Pediatric Immunization: Meeting the Challenges of the 21st Century

	Introduction Robert B. Belshe, MD Course Chair Professor of Medicine, Pediatrics, and Molecular Microbiology St. Louis University School of Medicine St Louis, MO
	The 2009 Childhood Immunization Schedule Keith S. Reisinger, MD Medical Director Primary Physicians Research Practicing Pediatrician Pittsburgh, PA
	Safety, Efficacy, and Immunogenicity of Influenza, Rotavirus, Meningitis, and Varicella Vaccines Marguerite M. Mayers, MD Director, Pediatric Infectious Disease Clinic Children’s Hospital at Montefiore Professor of Clinical Pediatrics Albert Einstein College of Medicine New York, NY
	Improving the Quality of Immunization Care with Combination Vaccines Gary S. Marshall, MD Department of Pediatrics University of Kentucky Louisville, KY
	Practical Issues with Pediatric Vaccination Stan L. Block, MD, FAAP Professor of Clinical Pediatrics University of Louisville Professor of Clinical Pediatrics University of Kentucky President Kentucky Pediatric Research Bardstown, KY

Introduction

Childhood vaccination schedules have become increasingly complex in recent years. Combination vaccines can reduce complexity and increase coverage. However, constraints to optimal use of combination vaccines must be overcome. Other barriers to adequate vaccine coverage and timeliness include parental concerns about the need for vaccinations, as well as effectiveness and safety of vaccines. Logistic and policy issues also affect pediatric practices.

Vindico Medical Education organized a panel of experts to discuss the vaccine schedule; safety, efficacy, and immunogenicity of some important single-purpose vaccines; benefits of using combination vaccines; and practical constraints that must be acknowledged and addressed to improve immunization care quality.

I thank the panel for their contributions to the discussion and the development of this monograph, which will enhance practitioners’ understanding of this critical aspect of our children’s health care.

Robert B. Belshe, MD
Course Chair

The 2009 Childhood Immunization Schedule

Keith S. Reisinger, MD

Until the 1990s, few immunizations were recommended from birth to 6 years. These included 4 vaccinations for 8 diseases: diphtheria-pertussis-tetanus (DPT) vaccine, oral polio vaccine (OPV), and measles-mumps-rubella (MMR) vaccine. During the past 10 years, a tremendous change occurred in the number of pediatric vaccines, and because of these changes, the complexity of the immunization schedule can be overwhelming (Table 1).¹

Familiarity with current Advisory Committee on Immunization Practices (ACIP) recommendations is essential for healthcare practitioners working with children.²

Complete details about each of these vaccines are included on the CDC Web site.^2,3 Salient features are summarized here.

Hepatitis B Vaccines

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A plasma-derived hepatitis B (HepB) vaccine became available in the United States in 1981 and was discontinued in 1992 because of the advent of a recombinant vaccine that became available in 1986.³ Initially targeted to high-risk groups, the vaccine was not widely used and had little impact on the disease. A recommendation for universal childhood vaccination beginning in infancy was implemented in 1991. The HepB vaccination series is implemented while the newborn is in the hospital. If the mother is hepatitis B surface antigen (HBsAg) positive, the neonate should be given HepB immunoglobulin within 12 hours of birth.

Two HepB vaccines are available. The typical 3-dose schedule is birth, 2-, and 6-months of age. The second dose may be given as early as 1 month of age; however, the third dose should be given no earlier than 24 weeks of age. If the mother is HBsAg positive, the infant should be tested for both antigen and antibody after at least 3 vaccine doses have been given, at age 9 through 18 months. A fourth dose from combination vaccines that contain HepB administered after the birth dose is acceptable.

Rotavirus Vaccines

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Two rotavirus vaccines, both live oral vaccines, are currently licensed in the United States. RV5, the pentavalent rotavirus vaccine that received FDA approval in 2006, is a human-bovine reassortant.⁴ RV1, the monovalent rotavirus vaccine, became available in 2008 and is an attenuated G1P1A[8] virus strain.

Both vaccines underwent large phase 3 studies, with approximately 70,000 subjects for each of these vaccines. The product information sheets are based on the research protocols followed for each vaccine. For example, RV5 is a 3-dose series, and RV1 a 2-dose series (Table 2). ACIP recommendations aim to achieve harmony between the 2 vaccines when differences occur.

Although a severe allergic reaction to a previous dose is a contraindication, this vaccine is usually given with numerous other vaccines. Accordingly, it is difficult to attribute a severe allergic reaction to a specific vaccine.

Diphtheria and Tetanus Toxoids, Acellular Pertussis (DTaP) Vaccines

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Pertussis vaccines have been available since 1914, and the trivalent DPT vaccine became available in 1948. Early vaccines were fraught with local and systemic side effects and may have provided the initial impetus for the antivaccine movement. Acellular pertussis was incorporated into the vaccine (DTaP) and has been in general use for more than a decade. The 5-dose series can begin as early as age 6 weeks. However, in a pertussis outbreak it can be given as early as 4 weeks of age. Dosing typically occurs at ages 2, 4, and 6 months, with the fourth dose at 15 to 18 months, provided at least 6 months have elapsed since the third dose. The final dose should be given at age 4 to 6 years. The ACIP recommends using the same DTaP product for the entire series, but cautions against withholding vaccines if the same brand is not available or is unknown.

Haemophilus influenzae Type b (Hib) Conjugate Vaccines

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Prior to the approval in 1991 of the conjugated Hib vaccine, invasive Hib disease caused extensive morbidity and mortality in children < 5 years of age.⁵ The vaccine is currently indicated for children aged =6 weeks, with vaccinations at 2, 4, and 6 months, followed by a booster at 12 to 15 months. If polyribosyl phosphate outer membrane protein (PRP-OMP) is used, a dose at 6 months is not necessary.

A vaccine supply shortage beginning in 2007 prompted a recommendation to withhold the booster dose to conserve vaccines for the very young. The booster was recently reinstated, and it is important for practices to ensure patients receive this fourth vaccine dose.⁶ The recommendation currently states that children for whom the booster dose was deferred should receive it at the next routinely scheduled visit or medical encounter. At the time of the update, the supply was not adequate to support proactively contacting children whose booster dose was delayed.

Pneumococcal Vaccines

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The 7 valent pneumococcal conjugated vaccine (PCV7) became available in 2000, and is > 90% effective against invasive disease caused by the vaccine serotypes, with lesser effectiveness against pneumonia and acute otitis media.3 PCV7 is recommended for all children aged < 5 years, with 4 doses typically given at ages 2, 4, 6, and 12 to 15 months. However, it can be started as early as 6 weeks of age. The minimum interval between the first 3 doses is 4 weeks, and between the third and fourth dose is 8 weeks. Children aged 24 through 59 months who are not completely vaccinated should receive 1 dose. The 23-valent pneumococcal polysaccharide vaccine (PPSV23) should be administered to children aged 2 years or older with certain underlying medical conditions, including a cochlear implant. A 13-valent vaccine is nearing approval and is expected to be dosed in a similar fashion.

Polio Vaccine

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The United States has been vaccinating against polio for over 50 years, with the last case of indigenously acquired polio caused by wild type poliovirus in 1979; however, vaccine-associated paralytic polio can occur in rare instances following the use of the live, attenuated oral polio vaccines (OPV). Therefore, using only inactivated polio virus (IPV) vaccine was recommended starting in 2000, and the OPV is no longer available in the United States. The vaccine comprises a 4-dose injection series: 2, 4, and 6 to 18 months, with a 4- to 6-year booster, although the first vaccine may be administered as early as 6 weeks of age. The minimum interval between the 3rd and 4th doses is 6 months.

Influenza Vaccines

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Recent changes in influenza vaccine recommendations had a major impact on pediatric practices. Reducing morbidity and mortality from influenza no longer focuses only on protecting the elderly and people at high risk. The importance of protecting the very young is acknowledged not only because they suffer significant morbidity from influenza, but because they are often the major transmitters of the influenza virus. This major change in recommendations from infants and high-risk children to infants and toddlers, and recently to all individuals aged 6 months through 18 years, presents a major challenge for pediatricians. Achieving this goal will require partnering with schools and establishing other vaccination venues. The impact of novel H1N1 on the 2009 influenza season cannot currently be predicted. There has been rapid development of novel H1N1 vaccines in the late summer of 2009 and it is likely that there will be some availability for high-risk groups by mid to late October.

There are 2 types of influenza vaccines: trivalent inactivated vaccines (TIV) have been available for almost half a century, and the live-attenuated influenza vaccine (LAIV) was approved within the last decade. Currently, a single TIV product is approved for children aged as young as 6 months. Other TIV vaccines are available for children aged =4 years. In 2007, the LAIV was approved for an expanded indication including children aged =2 years; however, it is not indicated for asthmatics and those with recurrent wheezing. The manufacturing of influenza vaccines involves reproduction in eggs, therefore severe egg allergy is a contraindication.

Measles, Mumps, Rubella Vaccine

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Measles vaccine became available in 1963, followed by the measles-mumps-rubella (MMR) combination in 1971, with a change in antigens in the late 1970s. The single component measles vaccine is no longer manufactured in the United States. Measles was initially recommended as a 1-dose lifetime vaccine. This was changed in the early 1990s in response to a measles outbreak. The first dose should be administered between the ages of 12 and 15 months. The second dose is generally recommended at age 4 to 6 years; however, it can be given as soon as 1 month after the initial dose.

Varicella Vaccine

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Varicella vaccine was approved in 1995 after more than a decade of research. It was originally recommended as 1 dose given between the ages of 12 months and 12 years; however, since 2005 two doses have been recommended, with the first dose given between 12 and 15 months and the second at age 4 to 6 years.⁷ The second dose may be administered before age 4; however, at least 3 months must have elapsed since the first dose. For children aged 12 months through 12 years, the minimum interval between doses is 3 months, although if the second dose was administered at least 28 days after the first dose it is accepted as valid.

Hepatitis A Vaccines

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The 2 hepatitis A (HepA) vaccines were approved in 1995 and 1996. Although hepatitis A in the very young is a generally mild disease and is often unrecognized, this age group is the major transmitter of the disease. Initially, HepA immunization was recommended for high-risk individuals. This had no effect, mainly because it was poorly implemented. Subsequently, HepA vaccine was targeted for states that experienced a significant increase in disease incidence. After a dramatic decline was noticed, the ACIP recommended HepA immunization for all children aged 12 through 23 months, with catch-up for children aged >2 years. HepA vaccination is also recommended for children aged >1 year who live in areas where vaccination programs target older children, or who are at increased risk of infection. The vaccination follows a 2-dose schedule, with 6 to 18 months between doses.

Meningococcal Vaccines

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Meningococcal conjugate vaccine is indicated for children aged 2 to 10 years with high-risk conditions such as terminal complement deficiency and asplenia. The meningococcal polysaccharide vaccine should only be used if the conjugate product is unavailable. Individuals who received the polysaccharide vaccine 3 or more years previously who remain in a high-risk group should be revaccinated with the conjugate vaccine.

Final Words of Advice

The importance of proper storage of vaccine products cannot be overemphasized. Each office should have a person responsible for assuring vaccines are stored at the proper temperature, and that refrigerator temperatures are monitored and remain in the recommended range.

ACIP recommendations are formulated to provide optimal protection against vaccine-preventable diseases. The schedules represent a mixture of biology, logistics, and practicality. Although marketing messages must adhere to labeling information, ACIP recommendations that deviate from the label should be followed.

References

1. CDC. 2009 Child and adolescent immunization schedules. Vaccines and Immunizations. Available at: http://www.cdc.gov/vaccines/recs/schedules/child-schedule.htm.
2. CDC. ACIP recommendations. Vaccines and Immunizations. Available at: http://www.cdc.gov/vaccines/pubs/ACIP-list.htm.
3. CDC. Epidemiology and prevention of vaccine preventable diseases. 11th Edition, 2009. Available at: http://www.cdc.gov/vaccines/pubs/pinkbook/pink-chapters.htm.
4. CDC. Vaccine-preventable diseases: Rotavirus vaccination. Vaccines and Immunizations. Available at: http://www.cdc.gov/vaccines/vpd-vac/rotavirus/default.htm.
5. CDC. Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older recommendations of the ACIP. MMWR. 1991; 40(RR-1): 1-7.
6. CDC. Updated recommendations for use of Haemophilus influenzae type b (Hib) vaccine: Reinstatement of the booster dose at ages 12 -15 months. MMWR. 2009; 58(24): 673-674.
7. CDC. Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2007; 56(RR-4): 1-40.

Safety, Efficacy, and Immunogenicity of Influenza, Rotavirus, Meningitis, and Varicella Vaccines

Marguerite M. Mayers, MD

Safety, efficacy, and immunogenicity are essential characteristics of all vaccines. Safety concerns relate to adverse events following administration, vaccine failure, and administration errors. Efficacy is related to immunogenicity and it defines the ability of the administered vaccine to prevent the disease or condition that it was designed to prevent. Immunogenicity is the measured host response to the antigen presented, which should correlate with protection against the targeted disease.

General Vaccine Safety

All vaccines licensed by the FDA are safe and effective. Public concern about vaccine safety emanates from 4 sources:

• Diseases vaccines protect against are no longer common, and the public may not be aware that widespread vaccine coverage has caused this reduction.
• There is a lack of trust in large organizations, especially the medical establishment, and a loss of connection/trust with public health programs in spite of the fact that the public identifies the physician as its most trusted source of vaccine information.
• The media focuses on rare side effects rather than protective benefits.
• The Internet, unfiltered and without critical examination, may be a major source of misinformation.

Vaccines or their ingredients have been spuriously linked to serious diseases like autism and mercury poisoning. These misconceptions have led to delayed immunization or suboptimal immunization rates with subsequent disease outbreaks. Expected side effects of vaccines are minor. Although they very rarely may be life-threatening (eg, anaphylaxis), risks should be weighed against the benefit to the individual and society.

Accurate and understandable discussions with parents should supplement the vaccine safety information sheets (VIS) mandated by the government to accompany each vaccine. It should be emphasized that temporal association of an event with a vaccine does not prove causality, and parents should be told that effective systems are in place to examine adverse outcomes and to determine if causality actually exists.

Side effect monitoring systems include prelicensure clinical trials, postlicensure epidemiologic studies designed to pick up rare events, and the Vaccine Adverse Event Reporting System (VAERS), which is a passive surveillance system that accepts reports of side effects after administration of the vaccine, vaccine failure, or vaccine administration errors.¹

In addition, the Vaccine Safety Datalink (VSD) provides active surveillance through a collaboration between the CDC and several large HMOs, actively mining their large medical databank for vaccine administration data and possible adverse outcomes.² An advantage of this collaboration is the known population denominator in the database which allows the calculation of incidence rates.

The Clinical Immunization Safety Assessment Network, which is a collaboration of the CDC and academic centers, endeavors to enhance scientific understanding of adverse events and to provide evidence-based recommendations to clinicians.³ The network’s mission is to conduct clinical research on adverse events, provide clinicians with an evidence base with which to make informed decisions, assist in developing exclusion criteria for at-risk individuals, and ultimately to enhance public confidence in vaccination programs.

The 15-member Immunization Safety Review Committee of the National Academy of Science Institute of Medicine was commissioned by the CDC and NIH to provide independent advice to vaccine policymakers, and to specifically address causality between a vaccine and specific side effects.⁴

Finally, the Brighton Collaboration is an international organization that develops guidelines to facilitate sharing and comparing of data among vaccine safety professionals.⁵

Seasonal Influenza

Annual influenza vaccination is necessary to accommodate global antigenic drift of the virus. A trivalent inactivated vaccine (TIV) and a live-attenuated influenza vaccine (LAIV) are available, both of which are effective, with efficacy estimates of 50% to 95% depending on the match between the vaccine strain and the circulating virus. A randomized controlled study comparing the 2 vaccines in children aged 6 through 59 months during the 2004-2005 influenza season demonstrated 55% fewer cases of influenza confirmed by culture in the LAIV group compared with the TIV group.⁶ In addition, compared with the TIV group, efficacy in the LAIV group was higher in those exposed to either a vaccine-matched or antigenically drifted virus.

VSD data from 215,600 children aged < 18 years which included 8,476 children aged 6 to 23 months revealed there was no increase in biologically plausible, medically attended events during 2 weeks after TIV vaccination compared with control periods 3 to 4 weeks before and after vaccination.⁷ Premarketing LAIV studies revealed < 1% of serious side effects in both children aged 5 to 17 years and adults. In subsequent studies, >2.5 million individuals were vaccinated with no new safety concerns.

The randomized controlled trial comparing TIV with LAIV excluded those with medically diagnosed or treated wheezing in the previous 42 days and those with a history of severe asthma.⁶ Overall, medically significant wheezing was similar between the 2 groups, although wheezing in children aged < 2 years was observed more frequently in the LAIV group compared with the TIV group. The difference was primarily due to an increased incidence in children aged < 12 months.⁶

The development of Guillain Barré syndrome (GBS) within 6 weeks of a dose of influenza vaccination is a precaution to further doses according to the Advisory Committee on Immunization Practices (ACIP).⁸ The LAIV prescribing information cautions that if GBS occurred with any prior influenza vaccination,⁹ a decision to give the vaccine should be based on careful consideration of the potential benefits and risks. As warranted, antiviral prophylaxis may be provided.

Rotavirus

Rotavirus vaccines provide an example of the VAERS at work. The first rotavirus vaccine (RotaShield; Wyeth) was licensed and recommended for routine use by the ACIP in the late 1990s, after prelicensing studies in approximately 12,000 infants. There were 5 cases of intussusception in vaccinated infants compared with 1 case in the placebo group, which was not statistically significant. Diligent postmarketing surveillance through the VAERS system revealed an association between the vaccine and intussusception, prompting a case-control study that documented a significant increase in intussusception in vaccinated infants, resulting in withdrawal of the vaccine from the market. The attributable risk of intussusception was one in 11,000 doses, which explained its lack of statistical significance in pre-licensure trials.

The two rotavirus vaccines licensed currently, RV5 (RotaTeq, Merck), licensed in 2006, and RV1 (Rotarix, GlaxoSmithKline) licensed in 2008, received more extensive preclinical testing, involving more than 70,000 infants for each vaccine with no risk of intussusception demonstrated.^10,11 More than 14 million doses of RV5 have been administered postlicensure, and there is no additional risk of intussusception up to 42 days post-vaccination. Postlicensure monitoring of RV1 is also underway.

The vaccines are 74% to 87% effective against any rotavirus diarrhea, and 85% to 98% effective against severe rotavirus diarrhea. Post-licensure surveillance of these vaccines continues to supports this effectiveness.

Meningococcal Meningitis

Polysaccharide Vaccine

MPSV4 was licensed in 1978 and is formulated to induce protection against meningococcus A, C, Y, and W-135.¹² Multiple doses may cause tolerance to the A and C polysaccharide, and these antibody titers decrease substantially during the first 3 years following a single dose of vaccine.

This vaccine has an excellent safety profile. Thirty-eight side effects were reported through VAERS after >4.5 million doses, with more than half occurring with contemporaneous administration of other vaccines. Four cases of GBS in adults and one case in a child have been reported after receipt of meningococcal polysaccharide vaccine.

Conjugate vaccine.

The quadrivalent conjugate vaccine, MCV4, protects against the same serotypes as MPSV4. It was licensed in 2005 for patients aged 11 through 55 years and received approval of an expanded indication in 2007 to include children aged 2 to 10 years with underlying conditions which predispose them to invasive meningococcal disease. Approval of the vaccine was based on serum bacterial antibody response, which was noninferior to that produced by the polysaccharide vaccine. Conjugate vaccines are preferred over polysaccharide vaccines because their T-cell-dependent response is stronger in infants and children, priming immunologic memory that allows a booster response when subsequent doses are given. Accordingly, the conjugate vaccine is expected to provide longer protection than the polysaccharide vaccine. MCV4 is the vaccine of choice for all vaccine candidates in the indicated age range.¹³

MCV4 and other newly approved vaccines including two tetanus-diphtheria-pertussis (Tdap) vaccines, (both approved in 2005) and HPV (Gardasil, Merck, approved June 2006) increase syncope in adolescents. According to VAERS, fainting in the adolescent population has more than doubled since the approval of these 3 vaccines. The current recommendation, therefore, is for those who are vaccinated to be observed (sitting or lying down as appropriate) for 15 minutes after receiving the vaccine.¹⁴

Another safety concern in the postlicensure period was a possible increased risk of GBS in the first 6 weeks after vaccination.¹⁵ Subsequent evaluation after 15 million doses revealed only 24 cases of GBS in adolescents aged 11 to 19 years.¹⁶ There was a suggestion of a small but not statistically significant increase over background rate of this rare disease.

In addition to the VAERS and VSD systems, a postlicensure case-control study of GBS after MCV4 is in progress. Attempting to correlate a disease with a very low prevalence (1/100,000 person-years) to a discrete 6-week time window after MCV4 vaccination requires an extremely large sample. Data from 4.5 million adolescents aged 11 to 18 years revealed that none of the 26 confirmed cases of GBS had received MCV4 or other vaccinations within 42-days.¹⁷ These data suggest the incidence of GBS is not greater in vaccinated compared with unvaccinated adolescents. The current recommendation is to continue to monitor and vaccinate.

Varicella

After licensure in 1995, the varicella vaccine was indicated as 1 dose in children aged 12 months to 12 years, with 2 doses for those aged =13 years. One dose protected 70% to 90% of children against any disease and 95% against severe disease. Although vaccine uptake was initially slow, by the year 2000 coverage was about 85% throughout the country. Starting in the early 2000s, however, breakthrough disease caused by wild-type varicella was observed. Those at greatest risk were vaccinated at a younger age or were further postvaccination. Although most cases were mild, 30% had moderate (50 to 250 lesions) to severe (>500 lesions, hospitalization, or complications) illness, and there were two deaths. Children with mild disease, which often went unrecognized, were contagious and presented a major infection-control risk.

Therefore, the ACIP expanded its recommendation in 2005 and 2006 to a 2-dose schedule with the first being given at age 12 to 18 months and the second at age 4 to 6 years. The second dose provides a >10-fold increase in geometric mean antibody titer, which correlates with protection. A catch-up dose was recommended for all others.¹⁸

Side effects are typically mild and transient. There may be minor pain and redness at the injection site, where after approximately 21 days a rash may occur. A disseminated rash within the first two weeks is usually due to the individual’s acquisition of wild-type varicella and not a side effect of the vaccine. Fever can occur for up to 42 days postvaccination.

Combination Vaccine: MMRV

By adding varicella to the measles-mumps-rubella (MMR) vaccine, the MMR-varicella (MMRV) vaccine was developed to reduce the number of needle sticks in the routine vaccine schedule. In addition, the risk of breakthrough varicella was 2.5-fold increased in those who were vaccinated with varicella < 30 days after receiving the MMR vaccine; while there was no increased risk if the varicella vaccine was given with or >30 days after MMR.¹⁹

Prelicensing studies of MMRV showed that combining the 2 vaccines at standard doses did not produce an adequate antibody response for varicella. Therefore, the vaccine was reformulated with more antigen. The vaccine was licensed in 2005 for children aged 12 months through 12 years, with the first dose recommended at age 12 to 15 months, and the second at 5 to 6 years.

In the initial 2007 recommendation regarding the vaccine, the ACIP supported the combination vaccine over the individual components. Overall, rates of fever during the 42 days following MMRV vaccination in 480 children aged 12 to 23 months were not increased compared with those when the two vaccines were given separately. However, 5 to 12 days postvaccination, there was a significantly increased incidence of fever in children receiving MMRV compared with those receiving separate MMR and varicella vaccines (27.7% vs. 18.7%, P =.034), and more measles-like rash in those who received the MMRV vaccine.²⁰

VSD data were accessed to investigate further a causative association between febrile seizures and the MMRV vaccine. At 7 to 10 days postvaccination, there were 9 febrile seizures per 10,000 vaccinations in the 43,353 children in the MMRV group, compared with 4 per 10,000 in the 314,599 children vaccinated separately, with an adjusted odds ratio of 2.3 (P< .0001; 95% CI 1.6-3.2) for chart-verified febrile seizures.²¹ Despite this, the 30- and 42-day febrile seizure rates were not different between groups, suggesting a seizure event that was destined to occur in this age group may have been precipitated by the vaccine, rather than being a case of a true vaccine-induced febrile seizure.^22-24 However, based on the 7 to 10-day data, the ACIP reversed its recommendation in 2008 and no longer expresses a preference for the MMRV over separate vaccines.²⁵

References

1. CDC. Vaccine Adverse Event Reporting System (VAERS). Vaccine Safety. Available at: http://www.cdc.gov/vaccinesafety/vaers.
2. CDC. Vaccine Safety Datalink (VSD) Project. Vaccine Safety. Available at: http://www.cdc.gov/vaccinesafety/vsd.
3. CDC. Clinical Immunization Safety Assessment (CISA) network. Vaccine Safety. Available at: http://cdc.gov/vaccinesafety/cisa/.
4. Institute of Medicine of the National Academies. Immunization safety review. Available at: http://www.iom.edu/?id=4705&redirect=0.
5. The Brighton Collaboration. Setting standards in vaccine safety. Available at: http://www.brightoncollaboration.org/internet/en/index.html.
6. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007; 356(7): 685-696.
7. France EK, Glanz JM, Xu S, et al. Safety of the trivalent inactivated influenza vaccine among children: A population-based study. Arch Pediatr Adolesc Med. 2004; 158(11): 1031-1036.
8. CDC. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2008; 57(RR-7): 1-60.
9. Flumist [package insert]. Gaithersburg, MD: MedImmune Vaccines, Inc; 2008.
10. Committee on Infectious Diseases. Policy statement prevention of rotavirus disease: Updated guidelines for use of rotavirus vaccine. Pediatrics. 2009; 123(5): 1412-1420.
11. Haber P, Patel M, Izurieta HS, et al. Postlicensure monitoring of intussusception after RotaTeq vaccination in the United States, February 1, 2006, to September 25, 2007. Pediatrics. 2008;121(6): 1206-1212.
12. CDC. Epidemiology and prevention of vaccine preventable diseases. Vaccines and Immunizations. 11th Edition, 2009 May. Available at: http://www.cdc.gov/vaccines/pubs/pinkbook/pink-chapters.htm.
13. CDC. Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2005; 54(RR-7): 1-21.
14. CDC. Syncope after vaccination - United States, January 2005-July 2007. MMWR. 2008; 57(17): 457-460.
15. CDC. Update: Guillain Barré syndrome among recipients of menactra meningococcal conjugate vaccine - United States, June 2005-September 2006. MMWR. 2006; 55(41): 1120-1124.
16. CDC. GBS and menactra meningococcal vaccine. Vaccine Safety. Available at: http://www.cdc.gov/vaccinesafety/updates/gbsfactsheet.htm.
17. Baker C. IN: ACIP Summary Report, February 25-26, 2009. Atlanta, GA. Available at: http://www.cdc.gov/vaccines/recs/acip/downloads/min-feb09.pdf.
18. CDC. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP) 2007. MMWR. 2007; 56(RR-6): 1-54.
19. Centers for Disease Control and Prevention. Simultaneous administration of varicella vaccine and other recommended childhood vaccines - United States, 1995-1999. MMWR. 2001; 50(47): 1058-1061.
20. Shinefield H, Black S, Digilio L, et al. Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr Infect Dis J. 2005; 24(8): 665-669.
21. CDC. Update: Recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR. 2008; 57(10): 258-260.
22. Food and Drug Administration. Measles, mumps, rubella and varicella virus vaccine live. Vaccines, Blood & Biologics. 2009. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/QuestionsaboutVaccines/ucm070425.htm.
23. Kulldorff M. Sequential Analyses for Drug and Vaccine Safety Surveillance. Available at: http://www.matstat.umu.se/aktuellt/vinterkonf/v-konf-08/No%203%20MKmaxSPRTBorgafj%E4ll2008.ppt.
24. Rhorer J, Ambrose CS, Dickinson S, et al. Efficacy of live attenuated influenza vaccine in children: A meta-analysis of nine randomized clinical trials. Vaccine. 2009; 27(7): 1101-1110.
25. CDC. Update: Recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR. 2008; 57(10): 258-260.

Improving the Quality of Immunization Care with Combination Vaccines

Gary S. Marshall, MD

The childhood vaccination schedule has undergone dramatic changes. The current schedule (ages 0-6 years) includes 11 separate vaccines, and its complexity places two quality measures at risk: coverage rates and timeliness. Combination vaccines provide a solution to this problem, allowing an improvement in the quality of immunization care.

Coverage Rates and Timeliness

Coverage status of some vaccines meets established goals; for example, nearly 100% of children have =3 DTaP vaccinations (Figure 1).^1,2 With each vaccine addition, however, coverage rates decrease, such that 30% of children are not getting all the vaccines they should by age 2 years.

In addition to deficits in coverage, National Immunization Survey (NIS) data from nearly 15,000 children revealed that 74% experienced a delay in getting at least one vaccine, of whom 37% were severely delayed (cumulatively delayed more than 6 months). Twenty-three percent of children considered fully covered through age 2 years were severely delayed. These delays result in children being undervaccinated despite being covered.

It is increasingly difficult to get parental consent with each increase in the number of vaccinations.³ In addition, many pediatricians and staff members do not believe more than four shots should be given in one visit, although no limit is imposed by the American Academy of Pediatrics (AAP) or the Advisory Committee on Immunization Practices (ACIP).

Not all doses due were administered at 37% of 2,224 vaccination visits between the ages of 2 and 8 months, with a strong correlation between percent with a deferral and number of vaccine doses due.4 When three or fewer, four, or five vaccine doses were due, 26%, 34%, and 48% of doses, respectively, were deferred (P< .001).

Therefore, deferrals ultimately lead to lower coverage rates and potentially bad outcomes. In addition to increased risk of disease and outbreaks, administrative and programmatic costs are increased for assessing, tracking, and rescheduling deferred doses.

Combination Vaccines

If complexity is reduced with combination vaccines, fewer doses may be deferred and improved coverage and timeliness may result. There are several additional benefits from using combination vaccines:

• Decreased number of injections
• Decreased pain
• Decreased anxiety
• Decreased injection risks to patient
• Decreased visits
• Simplified schedule
• Increased vaccine compliance
• More efficient well-child visits
• Easier introduction of new vaccines
• Freed space for new vaccines
• Decreased preparation time
• Reduced sharps injury potential
• Decreased administration costs and overhead
• Decreased vaccine wastage
• Easier storage
• Improved record keeping and tracking
• Better inventory management
• More efficient federal documentation
• Increased billing efficiency

These benefits led the AAP and ACIP to state in 1999 that the “… use of combination vaccines is preferred over separate injection of their equivalent component vaccines.”⁵ Combinations such as DTaP have been available for several years, and since 1996, 7 additional combination vaccines have been licensed for pediatric immunization in the United States (Table 1).

Combination vaccines must be formulated to provide at least equivalent protection and safety compared with the vaccines for the individual diseases. There are potential in vivo interactions after combining antigens; therefore, the components may be present in amounts different from those in individual vaccines. For example, the MMRV vaccine includes a higher titer of both varicella and mumps virus compared with separate MMR and varicella vaccines. This may be why there is increased fever following immunization with MMRV compared with MMR plus varicella. Increased antigen was necessary to overcome the interference between the viruses as they replicated at the injection site.⁶ Additional physical and chemical interactions that can occur include competition for antigen presentation and carrier-induced epitopic suppression.

No major reactogenicity issues have been experienced with any of the combination vaccines. Although low-grade fevers may occur when DTaP-HepB-IPV is given concomitantly with pneumococcal conjugate vaccine (PCV7), medical intervention is usually not required.

The high valency combination of DTaP-HepB-IPV allows reducing shots by 5. If the birth dose of HepB is followed by DTaP-HepB-IPV vaccine at age 2, 4, and 6 months, the extra dose of HepB is not a safety issue, nor is it affected by Vaccines for Children (VFC) program policies.

DTaP-Hib-IPV vaccine use reduces total shots by 6 or 7, based on whether 3- or 4- doses of Hib were previously used. Even though a child who receives DTaP-Hib-IPV in 4 consecutive doses by 18 months of age has received 4 doses of IPV, a final dose at 4–6 years of age is recommended.

The Effect of Combination Vaccines on Coverage and Timeliness

A 2006 German study reviewed the number of children who were on time for full immunization with Hib, polio, and hepatitis B as vaccines increased in valency.⁷ The investigators reported that monovalent vaccines were followed initially by DTaP-Hib, then DTaP-Hib-IPV, and finally the single-shot hexavalent vaccine DTaP-Hib-IPV-HepB. On-time immunization coverage increased with each increase in antigens available as a combination vaccine.

In the United States, an initial study of more than 18,000 Medicaid recipients compared outcomes in children who received combination HepB-Hib or DTaP-HepB-IPV (n=16,007) vaccines with children not exposed to combination vaccines (n=2,814).⁸ Multivariate analysis adjusting for confounders such as gender, birth quarter, provider quality, and race revealed that the odds of being covered for DTaP, IPV, and vaccine series (4:3:1 [4 DTaP, 3 IPV, 1 MMR], 4:3:1:3:1 [4:3:1, 3 Hib, 1 varicella], 3:3:3 [3 DTaP, 3 IPV, 3 Hib]) by age 2 years were better for children in the combination vaccine cohort compared with the reference cohort.

A second study investigated the impact of DTaP-HepB-IPV vaccine on coverage in a managed care population.⁹ Matching 865 eligible vaccinated children with unvaccinated children controlled for confounders, coverage rates were significantly higher in the combination cohort compared with the matched reference controls (P?.002). Similarly, on-time rates were significantly higher for HepB and IPV in the combination vaccine cohort (P=.001).

Another Medicaid study evaluated 2,380 children who were fully exposed to the combination DTaP-HepB-IPV vaccine compared with 2,672 children who were fully exposed to DTaP but not the combination vaccine.¹⁰ Results were consistent with the other studies: unadjusted coverage rates were significantly better in children exposed to 3 doses of the combination vaccine vs. three doses of the monovalent vaccine (P=.0006). On-time rates were also significantly better, and there were fewer cumulative days undervaccinated in the combination cohort (P=.0017).

In summary, recommended vaccinations for children follow a complex schedule, which can be simplified by using combination vaccines. This can result in fewer deferred doses, improved timeliness and coverage, and hopefully better outcomes.

References

1. CDC. National, state, and urban area vaccination levels among children aged 19-35 months - United States, 2002. MMWR. 2003; 52(31): 728-732.
2. CDC. National, state, and local area vaccination coverage among children aged 19-35 months -United States, 2007. MMWR. 2008; 57(35): 961-966.
3. Meyerhoff A, Jacobs RJ, Greenberg DP, Yagoda B, Castles CG. Clinician satisfaction with vaccination visits and the role of multiple injections, results from the COVISE study (Combination Vaccines Impact on Satisfaction and Epidemiology). Clin Pediatr. 2004; 43(1): 87-93.
4. Meyerhoff AS, Jacobs RJ. Do too many shots due lead to missed vaccination opportunities? Does it matter? Prev Med. 2005 Aug; 41(2): 540-544.
5. American Academy of Pediatrics. Combination vaccines for childhood immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). Pediatrics. 1999; 103(5): 1064-1077.
6. CDC. Update: Recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR. 2008; 57(10): 258-260.
7. Kalies H, Grote V, Verstraeten T, Hessel L, Schmitt HJ, von Kries R. The use of combination vaccines has improved timeliness of vaccination in children. Pediatr Infect Dis J. 2006; 25(6): 507-512.
8. Marshall GS, Happe LE, Lunacsek OE, et al. Use of combination vaccines is associated with improved coverage rates. Pediatr Infect Dis J. 2007; 26(6): 496-500.
9. Happe LE, Lunacsek OE, Marshall GS, Lewis T, Spencer S. Combination vaccine use and vaccination quality in a managed care population. Am J Manag Care. 2007; 13(9): 506-512.
10. Happe LE, Lunacsek OE, Kruzikas DT, Marshall GS. Impact of a pentavalent combination vaccine on immunization timeliness in a state Medicaid population. Pediatr Infect Dis J. 2009; 28(2): 98-101.
11. National Conference of State Legislatures. Immunizations. April 2009. Available at:http://www.ncsl.org/IssuesResearch/Health/ImmunizationsPolicyIssuesOverview/tabid/14383/Default.aspx.

Practical Issues with Pediatric Vaccination

Stan L. Block, MD, FAAP

Several criteria must be fulfilled for parents to accept a vaccine for their child.^1,2 The most critical factor is vaccine effectiveness. Another key issue is the durability of the protection, particularly with regard to meningococcal and the quadrivalent human papillomavirus (HPV4) vaccines. Parents want to know how long protection lasts, and if and when a booster dose is needed. In addition, the disease must be considered severe enough to warrant giving the vaccine. The varicella vaccine was met with resistance by parents who thought chickenpox was not worth immunizing against because the disease is perceived as minor. Parents are concerned about side effects, and may believe vaccines cause major adverse effects such as fever, syncope, febrile seizures, thrombophlebitis, Guillain Barré syndrome (GBS), encephalitis, and autism. In addition to providing accurate responses to these concerns, physician recommendation is critical. If the physician is not an advocate, vaccine acceptance will suffer measurably.

Practitioner Barriers to Immunization

Office time is required to explain the importance of the vaccines, the disease, how it can affect their child, and side effects. With 10 to 12 minutes to do a full exam, to discuss the health situations that brought the child to the office, and to complete the components of a well-child visit, time is usually not available to discuss all of the vaccine issues for many children.

Calculation of vaccine supplies needed and the inventory management necessary to avoid both waste and lack of availability can affect profitability if predictions are not accurate. When transitioning to combination vaccines, using extant supplies of individual doses may delay introducing the combination as standard practice. This comprises an ethical issue if a less desirable regimen is chosen to ensure efficient inventory usage.

Inconsistent insurance policies can affect immunization practices. If each vaccine and each administration constitute reimbursable charges, combination vaccines may produce a disincentive. In a recent survey, more than one-fifth of practitioners did not adopt combination vaccines because of inadequate reimbursement.³ A survey of 355 pediatricians, with respect to practice revenue related to use of DTaP-Hib-IPV combination vaccine, revealed that < 1% expected a significant decrease, while 11% expect a moderate decrease.⁴ Reduced administrative and nursing time required with combination vaccines may compensate for reimbursement disadvantages when using component vaccines.

Parental Barriers to Immunization

Parental barriers to immunization range from access to attitudes.^5-7 Rural and inner city areas often have inadequate or inopportune access to vaccination clinics or practitioners. Parents frequently have misconceptions about disease severity, especially rotavirus and chickenpox. Office staff must counteract Internet myths, although informed consent forms can be discouraging when nearly all vaccine information sheets “disclose” that most standard vaccines can cause death, and other severe events such as brain damage or GBS.

The most controversial vaccines to parents are usually influenza, HPV4, meningococcal conjugate vaccine (MCV4), and diphtheria/tetanus toxoids/acellular pertussis (DTaP). Responding to concerns can require substantial practitioner and office staff time. The HPV4 vaccine may be rejected by parents who believe their child is still too young for the vaccine, even though it is indicated for girls as young as 9 years of age and the Advisory Committee on Immunization Practices (ACIP) recommended vaccine age is 11 to 12 years. Vaccine safety concerns also include fears that the vaccine may cause the very disease that it was intended to protect against. Practitioners must allay parents’ fears and, if possible, emphasize that their own children receive the same vaccines.

Practitioners must often judge whether the child or teen to be vaccinated is too ill to receive the vaccine. It can be challenging to explain that a vaccine may still be administered to a child having a low grade fever or sore throat. Practitioners may exercise too much caution and not vaccinate a child with an upper respiratory tract infection (URI) or a minor illness of any sort. Vaccine contraindications which include egg allergy require that the practitioner accurately determine if the child truly does have an egg allergy by asking the parents, for example, if their child can uneventfully eat cake or pancakes.

Secrets to In-office Vaccination Success

Physicians must be convinced that the disease is common enough, significant enough, and transmissible enough to warrant vaccination. They must be convinced that the vaccine is effective, safe, economical, and reimbursable. Parents must know that the vaccine is acceptable to the practitioner. Anticipate and counteract objections with appropriate and accurate information in layman’s terms.

Physicians are the primary as well as the most trustworthy source for vaccine information (Figure 1).⁸ Nurses and pharmacists rank second and third in trustworthiness.

Aids to Achieve Vaccination Goals: Private Practice Model

The office should have a response plan both for children who do not receive vaccinations and for children who receive delayed vaccinations. Some parents do not want any vaccines for their children, and others believe the schedule should be delayed until their baby is older. The office should be prepared for these parents and have a standard policy regarding their treatment and place in the practice. Medico-legally, the clinician must document at each visit the vaccine discussion. VIS sheets should be given, and parents must be made aware of all the morbidities and possible mortality that the vaccine would prevent.

During every office visit, it is essential to check if vaccinations are up-to-date. Staff members dedicated to this task can greatly improve vaccination success rates. This is particularly valuable for sick visits. Physicians often do not have or take time to check. When a child is in for a well-child visit, charts are scrutinized and vaccination requirements should be known. Although nurses and other office staff can be proactive in determining vaccination status at all office visits, delegating screening does not totally relieve the physician obligation to be diligent.

Electronic medical record (EMR) pop-ups can assist coverage. EMR pop-ups can alert whether a child needs a particular vaccine. The “Televox” phone appointment reminder can also inform when vaccines are due or when the flu vaccine is available. More traditional reminders are still effective, such as reminders on bills and at check-in, especially for seasonal vaccines like influenza.

Examination room pamphlets are valuable, particularly for the more complex vaccines, such as HPV4 or meningococcal. Office posters can also be helpful, particularly for seasonal influenza vaccination.

Vaccine Challenges: Four Stages

Stage One: Infant primary series. Safety is a major concern for parents bringing infants to the office for their primary immunization series. They are worried about autism, thimerosal, and that the immunization causes the disease it is supposed to be protecting against. The physician must allay those fears, especially for first-time parents. Combination vaccinations can relieve much of the stress about the number of shots, for example by allowing their baby to get 2 instead of 4 shots. There is a slight increase in office cost for combination vs. component vaccines.

Stage Two: The toddler stage. Delayed vaccines during this stage are often due to parental forgetfulness. Safety concerns also affect parents during this stage. Parents of a child aged 12 months who is due for the measles-mumps-rubella vaccine (MMR) may especially be concerned about autism in light of all of the media coverage and misinformation. Deciding to use the MMR-varicella (MMRV) combination is an issue for practitioners more than it is for the parents. The absolute rate of febrile seizures within 30 days is the same whether one uses separate MMR and varicella vs. MMRV. Physicians should implement routine hepatitis A vaccines. The toddler’s response to and memory of the pain of vaccination may affect their acceptance of a simple ear or chest examination on the next several visits.

Stage Three: Preschool immunizations. The 3 or 4 shots given at the preschool well visit can be reduced to 2 by using combination vaccines. Giving the second dose of MMR and/or varicella vaccines at any time 3 months after the 12 to 15 months dose rather than waiting until this stage may be considered.

Stage Four: Adolescent vaccines. This stage comprises 3 subcategories. The first category comprises children aged 11 and 12 years. Vaccines can be given with the routine school physical exam. Tetanus booster at this age is a school requirement. Substituting tetanus/diphtheria/acellular pertussis (Tdap) is more prudent. MCV4 is highly recommended and is often a precollege requisite, and should thus be administered with other adolescent vaccines to boys and girls. Girls also should receive the HPV4 vaccine series. Assuring that girls get the 2 additional booster HPV4 doses can be a challenge. The second category includes those aged =12 years who need catch-up vaccinations. The third category covers older individuals who come in for either preventive or nonpreventive care visits. Preventive care visits include a focus on vaccine needs. However, it is important to take advantage of nonpreventive care visits, which can be an ideal time to catch up on the occasional skipped or missed vaccinations. Nursing staff can prepare the adolescents to expect a vaccination at this visit if needed. Be diligent in recommending Tdap vaccines for postpartum mothers.

The lack of mandated well visits during the teenage years can be a barrier to immunizing adolescents.⁹ However, additional opportunities may be missed when providers simply forget to vaccinate when adolescents are in the office. Providers may misunderstand vaccine contraindications. Adolescent transportation can also be a problem. Once the adolescent reaches age 19 years, they often do not have insurance coverage unless they attend college. Immunization registries would be valuable for tracking adolescent vaccinations; but they are rare in this age group.

Families often have little motivation to get adolescents vaccinated, and they underestimate the risks posed by vaccine-preventable diseases. Many states do not require adolescent immunizations, despite data showing that mandated vaccines achieve a very high uptake.

Vaccine safety is a concern for the adolescents as well as the parents. “Needle phobia” is common, whereby adolescents will refuse to be vaccinated because they “hate shots.”

Adolescent vaccination uptake can be improved by assuring the family has a doctor that they visit regularly to serve as a “base.” This greatly facilitates tracking. On the other hand, being told the vaccine was received elsewhere requires verification that may result in immunization delays. Mandating physicals with concomitant vaccination can improve coverage. The female contraceptive exam is an ideal time to vaccinate girls who missed any vaccines.

Insurance companies may not provide 100% coverage, or may not cover some vaccines at all. Parents may object to using Health Savings Account funds (with their high deductibles) for vaccines.

In-school vaccination can help, although it also creates fragmented care. Without a registry, it can be difficult to verify which vaccines were actually given.

Adolescent In-office dilemmas

• Parental permission logistics can be time-consuming and frustrating. Divorced parents may not agree on getting vaccinations, and considerable time can be expended attempting to locate parents.
• Pregnancy screening by history for adolescent girls who are in the office with their parents can be quite a sensitive issue. Although the HPV4 vaccine is an FDA Pregnancy Category B vaccine, the only vaccine actually considered standard of care during pregnancy is the influenza vaccine, which interestingly is a category C vaccine. Thus administering HPV4, MCV4, or Tdap to an adolescent girl requires discreet screening for sexual activity and contraceptive use.
• To avoid syncope, offices should require adolescents to remain seated for 15 minutes after being vaccinated with any vaccine.

In conclusion, practitioners and office staff must diligently screen each pre-adolescent and adolescent for recommended vaccinations. They should allow for conversations about parental concerns and questions regarding their child’s needed vaccines. Be respectful and patient, and document unproductive visits.

References

1. Davis K, Dickman ED, Ferris D, Dias JK. Human papillomavirus vaccine acceptability among parents of 10- to 15-year-old adolescents. J Low Genit Tract Dis. 2004; 8(3): 188-194.
2. Zimet GD, Mays RM, Sturm LA, Ravert AA, Perkins SM, Juliar BE. Parental attitudes about sexually transmitted infection vaccination for their adolescent children. Arch Pediatr Adolesc Med. 2005; 159(2): 132-137.
3. Gidengil CA, et al. Presented at: Annual Meeting of the Pediatric Academic Societies; May 3, 2009; Baltimore, MD.
4. Freed GL, Cowan AE, Clark SJ, Santoli J, Bradley J. Use of a new combined vaccine in pediatric practices. Pediatrics. 2006; 118(2): e251-e257.
5. Gershon AA, Gardner P, Peter G, Nichols K, Orenstein W. Quality standards for immunization. Guidelines from the Infectious Diseases Society of America. Clin Infect Dis. 1997; 25(4): 782-786.
6. Fedson DS. Adult immunization. Summary of the National Vaccine Advisory Committee Report. JAMA. 1994; 272(14): 1133-1137.
7. Daley MF, Crane LA, Chandramouli V, Beaty et al. Influenza among healthy young children: Changes in parental attitudes and predictors of immunization during the 2003 to 2004 influenza season. Pediatrics. 2006; 117(2): e268-e277.
8. Oster NV, McPhillips-Tangum CA, Averhoff F, Howell K. Barriers to adolescent immunization: A survey of family physicians and pediatricians. J Am Board Fam Pract. 2005; 18(1): 13-19.
9. Keane MT, Walter MV, Patel BI, et al. Confidence in vaccination: A parent model. Vaccine. 2005; 23(19): 2486-2493.