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Immunization Against Viral Respiratory Disease: A Review

Greenberg, Harry B. MD*; Piedra, Pedro A. MD

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The Pediatric Infectious Disease Journal: November 2004 - Volume 23 - Issue 11 - p S254-S261
doi: 10.1097/01.inf.0000144756.69887.f8
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Respiratory viruses are a major cause of childhood morbidity and mortality. Most respiratory viruses are seasonal, with peak infections usually occurring during winter in temperate regions. Acute respiratory infections, particularly those caused by respiratory syncytial virus (RSV)1 and influenza virus,2 account for a major portion of medically attended illness and hospitalization of children younger than 5 years of age. It is worth emphasizing that complications secondary to viral-induced respiratory disease (eg, otitis media, pulmonary disease, secondary bacterial infections) are not limited to high risk children but also frequently affect otherwise healthy children.3,4 For example, during the 2003–2004 influenza season in the United States, >152 influenza-related deaths occurred in children of whom approximately three-fourths were previously healthy.5

RSV is the principal cause of hospitalization in the first year of life for children in most parts of the world, and nearly 100% of children in the United States are infected with the virus by age 3.6 Each winter, RSV infects up to 80% of children younger than 2 years of age.7–10 RSV infections are most severe in premature infants, and from 1990 through 1999 RSV was the leading viral cause of infant death in this group.8 Infants admitted to the hospital for RSV infection often require oxygen supplementation, intensive care and mechanical ventilation. Several distinct disease syndromes are associated with RSV infection in children: bronchiolitis in infants; sudden infant death syndrome/apnea; and postinfection wheezing and childhood asthma. Currently no licensed vaccine is available for RSV prevention.11–13

Recent data have implied that childhood influenza is a greater medical problem than originally perceived because it can cause excess hospitalizations, medical visits and antibiotic prescriptions in healthy children, especially those younger than 2 years of age. Of all the respiratory viruses, influenza has the highest incidence of infection and therefore is also the most vaccine-preventable respiratory illness.14 Although school age children do not usually have to be hospitalized for influenza infections, they do experience the highest influenza infection rates and are therefore the prime source of infection in a community. In children up to 4 years of age, the hospitalization rate is ∼500 per 100,000 children with high risk medical conditions and 100 per 100,000 children without high risk conditions.2 The burden of influenza disease is also underscored by the fact that it leads to >25 million physician visits each year15 with direct medical costs in the United States ranging from $1 to 3 billion.16 Complications of influenza in children range from acute otitis media, sinusitis, bronchitis and pneumonia to rare episodes of encephalitis, myositis, myocarditis, febrile seizures, encephalopathy and Reye's syndrome. Because school age children tend to be the primary vectors of influenza epidemics,17 they are the optimal target for immunization to prevent influenza in the general population through herd protection.

Other troublesome respiratory viruses include human metapneumovirus, which infects 5-6% of hospitalized children with respiratory tract infection, most of them younger than 5 years of age.18 Human metapneumovirus and RSV have similar clinical presentation in children.19 Parainfluenza viruses as a group cause the second highest number of hospitalizations for lower respiratory tract infection in children younger than 18 years of age.20 Parainfluenza virus infections cause a spectrum of respiratory illness similar to RSV, although they typically result in fewer hospitalizations. Adenoviruses are another important cause of acute respiratory illness in children, causing ∼5% of the lower respiratory tract illnesses. A vaccine for the general population is not available. Other viruses like rhinoviruses and enteroviruses contribute to the overall burden of respiratory disease during childhood.21 Severe acute respiratory syndrome (SARS) is an emerging respiratory virus that was first recognized in Hong Kong during a 2003 epidemic.22 Morbidity was high after SARS with approximately one-fourth of patients requiring intensive care unit care/mechanical ventilation support. SARS morbidity and mortality appear to be less severe in children than in adults. Mortality ranged from 3 to 7% with good supportive care but tended to be higher in persons with comorbid conditions or older than 40 years of age. The etiologic agent of SARS is a newly identified coronavirus. Vaccines for these viruses are being investigated but are not yet available.

Vaccine History.

In the past 100 years, vaccines have been one of the most effective tools for preventing communicable disease and death. The first viral vaccine was developed against smallpox in the 18th century, when the disease killed thousands of infants and young children. Through worldwide vaccination programs, smallpox was also the first viral infection declared eradicated worldwide by the World Health Organization (WHO) in 1977. In 1951–1954, polio infected >16,000 Americans annually. Polio vaccine was introduced soon afterward, and subsequent vaccination programs led to its eradication in the United States in 1972 and from the Western Hemisphere by 2000.23 WHO declared the European region polio free in 2002.24 By the end of the 20th century, the U.S. Centers for Disease Control and Prevention (CDC) reported that the number of childhood vaccinations had reached an all time high and that morbidity and mortality from diphtheria, pertussis, tetanus, measles, mumps, rubella and Haemophilus influenzae type b were at record low levels (Table 1). 23

Vaccine Facts

Because viral respiratory illness represents a major burden to children, parents and society worldwide, WHO is spearheading a mission to develop and distribute effective vaccines to prevent/reduce key viral respiratory diseases. Their mission is largely based on the fact that acute respiratory infections overall cause an estimated 3.9 million deaths each year and are the leading cause of death in children younger than the age of 5 years. Respiratory viruses, such as RSV and influenza virus, are 2 common etiologies of acute lower respiratory tract disease in children. Viral-induced respiratory infections cause substantial mortality and morbidity in children living in developing countries and still cause substantial morbidity in a sizeable proportion of children who reside in industrialized nations. Accordingly vaccination of susceptible populations (eg, at risk children) is the most effective means of reducing disease, societal burden and death from viral diseases.20

Viral Respiratory Disease and Vaccines.

The goals of any vaccination program for viral respiratory infections include the prevention of lower respiratory tract infections, prevention of infection-associated morbidities such as acute otitis media, hospitalization and mortality not only among children but also among all members of the community. Indirect benefits of a successful program could include a reduction in the sequelae of respiratory infections, such as wheezing, asthma, sinusitis and otitis media, and a decrease in inappropriate antibiotic use for viral infection, which in turn would reduce the emergence of antibiotic resistance.

The remainder of this article focuses on recent vaccine developments directed at 2 key viral respiratory illnesses in children: influenza and RSV.


Vaccination is the primary mode of influenza prevention. Two types of vaccine are available for influenza immunization. Both contain the same 3 influenza strains, A(H3N2), A(H1N1) and B, most likely to cause infection in the upcoming season. The segmented RNA genome and the high genetic mutation rate of the influenza virus facilitate genetic changes, enabling it to evade host immunity. These changes necessitate yearly adjustment in the influenza subtypes present in the vaccines. The influenza virus evolves genetically by 2 mechanisms: antigenic shift and antigenic drift.

Antigenic shift, usually caused by the reassortment of gene segments between 2 virus strains, is a profound antigenic variation that occurs only in influenza type A viruses. In circulating human viruses, antigenic shifts bring about a strain with a new, highly distinct antigenic profile. Shift events can involve gene reassortment among influenza A strains from mammalian species and humans. For instance, genome segment reassortment can occur in a pig infected with both human and avian influenza viruses, if both successfully replicate their genome. Antigenic shift occurs infrequently, but when it happens it can cause a pandemic. For example, avian strains of influenza have been implicated in the influenza pandemics of 1918, 1957 and 1968.

Antigenic drift is a relatively minor antigenic variation within a subtype, in particular a point mutation, that may occur in both influenza types A and B viruses. Drifted strains could cause a new epidemic if the strain of the previous year does not provide cross-protection against the drifted strain. Strain drift occurs regularly, about every second year and is the main reason for the almost annual changes in the vaccine composition (Fig. 1).25

Characteristics of antigenic shift and drift in the influenza virus.25

Trivalent Inactivated Vaccine (TIV).

Currently TIV is the most widely used influenza vaccine. Administered intramuscularly, TIV is indicated for all persons older than 6 months of age.26 Although effective, only about 80–90 million doses of TIV have been available annually in the United States during the past few influenza seasons. This leaves unprotected at least 100 million people who should be vaccinated, according to guidelines of the CDC.27 Currently <10% of healthy children, <30% of healthy adults and <30% of high risk children are vaccinated against influenza.1

This situation was complicated in the 2003–2004 influenza season when the antigenically drifted A/H3N2/Fujian strain was the predominant circulating strain (83%) but was not included in the vaccines. Consumer demand for vaccine increased after reports of flu-related deaths in children in November. TIV doses were depleted in some parts of the United States, although some areas had an excess supply. In general, the efficacy of TIV has varied in clinical studies. Efficacy in healthy adults younger than 65 years of age has been between 70 and 90%. Studies in children have shown efficacy from ∼30–90%, with lower efficacy in younger children.28 TIV is well-tolerated, and its side effects are similar to those seen in placebo groups, except that it has a higher rate of injection site reactions.

Live Attenuated Influenza Vaccine.

A live, cold-adapted, attenuated influenza virus vaccine (LAIV) indicated for healthy persons 5–49 years of age was available for the first time in the United States during the 2003–2004 influenza season.29 Delivered by large particle intranasal mist, LAIV has been shown to be 70–90% effective in most patient populations.26,30,31

LAIV Efficacy in Children.

Several studies examined the effectiveness of LAIV in children. In a 2-year multicenter, double blind, placebo-controlled pediatric efficacy trial, Belshe et al31,32 found that both a 1-dose and a 2-dose regimen of LAIV were ∼90% effective against both influenza [A(H3N2) and B] strains circulating during the first study season. In the second year, the major circulating influenza virus [A/Sydney (H3N2)] was a drift variant not included in the vaccine. LAIV was highly effective (86%) against the drift variant as well.

Recently data from an ongoing series of community-based nonrandomized, open label studies in Texas were published. In this series, LAIV was given to children 18 months–18 years of age during the influenza seasons from 1998 through 2001. Influenza A/Sydney/05/97 (H3N2) and B/Beijing/184/93-like strains were included in all 3 years. A/New Caledonia/20/99 (H1N1) replaced A/Beijing/262/95 (H1N1) in year 3. LAIV was found to be 79% effective against influenza A (H1N1) and B combined, 92% effective against influenza A (H1N1) alone and 66% effective against a new variant of influenza B.33,34

These studies showed the efficacy in children of the live attenuated vaccine against circulating strains whether or not they were contained in the vaccine. Efficacy against variant strains is an especially desirable characteristic in an influenza vaccine in view of the continuous shifting of circulating influenza strains.

LAIV Safety Studies.

Safety, along with efficacy, is a critical component of any vaccine evaluation. Several studies have found LAIV to be generally well tolerated, with side effects that do not differ significantly from those seen in placebo groups.28 One recently published study showed that LAIV was generally safe in children and adolescents but also indicated a potential increased risk of asthma/reactive airway disease in children 18–35 months of age. No increased risk of asthma/reactive airway disease was observed in other age groups, and no temporal clustering was found between the asthma event and receipt of the vaccine.35 Also, when the diagnoses asthma, reactive airway disease and wheezing were combined, no statistically significant differences were identified in any age group.35 In community-based nonrandomized, open label studies in Texas, 18,780 doses of cold-adapted, attenuated trivalent influenza vaccine (LAIV-T) were administered to 11,096 children from 1998 to 2002; 4529 doses of LAIV-T were administered to children 18 months–4 years of age. The LAIV-T vaccine was safe and not associated with an increase in health care utilization. Children 18 months–4 years of age tolerated LAIV-T as well as children 5-18 years of age. Approximately 10% of the children enrolled in this study had a history of asthma, reactive airway disease or wheezing. Further studies are planned to more fully evaluate this potential risk.36

Another important safety issue with live attenuated virus vaccines is whether the virus will be shed, and if so, whether it will revert to the wild type and cause illness and/or be transmitted to others. In a Finnish day-care center, 98 children were immunized with LAIV, and 99 children received placebo.37 Both groups had samples taken for culturing of influenza virus 3 times/wk for 3 weeks. Cultures showed that 1 placebo recipient shed an influenza B vaccine strain on day 15. This single case of transmission was detected in a highly susceptible group of subjects: very young children in day care. Prior transmission studies in older children or adults, in whom shedding is less prolonged and at lower levels and in whom susceptibility is less as well, had been negative.1 The single placebo recipient who shed vaccine had no symptoms that differed from those of the other placebo recipients. The vaccine virus cultured from the placebo recipient antigenically and genetically matched a virus shed by one of the other children in the playgroup who was vaccinated with LAIV. There was no evidence of phenotypic reversion of the vaccine strain shed by the placebo recipient or by any of the subjects who actually received vaccine. Vaccine viruses that were shed had the exact same phenotype as the vaccine strains in general: cold adaptive, temperature sensitive and attenuated in ferrets.

Viruses shed from all vaccines were also cultured and genetically sequenced. This was done to determine whether changes were occurring in the live, attenuated vaccine strains as the virus replicated in humans that might lead to a loss of its attenuation. Comparison of the sequence of shed vaccine strains with the sequence of the input vaccine indicated that there were no sequence changes in the sites linked to the attenuation or temperature-sensitive phenotypes of either the A or B vaccines.


Recognizing the high risk of influenza infection among children younger than 2 years of age, the CDC's Advisory Committee on Immunization Practices (ACIP) recently changed their recommendations for influenza vaccination to include children 6–23 months of age. For many health care providers, this brought up the question of whether all children should be vaccinated.

Several studies support the concept of immunization of all children, not only those at high risk. A survey conducted in Tecumseh, MI, collected data on acute respiratory infection in ∼10,000 persons. Data were collected using questionnaires to identify illness onset, specimens were collected to identify causative pathogens and blood was collected for serologic studies. The study identified influenza as the most frequent virus infection in children 5–19 years of age and showed that children as an age group had the highest average influenza infection rates during a 5-year period.14

Thus school age children are the main source of influenza infection in a community. Immunologically naive or relatively naive children spread the infection to each other in school and bring it home to their family members and other close contacts. Influenza infection peaks around February in the United States, a time when most children are grouped together in school.

Shedding of wild-type virus usually begins 24 hours before the onset of symptoms and can last 4–5 days after symptoms begin. Children may be infectious for a longer period, possibly >10 days, and young children may shed virus for almost 6 days before symptoms appear.

Influenza causes more serious and longer lasting illness than the common cold and can have debilitating complications in children, including acute otitis media, sinusitis, bronchitis and bronchiolitis, pneumonia and other respiratory tract infections. It could also lead to asthma and, rarely, encephalopathy. Mortality, although not high, does occur. In 2003–2004, there were 152 laboratory-confirmed deaths from influenza among children, three-fourths of whom were not considered to be at high risk; almost one-half of these children were of school age (between 5 and 17 years of age). Mortality in children may actually be higher than this, given that these numbers are extrapolated from reports collected by the CDC each week from ∼900 health care providers around the country.1,5,38

Current ACIP vaccination recommendations focus on high risk persons and do not include the main vectors of influenza spread in the community, that is, school age children. Control of the spread of influenza through a universal immunization program for children could benefit both the children themselves and the community at large, including at risk populations.14,39 This was demonstrated by a long term obligatory vaccination program (1977–1987) in Japanese school age children that substantially reduced influenza-related mortality in all age groups, including the elderly, and prevented 37,000 to 49,000 deaths per year.40


Several factors have interfered with the development of an RSV vaccine. First, those children with the most severe RSV infections who are most in need of vaccination, newborns and young infants, have a weak immune response. In addition, circulating maternally derived antibody may interfere with the infant's immune response. Vaccine development was also greatly hindered by the experience in the mid 1960s with a crude formalin-inactivated, alum-precipitated RSV vaccine that potentiated RSV disease in clinical trials.41

Establishing Minimum Protective Threshold Levels of Anti-body.

Determining the antibody response needed for prevention of infection is key to producing a successful vaccine. Piedra et al reported that during the RSV season, those infants who had the highest level of serum neutralizing antibody titers (maternally derived antibody) were less likely to be infected with RSV than those who had lower levels (odds ratio, 0.83). The mean difference in antibody titers between infected and uninfected children was about 1 log, approximately a 2-fold difference.

During the second year of life, when the children as a group had the lowest level of neutralizing antibodies, RSV infection rates were at the highest and close to 70%. In their third year, when children were able to mount a somewhat better immune response and maintain it, the infection rate decreased to ∼60% and, as in the first season, there was a 2-fold difference in the mean serum neutralizing antibody titers between those who were infected with RSV and those who were not. This suggests that even a modest increase in neutralizing antibody titers may be beneficial. Thus the highest attack rate for RSV (close to 70%) occurred during a child's second RSV season. About 50% of children were infected in their first year and 60% in their third year (Fig. 2).42

RSV infection rates in children during their first 3 RSV seasons. The highest attack rate for RSV (close to 70%) occurs during a child's second RSV season.

Over time with repeated RSV infections, antibody titers increase and then plateau at ∼5–9 years of age.43

To determine the minimal protective level of serum neutralizing antibodies needed to protect an individual against severe RSV infection, Piedra et al43 correlated serum neutralizing antibody levels with RSV-associated hospitalization in individuals hospitalized for acute respiratory diseases during a 5-year period. They found that of children younger than 1 year of age with primary RSV infection and 1–4 years with primary RSV or reinfection, ∼40% were hospitalized. By the fifth year of life, the proportion of those hospitalized remained relatively steady at ∼5–10% and continued through 65 years of age and older.

Comparing the antibody levels at the time of hospitalization between those who were hospitalized due to RSV infection and those with infections caused by some other respiratory pathogen, it was observed that those who had RSV infection had lower levels of serum neutralizing antibodies to RSV than those not infected with RSV. Each 1 log 2 increase in titer decreased the likelihood of having an RSV-associated hospitalization by ∼20%.

Subsequently they separated the antibody titer data into quartiles and found that those patients who had antibody levels above the first quartile (≥6 log 2 for the RSV A virus or ≥8 log 2 for the RSV B virus) were less likely to have an RSV-associated hospitalization (odds ratio, 0.28). Such titers would produce an ∼70% reduction in RSV-associated hospitalization and would be a good target for an RSV vaccine to achieve.

Current Approaches.

Several possible formulations for an RSV vaccine are being investigated.

Subunit vaccines have focused on the first, second and third generation of the purified fusion protein (PFP-1, PFP-2 and PFP-3). The initial PFP-1 had relatively low concentrations of the G protein but enough to induce an antibody response.

The first and currently only maternal immunization study was conducted with the PFP-2 vaccine.44 Although very safe for infants, the vaccine was not very immunogenic. At the time of delivery, ∼6 weeks after maternal vaccination, the mean increase in serum neutralizing antibodies was only ∼2 logs. Maternal antibody decay in these children was about 1 log 2 in serum neutralizing antibody titer every 35 days. There was a significant increase in the production of IgG binding antibody to the fusion protein in the breast milk at 2 and 6 months compared with that in the placebo recipient. However, IgA binding antibodies to the fusion protein in breast milk did not increase significantly. The protective properties of the breast milk may have been substantially enhanced had both the IgG and IgA titers been boosted.

Live, attenuated vaccine formulations are cold-passaged, temperature-sensitive vaccines or genetically engineered vaccines. Live attenuated vaccines were initially either underattenuated or overattenuated, a problem that persists in research into this kind of vaccine. Live, cold-passaged, temperature-sensitive RSV vaccines have been tested in adults, seropositive children and infants. Although found to be safe and somewhat immunogenic in seropositive children, these vaccines were not sufficiently attenuated for use in infants, who are the most susceptible to RSV infection. In infants, the viruses frequently had prolonged replication with modest antibody titers. Some isolates lost their temperature-sensitive phenotype, and there was 20–25% transmission to unvaccinated contacts.45

Genetic engineering may provide better control of the changes required to make an RSV vaccine safe and immunogenic in young children. One promising approach uses reverse genetics to substitute an RSV surface glycoprotein for one of the surface glycoproteins of the bovine parainfluenza virus.46,47

A polypeptide vaccine approach used BBG2Na (amino acids 130–230 of the G protein fused to the albumin-binding domain of the streptococcal G protein); however, this research has not moved forward because of safety issues.

In conclusion, an anti-RSV immunization program could include several strategies, including maternal immunization, primary immunization within the first year of life, immunization of high risk groups (as in the current influenza guidelines) and universal immunization.

Prophylaxis of RSV Infection.

Although no RSV vaccine has been developed, RSV prophylaxis is available for premature infants and for children with high risk conditions through palivizumab, a humanized monoclonal anti-RSV antibody. In clinical trials, palivizumab reduced RSV-related hospitalization rates by 55% in all patients and by 80% in infants of 32–35 weeks gestational age.48

A new drug for RSV prophylaxis is now in development that is 50–100 times more potent than palivizumab at reducing virus in both the lower and upper respiratory tract of test animals.49 The inhibition of nasal RSV replication could impact on wheezing and reactive airway disease and possibly prevent the development of asthma in high risk children.49


Although effective vaccines are available for some viral respiratory pathogens, such as influenza virus, there continues to be a lack of efficacious vaccines for the majority of the mucosally restricted respiratory viral pathogens. A continued effort is needed toward the development of safe and efficacious vaccines for prevention of all childhood viral illnesses. New approaches are vital towards WHO's goal of curbing these infectious diseases in all age groups in developed and developing nations.


Question: You said that the comparative trials between FluMist and TIV, the overall efficacy ranged from 38% to 53%. Was that for both groups or for a subset on FluMist?

Harry Greenberg, MD: The unpublished studies you mention, comparing Flumist and TIV, did not include placebo groups, so true efficacy rates cannot be calculated. The first study I showed you from Wyeth was a placebo-controlled trial. That was a large study in young children. And the overall efficacy in this study was 80% to 90%. That is almost identical with Dr Robert Belshe's earlier data.32 And there are now other studies from Texas that also show similar levels of efficacy for LAIV.

The 2 unpublished studies I mentioned which directly compared TIV to LAIV were primarily looking at either asthmatic children directly or at very young children who were prone to recurrent respiratory infections. Those studies were done first, to show safety in these populations because that is an important question; and second, to make sure that the live-attenuated vaccine was not inferior to inactivated vaccine. The differences I mentioned were the percentage of diminished efficacy of TIV versus LAIV in these 2 studies.

Question: Was there a serologic correlate of response to an infection in the child who had the vaccine strain in the Finnish study.37

Harry Greenberg, MD: The Finnish day-care study was not conducted with serology. As you can imagine, the Finnish parents—as parents of day-care age children in many places—saw no reason for their children to have blood samples drawn. Therefore the children only underwent nasal swabbing. There is no serology associated with that study.

Question: In addition to the misclassifications concerning wheezing illness versus 493 [code], at the ACIP meeting it was reported that if you looked at all the 493 codes, which is the code for asthma, and you examined the clinical record and selected only the children who actually had wheezing on the day they were seen with a 493 code, there was no significance. Can you comment on this?

Harry Greenberg, MD: I was not at that ACIP meeting and so cannot comment directly on your question. However, any rational analysis of the asthma data from the Kaiser study would have to say that it is absolutely biologically plausible to detect an asthma signal because many viral infections appear to have the ability to exacerbate asthma. If I had to predict, I would say that if you gave enough FluMist to enough children with asthma, you might be able to detect some increased amount of mild asthma exacerbations. But, I feel that you would have to give it to an awful lot of people to detect that signal and that the actual importance of this is very likely to be minimal compared with the beneficial effects of the vaccine in preventing flu and all its sequelae. However, the data, it would seem to me, it is not at all clear that what happened in the Kaiser study actually was a clear causal association of LAIV administration and subsequent asthma events. The reason I say that is because, as I showed in my presentation, there are data both supporting and refuting this association. There are now beginning to appear additional data with significant numbers of children that are not showing the association of LAIV and asthma. I think we are left simply with the fact that we need more data to really understand the level of risk, and I think such information will be developed by MedImmune in the coming couple of years.


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