicable diseases. Itvelopment of combination vaccines has had an important impact is appropriate to take satisfaction in the high overall rates ofon reducing the number of injections, a step that both reduces vaccination, but it is also essential that more be done to improveneedle use and facilitates compliance.[46] timely vaccination.

On the parental side of the equation, a wide variety of fearscontribute to delays in scheduled vaccinations or induce parents to Acknowledgmentsforego vaccinations altogether.[47] Some of the most commonly

BioCentric, Inc. provided editorial assistance. Funding for these servicesexpressed concerns regard excessive pain produced by multiplewas provided to BioCentric, Inc. by GlaxoSmithKline. The author has re-injections at the same visit, the potential for overstimulation of theceived no compensation associated with this article.

immune system, and the potential risks of immunization. A varietyof objective data are available to refute the legitimacy of these

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34. Kuter BJ, Weibel RE, Guess HA. Oka/Merck varicella vaccine in healthy children: 50. CDC. ACIP VFC vaccine resolutions [online]. Available from URL: http://final report of a 2-year efficacy study and 7-year follow-up studies. Vaccine

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35. Weibel RE, Neff BJ, Kuter BJ. Live attenuated varicella vaccine: efficacy trial inhealthy children. N Engl J Med 1984; 310: 1409-15 Correspondence: Prof. Fernando A. Guerra, 332 West Commerce, Suite 307,

36. Omer SB, Pan WK, Halsey NA, et al. Nonmedical exemptions to school immuniza- San Antonio, TX 782052489, USA.tion requirements: secular trends and association of state policies with pertussisincidence. JAMA 2006; 296: 1757-63 E-mail: fernando.guerra@sanantonio.gov

2007 Adis Data Information BV. All rights reserved. Pediatr Drugs 2007; 9 (3)