INFECTIOUS DISEASES IN CHILDREN October 2007
Pediatric Influenza Vaccine:
New Strategies and Clinical Advice

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Introduction Structure and strains of the influenza virus Robert B. Belshe, MD Disease burden of the influenza virus Peter F. Wright, MD Children as amplifiers of influenza James C. King, MD Efficacy of influenza vaccines David I. Bernstein, MD, MA Safety of influenza vaccines Keith S. Reisinger, MD, MPH Practicalities of influenza vaccination Stan L. Block, MD

Introduction

Seasonal influenza infection, particularly in children, represents a significant public burden, accounting for up to 20% of pediatrician visits. Children have been identified as a critical link in spreading influenza throughout the community. Because of these data, routine influenza vaccination is now recommended in children aged 6 to 59 months.

Vaccinating against influenza is challenging because the influenza type A and B viruses continually undergo changes known as antigenic drift. Trivalent inactivated vaccine has been used to vaccinate against seasonal influenza for more than 50 years. More recent developments have led to the live attenuated influenza vaccine (LAIV), which has been introduced for easier administration as a nasal spray. LAIV has demonstrated a high safety and efficacy level, although adverse events have been reported.

Vindico Medical Education convened a meeting with leading experts on vaccines and the transmission of disease during the Pediatric Academic Society annual meeting in Toronto in May 2007 to discuss the socioeconomic burden of pediatric influenza infection, compare and contrast available vaccines and provide practical tips for pediatric management of influenza vaccination.

Robert B. Belshe, MD
Course Director

Robert B. Belshe, MD, Course Director is professor of Internal Medicine and Infectious Diseases and director of the Center for Vaccine Development at the St. Louis University Health Center in St. Louis, Missouri.   David I. Bernstein, MD, MA, is director of Infectious Diseases, director of the Gamble Program for Clinical Studies and is the Albert Sabin Professor of Pediatrics at the Cincinnati Children’s Hospital Medical Center in Cincinnati, Ohio. Peter F. Wright, MD, is director of the Division of Pediatric Infectious Diseases at the Monroe Carell Jr. Children’s Hospital at Vanderbilt University in Nashville, Tennessee.   Keith S. Reisinger, MD, MPH, is medical director at Primary Physicians Research, Inc. in Pittsburgh, Pennsylvania. James C. King, MD, is a professor of Pediatrics, director of General Pediatrics and director of the Vaccine Studies Section at the University of Maryland Medical Center in Baltimore, Maryland.   Stan L. Block, MD, is a professor of Clinical Pediatrics at the University of Louisville in Louisville, Kentucky, and at the University of Kentucky in Lexington, Kentucky and is president of Kentucky Pediatric Research in Bardstown, Kentucky.

Structure and strains of the influenza virus
Robert B. Belshe, MD

Influenza is a large, single-stranded helically shaped RNA virus of the Orthomyxoviridae family (Figure 1).¹ The envelope surrounding the virus is covered with two glycoproteins; hemagglutinin (HA), which attaches the virus to the host cell, and neuraminidase (NA), which releases new viral particles from cells. It is the consensus that antibodies directed against HA, such as immunoglobulin G (IgG) or immunoglobulin A (IgA), are the primary mediators of protection against infection. The influenza virus also features a segmented genome. The genome consists of eight RNA segments that allow the virus to exchange genetic material with other viruses. This exchange of genetic material can result in viral modifications and, potentially, pandemic influenza.

Transmission and targets

The exact mechanism of transmission of the influenza virus is largely unknown. Although most respiratory viruses are transmitted primarily by fomites (objects that carry the virus), influenza appears to be transmitted by aerosol generated by sneezes and coughs. Because of this, preventive measures such as hand washing may not be as effective for influenza as with other viruses.

The primary target of influenza is the tracheal epithelium. Initial symptoms of influenza often include fever, substernal chest pain and cough, indicating tracheal infection. After the initial period, the virus may spread into the lungs, causing pneumonia, or into the upper respiratory tract, causing other upper respiratory illnesses such as sinusitis and otitis media.

A study tested the incubation period and kinetics of viral replication by administering the virus intranasally in healthy patients.² After approximately 30 hours, the virus had replicated and symptoms of illness were observed in adults. The virus was found to peak within approximately 24 hours of replication onset and then slowly decrease over approximately 4 to 5 days. In studies of naturally acquired influenza in children, the incubation period was similar to adults, but the viral replication occurred at higher levels and continues to be shed for 10 to 14 days after its peak.

Structure of the Influenza Virus Figure 1. The genome of the influenza virus consists of eight RNA segments that allow the virus to adapt genetic material from other viruses, which can lead to pandemic outbreak. Adapted from Hayden FG, Palese P. Clin Virol. 1997:911-942.

Nomenclature and subtypes

The World Health Organization has designed a naming system to identify individual influenza subtypes. Influenza subtypes should be identified by type, geographical source, isolate number, year of isolation, HA subtype and NA subtype. For example, an influenza A, HA and NA type 1 virus that originated in St. Louis and was isolate number 101 in 2007 should be referred to as: A/StLouis/101/2007/H1N1.

Sixteen known subtypes of influenza HA occur throughout the animal kingdom.³ Notably, the H1 and H3 subtypes have been found in swine, and the H3 and H7 subtypes occur in horses. Although horses and pigs were previously considered to be prime sources for spreading of influenza virus to humans, it is now generally accepted that birds are the root cause of new viruses moving into humans and other animals. All 16 subtypes have been observed in birds and, of these, the H1, H2 and H3 strains have been found to cause pandemics in humans. These subtypes have caused three major pandemics in the last 100 years.

The most devastating of these was the 1918-1919 pandemic, known as the “Spanish flu.” This was a type A/H1N1 virus that caused approximately 500,000 deaths in the United States and as many as 20 million deaths worldwide.⁴ The “Asian flu” pandemic of 1957-1958 was a type A/H2N2 virus that caused 70,000 deaths in the United States. The most recent pandemic, the “Hong Kong flu” of 1968-1969, was a type A/H3N2 virus and caused approximately 34,000 deaths in the United States.

Antigenic Shift Figure 2. New viral segments from avian viruses can combine with the virus circulating in humans to create a new strain.

Antigenic shift vs. drift

Antigenic shift, the process by which new HA subtypes combine with currently circulating viruses, was responsible for the 1957 and 1968 pandemics (Figure 2). Both viruses had five segments from the original 1918 virus with the addition of HA and one or two other genes from an avian virus.⁵ Although it is generally agreed upon that a new pandemic will eventually occur, whether its severity will mirror that of the 1918 virus or of the two later pandemics remains unclear. Although antigenic shift occurs infrequently, antigenic drift is observed on a continuing basis. This process involves the evolution of HA that causes changes in the amino acids to occur at antibody-binding sites. When this occurs, antibodies will no longer bind to that virus and the strain develops a selective advantage over older viruses that cue neutrality by circulating antibodies. This new virus then spreads to other individuals who cannot bind the virus. Antigenic drift occurs every year, but it has less impact than antigenic shift. However, antigenic shift results in reduced vaccine efficacy if the vaccine does not closely match the epidemic viruses.

Summary

A thorough understanding of the structure and transmission methods of the influenza virus is essential in our ongoing efforts to stave off a pandemic. Clinicians must continue to learn about the nature of the virus and its main targets to fight one of the bigger problems faced in medicine today.

References

1. Hayden FG, Palese P. In: Richman DD, Whitley RJ, Haden FG (eds). Clinical Virology. New York, NY: Churchill Livingstone; 1997:911-942.
2. Hayden FG, Treanor JJ, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza. JAMA. 1999;282:1240-1246.
3. Levine AJ. Viruses. New York, NY: Scientific American Library; 1992.
4. Glezen WP. Emerging infections: Pandemic influenza. Epidemiol Rev. 1996;18:64-76.
5. Taubenberger JK, Reid AH, Lourens RM, et al. Characterization of the 1918 influenza virus polymerase genes. Nature. 2005;437:889-893.

Disease burden of the influenza virus
Peter F. Wright, MD

Between 1989 and 1998, influenza was the leading cause of vaccine-preventable deaths in the United States. Out of millions of cases, approximately 500,000 deaths were attributed to influenza. In comparison, some of the other causes of vaccine-preventable deaths included 120,000 deaths due to pneumococcal disease and nearly 10,000 deaths due to hepatitis B.¹

The greatest influenza mortality can be seen among elderly individuals aged 65 years and older.² According to research, this age group has a rate of 98.3 deaths per 100,000 person-years; persons aged 50 to 64 years have a rate of 7.5 deaths per 100,000 person-years, and no other age group has a rate above 0.6 deaths per 100,000 person-years.³ Another group that has been shown to demonstrate increased influenza-related mortality is children; particularly, infants aged 6 months and younger. Studies concluded that the rate of mortality from influenza in children younger than 6 months of age was 0.88 deaths per 100,000 children.⁴ Children with comorbidities have even higher mortality rates. In one series of 149 fatal cases of influenza in children, 59% of those younger than 6 months of age had a chronic condition such as a neurologic or muscular disorder, a gastrointestinal disorder or an upper-airway abnormality. In children older than 6 months of age, 41% had an underlying chronic condition.

Estimates in Moderate and Severe Pandemic Influenza Scenarios Table. Possible results of future influenza pandemic based on extrapolation from past pandemics in the United States. Does not take into account the interventions that were not previously available. Data from U.S. National Vaccine Program Office.

Economic costs

Influenza represents a significant cost to the economy as well. An estimated 100 to 200 million days of illness each year lead to tens of millions of work and school days lost. In fact, it is estimated that 10% to 12% of all lost work and school days are a result of influenza infection. Between 85,000 and 550,000 hospitalizations occur each year due to influenza.⁵ Of these hospitalizations, between 34,000 and 51,000 cases result in death. All of these factors contribute to the annual direct cost of influenza, which is estimated to be between $3 billion and $5 billion annually (with indirect costs as high as $10 billion to $15 billion per year).

Although influenza vaccinations are often considered to be expensive, they can provide a per-patient savings. One analysis showed that a flexible vaccination scheme among children aged 6 months to 5 years could result in a cost savings of $21.28 per child.⁶ Another study found that a group-based vaccination scheme could result in a cost savings of $34.79 per child aged 5 to 17.⁶

Impact of pandemic

An important aspect to consider when discussing the costs of influenza is the potential cost of a future pandemic. Extrapolations from the pandemics of 1918, 1958 and 1968 can provide reasonable estimates of what the figures might amount to. If the next pandemic is severe (resembling that of 1918), then as many as 90 million cases of influenza could occur, resulting in 45 million outpatient visits and 9.9 million hospitalizations (Table).⁷ A total of 742,500 patients could require mechanical ventilation, and 1.9 million deaths are likely to occur. Our health care system does not have the infrastructure in place to handle such a surge.

Impact of Pandemic on Life Expectancy Figure. The 1918 influenza epidemic killed 40 million people and sickened 25% to 30% of the U.S. population.

Summary

The 1918 pandemic resulted in 40 million deaths worldwide, and between 25% and 30% of the world’s population fell ill (Figure, Page 6).⁸ Although the health care system has undergone significant advances since 1918, other difficulties, such as a significant population increase, exist. Readiness for a pandemic, general vaccination practices and prevention practices must be improved upon to ease the tremendous burden that influenza places on society.

References

1. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. 10th ed. Washington DC: Public Health Foundation, 2007.
2. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-186.
3. Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004;292:1333-1340.
4. Bhat N, Wright JG, Broder KR, et al. Influenza-associated deaths among children in the United States, 2003-2004. N Engl J Med. 2005;353:2559.
5. Cohen GM, Nettleman MD. Economic impact of ifluenza vaccination in preschool children. Pediatrics. 2000;106:973-976.
6. White T, Lavoie S, Nettleman MD. Potential cost savings attributable to influenza vaccination of school-aged children. Pediatrics. 1999;103:73.
7. Data from the US National Vaccine Program Office. http://www.hhs.gov/nvpo/.
8. Heinig R. The Flu Pandemic. New York Times Magazine. November 29, 1992.

DISCUSSION Robert B. Belshe, MD: Dr. Wright, you pointed out that in the United States, we really do not have surge capacity in our health care system, and that it is not obvious how one could even develop a system to handle a major outbreak. Peter F. Wright, MD: I see it often in our children’s hospital in the winter when a predictable respiratory syncytial virus (RSV) epidemic occurs, and suddenly people who should be admitted to the hospital are being turned away or are waiting for long periods under suboptimal conditions in emergency departments without access to the more intensive care that might be necessary. When they were actually building our children’s hospital, they asked if we were going to have an RSV vaccine in 4 or 5 years because they thought that if we had an effective vaccine for RSV, then they would build the hospital smaller. I told them they probably should not count on that yet. But nobody asked me how to build a hospital that would manage a pandemic flu. James C. King, MD: I think the current cost savings estimates tend to be conservative. For example, the cost of missing a day of school is often not considered in the equation because it is hard to put a financial marker on that. Another thing that is not considered is those who tend to trudge to work with flu as adults. Even though they may miss 3 or 4 days, they are missing more than that in terms of work productivity and, again, that number is difficult to calculate. I think the cost is substantially more than $10 billion or $20 billion a year. Stan L. Block, MD: The statistics discussed by Dr. Wright were 1990s costs, which are probably half of the current costs today. Another indicator we see in practice is when schools close because of illness. When the schools close, it has a major economic impact because parents must miss work to stay home with their kids, and the school has to shoulder the cost. The schools will always shut down if they get an absentee rate above 10% because it costs them money to keep children in school if they have an attendance rate of 89% or less. Wright: I have always thought that the impact of influenza was disproportionately on the pediatricians in the community and that what we saw in the hospital was really the tip of the iceberg. Researchers are only beginning to define the rest of the iceberg.

Children as amplifiers of influenza
James C. King, MD

Mounting evidence suggests that children are amplifiers of influenza, meaning that they are more likely to spread the virus throughout the community than adults. Children are considered to be amplifiers of influenza for a number of reasons. Studies have shown that children are approximately two to three times as likely as adults to be infected.^1,2 They are also the first group to become ill with influenza during an outbreak and, once they are infected, they tend to shed greater quantities of the virus for a longer duration (up to 2 weeks compared with 1 to 2 days for adults). Children also have poorer hygiene than adults, and they generally have more contact with the community.

For the above reasons, children are much more likely than adults to spread influenza. Because of this, vaccinating school children may be one important tool to reduce the impact of epidemic and pandemic outbreaks. Also, if the incidence of influenza in children can be reduced, then they can remain in school.

Elementary School Absenteeism Figure. The figure represents absenteeism in relation to positive influenza cultures in Baltimore.

Transmission to others

Influenza is easily spread within the school system and is responsible for the majority of excess missed school days above those missed throughout the school year. In one unpublished analysis of absenteeism in two Maryland school districts, the incidence of flu appeared to be closely correlated with the peaks in school days missed (Figure).

School also appears to be one of the largest venues for virus transmission throughout the community. Family studies have shown that the presence of a school child is a major factor for introducing influenza to the rest of the family.^3,4 A recent study in Israel examined an influenza outbreak that occurred just as a teacher walkout closed the schools.⁵ Once the schools closed, there was a 42% reduction in diagnoses of respiratory tract infections among the entire community. There was also a 28% reduction in physician visits, a 28% reduction in emergency department visits and a 35% reduction in medication purposes. Once the schools reopened, these differences disappeared, indicating that schools play a major role in the spread of influenza throughout the community.

School-based vaccinations to reduce illness

The use of school-based immunization programs to reduce influenza transmission has been the subject of numerous studies. One large-scale study evaluated the effect of school-based vaccinations in 11 target schools in Maryland, Texas, Washington and Minnesota. The study also included 17 control schools where no vaccinations were given.⁶ Overall, 46% of the target schoolchildren (n=2,717) received live attenuated influenza vaccine (LAIV), whereas <2% of control school children received the vaccination.

Compared to the control group, families of those in the target schools had significant relative reductions in a number of outcomes. These included a 23% reduction in liberally defined influenza-like illnesses in children, a 35% reduction in CDC-defined influenza-like illnesses, a 36% reduction in pediatrician visits and a 42% reduction in prescription medications (P<.001 for all).

Perhaps more interesting were the downstream results of this experiment. The target school communities had a 36% relative reduction in influenza-like illnesses in adults (P<.01), a 36% relative reduction in work days lost (P<.05), a 26% reduction in adult physician visits (P=.06) and a 40% reduction in high school days lost (P<.01). Clearly, vaccinations in school children had a marked effect on adults and others in the community.

The communal impact of school-based vaccination

In support of these findings, study authors evaluated the communal effects of a mandatory vaccination policy for school children that occurred in Japan between 1962 and 1987. When the program was discontinued, the overall death rates as well as influenza-related deaths rose significantly among elderly people.⁶ Overall, the authors of the study estimated that universal vaccination of school children prevented between 37,000 and 49,000 deaths annually.

An additional study conducted in 1979 compared a school-based immunization program in Tecumseh, Michigan (86% coverage) with the neighboring community of Adrian, Michigan.⁷ There was a marked reduction in respiratory illnesses among adults in Tecumseh compared to those in Adrian, especially among 20- to 29-year-olds (12.7% vs. 8.8%, respectively).

Additionally, a recent Texas-based study found that vaccination of 20% to 25% of children in one community with LAIV resulted in significant reductions in medically attended acute respiratory illnesses among adults in the community without a vaccination program.⁸

Assessing the feasibility of non-mandatory programs

Although school-based vaccination programs appear to curb influenza transmission throughout the community, adopting such a program often meets with legislative and logistical barriers. Because of this, non-mandatory vaccination programs have also been evaluated. The success of the multicenter nasal influenza trial inspired the participating county of the Maryland public school system to request, rather than mandate, that all children in elementary school be vaccinated the following year.⁹ The non-mandatory program resulted in vaccination of 43% of all school children in the county. Notably, with the help of volunteers from neighboring hospitals, clinics and elsewhere in the community, the first 4,500 children were vaccinated in about 5 hours on the first day; overall, it took only 8 days to administer doses. Furthermore, 88% of vaccine-naïve children younger than 9 years old received a second dose.

Targeting children

Conducting vaccination programs within the school system is perhaps the most efficient way to target the source of influenza transmission. The children are a captive audience in this setting, and schools represent an ideal source for mass vaccination within a short period. School-based vaccination programs are also convenient for parents who may not have the time to vaccinate their children individually. Moreover, these large-scale vaccination programs often result in cost savings. School vaccinations may also be a good model for pandemic influenza response, and future efforts should be focused on evaluating the efficacy of school-based vaccination as pandemic control.

References

1. Monto AS, Sullivan KM. Acute respiratory illness in the community: Frequency of illness and the agents involved. Epidemiol Infect. 1993;110:145-160.
2. Fox JP, Hall CE, Cooney MK, et al. Influenza virus infections in Seattle families, 1975-1979. Am J Epidemiol. 1982;116:212-227.
3. Foy HM, Cooney MK, Allan I. Longitudinal studies of types A and B influenza among Seattle schoolchildren and families, 1968-1974. J Infect Dis. 1976;134:362-369.
4. Longini IM, Koopman JS, Monto AS, et al. Estimating household and community transmission parameters for influenza. Am J Epidemiol. 1982;115:736-751.
5. Heymann A, Chodick G, Reichman B, et al. Influence of school closure on the incidence of viral respiratory diseases among children and on health care utilization. Pediatr Infect Dis J. 2004;23:675-677.
6. King JC, Stoddard JJ, Gaglani MJ, et al. Effectiveness of school-based influenza vaccination. N Engl J Med. 2006;355:2523-2532.
7. Reichert TA, Sugaya N, Fedson DS, et al. The Japanese experience with vaccinating schoolchildren against influenza. N Engl J Med. 2001;344:889-896.
8. Piedra PA, Gaglani MJ, Kozinetz CA, et al. Herd immunity in adults against influenza-related illnesses with use of the trivalent-live attenuated influenza vaccine (CAIV-T) in children. Vaccine. 2005;23:1540-1548.
9. Davis M, Magder L, King JC. School-based influenza vaccination of elementary students reduces countywide school absenteeism. Presented at: Annual Meeting of the Pediatric Academic Society; May 5, 2007; Toronto, Canada.

DISCUSSION Robert B. Belshe, MD: Dr. King, you presented a very convincing case of why all children should be vaccinated. Why are they not being vaccinated? James C. King, MD: I am supportive of a universal recommendation to vaccinate school children. True, there are some economic issues when discussing vaccines for children, but it is likely that these programs will save a considerable amount of money in the long run once the indirect effects are considered. Peter F. Wright, MD: On the other hand, substantial progress is being made in the liberalization, or the rationalization, of our recommendations for the use of flu vaccine in children. Stan L. Block, MD: This is true, but there was so much variation in flu vaccine last year it was appalling. There were weeks where there was enough vaccination available, and weeks where there was absolutely none. More manufacturers are needed to deal with supply issues, which are going to potentially change as of this year. King: I think universal recommendations to immunize all school children against influenza is one way to stimulate the production of more influenza vaccine so that the system is ready for a pandemic. Instituting universal vaccination of children will help the country – and the world – to prepare for future pandemics. Keith S. Reisinger, MD: Another issue to point out is that Dr. Arnold Monto did the Tecumseh study when few children were in day care settings. Today, more than 70% of children spend 1 or more days per week in a day care setting. We all know that day care is a vast mixing ground for respiratory viruses. What do you think of the role day care plays in amplification? King: There was one study in San Diego where day care children were vaccinated. This was in the military population where most families had at least one parent vaccinated. Despite this fact, researchers saw downstream effects in the unvaccinated parent in terms of reduction of infection, work and school days lost by household members and medicaton used. I think the results of vaccination are probably even more dramatic in day care. They are much more likely to shed virus for a longer period and probably have less effective hygiene, making them even more likely to transmit influenza. This just extends the spectrum of targets for vaccination. Wright: One interesting concept in very young children is that each year seems to be a pandemic year, because they have never been infected with influenza before. As the children get older, there has been more penetration of influenza, but still, a significant number of young children are seeing influenza for the first time. I have often thought that we have a mini-pandemic each year within the population of young children. King: Many of the school systems now are offering classes for younger children. First, it was kindergarten, and now they’re offering pre-kindergarten, even going as low as 2 or 3 years of age. Many of these are public schools, so this offers an additional way to capture and vaccinate them. However, the variability of day care is so huge (if you count the unregistered ones) that it would be a difficult situation to try to manage in a day care setting in terms of mass vaccination strategies.

Efficacy of influenza vaccines
David I. Bernstein, MD, MA

Two approved influenza vaccines are available in the United States: trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV) (Table). TIV is delivered by intramuscular injection and can be given to children as young as 6 months. Children between 6 and 35 months of age receive one or two 0.25-mL doses (depending on history of vaccination), and children between the ages of 3 and 8 years receive the full 0.5-mL dose. Those older than 9 years should receive one 0.5-mL dose even if they are vaccine naïve.

LAIV, which is administered intranasally, is approved for children 2 years old up to adults 50 years old. Children between the ages of 2 and 8 years should receive one or two 0.5-mL doses based on their vaccination history, and those older than 9 years of age receive a single dose.

A refrigerator-stable formulation of LAIV that does not need to be stored in the freezer was approved by the FDA for use in 2007.

Table: Comparing TIV and LAIV

Methods of protection

The purpose of vaccination is to provide protection from influenza by either systemic or mucosal immunity or both. Immunoglobulin G (IgG) antibodies play a major role in the systemic serum antibody response and work primarily in the lower respiratory tract.¹ These antibodies are critical in preventing the most serious complications of influenza and pneumonia. Serum antibody protection is conferred by TIV and LAIV.

In contrast, immunoglobulin A (IgA) antibodies are found in the mucosal surfaces of the upper respiratory tract. IgA offers protection that is localized at the main site of viral replication; this method of action is found in LAIV only.²

Recent studies have also suggested that T cell- mediated immunity may provide protection against influenza as well.³ Lymphocytes help clear the virus, but their role in protection from infection remains unclear.

TIV vs. LAIV in Healthy Children Figure 1. Comparative efficacy as culture-confirmed modified CDC-ILI in children 6 to 59 months of age. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuation versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356:685-696.

Studies on efficacy

A number of studies have been performed to evaluate efficacy of TIV in healthy children. In general, the efficacy of the vaccine falls into the 60% to 70% range for culture-confirmed influenza. One study in particular looked at the vaccine’s efficacy over a number of years and found that, in years when the A/H1N1 virus was circulating, the vaccine had more than a 95% efficacy.⁴ In years when the A/H3N2 strain was targeted, the efficacy was 68%.

LAIV has been found to be efficacious in 73% to 93% of patients. One study by Robert Belshe, MD, and colleagues found LAIV to be 93% effective in a year when both A/H3N2 and B viruses were circulating.⁵ The following year, the A/H3N2 virus that circulated was mismatched to the vaccine. Despite this discrepancy, the vaccine had an 86% efficacy rate. The same study found that the vaccine also protected against otitis media when the child was infected with influenza.

In a meta-analysis of TIV and LAIV vaccine efficacy trials, the authors determined that vaccination resulted in an overall efficacy of 74% (95% CI, 57% to 84%) against culture-confirmed influenza.⁶ When data were analyzed by the vaccine type, TIV had an efficacy of 65%, compared to an 80% efficacy rate for LAIV.

A study evaluated the effectiveness of LAIV in nearly 20,000 children aged 18 months to 18 years over the 1998-1999, 1999-2000 and 2000-2001 seasons.⁷ In the 2000-2001 season, LAIV was found to be 92% effective against influenza A/H1N1 and 66% effective against influenza B. The combined efficacy of this vaccination was 79%.

TIV vs. LAIV in Healthy Adults Figure 2. Influenza vaccine efficacy in adults aged 18 to 46 years. Adapted from Ohmit SE, et al. N Engl J Med. 2006; 355:2513-2522.

Comparing vaccines

A recent study compared the relative efficacy of TIV and LAIV among 7,852 children between the ages of 6 and 59 months at 249 sites.⁸ Among all viral strains, there was an attack rate of 8.6% with TIV compared to 3.9% with LAIV; this represents a 54.7% reduction (P<.001) in the overall rate by LAIV. For cases of A/H1N1 where all strains matched the vaccine strains, an 88.8% reduction was observed with LAIV compaired to TIV (P<.001) (Figure 1). In cases of H3N2 strains where a mismatch between vaccine an circulating type was observed, there was a reduction of 79.1% with LAIV (P<.001). The two vaccines were similar with regard to efficacy against B viral strains, but this analysis demonstrated a significant reduction in infection in children who received LAIV for both matched and mismatched A viral strains.

Another study compared the two vaccines among adults aged 18 to 46 years during the same year (2004/2005).⁹ A total of 1,247 patients at one site participated in the study; patients were randomized 5-to-1 to receive LAIV or placebo. In a separate 5-to-1 randomization, TIV was compared with placebo.

Interestingly, TIV may have been more effective than LAIV in adults in one study. For overall influenza, TIV had an observed efficacy of 77% compared to 57% for LAIV; however, there was almost no difference between the two vaccines for influenza A/H3N2 strains (Figure 2). The study authors noted that the overall effectiveness of TIV appeared to be mainly due to the decreased ability of LAIV to protect against B strains: in cases of influenza B, TIV had an observed efficacy of 80%, compared with 40% for LAIV.

These two studies suggest that LAIV may be more effective in children while TIV may be more efficacious among adults. One possible explanation for the increased efficacy of LAIV in children is that this population does not have significant pre-existing immunity, and thus the live vaccine can replicate with more ease. This may result in a more robust immune response. Additional comparative research is needed for these assumptions to be confirmed. However, vaccination of children and high-risk individuals is still the best method of containing the virus and reducing transmission throughout the community. It is important to note, therefore, that both vaccines have been proven to be effective in both children and adults, and research in this field is ongoing.

References

1. Smith CB, Purcell RH, Bellanti JA, et al. Protective effect of antibody to parainfluenza type 1 virus. N Engl J Med. 1966;275:1145-1152.
2. Wright PF, Murphy BR, Kervina M, et al. Secretory immunological response after intranasal inactivated influenza A virus vaccinations: evidence for immunoglobulin A memory. Infect Immun. 1983;40:1092-1095.
3. Boyaka PN, Wright PF, Marinaro M, et al. Human nasopharyngeal-associated lymphoreticular tissues. Functional analysis of subepithelial and intraepithelial B and T cells from adenoids and tonsils. Am J Pathol. 2000;157:2023-2035.
4. Neuzil KM, Dupont WD, Wright PF, et al. Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: The pediatric experience. Pediatr Infect Dis J. 2001;20:733-740.
5. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med. 1998;338:1405-1412.
6. Negri E, Colombo C, Giordano L, et al. Influenza vaccine in healthy children: A meta-analysis. Vaccine. 2005;23:2851-2861.
7. Halloran ME, Longini IM Jr, Gaglani MJ, et al. Estimating the efficacy of trivalent, cold-adapted influenza virus vaccine (CAIV-T) against Influenza A (H1N1) and B using surveillance cultures. Am J Epidemiol. 2003;158:305-311.
8. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356:685-696.
9. Ohmit SE, Victor JC, Rotthoff JR, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med. 2006;355:2513-2522.

DISCUSSION Keith S. Reisinger, MD: My feeling about Dr. Ohmit’s study comparing the vaccines in adults is that some issues might have skewed the data.9 It was a large study but, actually, the number of positive cultures they had from the group was small. My point is that the issue of superior adult protection from one of the two types of vaccine has yet to be proven one way or the other. It might be exactly right that adults with LAIV behave differently than do children, but I think the issue is still up in the air. Peter F. Wright, MD: In another study of adults, the differences between live attenuated and inactivated vaccine was not so apparent.1 This makes sense to me, because going back to the earliest studies, which gave live attenuated vaccine to adults, a clinician would get minimal objective evidence that he or she were inducing immunity. David I. Bernstein, MD: I agree with your comments. I always thought that, if a patient were protected against vaccine virus replication, then he or she may also be somewhat protected from natural infection and disease. So, then if a patient’s immunity was low, he or she would get a boost from the live attenuated vaccine. If it was already at protective levels, then perhaps that person did not need the boost. Robert B. Belshe, MD: I want to return to two things that are important to emphasize. One is that despite the fact that Dr. Ohmit’s study was a well-run study and cautiously interpreted, it was small in terms of attack rate. Researchers need to revisit this issue with a large study to get a more precise estimate of the relative efficacy of the two vaccines. To expand on that thought, a clinician cannot study flu vaccine for 1 year and expect to know all about it. A large study that continues for at least 2 years will provide a better view of the relative benefits of these vaccines in adults. The second point I want to comment on is that contacts of high-risk persons need to be vaccinated. Clinicians tend to forget that group. When there is a child under 5 years of age, everybody in the household needs to get vaccinated with one of the two vaccines. Stan L. Block, MD: Yes, but is there enough flu vaccine supply to handle that? The answer is that there is not; there are going to be shortages again and again. Health care professionals are going to have to select certain individuals, or it is going to be a real nightmare. James C. King, MD: That should motivate companies to produce more vaccine. Wright: It does. The supply of vaccine has been going steadily up each year. And there are new manufacturers who are applying for licenses as we speak. Reference Negri E, Colombo C, Giordano L, et al. Influenza vaccine in healthy children: A meta-analysis. Vaccine. 2005;23:2851-2861.

Safety of influenza vaccines
Keith S. Reisinger, MD, MPH

Available influenza vaccines include the trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV). Inactivated vaccines have been in use for more than 50 years and have an excellent overall safety profile. However, there is still a common misconception within the general public that receiving the vaccine may cause influenza infection. Although clinical trials have shown this to be untrue, many patients continue to report flu-like symptoms following vaccination. In a study of 425 patients who received TIV, 6.2% reported fever, 18.9% reported fatigue and 16.0% reported feeling ill in the period after vaccine receipt.¹ However, the individuals in the study who received placebo reported virtually identical symptoms (6.1%, 19.4% and 17.5%, respectively). The only significant difference between the two groups in this study were related to adverse events at the site of injection.

One of the more severe adverse events that has been associated with TIV is development of Guillain-Barré syndrome (GBS). This association was first observed during the 1976 season and confirmed through surveillance performed during the 1992-1993 and 1993-1994 seasons. During these two seasons, a vaccination-associated relative risk increase of 1.5 was observed.² With the background incidence of GBS estimated to be 1 to 2 per 100,000, the excess incidence of GBS due to TIV has been noted to be approximately 1.0 to 1.6 per 100,000.³

Table: LAIV Selected Adverse Events Table. Adverse events in healthy adults aged 18 to 49 years. * P < .05 Source: Nichol KL, Mendelman PM, Mallon KP, et al. Effectivenss of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA. 1999; 282:137-144.

LAIV adverse events

LAIV has been studied for the past several decades. Common adverse events following administration of LAIV are mainly associated with the upper respiratory system (Table). In healthy adults aged 18 to 49 years who received the vaccine, 44.5% reported a runny nose compared to 27.1% who received placebo (P<.05). Cough, sore throat and fatigue were also slightly increased in adults after LAIV administration.⁴

Effects in children

A notable study evaluated the adverse events of influenza vaccination in 8,475 children aged 6 to 59 months who received LAIV or TIV.⁵ In this study, the only children excluded were those with a recent risk of wheezing, severe asthma and those who were immunocompromised. Medically significant wheezing (MSW) was used as the protocol – defined safety end point. (An earlier study indicated a possible association between LAIV receipt and wheezing.)

The rates of serious adverse events were similar between recipients of the two vaccines; LAIV was associated with a slight increase in runny and stuffy nose while TIV caused injection site reactions. The increase in runny and/or stuffy nose reported by children receiving LAIV was noted to occur on day 3 and days 8 or 9 following dosing. The study authors hypothesized that the symptoms occurring on these days may represent the times of greater viral replication.

There was no significant risk of MSW among children who were at least 2 years of age. There was, however, a significant increase in MSW among children younger than 24 months (3.2% LAIV vs. 2.0% for TIV). This difference was observed to occur primarily in children 6 to 11 months of age (3.8% in the LAIV group and 2.0% for TIV). The difference in MSW between the two vaccines was less apparent for those aged 12 to 23 months (2.8% and 2.0%, respectively).

LAIV in asthmatic children

A recent study examined the use of TIV and LAIV in more than 2,000 asthmatic children aged 6 to 17 years.⁶ No differences were observed in asthma exacerbation rates between the two vaccine groups. Hospitalization was uncommon and not significantly different between the two groups, nor was a difference noted in unscheduled clinic visits or an increased need for asthma medications.

Transmission of live vaccine virus

Another issue that must be considered with LAIV is the potential for vaccinated individuals to shed and transmit the vaccine virus. Dr. Timo Vesikari evaluated 197 children aged 9 to 36 months who attended day care in Finland, randomizing participants to placebo or LAIV.⁷ Nasal cultures were performed on the first 2 days after dosing and three times a week for the next 3 weeks. Extensive genotyping and phenotyping was performed on obtained isolates.

During the study, one confirmed case of influenza type B occurred in a placebo recipient who retained the phenotypic characteristics of LAIV. Also, four cases of influenza type A were cultured in the placebo group. These viruses could not be characterized as vaccine-related or wild-type due to inadequate samples. Including the single type B and all four type A vaccine types, the transmission rate was 2.4% (95% CI, 0.13% to 4.6%).

Several small studies in patients with HIV have been performed. Results of these studies have suggested that no prolonged shedding of vaccine virus, no significant increase in adverse events and no adverse effect on HIV viral load or T cell count occur.

References

1. Nichol KL, Lind A, Margolis KL, et al. The effectiveness of vaccination against influenza in healthy, working adults. N Engl J Med. 1995;333:889-893.
2. Langmuir AD, Bregman DJ, Kurland LT, et al. An epidemiologic and clinical evaluation of Guillain-Barre syndrome in association with the administration of swine influenza vaccines. Am J Epidemiol. 1984;119:841-879.
3. Advisory Committee on Immunization Practices. Morbidity and Mortality Weekly Report. 1998;47:1-6.
4. Belshe RB, Nichol KL, Black SB, et al. Safety, efficacy, and effectiveness of live, attenuated, cold-adapted influenza, vaccine in an indicated population aged 5-49 years. CID. 2004; 39:920-927.
5. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356:685-696.
6. Fleming DM, Crovari P, Wahn U, et al. Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr Infect Dis J. 2006;25:860-869.
7. Vesikari T, Karvonen A, Korhonen T, et al. A randomized, double-blind study of the safety, transmissibility and phenotypic and genotypic stability of cold-adapted influenza virus vaccine. Pediatr Infect Dis J. 2006;25:590-595.

DISCUSSION Robert B. Belshe, MD: It is important to discuss transmission of vaccine now that several million doses have been used in clinical practice. The CDC has been looking at adverse events and actually published a paper on the long-term surveillance in clinical practice with live vaccine. And, as I recall, no documented instances of transmission occurred. Keith S. Reisinger, MD: It is important to understand that shedding of vaccine virus does not necessarily lead to transmission nor does transmission equate to clinical disease. Belshe: The amount of virus shed is also considerably less than what is involved in typical transmission. Reisinger: One possible explanation that has been observed with regard to medically significant wheezing in children under 12 months of age is that the dose is too high. However, wheezing was not occurring during the times of viral replication. Most of the wheezing occurred 2 to 3 weeks post-dosing, pointing to a possible heightened immune response in young children. Stan L. Block, MD: We should probably talk about hospitalizations and Dr. Belshe’s studies for 6- to 12-month-olds vs. 12- to 24-month-olds because I just heard recently that the inhaled vaccine is probably not going to get approved for 24-month-olds. I remember seeing the 12- to 24-month-old group with wheezing having a higher hospitalization rate. Who is familiar with these data? Reisinger: Among children who received LAIV and had a previous history of wheezing, all-cause hospitalization was higher in every age bracket up through 48 months when compared to TIV recipients. Block: But where does it become statistically significant? Reisinger: It was not statistically significant in any one year, but, when the age groups were combined, it becomes a statistically significant event. James C. King, MD: One needs to balance this small adverse event rate against actual influenza infection. What is the risk to a child of becoming infected vs. the risk of an adverse event, such as wheezing? The real risk lies in not getting vaccinated.

Practicalities of influenza vaccination
Stan L. Block, MD

Last year, the Advisory Committee on Immunization Practices (ACIP) updated current recommendations for influenza vaccination.¹ In response to recent data highlighting the benefits of mass immunization of children, the ACIP now recommends vaccination of all children between the ages of 6 and 59 months. Furthermore, children between the ages of 6 months and 8 years should receive two doses if they are vaccine naïve or if they had only one dose in their first vaccination season. The ACIP now also recommends that all of the household contacts of high-risk individuals, such as anyone in a household with a young child, be vaccinated as well.

Additionally, the updated guidelines recommend more effective outreach programs and infrastructures designed to increase vaccination rates. Finally, the recommendations now suggest vaccinating through January and February, rather than stopping in December as had been previously advised by the ACIP.

Timing of vaccinations

One practical issue, particularly among the youngest recipients of vaccine, is timing of administration. A child who comes into a clinic in September at 4 months of age might not return for 5 or 6 months, making it difficult to adhere to the recommended dosing schedule. On the other end of that spectrum, if a 59-month-old child comes in before the vaccine is available for that year, he may not receive the vaccine because in 3 months, when the vaccine is available, he or she will be older than the recommended age of vaccination. A broader, more universal vaccination program among infants may help to increase vaccination rates and reduce such complexities and supply shortages, but vaccination schedules will undoubtedly continue to pose a challenge.

The second dose recommendation also represents a barrier to complete vaccination. Because a vaccine-naïve child needs two doses to have reasonable protection against influenza, he or she must be brought to the clinic twice. Research has shown that only 20% to 30% of those who need a second dose actually receive it. Furthermore, the crowded immunization shot schedule for children between the ages of 6 and 15 months often overshadows the need for an additional influenza shot.

Influenza Vaccination Survey — Practice and Family Barriers

Issues with ordering of vaccines

Practitioners also face challenges when ordering adequate amounts of the flu vaccine ahead of time. Having either too much or too little vaccine in a given year can have economic repercussions, and it is often difficult to estimate how many doses are required. When ordering influenza vaccine, clinicians must consider staff and families, as well as children and newborns. Among the 12- to 24-month-old group, most practices should assume that approximately 50% will be returning for a second vaccination even though this age group is often being seen at a number of different time points (1.5 doses per child). Among 2- to 3-year-olds, a 20% vaccination rate may be an adequate estimate, and many will require two doses because in previous years they would have received only one dose.

Among 4- and 5-year-olds, there is a chance that having enough live attenuated inactivated vaccine (LAIV) available will allow vaccinations to be administered at school physicals, but accounting for 25% of this age group will also add to the total vaccines required. And finally, for all age groups of children older than 5, approximately 10% to 20% will likely receive vaccines each year. Clearly, all of these estimates make it nearly impossible to accurately gauge how much vaccination should be ordered in a given year.

How many doses of each type of flu vaccine?

Once the number of doses has been calculated, determining how to order the ratio of the two available vaccines – and in what amounts – is another challenge. Ordering the trivalent inactivated vaccine (TIV) is difficult because it must be ordered 9 months in advance. To determine the number of patients who will need the TIV, practitioners must know how many children in their care suffer from wheezing or asthma, or other chronic medical conditions that call for TIV instead of LAIV. In most offices, 20% to 30% of the total number of children will fit these characteristics.

LAIV provides more flexibility, as it can be ordered prior to or during a season, so practitioners who use this vaccine have the option of replenishing within days once supplies are low. Up to 60% of patients in a given office can receive LAIV. Also, LAIV has an approximate $5.00 lower cost differential over TIV. However, in terms of ease of administration, LAIV does not require a syringe/needle and needs only minimal nursing time to be administered. Additionally, most children prefer a nasal spray to a shot.

Other barriers to immunization

Perhaps the most notable barrier to immunization is influenza’s seasonal aspect. The vaccine must be administered annually, and the two vaccine types will have limited windows (3 to 4 months for TIV, 6 to 7 months for LAIV). Additional hurdles include the fact that the vaccine is not mandated and guidelines are not well known, leaving pediatricians wondering to whom the vaccines should be given and how much time should be spent convincing families of the importance of vaccination. Misguided beliefs (among both parents and some practitioners) that influenza is not life-threatening and that the vaccine is not intended for healthy children also contribute to less-than-ideal vaccination coverage.

An analysis by the Centers for Disease Control and Prevention found that the upfront vaccine costs are the most frequently observed barrier to complete vaccination coverage for both practitioners and families. Additional obstacles include inability of practitioners to identify which children need the vaccine, the amount of time needed to discuss vaccine safety and efficacy and the need for extra visits (confirmed by a 2003 study)² (Figure). For families, the other barriers included a crowded infant vaccine shot schedule, safety concerns and the belief that influenza is not severe enough to warrant vaccination.

A study that focused on these parental attitudes as barriers and predictors of influenza vaccination found that physician recommendations and a parental perception that vaccination is the standard of practice both greatly increased the chances of a child being vaccinated.³ What keeps parents from having their children vaccinated? Less parental education, a preseason intent not to immunize and preconceived barriers.

Private practice immunization model

A good pediatric private practice model for vaccination entails offering each patient and his or her family vaccination at every clinic visit from September to December. However, this can begin earlier for LAIV, as it becomes available in July or August. Vaccinating at most acute care visits is a good way to ensure vaccination and to help the patient and practitioner to avoid extra visits. If possible, practices should offer walk-in vaccination hours on Saturdays and evenings, but research has suggested that it is difficult to encourage patients to attend these clinics unless influenza has already impacted the community. Local health departments should have standing orders to vaccinate all children, and school nurses could offer the vaccine to all students.

Increasing awareness among parents is crucial. Posters and fliers should be displayed and available as early as June. Mailings and handouts at each office visit will also help spread the message that vaccines are important.

Secret to success

As the data continue to demonstrate the benefits of universal vaccinations in children, barriers to immunization should be easier to overcome. The secret to a successful vaccination program in any office, however, is that the physician must first be convinced of its necessity. He or she must believe that influenza is common, significant and risky, and then that the vaccine is safe, effective, economical and acceptable to the patient. If these goals are achieved, then many of the practical obstacles can be overcome.

References

1. Advisory Committee on Immunization Practices. Prevention and control of influenza. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5510a1.htm?s_cid=rr5510a1_e. Accessed June 29, 2007.
2. Szilagyi PG, Iwane MK, Schaffer S, et al. Potential burden of universal vaccination of young children on visits to primary care practices. Pediatrics. 2003;112:821-828.
3. Daley MF, Crane LA, Chandramouli V, 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:e268-e277.

DISCUSSION Stan L. Block, MD: In Kentucky, my practice is one of the largest administrators of the nasal vaccine. In fact, everybody in my office is asked to get the nasal vaccine. The staff must be onboard, so it is up to us as clinicians to make them well aware of the importance of getting an annual flu vaccine. If clinicians believe in it strongly and with conviction, then nurses and office staff will mimic that behavior and relate the recommendations to patients. Robert B. Belshe, MD: If there were a universal recommendation to vaccinate all children under 18, then how would you implement it? Block: It would need to be school-based or state mandated. We know from the hepatitis B vaccine that the practitioners cannot get the older kids vaccinated in the office. There is no doubt about this. The hepatitis B vaccine was administered to about 15% of students annually until the schools began mandating it; now, nearly every child has received a hepatitis B vaccine, so we have proof that school-based programs work. Until it is administered at schools or mandated for schools, universal vaccination just will not happen; the uptake will continue to be 10% to 20% in older children and teens, as it is today. Belshe: You indicated you could get the live vaccine basically on demand. Is that the way you are doing it? Block: We have six pediatricians and one nurse practitioner and we have about 15,000 active candidates for the vaccine. We probably preordered 1,000 doses of TIV and about 2,000 or 2,500 doses of LAIV this year. But we do not know exactly how good the uptake is going to be, and who is going to come in. The other big issue is whether you can give LAIV to a child who has a runny nose or a cold. It needs to be emphasized that it can be given even if a patient has allergies or a runny nose and/or a cold because we did it in our studies and it successfully prevented the flu. Belshe: But LAIV should not be given if a patient has a fever. Keith S. Reisinger, MD: We use it if they can sniff. Block: Keep in mind, though, that they do not need to sniff the vaccine for it to be effective. You do not want to put that notion across; that the vaccination does not actually need to be inhaled, right? James C. King, MD: There is still a learning curve with the live vaccine. Because despite us giving it for free, in other states you can only get the vaccination rate up to about 40% or 50%. So, there is still some reservation about getting this vaccine. Luckily, I think that education is causing that reservation to slowly erode away.