Prevention & Control of Pediatric Influenza

Introduction The State of Influenza Vaccination in Children in 2008 Robert B. Belshe, MD Do the Data Support School-Based Influenza Vaccination? Pedro A. Piedra, MD The Practicalities of Universal Pediatric Influenza Vaccination Stanley L. Block, MD Discussion

Introduction

“Influenza? My kids never get the flu!” The truth is, however, that influenza is a serious health problem that is responsible each year for more than 50,000 deaths in the United States. And children are its primary transmitters. Effective vaccines are available that can prevent influenza and its complications; however, they are not optimally used. Who should be getting vaccinated? How are vaccine coverage recommendations being met? What are the strategies for implementation of a successful vaccination program? What are the barriers to achieving success in a vaccination program and how can these obstacles be overcome?

To answer these and other important questions, Vindico Medical Education organized a panel of influenza experts to share their knowledge and expertise in November 2008. They focused on the 2008 Advisory Committee on Immunization Practices (ACIP) recommendation that all children be vaccinated. They reviewed the status of influenza vaccination in children, shared the rationale for and results of community and school-based vaccination programs, and provided guidance for busy practitioners in healthcare clinics who may feel overwhelmed by the demands of influenza vaccination.

I thank the panel for their contributions to the development of this monograph, which summarizes the discussions to provide the reader with an understanding of the basis for and importance of this new vaccination recommendation and the role healthcare practitioners can play in making it a success.

Robert B. Belshe, MD
Course Chair

Robert B. Belshe, MD Professor of Medicine, Pediatrics, and Molecular Microbiology St. Louis University School of Medicine St. Louis, Missouri Pedro A. Piedra, MD Professor Department of Molecular Virology and Microbiology Baylor College of Medicine Houston, Texas Stanley L. Block, MD University of Louisville Professor of Clinical Pediatrics University of Kentucky President, Kentucky Pediatric Research Editorial Board Member Infectious Disesases in Children Bardstown, Kentucky

The State of Influenza Vaccination in Children in 2008

Robert B. Belshe, MD

There is a significant healthcare burden associated with influenza. Treatment is difficult due to a variety of factors, and thus the most effective means of reducing the burden is though vaccination. In order for vaccination programs to be successful, key aspects such as features of the virus and the optimal population to target for vaccination must be understood.

The Influenza Virus

A central feature of the influenza virus is its segmented genome, comprising 8 RNA segments.¹ This allows the virus to exchange genetic material with other influenza viruses. The reassortment of the gene segments can occur with animal influenza viruses, as well as other human influenza viruses. This process facilitates the abrupt evolution of novel influenza viruses that have an immune advantage; therefore, they spread fairly rapidly and drive the evolution of new viruses.

Another key feature of the virus is the surface proteins. Hemagglutinin (HA), which represents approximately 70% of the virus surface, is responsible for attaching the virus to respiratory mucosa and initiating infection.² If antibodies directed against the specific viral HA are present, then the host is protected against infection. Neuraminidase (NA) and the M2 ion channel protein are other important surface proteins. Drugs that target these 2 proteins are available; however, resistance to M2 ion channel inhibitors is increasing worldwide.³ In fact, the Centers for Disease Control and Prevention (CDC) recommended against their use for influenza treatment or prophylaxis starting with the 2005-2006 flu season.⁴ In addition, resistance to one of the neuraminidase inhibitors is also emerging. Accordingly, although these drugs can help control the spread of influenza and limit its complications, they are not a substitute for vaccination.

The Mechanism of Influenza Transmission

Many respiratory viruses are spread by fomites—dry secretions on toys or other objects that can carry the virus. Respiratory syncytial virus is a classic example of a virus believed to be transmitted primarily by fomites. When fomites are transferred to the mouth, nose, or eye, the virus is applied onto the mucosa and the infection is initiated. Hand washing is, therefore, an effective means of preventing transmission of viruses by fomites.

Influenza, however, is largely spread as an aerosol. Sneezing, coughing, and even speaking releases a large number of particles into the air, ranging in size from large droplets to small-particle aerosols. These projected particles are inhaled by a new host, promoting the transmission of influenza and reducing the ability to control disease spread by simple behaviors such as hand washing. Masks may provide benefit at blocking transmission, but they are not effective against the small-particle aerosols.⁵

The Healthcare Burden of Influenza in the United States

The burden of influenza is large and is, in fact, increasing, with more than 50,000 deaths from influenza each year in the United States.⁶ Approximately 36,000 are direct deaths; that is, the death certificate includes a diagnosis of influenza or pneumonia associated with influenza. Indirect deaths account for the remainder of approximately 15,000 deaths. However, this total is difficult to accurately quantify.

Influenza Vaccines

Due to the large healthcare burden of influenza and the potential for resistance to current pharmacological agents to develop, prevention through vaccination seems to be the most effective strategy for management of influenza. There are currently 2 influenza vaccine types available. The injectable trivalent inactivated influenza vaccine (TIV) is safe and efficacious in preventing influenza when a good antigenic match exists. The TIV is most effective in healthy young adults and less effective in children and the elderly. This vaccine also has been shown to prevent the complications of influenza, including death and hospitalization for pneumonia and influenza.^7-8 A trivalent live-attenuated influenza vaccine (LAIV), which is administered intranasally, is also available.⁹ Clinical studies have demonstrated that this vaccine is safe and efficacious in up to 95% of children and effective in preventing influenza’s complications.

The “flu shot,” or TIV, has been available longer than the LAIV and is currently approved for use in people older than 6 months.^7-8 The injectable influenza vaccines are purified, split-virus vaccines, in which the cultured virus is inactivated and chemically disrupted to yield the surface HA and NA antigens. Of the antigen component in the vaccine, only the HA content is standardized.

The newer vaccine, the LAIV, is also trivalent; however, it has several differences compared to the traditional vaccine. It is a live-attenuated vaccine and is indicated for the active immunization of people aged 2 to 49 years against influenza disease caused by influenza virus subtypes A and B that are included in the vaccine.⁹ The LAIV represents the entire virus, containing 6 internal gene segments of the attenuated master donor virus and the 2 gene segments that encode for the surface HA and NA antigens from the specific wild-type viruses that are expected to circulate during the influenza season. Accordingly, although the vaccine virus strains maintain the replication characteristics and phenotypic properties of the master donor virus, they express both the HA and NA characteristics of the recommended wild-type viruses. Although antibodies directed against antigens other than the HA and NA antigens may not be protective, the resultant cytotoxic T-cell response may facilitate clearance of the virus and recovery from illness.¹⁰

The LAIV is administered as a nasal spray. Because it contains a live, attenuated virus, the virus replicates once it enters the nose and induces immunity to several virus components. However, the strains are genetically engineered not to cause disease or classic flu-like symptoms. The vaccine also helps confer mucosal immunity by stimulating the production of secretory immunoglobulin A (IgA). The cumulative effect, therefore, is to induce an immune response that more closely resembles that occurring after a natural infection, involving both a mucosal and a systemic response. Because it is cold adapted and temperature sensitive, the virus does not replicate in the lower airways; that is, it replicates at approximately 34° C, the temperature in the nasopharyngeal region of upper airways, but not at the 37° C environment in the lower airways.¹⁰ In the lungs, the vaccine stimulates the production of serum immunoglobulin G (IgG) antibodies.

A head-to-head clinical trial evaluating the efficacy of the intranasal LAIV compared with the injectable TIV enrolled more than 8000 children.¹¹ They were vaccinated in October with the first dose of vaccine and received a second dose 1 month later if this was the first year they were being vaccinated. Eighty percent of the children had not been vaccinated previously and received a second dose of vaccine. In the group of children who received the TIV, approximately 9% developed breakthrough influenza despite being vaccinated. In contrast, children who received the LAIV had a much lower incidence of breakthrough influenza, resulting in greater than 50% reduction in attack rate of culture-positive influenza compared with those who received the TIV (Figure 1).

A review of data from the Comparative Efficacy Study of the LAIV versus the TIV reveals a significant benefit with the LAIV. For example, per 100,000 children vaccinated with the LAIV, more than 4000 fewer cases of the flu would be expected, as would more than 7000 fewer outpatient visits.¹²

In a cost analysis of these data, despite the fact that the LAIV costs $7 more per dose than the standard flu shot, greater efficacy of the LAIV results in more than $45 saved per child, which translates into $4.5 million saved per 100,000 children. Another significant benefit is that children who do not get influenza do not transmit it to their siblings, their parents, and other contacts. Adding this compounded benefit results in a savings of $7 million for every 100,000 children vaccinated with the LAIV compared with the TIV.

Vaccination Approaches

Historically, vaccination efforts were focused on the population that is at high risk for hospitalization and death. Success in identifying and vaccinating this population, however, has been moderate and has not produced the desired reduction in the burden of disease. As a result, this approach has been modified to focus on the 30 to 60 million infections that occur in the community, many of which are in children. Accordingly, vaccine efforts are being refocused to immunize children—the primary transmitters of the flu—in addition to high-risk groups including the elderly.

In the classic study by Elveback and colleagues performed more than 30 years ago, a stochastic simulation epidemic model was used to suggest appropriate immunization practices among school-aged children.¹³ The model proposed that the spread of influenza virus from person to person is predicated on key dynamics that include population factors such as age, family structure, neighborhood, school, and infecting-agent characteristics; and individual factors such as contact, infection, and response to infection. Immunologically naïve children appear to be the catalysts or index cases for most influenza epidemics, initially spreading infection to school-aged companions, followed by family members and close contacts of school-aged children, and subsequently to the community at large. Schools provide an important pathway for interfamily spread, which ultimately leads to an epidemic as the wider community becomes infected. People most at risk for acquiring influenza infection in the community setting are those with risk factors for complications, the elderly, and close social contacts of the primary cases.

In the Houston Family Study, which was conducted from 1976 to 1984, families were enrolled upon the birth of a child.¹⁴ Age-specific infection rates were monitored and almost 50% of cases in the 145 families were in children aged 6 to 10 years (Figure 2). In the 4 age ranges that included children younger than 2 years to 18 years, the incidence of influenza was considerably higher than that in adults. In addition, the risk of lower respiratory tract illness associated with influenza virus infection was highest in children younger than 2 years. Thus, it appears that influenza is most prevalent in young children.

Influenza Vaccination Recommendations – The 2008 Update

The 2008 Advisory Committee on Immunization Practices (ACIP) recommendations for the prevention and control of influenza responded to the role of children as primary transmitters of influenza.¹⁵ It expanded the recommendation by including all children aged 6 months to 18 years as a target group for the influenza vaccine. This addition of children aged 5 to 18 years adds 30 million new patients who should be vaccinated. In accordance with the fact that the annual influenza epidemic in children has important public health implications, it follows that, if the majority of children are vaccinated, then it should have a major impact on the spread of influenza in the entire community.

The other target groups that should be vaccinated were unchanged from previous recommendations.¹⁶ All adults aged 50 years and older, residents of chronic care facilities, people with chronic underlying diseases (chronic pulmonary, metabolic, or cardiovascular disorders), and pregnant women should be vaccinated. In addition, all household contacts of high-risk people should be vaccinated, which includes approximately 80 million people.

It is assumed that influenza vaccination for everyone will eventually be recommended. The inclusion of a universal vaccine recommendation for all children is a step in that direction.

The Status of Childhood Influenza Vaccination

In the 2004-2005 season, despite a recommendation that all children aged 6 to 23 months should be vaccinated, fewer than one half of children received 1 dose of the vaccine and a much smaller percentage received the recommended 2 doses for the first year vaccinated (Figure 3).¹⁶ In addition, only 25% to 42% of most other target groups were vaccinated. Significantly, only 10.8% of children aged 5 to 17 years who were household contacts of high-risk people were vaccinated. Therefore, a logical response to this unsatisfactory achievement was to recommend vaccination for all children older than 6 months.

In conclusion, influenza is a serious healthcare issue that is responsible each year for more than 50,000 deaths, 142,000 hospitalizations, and $3 billion to $5 billion in direct medical costs. However, influenza can be prevented. Two vaccines are currently available: an inactivated injectable vaccine that has up to 90% efficacy and a live-attenuated cold-adapted intranasal vaccine with up to 95% efficacy. Antiviral drugs are not a substitute for vaccination.

Children have the highest annual attack rates of influenza and are the main transmitters of the flu. Fewer than 50% of children, however, are receiving even 1 dose of vaccine, while 2 doses should be given to children younger than 9 years old the first time they are vaccinated. An improvement in vaccination rates among school-aged children is an important goal to reduce the overall spread of influenza in the community and to decrease the burden of disease.

References

1. Steinhauer DA, Skehel JJ. Genetics of influenza viruses. Annual Review of Genetics. 2002;36:305-32. Epub 2002 Jun 11.
2. Malhotra A, Krilov LR. Influenza and respiratory syncytial virus. Update on infection, management, and prevention. Pediatric Clinics of North America. 2000 Apr;47(2):353-72, vi-vii.
3. Belshe RB, Burk B, Newman F, Cerruti RL, Sim IS. Resistance of influenza A virus to amantadine and rimantadine: results of one decade of surveillance. Journal of Infectious Diseases. 1989 Mar;159(3):430-5.
4. CDC. CDC recommends against the use of amantadine and rimantadine for the treatment or prophylaxis of influenza in the United States during the 2005-06 influenza season. Available at: www.cdc.gov/fl u/han011406.htm.
5. Fabian P, McDevitt JJ, DeHaan WH, Fung RO, Cowling BJ, Chan KH, Leung GM, Milton DK. Influenza virus in human exhaled breath: an observational study. PLoS ONE. 2008 Jul 16;3(7):e2691.
6. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA: The Journal of the American Medical Association. 2003 Jan 8;289(2):179-86.
7. Fluzone [prescribing information]. Swiftwater, PA: Sanofi-Pasteur, Inc; 2006.
8. Fluvirin [prescribing information]. Emeryville, CA: Novartis Vaccines and Diagnostics, Inc; 2006.
9. FluMist [prescribing information]. Gaithersburg, MD: MedImmune Vaccines, Inc; 2008.
10. Cox RJ, Brokstad KA, Ogra P. Influenza virus: immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines. Scandinavian Journal of Immunology. 2004 Jan;59(1):1-15.
11. Belshe RB, Edwards KM, Vesikari T, Black SV, Walker RE, Hultquist M, Kemble G, Connor EM; CAIV-T Comparative Efficacy Study Group. Live attenuated versus inactivated influenza vaccine in infants and young children. New England Journal of Medicine. 2007 Feb 15;356(7):685-96.
12. Luce BR, Nichol KL, Belshe RB, Frick KD, Li SX, Boscoe A, Rousculp MD, Mahadevia PJ. Cost-effectiveness of live attenuated influenza vaccine versus inactivated influenza vaccine among children aged 24-59 months in the United States. Vaccine. 2008 Jun 2;26(23):2841-8. Epub 2008 May 6.
13. Elveback LR, Fox JP, Ackerman E, Langworthy A, Boyd M, Gatewood L. An influenza simulation model for immunization studies. American Journal of Epidemiology. 1976 Feb;103(2):152-65.
14. Glezen WP, Taber LH, Frank AL, Gruber WC, Piedra PA. Influenza virus infections in infants. The Pediatric Infectious Disease Journal. 1997 Nov;16(11):1065-8.
15. CDC. MMWR Morbidity and Mortality Weekly Report. 2008;57:1-60.
16. CDC. MMWR Morbidity and Mortality Weekly Report. 2006;55:1-42.

Do the Data Support School-Based Influenza Vaccination?

Pedro A. Piedra, MD

The goals of an influenza vaccination policy should be to reduce influenza-related mortality, reduce influenza-related hospitalization, control seasonal influenza, reduce cost, and/or augment the health-related quality of life.

Immunization Policies: Are they Working?

Historically, influenza vaccination coverage in recommended population groups has fallen short of reaching numbers that can allow achievement of these goals (Figure 1).¹ People aged at least 65 years have had the best vaccination rate, ranging between 60% and 70% for the last 10 years. However, healthcare workers, who provide care to patients who may be vulnerable and who should support influenza prevention strategies, have poor immunization coverage, ranging from 32% to 43% in the last 10 years. In summary, the overall trend through 2005, with the exception of the elderly, was vaccination coverage of 10% to 50% in recommended groups.

In response to the new Advisory Committee on Immunization Practices (ACIP) recommendation for universal vaccination of children aged 6 months to 18 years, immunization providers should begin efforts to offer influenza vaccination to all children in this age range. The ACIP expects that, by the 2009-2010 influenza season, a standard of offering universal vaccination of all children will be in place.² In addition, with the progression into the next influenza season, success at achieving the Healthy People 2010 goals for influenza vaccination can be evaluated.³ However, current trends suggest that achieving the Healthy People 2010 goals, which include 90% vaccination of both noninstitutionalized people aged at least 65 years and institutionalized adults, and 60% for the other risk groups, is a lofty target.

School-aged children have the highest influenza attack rate and are relatively naïve to influenza. Accordingly, influenza outbreaks frequently start in the school setting where naïve children are susceptible (Figure 2).⁴ Infected children spread the virus within the school environment and in the community, primarily to susceptible family members. In addition, most adults go to work when they have a respiratory illness, enhancing the spread of the influenza virus.

Considering this process, it seems logical that, if efficient vaccination coverage of school-aged children was in place, influenza outbreaks could be avoided.⁵ Seasonal influenza could be controlled by protecting the group with the highest attack rate for influenza, who are also those most likely to transmit influenza to other susceptible persons in the community. This “herd protection” may be a practical approach to control epidemic influenza. Moreover, unlike other populations of people, school children are an easily accessible population. These factors contributed to the rationale for the universal vaccination of school children.

Vaccination of School-Aged Children: Does It Work?

Vaccination of school-aged children is not a new idea. The first proof of concept study, published 40 years ago, was done during the last global (Hong Kong) influenza pandemic of 1968.⁶ At that time, standard influenza vaccination was rarely provided outside the military. In the study, 85.8% of children and 89.2% of school personnel were vaccinated in their schools in Tecumseh, Mich., with a single dose of influenza vaccine A/Aichi/2/68 (H3N2). In addition to a significant decrease in weekly respiratory illness rates in the school children, the decrease extended to other age groups that were not vaccinated, and there were no increases in school absenteeism in Tecumseh during the 10-week pandemic. In fact, the community illness rate in excess of baseline in Adrian, a neighboring community, was 3-fold higher than in Tecumseh. In the subsequent influenza type B epidemic in February 1969, Tecumseh and Adrian were equally affected. This was the first community trial to demonstrate herd protection against influenza-related illness.

Additional evidence of herd immunity emerged from a retrospective epidemiologic study in Japan.⁷ After the Asian influenza epidemic of 1957 that claimed approximately 8000 lives, with a clear association between outbreaks and school sessions, a nationwide vaccination program for school-aged children was launched in 1962, and it was made mandatory in 1977. The effect of these programs was obvious: the excess death rate 5-year moving average declined by 50% between 1962 and 1972 and by 40% between 1972 and 1987, despite a doubling in the number of elderly persons. During the 10-year period that the vaccination law was in place, vaccination rates in school children ranged between 50% and 85%. In addition to a significant reduction in pneumonia and influenza-related deaths that ranged from 10,000 to 12,000 per year, all-cause mortality was reduced by 37,000 to 47,000 per year. One death was prevented for every 420 school children vaccinated. After 1987, when influenza vaccination of school children became voluntary, the number of excess deaths began to rise; and death rates rose steeply after 1994, when the immunization program was abandoned. Excess deaths attributable to pneumonia and influenza are now similar to the rate before the program was begun in 1962. These trends support the theory that the lower rate of excess deaths between 1962 and 1987 was due to vaccine-induced herd immunity.

A recent study in the United States evaluated the effectiveness of school-based influenza vaccination with the live-attenuated influenza vaccine (LAIV) in 11 clusters of elementary schools in 4 states.⁸ Each cluster included 2 control schools and 1 intervention school, with an approximate 47% vaccination coverage achieved in the intervention schools. Influenza-related morbidity in the schools and in the family members of children from those schools was compared with that of control schools during the predicted week of peak influenza activity in the influenza season. There was a significant reduction in febrile illnesses in families with children in the intervention schools compared with the control school group, not only in children but also in adult family members as well (Figure 3). In addition, high school student absenteeism was reduced in families in the intervention group, despite the fact that middle school and high school students were not being vaccinated. Therefore, the herd effect was observed in both adults and older children in intervention school households.

Central Texas has followed a community-based approach to mass vaccination of children for several years using the LAIV.⁹ The program includes 2 intervention cities and 3 comparison cities. When the influenza seasons began in both the intervention and comparison communities, the rates of medically attended acute respiratory illness (MAARI) increased; and decreased when the outbreaks ended. In 1998, the baseline year prior to starting the program, MAARI rates in the 2 groups were similar.⁹ When the vaccination program was started in the next year, achieving 15% vaccination in the community, there was an approximate 8% reduction in MAARI, which represents approximately 400 fewer medically attended visits for adults. Similarly, in the second year, vaccination coverage of approximately 15% was achieved; however, the difference between peak MAARI rates in the comparison versus intervention communities reached approximately 18%, suggesting duration of protection may extend beyond one year. This vaccination rate of approximately 15% of children aged 18 months though 18 years continued for the first 4 years of the program. Despite this low vaccination rate, MAARI in adults were reduced by 8% to 18%, accounting for 400 to 1000 saved clinic visits per year.

In 2003-2004, an especially virulent outbreak occurred early in the season. Vaccination was ongoing throughout the outbreak, achieving 30% coverage of children aged 5 to 18 years, and an almost immediate benefit was demonstrated by reduced influenza-related morbidity in children who received the influenza vaccine.¹⁰ This occurred despite the vaccination being given during the outbreak. Moreover, the dominant circulating virus was antigenically distinct from the vaccine strain.

When vaccination coverage increased to approximately 30%, as in 2004-2006, herd protection was broadened, to include not only middle-aged and older adults, but also younger adults and children who were not vaccinated.¹¹ In fact, in the 2005-2006 season, a second wave of influenza caused by influenza type B may have been averted in the intervention communities, while it was detected in the comparison communities.¹²

The Ingredients of an Effective School-Based Influenza Vaccination Program

Several important components must be in place for a successful program to be implemented and sustained. Educating the community about the burden of influenza is essential. Moroever, the program should be supported by both public and private healthcare providers. Importantly, the influenza vaccine should not be offered to students only; school staff should be included as well. Program logistics should be streamlined, particularly the consent process. Finally, the benefits of the program should be monitored by documenting specific outcomes, including student absenteeism and influenza-like illness.

Acknowledging the benefits of vaccinating school-aged children, we initiated a school-based influenza vaccination program in Central Texas in 2007 that uses both the TIV and the LAIV. In the first year of the school-based influenza vaccination program, the focus was on elementary schools and included 7 independent school districts with 25 elementary and pre-parochial schools. Vaccination teams were at each school for approximately half a day, vaccinating more than 5000 children and 1000 staff members. In this program, most children were vaccinated with the LAIV and approximately 15% received the TIV because of contraindications.

In conclusion, increasing immunization rates among school children reduces the influenza illness burden not only in children, but also in their families and in the communities.

References

1. Lu P, Bridges CB, Euler GL, Singleton JA. Influenza vaccination of recommended adult populations, U.S., 1989-2005. Vaccine. 2008 Mar 25;26(14):1786-93. Epub 2008 Feb 14.
2. CDC. MMWR Morbidity and Mortality Weekly Report. 2008;57:1-60.
3. ACIP. MMWR Morbidity and Mortality Weekly Report. 2004;53:1-40.
4. Elveback LR, Fox JP, Ackerman E, Langworthy A, Boyd M, Gatewood L. An influenza simulation model for immunization studies. American Journal of Epidemiology. 1976 Feb;103(2):152-65.
5. Glezen WP. Emerging infections: pandemic influenza. Epidemiologic Reviews. 1996;18(1):64-76.
6. Monto AS, Davenport FM, Napier JA, Francis T Jr. Modification of an outbreak of influenza in Tecumseh, Michigan by vaccination of schoolchildren. Journal of Infectious Diseases. 1970 Jul-Aug;122(1):16-25.
7. Reichert TA, Sugaya N, Fedson DS, Glezen WP, Simonsen L, Tashiro M. The Japanese experience with vaccinating schoolchildren against influenza. The New England Journal of Medicine. 2001 Mar 22;344(12):889-96.
8. King JC Jr, Stoddard JJ, Gaglani MJ, Moore KA, Magder L, McClure E, Rubin JD, Englund JA, Neuzil K. Effectiveness of school-based influenza vaccination. The New England Journal of Medicine. 2006 Dec 14;355(24):2523-32.
9. Piedra PA, Gaglani MJ, Kozinetz CA, Herschler G, Riggs M, Griffith M, Fewlass C, Watts M, Hessel C, Cordova J, Glezen WP. Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Vaccine. 2005 Feb 18;23(13):1540-8.
10. Piedra PA, Gaglani MJ, Kozinetz CA, Herschler GB, Fewlass C, Harvey D, Zimmerman N, Glezen WP. Trivalent live attenuated intranasal influenza vaccine administered during the 2003-2004 influenza type A (H3N2) outbreak provided immediate, direct, and indirect protection in children. Pediatrics. 2007 Sep;120(3):e553-64. Epub 2007 Aug 13.
11. Piedra P, et al. 9th Annual Conference on Vaccine Research, Baltimore, MD; May 8, 2006.
12. Piedra P, et al. Prevention of the Influenza B Outbreak during the 2005-06 Influenza Season through a Universal Vaccination Program in Children. 2007 Pediatric Academic Societies, Toronto, Canada (publication no. 8755.1); May 8, 2007.

The Practicalities of Universal Pediatric Influenza Vaccination

Stanley L. Block, MD

The new Advisory Committee on Immunization Practices (ACIP) recommendations for influenza vaccination were reviewed earlier in this monograph. The significant addition is the recommendation for vaccination of all children aged 6 months to 18 years by the 2009-2010 flu season.¹ Acknowledging the mediocre coverage achieved in population groups that were previously recommended for vaccination, what can be done to assure vaccination services are provided to the 73.6 million children the recommendations now encompass? Until viable school-based vaccination programs are established, the healthcare practitioner must shoulder this burden of working toward vaccination for all children, which requires significant planning and management if vaccination implementation is to be a success.

Vaccination coverage is falling behind target. Based on data from immunization information system (IIS) sentinel sites in 8 states, the vaccination rate during the 2007-2008 influenza season was 40.8% for children aged 6 to 23 months who received at least 1 dose of the vaccine.² Only 22.1% were fully vaccinated; that is, almost 50% of those vaccinated did not return for the second dose. The percentages were even lower for children aged 24 to 59 months, with only 22.2% receiving 1 vaccination and 16.5% of eligible patients receiving both doses.

Barriers to Pediatric Influenza Vaccination

Vaccination planning must account for and, when possible, respond to the many barriers to immunization.^3-5

Vaccine is not mandated

One important example of such a barrier to influenza immunization is the fact that the vaccine is not mandated. This will always be a constraint to achieving adequate coverage.

Missed opportunities

In order to maximize the success of influenza prevention through vaccination, the practitioner must maximize every opportunity available to vaccinate a patient. For example, it is vital that a clinician offers pregnant patients the influenza vaccine. In a recent randomized study comparing the influenza vaccine with the pneumococcal vaccine in 340 pregnant women, proven influenza illness in infants aged up to 6 months old whose mothers had received influenza vaccine was reduced by 63%.⁶ Accordingly, in this study, a substantial protective effect against influenza was achieved not only in the mothers, but also in their young infants. These data should provide additional motivation for healthcare practitioners to be advocates for influenza vaccination in their pregnant patients. Another important opportunity for vaccination that is often missed is children who visit the clinic with a mild illness. In most cases, the influenza vaccine can still be given. Practice-based immunization promotion programs can help to overcome the barrier of missed opportunities for immunization.

Unpredictability

Also, the unpredictable nature of the influenza season often interferes with efforts to achieve adequate vaccination. The season may start as early as October or as late as March, and has been experienced as late as April or May. The vaccine supply also has a history of being unpredictable, making it difficult for practices to maintain adequate inventories without being left with possible nonreturnable surplus at the end of the season.

The injectable trivalent inactive influenza vaccine (TIV) must be ordered 9 months in advance, and the inability to predict both the timing and severity of outbreaks precludes accurate planning. Orders for the intranasal live-attenuated influenza vaccine (LAIV), however, can usually be shipped within 3 or 4 days. Being able to order as needed provides an advantage from the supply management perspective. In addition, the LAIV can be ordered as early as mid-July, although early August is more common.

Issues with access to vaccine

Families may also have poor access to the influenza vaccine; for example, distance to and accessibility of clinics, and loss of time at work may be prohibitive. However, accessibility is an advantage of school-based immunization programs, along with office-based evening and Saturday vaccine hours.

Durability of protection from vaccination

Another logistical issue is the durability of protection from the vaccination. There is an approximate 3-month window for vaccination with the TIV.⁷ If children are vaccinated in September, but the influenza season does not arrive until March or later, is the child protected? Durability of the flu shot is not well known; however, the nasal LAIV has been shown in 4 studies to provide 77% to 100% protection against A strains of influenza virus 12 months after being vaccinated. Protection was 56% during the second year without revaccination.⁸ The durability of the LAIV allows it to be given as early as August and September, assuring coverage of an early outbreak. In addition, the trend is moving toward an expanded vaccination season by extending the use of both vaccines into January, February, and March. The half-life of antibody suggested that children immunized with TIV in the fall should have immune responses sustained throughout the ensuing influenza season.⁹

Perceptions

Perceptions about the influenza vaccine are not always correct. This is where the practitioner can have an impact. A common misconception is that the influenza vaccine is not meant for healthy children. In addition, antigenic drift can result in significant rates of vaccine failure, as noted with TIV. This can cause parents to doubt the overall effectiveness of the influenza vaccines. Moreover, many people do not regard influenza as a serious illness. Some believe the vaccine actually causes the flu or some have heard reports of rare, but serious, adverse events following influenza vaccine. The general aversion children have for shots also contributes to negative perceptions. In addition, many believe the vaccination is for only adults and the elderly—not for children. Also, the vaccine is propagated in embryonated hens’ eggs, thus it may contain trace amounts of residual egg proteins and should not be administered to patients who have egg allergies. Many parents may claim a child has an egg allergy when, in fact, he or she does not. Finally, one of the most difficult obstacles to overcome is when parents assert that neither they nor their children ever becomes infected with influenza.

In a study of parental attitudes toward influenza immunization before and after the 2003-2004 season, the most positive influence included the recommendation of the physician.⁵ More than three-fourths of patients who are advised by their physicians to be vaccinated will accept it. Another positive predictor was the perception that the influenza vaccine was a social norm. When parents believed everyone was receiving it, they were more likely to have their children vaccinated. Negative predictive perceptions were an inadequate supply of vaccine, interference of illness with vaccination, and lack of knowledge regarding recommendations for childhood influenza vaccinations. Lower level of education among parents was also a barrier; in addition, some parents made the decision before the season started not to get vaccinated. Interestingly, perceived susceptibility to influenza and its severity had no influence.

Time and money

A significant constraint to office-based vaccination programs is time the practitioner needs to educate parents on rationale for the influenza vaccine, its safety issues, and its misperceptions. In addition to physician time, considerable nursing time is required. Frequently, special nursing clinics must be set up to meet the transient high demand for influenza vaccinations, along with extensive record-keeping.

Financial barriers to vaccination include manufacturers’ no-return policies for unused doses and unknown, fluctuating, or insufficient insurance reimbursement for nasal versus thimerosal-free injectable versus thimerosal-containing injectable vaccines.

Overcoming barriers to immunization

A confident, positive attitude by practitioners is necessary to optimize their part in the universal vaccination of children. Practitioners must acknowledge the seriousness of influenza disease and must support the value and safety of the vaccine, or vaccination goals will not be met.

Considerations for the clinic

Vaccine-naïve children aged younger than 9 years should receive 2 vaccine doses. Practitioners must attempt to vaccinate them during both well visits and acute-care visits for minor illnesses or trauma. In young children, routine checkups are an ideal time to vaccinate. With the nasal vaccine available for children aged 24 months and older as early as July, practitioners should be alert for vaccination opportunities in older children during annual physical examinations and sports-related or other required visits.

Another caveat to flu vaccinations is the fact that nearly one-half of vaccine-naïve children receive only a single dose of vaccine for the season. Although 2 doses are considered necessary for vaccine-naïve children initially, data on administration of a single dose of the nasal LAIV showed 89% effectiveness versus placebo.¹⁰ One dose of the TIV, however, has effectiveness between 10% and 50%.¹¹ Single-dose data then become a critical consideration for vaccinations given to this group late in the season. Furthermore, if antigenic drift occurs between the flu vaccine strains and the circulating influenza, the LAIV has demonstrated higher rates of protection than the TIV.¹²

An office influenza vaccination program can be more effective when nurses screen at each office visit, determining whether the patient has had the vaccine, along with the correct number of doses at the right time. In addition, electronic medical records can have pop-up flags for patients who need the vaccine. Reminders can be included in billing and the reception sign-in sheet can include a prompter about influenza vaccination. Placing vaccine posters in each examination room can remind both the family and the physician during each visit.

Although walk-in clinic days on Saturdays and evenings are useful, my experience has been that appointments should be made for about twice the capacity, because typically about one-half do not keep their appointments. Also, flu vaccination clinics scheduled closer to the flu season (late October/November) are more successful.

Practitioners should also work with schools, local health departments, and pharmacies on standing orders for pediatric patients. Although high school and middle school nurses can administer the vaccine; menstruating girls must be discretely screened for potential pregnancy before receiving the LAIV.

There are several other issues that should be taken into consideration in the effort to implement universal pediatric influenza vaccination.

Understand the differences in efficacy, safety, adverse event profile, and precautions of the available vaccines

Familiarity with the vaccines should be maintained beyond simply knowing that 1 is intranasal and 1 is injectable.

Parental acceptance

Most parents are more likely to accept the vaccination when the clinician recommends it and therefore the clinician should provide each parent with accurate information.

Evolving patient ages

In addition to the narrow 3-month window during which the TIV can be given, dealing with age issues can be problematic. For example, if an infant aged 5.5 months is in the office in January, should an off-label vaccination be given and will it be reimbursed? The LAIV is indicated only in children older than 24 months.

Cost

The nasal vaccine acquisition unit cost is slightly higher than that of the TIV. Adequate insurance coverage for either vaccine type is approximately 90%.

Vaccination burden in 1 visit

Considering vaccination schedules is important. If it is time for 2 to 4 vaccinations for preschool or middle school children, the nasal vaccine may be preferable.

Contraindications

Be alert for contraindications and precautions. Both the LAIV and TIV are contraindicated in patients with (true) egg allergy. The LAIV is contraindicated for pregnant patients, those younger than 24 months, and recently treated asthmatic patients.

Thimerosal

Thimerosal is a preservative contained in some formulations of the injectable influenza vaccines, particularly the multidose vials. Although thimerosal has not been shown to cause sequelae in children, some parents will only accept a thimerosal-free injectable vaccine for their child. The intranasal LAIV does not contain thimerosal.

In conclusion, the practitioner faces many challenges in implementing a successful influenza vaccination program aimed at achieving universal vaccination in children. In-office and out-of-office strategies can be used to remove many of these barriers. Most importantly, practitioners must be advocates for immunization and must be ready to address these challenges using an education and efficiency-oriented approach.

References

1. CDC. Media relations. Available at: http://www.cdc.gov/od/oc/media/pressrel/2008/r080227.htm.
2. CDC. Influenza vaccination coverage among children aged 6-59 months--eight immunization information system sentinel sites, United States, 2007-08 influenza season. MMWR Morbidity and Mortality Weekly Report. 2008 Sep 26;57(38):1043-6.
3. Gershon AA, Gardner P, Peter G, Nichols K, Orenstein W. Quality standards for immunization. Guidelines from the Infectious Diseases Society of America. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 1997 Oct;25(4):782-6.
4. Fedson DS. Adult immunization. Summary of the National Vaccine Advisory Committee Report. JAMA: the journal of the American Medical Association. 1994 Oct 12;272(14):1133-7.
5. Daley MF, Crane LA, Chandramouli V, Beaty BL, Barrow J, Allred N, Berman S, Kempe A. Influenza among healthy young children: changes in parental attitudes and predictors of immunization during the 2003 to 2004 influenza season. Pediatrics. 2006 Feb;117(2):e268-77.
6. Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, Omer SB, Shahid NS, Breiman RF, Steinhoff MC. Effectiveness of maternal influenza immunization in mothers and infants. The New England Journal of Medicine. 2008 Oct 9;359(15):1555-64. Epub 2008 Sep 17.
7. CDC. Notice to Readers: Expansion of Use of Live Attenuated Influenza Vaccine (FluMist®) to Children Aged 2--4 Years and Other FluMist Changes for the 2007--08 Influenza Season. MMWR. Morbidity and Mortality Weekly Report. 2007;56(46);1217-1219.
8. Ambrose CS, Yi T, Walker RE, Connor EM. Duration of protection provided by live attenuated influenza vaccine in children. The Pediatric Infectious Disease Journal. 2008 Aug;27(8):744-8.
9. Wright PF, Sannella E, Shi JR, Zhu Y, Ikizler MR, Edwards KM. Antibody responses after inactivated influenza vaccine in young children. The Pediatric Infectious Disease Journal. 2008 Nov;27(11):1004-8.
10. Belshe RB, Mendelman PM, Treanor J, King J, Gruber WC, Piedra P, Bernstein DI, Hayden FG, Kotloff K, Zangwill K, Iacuzio D, Wolff M. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. The New England Journal of Medicine. 1998 May 14;338(20):1405-12.
11. Jackson LA, Neuzil KM, Baggs J, Davis RL, Black S, Yamasaki KM, Belongia E, Zangwill KM, Mullooly J, Nordin J, Marcy SM, DeStefano F. Compliance with the recommendations for 2 doses of trivalent inactivated influenza vaccine in children less than 9 years of age receiving influenza vaccine for the first time: a Vaccine Safety Datalink study. Pediatrics. 2006 Nov;118(5):2032-7.
12. Belshe RB, Edwards KM, Vesikari T, Black SV, Walker RE, Hultquist M, Kemble G, Connor EM; CAIV-T Comparative Efficacy Study Group. Live attenuated versus inactivated influenza vaccine in infants and young children.The New England Journal of Medicine. 2007 Feb 15;356(7):685-96.