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Chapter 16 – Influenza vaccine-live
Effective prophylaxis to prevent influenza virus infection is unquestionably valuable in view of the recurrent and enormously widespread disease caused by influenza viruses. Vaccine development for the control of influenza is desirable based on observations that recovery from infection is accompanied by antibody development that confers resistance to reinfection and that circulating antibody levels similar to those observed in convalescent patients can be obtained by vaccination. The use of trivalent inactivated influenza virus vaccine (TIV) in humans has been the subject of numerous studies, with an emphasis on providing an effective vaccine with minimal reactogenicity. The results in field prophylaxis studies have been inconsistent, owing partly to transient protection related to the decline of vaccine-related homologous antibody and to constant changes in the two surface antigens of the circulating viruses. The primary strategy for partial containment of influenza has been to concentrate efforts on prevention by vaccination of persons known to be at high risk. However, the variable efficacy of the inactivated vaccine, short duration of effect, adverse reactions on parenteral administration, and failure to induce local or cellular immunity have stimulated additional research. An alternative approach to influenza immunization using live, attenuated virus administered by nasal spray has been successful. It is the purpose of this chapter to review the research that led to the licensing of the Live Attenuated Influenza Virus Vaccine (LAIV).


Live, intranasal for use in humans
Why the disease is important
Influenza is the most common cause of lower respiratory tract infections. It was estimated that, if one included all age groups, approximately 48 million cases of influenza occur in the United States each winter. However, this number varies depending on the susceptibility of the population to the virus and the infectiousness of the virus during an outbreak. Of the 48 million persons with influenza annually, approximately 36,000 die.[7] During major influenza epidemics in the United States, more than 40,000 influenza-associated deaths have occurred. In recent decades, more than 90% of the deaths attributed to influenza occurred among persons 65 years or older.[8] Influenza type A infection occurs most frequently and is responsible for the greatest amount of morbidity and mortality. Although influenza B does not cause pandemics, it is responsible for regional epidemics that are less severe than influenza A epidemics.
Epidemic influenza tends to superimpose its profile on the existing pattern of respiratory disease. Influenza incidence rates vary with the nature of the epidemic virus strains and the population affected. Rates calculated from surveillance of individuals with upper respiratory illness suggest that influenza is responsible for roughly 10% to 20% of all respiratory illnesses per epidemic year,[9,10] with rates for influenza A being somewhat higher than those for influenza B. Nevertheless, an illness rate of 83% was observed in one epidemic season during an influenza B outbreak in an isolated Alaskan village.[11] Using the National Health Survey analysis of 101 million medically attended respiratory illnesses for 1977 to 1978, it has been estimated that 20 million cases could be attributed to influenza.[12] Most studies have found infection rates in preschool- and school-age children to be much higher than in adults, particularly during influenza B epidemics.[9,10,13,14] Consequently, families with school-age or younger children suffer disproportionately from influenza[12,13] as the result of frequent primary introduction from family members younger than 20 years of age.[13,15] These findings support the idea that influenza infects individuals with the lowest prior immunity and that children are a common source of influenza in the community.
Clinical description
Influenza viruses are spread from person to person primarily through coughing and sneezing of infected persons. The incubation period for influenza is 1 to 4 days, with an average of 2 days.[16] Adults and children typically are infectious from the day before symptoms begin until approximately 5 days after illness onset. Children can be infectious for a longer period, and very young children can shed virus for up to 6 days before their illness onset. Severely immunocompromised persons can shed virus for weeks.
Uncomplicated influenza illness is characterized by the abrupt onset of systemic and respiratory signs and symptoms (e.g., fever, myalgia, headache, severe malaise, nonproductive cough, sore throat and rhinitis). Respiratory illness caused by influenza is difficult to distinguish from illness caused by other respiratory pathogens on the basis of symptoms alone. Reported sensitivities and specificities of clinical definitions for influenza-like illness that include fever and cough have ranged from 63% to 78% and 55% to 71%, respectively, compared with viral culture. Sensitivity and predictive value of clinical definitions can vary, depending on the degree of co-circulation of other respiratory pathogens and the level of influenza activity.
Influenza illness typically resolves after a limited number of days for the majority of persons, although cough and malaise can persist for more than 2 weeks. Among certain persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead to primary influenza viral pneumonia, secondary bacterial pneumonia, or occur as part of a co-infection with other viral or bacterial pathogens. Influenza infection also has been associated with encephalopathy, transverse myelitis, Reye syndrome, myositis, myocarditis and pericarditis.
Virology
Because of the complexity of the subject, it is beyond the scope of this chapter to address all aspects of influenza virology. Therefore, this section presents a simple review emphasizing those areas relevant to live virus vaccines. For a comprehensive review of the biology of influenza viruses, the reader is directed to another text.[17]
Orthomyxoviruses have segmented, single-stranded, negative-sense RNA genomes. Because they lack the proofreading enzymes that maintain the fidelity of DNA replication, influenza viruses are subject to high rates of mutation during replication of their single-stranded RNA genome[18,19] and to high-frequency gene reassortment during mixed infections because of their segmented genome.[20,21] Because of these factors, influenza viruses undergo continual genetic changes that may affect their growth in vitro and in vivo, their pathogenicity in humans and animals, and the epidemiology of the resultant disease.[19] New antigenic changes, occurring by one or both of these mechanisms, allow the virus to overcome existing immunity in previously infected hosts.
Plaquing systems developed for influenza virus[22] and later modified by the addition of trypsin in the overlay medium[23] have allowed the determination of reassortment, reversion, and reactivation rates. Plaquing provided a cloning system for influenza virus, enabling the isolation of temperature-sensitive (ts) mutants.[24,25] These conditional lethal mutants, most of which varied from the parent by only a single mutational step, were used to map the influenza genome and dissect the viral replication cycle.[26] Biophysical analyses such as polyacrylamide gel electrophoresis were used to identify the genes having these mutations.[27,28] Similar analyses were performed using reassortants made between strains of influenza viruses showing clear differences in the electrophoretic mobility of their RNA genome segments.[29–33] The ability to clone specific mutants, organize them into complementation groups, and then correlate these groupings with phenotype and the RNA segment containing the mutation has allowed researchers to map the influenza virus genome, assigning each RNA segment to the encoded proteins and functions[34] (Table 16-1).

Table 16-1   -- Products of Influenza A and B Virus Genes
RNA        Gene Products        Functions
1        PB2        Viral polymerase component involved in synthesis of capped messenger RNAs (mRNAs) and endonuclease, which cleaves host cell mRNA
2        PB1        Viral polymerase component with RNA transcription and replication activities
        PB-1 F2

  • Viral protein generated from an alternate reading frame, triggers cell apoptosis
    3        PA        Viral polymerase component involved in RNA replication
    4        HA        Virion surface attachment and fusion glycoprotein, major antigenic determinant
    5        NP        Major nucleocapsid structural component and type-specific antigen
    6        NA        Virion surface glycoprotein with receptor-destroying enzyme activity, major antigenic determinant
            NB        Glycoprotein membrane ion channel found only in type B
    7        M1        Membrane matrix protein and type-specific antigen
            M2        Nonglycosylated membrane ion channel, found only in type A
    8        NS1        Nonstructural protein—unique post-transcriptional regulator that inhibits the nuclear transport of poly(A)–containing mRNAs and inhibits pre-mRNA splicing by binding to a specific region of U6 small nuclear RNA
            NS2        Cellular and virion protein of unknown function
    Recently described by Chen et al.[34]
    More recent investigations have examined influenza virus using a variety of molecular biology techniques: monoclonal antibodies,[35–38] cloning of isolated genes and expression of the encoded proteins,[39] sequence analyses of cloned gene segments or direct sequencing of the virion RNA[40,41] or sequencing using polymerase chain reaction techniques, and transfection of specifically modified genes.[42–46]
    The mechanisms of antigenic drift and shift have been examined,[46] and the structure and function of the surface hemagglutinin (HA) and neuraminidase (NA) molecules and their antigenic and reactive sites have been elucidated.[46–49] Genes other than HA and NA also have been shown to change by the mechanisms similar to those responsible for antigenic shift and drift,[46] and sequence data have been compiled, allowing viral evolution and the rate of change of individual genes to be determined.[46,50–52]
    Methods of attenuation
    The segmented and single-stranded RNA genome of influenza virus has a direct and immediate impact on its antigenicity, epidemiology, and hence the manner in which this virus may be controlled. Influenza A viruses exhibit both antigenic drift[53] and antigenic shift,[46] whereas influenza B viruses show only antigenic drift.[54] Antigenic drift is caused by the individual mutational changes in nucleotide sequence that occur because of the infidelity inherent in the replication of RNA genomes, with advantageous mutations becoming ‘fixed’ in genomes of the replicating population. Although not subject to antigenic mediation, other genes also undergo this same mutational drift.[54] The rate of drift can vary among genes and viral types.[49,55–57] Antigenic shift, however, requires complete replacement of one or both of the surface glycoprotein genes. The accepted explanation is that these new genes are acquired through reassortment between human and animal influenza A viruses.[49] Burnet and Bull[58] suggested that attenuated live influenza virus suitable for vaccines might be produced by egg passage of the virus because of its inherent genetic instability. Thus, early on, investigators took advantage of the high mutation rate by passing the virus in nonhuman hosts and generating host-range (hr) mutant viruses for use as live virus vaccine candidates. Vaccines made by this method have not been shown to be reliably attenuated[59] and could result in disease. Attempts to further attenuate hr viruses in the presence of heated guinea pig serum produced a vaccine strain that was clinically safe in adults[60,61] but caused fever in children.[62] Thus hr viruses have been abandoned as potential vaccine candidates.
    The high rate of genetic reassortment in orthomyxoviruses can be employed to quickly generate vaccine strains containing the genes for the surface antigens (HA and NA) of newly emergent wild-type (wt) viruses, while retaining other genes from attenuated strains.[63] Attenuated master strains must be shown to not cause significant illness in humans and to pass the property on to reassortants through the donation of genes other than the HA and NA genes.
    Attenuated master strains have been made by several methods. They can be separated into three main classes: hr, temperature sensitive (ts), and cold-adapted (ca) mutants. Those master strains that have been used to generate live influenza reassortant vaccines for trials in humans are listed in Table 16-2.[61,64–95]

    Table 16-2   -- Influenza Master Strains Used in the Preparation of Live Reassortant Virus Vaccines
    Master Strain        Currently in Use        References
    hr Mutants
    A/Puerto Rico/8/34 (H1N1)        No        [61,64–72]

    A/Okuda/57/(H2N2)        No        [73]

    A/Mallard/6750/78 (H2N2)        No        [73–77]

    A/Mallard/Alberta/88/76 (H3N8)        No        [74–76, 78–81]

    ts Mutants
    ts 1[E]        No        [82]

    ts1A2        No        [67]

    ca Mutants
    A/Ann Arbor/6/60 (H2N2)        Yes        [68, 83–85]

    B/Ann Arbor/1/66        Yes        [86–91]

    A/Leningrad/134/17/57        Yes        [88, 92–95]

    A/Leningrad/134/47/57        Yes        [89, 91]


    Although hr mutants were abandoned as vaccine candidates, they have been used as master attenuated strains in reassortant vaccines. Live reassortant vaccines made using A/Puerto Rico/8/34 (H1N1) (PR8) as the attenuating master strain have proved unsatisfactory because the six nonsurface antigen genes of PR8 did not reliably confer attenuation in combination with some wt surface genes. There was no simple means of determining which reassortants were attenuated and which were not.[64] Similar problems were noted with the A/Okuda/57 (H2N2) virus, which had 280 passages in eggs and had been used in Japan.[65]
    Ts master strains were generated by reassortment between A/Hong Kong/68 (H3N2) wt virus and ts mutants of A/Great Lakes/389/65 (H2N2) virus that had been grown in the presence of 5-fluorouracil.[66,67,69,82] Although some ts mutants were shown to be attenuated in adults and children, several reverted to virulence after passage in humans. Ts mutants have been abandoned because of this genetic instability.[96]
    History and development of cold-adapted intranasal live, attenuated vaccine
    The ca and ts A/AA/6/60 virus was derived in primary chick kidney (PCK) cells from a virus originally isolated from an ill child and was shown to produce clinical symptoms in ferrets. This virus was adapted to growth at 25°C, and a clone was selected by seven serial plaque-to-plaque purifications. This clone met the following criteria: high and equivalent virus yield in PCK cells and eggs at 33°C and 25°C, retention of ca and ts (reduction in replication titer at 39°C) markers in tissue culture, and attenuated behavior in ferrets. The ca B/AA/1/66 master strain was developed in the same manner, although it took fewer intermediate passages to achieve the final ca variant for type B virus than for type A.[87] The wt B/AA/1/66 influenza virus was restricted for growth at 36°C at the time of isolation, and therefore the ts phenotype is defined by a reduction in replication titer at 37°C compared with the achievable titer at 25/33°C.[83,87]
    Cold adaptation has become the major means of generating live virus vaccines in master attenuated viruses.[97] Several methods have been used for cold-adapting influenza A virus. A/Ann Arbor/6/60 (H2N2) (A/AA/6/60) virus has been grown at successively lowered temperatures in PCK cells until a virus was derived that grows as well at 25°C as it does at 33°C. All three polymerase genes have been shown to contribute to the attenuated phenotype of the ca A/AA/6/60 master strain.[98] The A/AA/6/60 virus derived in this manner has been shown to be both ca and ts. Ca implies that the virus will grow well at a reduced temperature (25°C) compared to permissive temperature (33°C), and ts implies that the vaccine virus replication is reduced by at least 2 logs of the median tissue culture infective dose (TCID50) at the higher temperature 39°C. Sequencing evidence has been found for changes in all eight genes of the attenuated ca A/AA/6/60 virus from its virulent wt counterpart.[24] Recently, Lu et al[98a] used reverse genetics to identify the four major attenuating loci of the ca A/AA/6/60 ca strain. They are at base positions 1,195 and 1,766 of the PB1 gene, 821 of the PB2 gene, and 146 of the NP gene. There have been numerous human trials with reassortants made using ca A/AA/6/60 virus and using ca B/Ann Arbor/1/66 viruses as master strains and, in all cases, attenuation, antigenicity, and genetic stability have remained unaltered and consistent.[86,87,88,89] The PA gene has been shown to be a major determinant of attenuation for the ca B/AA/1/66 vaccine strain.[99]
    A ca master strain has also been used in Russia. Unlike the aforementioned ca A/AA/6/60 virus, the Russian master strain, A/Leningrad/134/57 virus, was produced by multiple passages primarily at 25°C or 26°C and not by a gradual lowering of incubation temperatures. The original ca master strain A/Leningrad/134/17/57[92,100,101] was passaged an additional 30 times in embryonated eggs at 25°C to generate a new ca master strain, A/Leningrad/134/47/57 virus.[93] Reassortants made between this latter ca master strain and wt A/Leningrad/322/79 (H1N1) or A/Bangkok/1/79 (H3N2) virus were shown to be attenuated and immunogenic in children.[94] The A/Leningrad/134/47/57 master strain has been shown to contain changes in at least one of the polymerase genes as well as in the HA, NA, nucleocapsid protein (NP), and matrix (M) genes.[102] A/Aichi/2/68 virus has been adapted to growth at 25°C in a manner similar to that used for the Russian master strain, but with fewer passages.[97] This virus has been tested in both ferrets and human volunteers and is also immunogenic and attenuated.[103–105]
    Reverse genetics
    The genome of influenza virus is divided among 8 different negative sense RNA segments. The viral RNAs cannot function as mRNAs to produce proteins; viral polymerase proteins carried in with the virion must first produce mRNAs from the viral gene segments in order to initiate replication of the viral genome. These properties of the genome along with the absolute requirement for a specific sequence at each end of the viral RNA segments made influenza virus refractory to genetic manipulation. Eventually, systems were developed that enabled construction of recombinant influenza viruses with defined genetic compositions through the use of recombinant DNA. Originally, these reverse genetics techniques required transfection of a synthetic RNA with exact 5′ and 3′ termini into influenza virus infected cells; infection with this helper virus provided all the necessary proteins to replicate and package the synthetic RNA. In general, the synthetic RNA had to encode a protein that offered a selective advantage to the recombinant virus allowing the recombinant to be purified away from the helper virus used to provide the viral proteins.[106a] In recent years, reverse genetics techniques have advanced that allow recombinant influenza viruses to be produced entirely from cloned plasmid DNAs.[106b,106] Two different types of plasmids are combined in this technique. One set of plasmids produces mRNAs in the transfected cell that express, minimally, the 4 polymerase proteins, PB1, PB2, PA and NP. In addition the remaining plasmids must produce synthetic RNAs that are indistinguishable from the viral RNAs; this mimicry is achieved by using a cellular promoter, such as the RNA polymerase I promoter, and polymerase termination signal sequences that instruct the transfected cell to express synthetic viral RNA transcripts with highly defined termini. This combination of plasmids in a cell results in expression of the viral polymerase which replicates and transcribes the synthetic viral RNAs, resulting in the assembly of an infectious, recombinant influenza virus. These plasmid rescue techniques obviate the need for a selective advantage to the recombinant virus, since only plasmid DNAs encoding the desired genetic composition are used to transfect the cell. Plasmid rescue techniques have advanced basic research on influenza virus as well as vaccine development.
    One application of reverse genetics is exemplified by the construction of pandemic vaccine viruses by plasmid rescue. The HA and NA viral RNA gene segments are cloned by RT-PCR techniques into the appropriate expression vector. Often, virulence determinants, such as the polybasic cleavage signal between the HA1 and HA2 subunits of the H5N1 HA is modified or removed by recombinant DNA techniques. The HA and NA gene segments are combined with plasmid DNA's encoding the other six gene segments of a vaccine strain such as cold-adapted A/Ann Arbor/6/60 and used to cotransfect a cell. The resulting recombinant virus contains six internal gene segments of the vaccine strain combined with the two antigen encoding gene segments, HA and NA. Importantly the HA gene segment no longer carries an endogenous virulence determinant. These types of recombinants are expected to be useful in the preparation for pandemic influenza planning.
    Pathogenesis as it relates to prevention
    The pathology of influenza virus has been reviewed extensively.[107–110] The virus contacts the mucous lining of the respiratory tract and then attaches to ciliated columnar epithelial cells after release from the mucous layer.[110,111] The viral NA is probably involved in its release from mucous receptors and the liquefaction of the mucous layer. The ciliated columnar epithelial cell is most likely the major site of infection.[111] Bronchitis and tracheitis are common,[112] and there may be some lung involvement.[113] Otitis media is common in children. Viremia has been reported only sporadically[114,115] amidst numerous negative reports.[116–118] Influenza B demonstrates pathology similar to that of type A and is common in children.
    Cleavage of the HA precursor protein into HA1 and HA2 proteins by post-translational processing is necessary for the glycoprotein to become membrane fusion competent.[119,120] Neuraminidase activity is often complementary to HA receptor specificity, allowing the two to act in concert.[121]
    Influenza in humans is usually restricted to infection primarily of the trachea and upper respiratory tract, although, during severe pandemic periods, lung lesions may more commonly be present.[122] The amount of virus produced probably determines the extent and severity of symptoms.[96,123]
    The most precise diagnosis of influenza is obtained by viral isolation in embryonated eggs or in cell cultures of nasopharyngeal or tracheal aspirates, or by using reverse transcriptase-polymerase chain reaction. Serologic diagnosis can be made by demonstrating fourfold rises in hemagglutinin-inhibiting (HAI) or complement-fixing antibodies.
    The pattern of influenza infection is generally one of high morbidity and low mortality, although outbreaks also are reflected in excess mortality from subsequent pneumonia and hence an increase of total mortality. An epidemic may be defined by both serology and virus isolation to determine the dates of incidence and prevalence[12] and the impact of health on families and communities.[9,124]
    By using excess mortality and morbidity resulting from influenza as an index, Collins[125] compiled an impressive record of influenza-associated mortality extending from 1887 through 1956. Over the period analyzed, the intervals between outbreaks and the sites affected varied greatly: After a decade of relative quiescence, the pandemic of 1889 to 1890 erupted violently and unexpectedly. The death toll between 1891 and 1892 was even greater, and high, sharp peaks of excess mortality recurred through 1908. Afterward, the disease was apparently much less virulent until the catastrophic pandemic of 1918 to 1920, in which over 20 million lives were lost worldwide. Subsequently, moderate to severe outbreaks have been amply documented.[123,126] Improved surveillance of influenza has been used as an accurate indicator and a valuable predictor of epidemic activity.[127]
    Immunity induced by natural infection
    Naturally acquired immunity to influenza is mediated by serum antibodies and by antibodies present at the mucosal surface of the respiratory tract. In addition to serum and mucosal antibodies, natural infection with influenza also stimulates influenza-specific T cells that are thought to play a role in recovery. Innate immune responses also may contribute to resistance to influenza infection, such as production of interferon or other antiviral factors by macrophages. Thus it appears that multiple mechanisms have evolved in humans to provide resistance to influenza.[128]
    Immunity following natural infection provides long-lived protection against homologous influenza virus infection and disease in the absence of antigenic shift or drift. This effect was illustrated during the 1977 influenza season when H1N1 re-emerged after a 20-year absence. Epidemiologic surveys revealed that, compared to individuals born after 1955, individuals born before 1955 had a lower influenza attack rate in 1977. This is presumed to be due to prior exposure to nearly identical H1N1 strains in the 1950s. Immunity acquired by natural infection also can provide protection against influenza strains that have undergone antigenic drift. In British board-ing school studies, protection provided by natural infection was compared with protection achieved by vaccination with inactivated influenza vaccine. The authors concluded that natural immunity afforded heterotypic protection against drifted strains that circulated 18 months later, whereas inactivated influenza vaccine did not.[129,130] These studies demonstrated that, although both natural infection and vaccination with inactivated vaccine stimulate serum HAI antibodies and provide protection against homologous wild-type influenza strains, the protection associated with natural infection is longer lived and broader than that induced by inactivated vaccine. Importantly, the fact that the differences in protection could not be accounted for by differences in serum HAI titers demonstrates that multiple immune mechanisms induced by natural infection confer resistance to influenza.
    Immunity as it relates to vaccine prevention
    In order to prove that the influenza vaccines are effective, it is necessary to vaccinate a population prior to an influenza epidemic and compare the infection rates in vaccinated subjects with a group given a placebo. Case definitions of influenza vary according to study and may include culture-positive infection,[131,132] further fourfold antibody increase during the influenza epidemic, or clinical observations of influenza-like illnesses.[133] Specific point estimates of vaccine efficacy may be obtained by using culture-positive identification of cases, which eliminates clinical syndromes caused by other intercurrent viral infections. Efficacy field trials with culture-positive endpoints are optimally conducted in young children.[131,132] This population suffers a high attack rate of influenza, and, when young children are infected with influenza, they shed high quantities of wild-type virus for several days. This makes culture methodology a sensitive and specific case-finding method. Adult efficacy trials more commonly are conducted using clinical endpoints such as febrile respiratory illness.[133] Influenza is the most common cause of febrile respiratory illness in adults, and using cultures to identify influenza infection is problematic because adults may shed virus in low quantity and for brief duration. Use of fourfold antibody rise in paired sera obtained pre- and postepidemic is also often used in adult studies, with case definition being any subject with a further fourfold antibody rise in response to the epidemic virus. However, subjects with vaccine-induced antibody may not produce sufficient antibody during the subsequent natural infection to result in a detectable, fourfold antibody increase. Therefore, this definition has inherent bias, unlike either the clinical endpoint for adult studies described above or the virus isolation endpoint for the pediatric efficacy trials as noted above.
    Vaccine effectiveness and vaccine efficacy may be confused. In this chapter we refer to vaccine efficacy (ve) as the specific reduction in attack rates of laboratory-confirmed influenza (culture-positive cases), and ve is represented mathematically as
    where Rv = attack rate in vaccinees and Rp = attack rate in placebo recipients. Vaccine effectiveness refers to the reduction in clinical events that may be expected to be associated with influenza, but could also be caused by other agents. Reduction of fever during the influenza season in all vaccinees compared to all placebo recipients, regardless of the culture result, is an example of vaccine effectiveness.[131–134]
    Strategy and advantages of the ca reassortant vaccines
    Cold adaptation was found to be a reliable and efficient procedure for the derivation of live, attenuated influenza virus vaccines for humans. In addition, the process of genetic reassortment with the transfer of the six internal genes from a stable attenuated ca master donor strain of type A (A/AA/6/60) or type B (B/AA/1/66) to the new prevailing wild-type epidemic strain has yielded consistently attenuated cold-reassortant vaccines with the desired 6:2 gene profile for human use. These live ca reassortant vaccines for types A and B influenza viruses, developed at the University of Michigan, have been shown to have the proper level of attenuation and immunogenicity, and low or absent transmissibility combined with proven genetic stability, and are produced in acceptable tissue culture substrates or specific pathogen-free chicken eggs.[97]
    Figure 16-1 presents the classical co-infection of the master donor viruses with wild-type influenza to develop a 6:2 reassortant vaccine strain.

            Figure 16-1  Diagram illustrating the process of genetic reassortment to generate vaccine strains.
    The cold-adapted master strain (upper left) is mated in tissue culture with a wild-type virus (upper right). Reassortant virus with the desired combination of attenuating genes (six ‘internal’ genes) and contemporary HA and NA genes is selected for use in the vaccine. HA and NA genes are updated annually to exactly match those in the inactivated vaccine.
    Characteristics of LAIV
    Influenza Virus Vaccine, Trivalent, types A and B, Live Cold-Adapted (LAIV) consists of approximately Fluorescent Focus Units (FFU)/dose of each influenza A/H1N1, influenza A/H3N2, and influenza B vaccine strain. The exact strains are updated each year to antigenically match the antigens recommended by national health authorities. LAIV is sprayed into the nose using a simple syringe-like device that delivers a 0.1-mL volume of a large-particle aerosol into each nostril for a total volume of 0.2 mL (Fig. 16-2). Vaccination of children requires minimal cooperation to allow spraying the vaccine intranasally. The device is easy to use, and the vaccine is readily accepted and preferable to many over a parenteral injection by needle and syringe.

            Figure 16-2  Transilluminated illustration of large-particle aerosol generated for intranasal administration. The tip of the applicator is inserted into the anterior nares and the plunger depressed to administer the live, attenuated vaccine to a nostril. Removing the flange on the plunger allows a second spray to be administered into the other nostril.
    Formulations of LAIV
    LAIV is currently manufactured by MedImmune Vaccines in specific pathogen-free (SPF) hen's eggs. Monovalent bulk vaccine is produced for each reassortant 6:2 vaccine strain in the formulation by inoculating 9–11 day old embryonated SPF eggs with the individual vaccine seeds. Following incubation for 2–3 days, the allantoic fluids of the SPF eggs are harvested, clarified by centrifugation and stabilized by the addition of sucrose-phosphate-glutamate (SPG) buffer to create monovalent bulk vaccine. As currently formulated, monovalent bulks of each of the 3 strains in the formulation are combined along with SPG to achieve a titer of approximately 107 FFV50/dose and filled into the sprayer device.
    A refrigerated-stable (i.e., 2–8°C) formulation of LAIV has been developed and is FDA approved for use in the U.S. Frozen LAIV (FluMist) and refrigerator-stable LAIV are made from the identical 6:2 cold-adapted reassortant influenza strains and contain comparable concentrations of each virus strain per dose. Refrigerated stable LAIV is also produced by inoculating SPF eggs with each of the vaccine seeds and the allantoic fluids harvested. The primary change for this formulation compared to frozen FluMist is the addition of an ultracentrifugation step using a density gradient following harvesting of the allantoic fluids. This step concentrates the virus, enabling the refrigerator stable formulation to be delivered in a smaller volume (0.2 mL) compared to frozen FluMist (0.5 mL). The ultracentrifuged, concentrated monovalent bulks are combined and stabilized by the addition of SPG, arginine and hydrolyzed porcine gelatin prior to filling in the sprayer. Pre-clinical characterization has demonstrated that the two formulations are comparable with respect to biological, physical, and biochemical features. Both the frozen and refrigerated stable forms of LAIV are free of preservatives, however, due to production of the vaccine in SPF hen's eggs, these vaccines should not be administered to individuals with egg allergies.
    Production of influenza vaccines in eggs is used by many manufacturers; however, this process is difficult to rapidly scale up and the flocks are potentially susceptible to avian pathogens that could influence the amount of vaccine that could be manufactured, especially during a pandemic. Cell culture production of the vaccine is a promising area for exploration in that the systems are more controllable and scalable than eggs and the technology to produce biologics in cell culture are used routinely in the industry. Influenza viruses including LAIV 6:2 reassortants can be grown to relatively high titers in Madin Darby Canine Kidney (MDCK) cells and these cells are being evaluated for their suitability as substrates to manufacture LAIV at large scale in the future.
    Immunogenicity of LAIV
    Immunogenicity in children
    Among seronegative children, a single vaccination with LAIV of 106 or 107 TCID50, provided 91% seroconversion (four-fold rises) to the H3N2 strain, 48% seroconversion to the B strain, and 16% seroconversion to the H1N1 strain.[135] This observation may be due to viral competition or interference from the H3N2 and B viruses and is easily overcome with use of a second dose. Administration of two doses of LAIV separated by 60 ± 14 days induced fourfold or greater HAI titers in 96%, 96%, and 61% of children against H3N2, B, and H1N1, respectively.[131] Two doses of LAIV given a mean of 35 days apart (range, 28 to 60 days) containing the type A/Shenzhen H1N1 strain elicited a fourfold or greater rise in serum HAI response in 87% of seronegative children.[136] In this regard, it is much like using two doses of TIV as the primary vaccine in young children to develop an optimal antibody response, followed by a single annual revaccination in subsequent years. In children 6 to 35 months of age who received 2 doses of the 2004–05 formulation of either LAIV or TIV separated by 35 ± 7 days, overall serum immune responses were higher for LAIV compared to TIV in baseline seronegatives.[136a] Following dose one, for matched A/H3N2, the HAI antibody titer GMT for LAIV (121.8) was significantly higher than that for TIV (4.3), and seroconversion rates were also significantly higher (100% and 29.4%, respectively). Following dose two, seroconversion rates for the H3N2 strain were 100% for both vaccines, but GMT was significantly higher among LAIV recipients compared to TIV. No difference in seroconversion rates were found for influenza B (LAIV, 78% vs TIV, 57%, pns).
    Immunogenicity in adults
    A single-dose regimen in adults is supported by epidemiologic data indicating that the majority of adults are likely to be immunologically primed to influenza strains that have circulated in recent years and therefore should require only a single dose of vaccine to stimulate a protective immune response to current drift strains. The immunogenicity and efficacy results obtained in adults confirm that one dose of LAIV in adults conferred a high level of protection against laboratory-documented influenza illness due to wild-type H1N1, H3N2, or B strains, even though only a modest proportion of subjects developed a serum HAI titer of 1:32 or greater following vaccination and none developed four-fold rises from baseline.[137] These results suggested that a serum HAI titer of 1:32 or greater is not a correlate of protection with a strong negative predictive value for adults following immunization with LAIV. The results suggest that other important immunologic contributors to protection following immunization with LAIV, such as nasal immunoglobulin A (IgA) antibodies, could provide protection in the absence of a robust serum HAI response.[138,139] The mechanism(s) whereby vaccination with LAIV provides protection against influenza appear to mimic that of natural infection and to differ from that of TIV. TIV is believed to induce little secretory IgA and is not expected to stimulate CD8+ cytotoxic T cells; this assertion is supported by previous studies in which adults immunized with either monovalent cold-adapted influenza virus vaccine (LAIV) or TIV were protected from challenge, although they had developed different serum HAI antibody (higher with TIV) and nasal IgA response profiles (higher with LAIV) following vaccination.[140] Additionally, a study in older adults showed that administration of TIV and LAIV together resulted in a greater induction of cytotoxic T cells compared to individuals immunized with TIV alone, indicating that LAIV may be responsible for greater cellular responses.[160]
    Correlates of immune protection induced by LAIV
    Many studies have characterized the immune response to cold-adapted influenza vaccines derived from the Maassab cold-adapted master strains that are used to produce LAIV. Because LAIV is a live, attenuated vaccine that is administered by the natural intranasal route of infection, the resulting immune response is expected to elicit the multiple immune mechanisms induced by natural infection with wild-type influenza viruses. Previous clinical studies have documented that influenza-specific IgA nasal antibodies, serum antibodies, T-cell responses, and interferon are produced in response to intranasal immunization with LAIV.[140,141]
    Challenge studies with vaccine strains in children[139] or wild-type influenza in adults have elucidated some correlates of protection. Both serum and nasal wash antibodies in children and adults induced following immunization with LAIV are associated with protection from infection.[139] A high rate of serum HAI responses following immunization with LAIV predicts a high rate of protection against influenza in children.[131,132,134,139] However, immunization with LAIV regardless of post-vaccination titers also provided high protection suggesting that HAI responses have a high positive predictive value but a low negative predictive value as correlates of immunity. Other important contributors to immunity, such as serum neutralizing antibodies, nasal IgA antibodies, or cytotoxic T cells, may provide protection.[139,142]
    In order to evaluate the efficacy against H1N1 and also to obtain potential correlates of immune protection, children vaccinated previously with LAIV participated in a challenge study using H1N1 monovalent vaccine as the challenge virus. The endpoint was shedding of vaccine virus; despite the 5- to 8-month interval between vaccination and challenge, vaccine provided high efficacy (83%; 95% confidence interval, 60% to 93%) against shedding of type A/H1N1 challenge virus. Both serum antibody and nasal wash antibody were measured before H1N1 challenge, and there were significant differences in serum HAI antibody and nasal wash IgA antibody between the vaccinated children and the placebo subjects prior to challenge. Previously vaccinated subjects had significantly higher nasal wash and serum antibody titers. The presence of any serum antibody or nasal wash IgA significantly correlated with protection from viral shedding.[139]
    Most studies of correlates of immune protection against influenza have focused on serum HAI antibody.[143–146] The multiple studies of serum HAI antibody indicate that clearly HAI antibody level does correlate with protection, but the absolute amount needed to confer protection remains variable.[138,142–146] The data suggest that H3N2 levels may need to be higher than HAI antibody to H1N1 or B; also the presence of nasal IgA with or without serum HAI antibody confounds analysis of correlates of protection. Clements et al. compared the correlates of immune protection induced by live, attenuated intranasal vaccine with inactivated parenteral vaccine after experimental challenge with wild-type influenza in adults.[147] A series of studies in which healthy adult volunteers were vaccinated with either inactivated or intranasal live, attenuated vaccines, followed by challenge with wild-type H1N1 or H3N2 viruses, revealed that serum HAI antibody titer correlated with protection against viral replication after inactivated vaccine but not live vaccine; in contrast, live vaccine induced nasal IgA antibody, which correlated with protection.[147]
    Interference between strains
    Interference between strains of closely related viruses during vaccination is a well-recognized phenomenon. Oral polio vaccine is the classical example cited because type 2 tends to overgrow types 1 or 3 after dose 1; multiple doses are given to overcome this interference. Multiple doses of oral rotavirus vaccine also have been given to ensure more solid immunity. Although the multivalent viral vaccine for measles, mumps, and rubella (M-M-R® is immunogenic after a single dose, two doses are recommended to provide optimal protection. Interference between type A influenza H1N1 and H3N2 was previously identified.[148] A two-dose strategy as the primary regimen for influenza vaccination in young children optimizes a seroprotective response and successfully overcomes interference if it occurs.[131,136] Subsequent annual revaccination requires only a single dose.

    Heterotypic antibody data
    One of the potential advantages of a live influenza vaccine is that it might be expected to stimulate broader immunity against antigenic drift strains, as demonstrated in young children. The basis for this expectation is that a live, replicating vaccine virus would present to the immune system a complete complement of influenza virus antigens in their native configurations. As a result, neutralizing antibodies would be produced to both surface proteins, HA and NA, and stimulate secretory antibodies in the respiratory tract as well as serum antibodies. In addition, highly conserved antigens such as M and NP may be presented in an immunologic context appropriate for stimulation of cross-reactive cytotoxic T cells and antibodies. Immune responses to native HA and NA antigens as well as internal proteins probably account for the observation that natural infection with a new strain induces some protection against drift strains that arise during the subsequent influenza seasons.
    Multiple efficacy trials have demonstrated that immunization with LAIV can protect against antigenically drifted influenza strains, in addition to providing protection against homologous influenza strains.[132,133,140,149] In the more recent pivotal efficacy field trial of LAIV in children, the drifted variant A/Sydney/(an H3N2 virus) caused the majority of disease in year 2 of the study.[132] LAIV contained A/Wuhan as its H3N2 antigen; Wuhan and Sydney were significantly different antigenically as determined by ferret antisera. LAIV was 86% efficacious at preventing culture-confirmed influenza from A/Sydney. In that same year an effectiveness study of LAIV in adults 18–64 years of age demonstrated significant reduction in work lost among vaccinated adults versus placebo recipients,[133] whereas a similar effectiveness study conducted by the Centers for Disease Control in more than 1,000 adults 18–64 years of age with the TIV in the same season demonstrated no protection compared to placebo recipients.[133a]
    The weight of evidence is that both natural infection[132] and immunization with LAIV[132,133,140,149] can provide protection against drifted strains. This remains an advantage of a live influenza vaccine because drift strains arise unexpectedly in some seasons. To address the issue of whether LAIV stimulated immunity that was cross-reactive with antigenic drift strains, serum specimens obtained during the 1996 to 1997 pivotal efficacy trial were tested in HAI assays against a variety of H3N2 drift strains isolated during influenza seasons immediately preceding or following the 1996 to 1997 efficacy trial. Antigenic characterization performed with strain-specific ferret antiserum by the Centers for Disease Control and Prevention indicated that the strains included in the analysis were antigenic variants representative of the spectrum of H3N2 strains circulating during recent influenza seasons. The A/Sydney/5/97 (H3N2) strain was of particular interest because it was the predominant H3N2 strain circulating during the 1997 to 1998 influenza season and had undergone significant antigenic drift from the H3N2 vaccine strain A/Wuhan/359/95. Results of the analysis (Fig. 16-3) indicated that children vaccinated with LAIV developed serum HAI antibodies that cross-reacted with H3N2 strains that circulated either before or after the Wuhan strain. Specifically, following two doses of LAIV, more than 90% of seronegative children seroconverted to the A/Thessalonika/1/95, A/Nanchang/933/95, A/Wuhan/359/95, and A/Sydney/5/97 strains, and approximately 80% and 50% seroconverted to the A/Russia/1319/95 and A/Johannesburg/33/94 strains, respectively, (Fig. 16-3). In addition, LAIV can induce cross-reactive HAI antibody against antigenically drifted H1N1 and B viruses in seronegative children.[150] In children 6 to 35 months of age who received 2 doses of the 2004–05 formulation of either LAIV or TIV separated by 35 ± 7 days, post dose one and post dose two GMTs and seroconversion rates to the 2 mismatched strains that circulated in the 2004–05 Northern Hemisphere season (A/H3N2 and B) were higher in baseline seronegatives in the LAIV group.[136a] These differences were statistically significant post dose one and post dose two for both seroconversion rates and GMTs for mismatched A/H3N2. For the mismatched B strain, the seroconversion rate was statistically significantly higher for LAIV post dose two. These results support the conclusion that LAIV stimulated a cross-reactive antibody response in children, and may provide a high level of protection against antigenic drift strains in an influenza season in which there is a similar suboptimal match between the vaccine strain and the epidemic strain.

            Figure 16-3  Percentage of children given two doses of live, attenuated influenza vaccine (dark bars) or two doses of inactivated influenza vaccine (light bars) with HAI antibody postvaccine to the indicated variant of H3N2. Vaccines contained Nanchang antigen (inactivated vaccine) or Nanchang-like antigen (live vaccine containing A/Wuhan/359/95). P values indicate significant differences. The children given inactivated vaccines were younger than the children given live, attenuated vaccine. H3N2 virus antigens: Sydney, A/Sydney/5/97; Nanchang, A/Nanchang/933/95; Thess., A/Thessalonika 1/95; Russia, A/Russia/1319/95; Johann., A/Johannesburg/33/94.
    (Data from Belshe RB, Gruber WC. Prevention of otitis media in children with live attenuated influenza vaccine given intranasally. Pediatr Infect Dis J 19(suppl):S66-S71, 2002.)

    Duration of immunity induced by LAIV
    Longer term persistence of immunity may emerge as a characteristic of the host response induced by both LAIV vaccine and natural infection compared to TIV recipients with longer follow-up of vaccine recipients.[132,134,139,151] Serum HAI antibodies and nasal IgA antibodies persist following immunization of children with LAIV, and this persistent immunity may provide protection against antigenic drift strains.[132,152,153] For example, in children initially 15–71 months of age, serum HAI seropositivity rates following 2 doses of LAIV in the first year were 99%, 98%, and 75% to the H3N2, B, and H1N1 strains, respectively; prior to re-vaccination one year later, the seropositivity rates were 100%, 92%, and 46%.[152] Nevertheless, the strains represented in LAIV need to be updated annually to provide optimal protection against newly emerging strains. Additional studies should be done to further understand the public health benefits of this vaccine in regard to duration of immunity.

    Efficacy/effectiveness of LAIV
    Adults
    The results of a wild-type challenge study following a single vaccination with LAIV or inactivated vaccine (TIV) in adults is shown in Table 16-3. Placebo subjects had significantly more infection and illness than either vaccine group. LAIV had 85% efficacy and TIV had 71% efficacy against infection and illness after experimental challenge with H1, H3, or B viruses.[137]

    Table 16-3   -- Summary of a Wild-Type Influenza Challenge Efficacy Study in Adults After Live Attenuated (LAIV) or Inactivated (TIV) Vaccine
    Vaccine        Number Vaccinated and Challenged        Number with Infection and Illness (%)        Efficacy


  • LAIV        29        2(7)        85%
    TIV        32        4(13)        71%
    Placebo        31        14(45)        —
    Strains in the LAIV were antigenically matched to TIV and were A/Shang- dong/9/93 (H3N2), A/Texas/36/91 (H1N1)—like, and B/Panama/45/90 cold-adapted reassortant virus. TIV was the formulation used in 1994/95 (Fluvirin; Evans Medeva). Challenge wild-type viruses were homologous A/Shang-dong/9/93 (H3N2), A/Texas/36/91 (H1N1), and B/Panama 45/90.
    Results of challenge with virulent H1N1, H3N2, and B viruses are combined.[137]
    A summary of key effectiveness results following a single dose of LAIV or placebo in healthy working adults is shown in Table 16-4. Vaccine significantly reduced the number of severe febrile illnesses and days of febrile upper respiratory tract illnesses among healthy, working adults. Vaccine also led to lower rates of work absenteeism, health care provider visits, and the use of prescription antibiotics and nonprescription medications. These benefits were observed during a season in which the predominant circulating influenza virus strain, A/Sydney/5/97 (H3N2), was not well matched to the A/Wuhan/359/95 strain contained in the vaccine.[133] In contrast, a similar effectiveness study of the TIV in similarly aged adults conducted in the same influenza season demonstrated no protection compared to placebo recipients.[133a]

    Table 16-4   -- Effectiveness of LAIV
  • in Healthy, Working Adults (Ages 18 to 64) During Influenza A/Sydney Outbreak of 1997 to 1998
    Outcome        Reduction (95% CI) in Indicated Outcome in Vaccinated vs. Placebo Recipients
    Number of severe febrile illnesses        19% (7%–29%)
    Days of FURI        25% (14%–35%)
    Days of missed work for FURI        28% (16%–39%)
    Days of antibiotic use for FURI        45% (35%–54%)
    Days of health care provider visits for FURI        41% (30%–50%)
    Data from Nichol KL, Mendelman PM, Mallon KP, et al for the Live Attenuated Influenza Virus Vaccine in Healthy Adults Trial Groups. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA 282:137–145, 1999.
    CI, confidence interval; FURI, febrile upper respiratory illness.

    *        LAIV composition consisted of viruses antigenically equivalent to TIV for the 1997 to 1998 influenza season. These included A/Shenzhen/227/95 (H1N1), A/Wuhan/359/95 (H3N2) (a Nanchang-like virus), and, a B/Harbin/7/94-like virus.


    Safety and efficacy of LAIV in the elderly
    The safety and tolerability of LAIV when co-administered with TIV in 200 high-risk adults has been evaluated. Participants greater than or equal to 65 years of age with at least one additional risk factor for influenza morbidity received TIV co-administered with either LAIV or placebo. The safety and tolerability of LAIV plus TIV following vaccination was similar to that of placebo plus TIV with the exception of a higher incidence of sore throat (15% vs. 2%).158b
    The rationale for this combined approach to potentially offer improved efficacy over TIV alone in the elderly was initially shown by Treanor et al.[159] Extensive safety data have been collected on LAIV in persons over 65 years of age during a vaccine trial assessing the combined efficacy of LAIV plus TIV versus TIV alone. Subjects over 65 years of age with chronic underlying conditions, including chronic obstructive pulmonary disease or heart disease were enrolled in the trial. No adverse events were associated with LAIV. Combined vaccine efficacy revealed a 15% reduction in attack rate in subjects receiving both TIV and LAIV compared to those receiving TIV alone, but this did not achieve statistical significance.[160]
    LAIV has been administered to small numbers of adults and children with asymptomatic or mildly symptomatic human immunodeficiency virus infection.[161,162,162a] These studies were conducted to assess safety in the event that LAIV was inadvertently given to immunosuppressed persons rather than to support use of LAIV in these populations. No untoward events or prolonged viral shedding resulted.
    Children
    LAIV was highly efficacious in the pivotal randomized controlled trial in children 15 to 71 months of age (mean 42 ± 16.6 months) conducted over two influenza seasons (Table 16-5 and Fig. 16-4). In year 1, children received either one dose or two doses of LAIV or placebo given 60 ± 14 days apart, and, in year 2, children received a single revaccination according to the original randomization. In year 1 of the study, there was 95% efficacy against H3N2 (Wuhan- or Nanchang-like viruses) and 91% efficacy against B. In year 2, the epidemic consisted largely of a variant not contained in the vaccine, influenza A/Sydney. In year 2, the epidemic of A/Sydney/5/97-like viruses caused 66 of 71 cases, with the remaining cases associated with A/Wuhan/359/95-like viruses (4 cases) or influenza B (1 case). Vaccine was 100% efficacious in year 2 against strains included in the vaccine and 86% efficacious against the variant, A/Sydney/5/97. Overall, during the 2 years of study, vaccine was 92% efficacious at preventing culture-confirmed influenza (see Fig. 16-4).

    Table 16-5   -- Occurrence of Influenza in Years 1 and 2, Efficacy of Vaccine, and Efficacy Against H 1N1 Vaccine Virus Challenge
            Year 1        Year 2        H1N1 Vaccine Virus Challenge[†]

    Epidemic Virus        Vaccine
  • (N = 1070)        Placebo (N = 532)        Efficacy (95% CI)        Placebo (N = 917)        Efficacy (N = 441)        Vaccine (%)        Placebo (N = 144)        Efficacy (N = 78)        (95% CI)
    A/Wuhan/359/95-like (H3N2)        7        63        95 (88–97)        0        4        100 (54–100)                           
    A/Sydney/5/97-like (H3N2)        —        —        —        15        51        86 (77–93)                           
    B        7        37        91 (79–96)        0        1        100 (84–100)        —        —        —
    H1N1        0        0                 0        0                 6        19        83 (60–93)
    Any type        14        94 (100)[‡]
    93 (87–96)        15        56        87 (78–93)        —        —        —
    Data from Belshe et al.[131,132]
    *        The composition of vaccine in year 1 was A/Texas/36/91-like (H1N1), A/Wuhan/359/95-like (H3N2), and B/Harbin/7/94-like. In year 2 the vaccine composition for H3N2 and B was the same as year 1 and the H1N1 component was A/Shenzhen/227/95-like.
    †        The challenge virus was A/Shenzhen/227/95-like (H1N1) cold-adapted reassortant monovalent vaccine, titer 107.0.
    ‡        Six children had two illnesses, one caused by influenza A and one caused by influenza B. CI, confidence interval.


            Figure 16-4  Efficacy of live, attenuated influenza vaccine (FluMist) in a 2-year pediatric efficacy trial is indicated by differences in Kaplan Meier plot of the percentage of children developing culture-confirmed influenza in placebo or vaccine groups. Dashed lines represent 95% confidence interval. *Months from the start of the study. The composition of vaccine in year 1 was A/Texas/36/91-like (H1N1), A/Wuhan/395/95-like (H3N2), and B/Harbin/7/94-like. In year 2, the vaccine composition for H3N2 and B was the same as year 1 and the H1N1 component was A/Shenzhen/227/95-like.
    (Belshe RB, Gruber WC, Mendelman PM, et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr 136:168-175, 2000).          



    Influenza-associated otitis media was significantly reduced in each year of the study. In year 1, there was only one case of influenza-associated otitis media in the vaccine group, but there were 20 cases of otitis media among the placebo recipients associated with culture-positive influenza (vaccine efficacy = 98%). In year 2, only two cases of otitis media were associated with influenza in the vaccine group, but 17 occurred in the placebo recipients (vaccine efficacy = 94%). Cases of lower respiratory disease associated with culture-positive influenza also were significantly reduced in the vaccine group; only 1 case occurred in the 2 years in the vaccine group, but there were 11 cases in the 2 years in the placebo recipients (vaccine efficacy = 95% against influenza culture-positive lower respiratory disease).
    Several measures of vaccine effectiveness were assessed as indicators of benefit from annual vaccination (Table 16-6). In both study years there was a significant reduction in all febrile illness (regardless of result of viral cultures). In year 1, a significant reduction in febrile otitis media and reduction in associated antibiotic use was observed in the vaccine group. Similarly, vaccinated children also visited health care workers significantly less often.

    Table 16-6   -- Effectiveness of Live, Attenuated Influenza Vaccine in Children in 1996 to 1997 (Year 1) and 1997 to 1998 (Year 2)
            % Reduction in Indicated Effectiveness Measure, Vaccine Group vs. Placebo
    Effectiveness Measure

  • Year 1        Year 2
    Febrile illness        21[†]
    19[†]

    OM        9        8
    Febrile OM        33[†]
    16
    Febrile illness with Abx        29[†]
    13
    Febrile OM with Abx        33[†]
    18
    Days of missed day care        11        18[†]

    Days of parent missing work        18        6
    Visits to doctor        13[†]
    8
    Data from Belshe RB, Gruber WC. Prevention of otitis media in children with live attenuated influenza vaccine given intranasally. Pediatr Infect Dis J 19(suppl):S66–S71, 2000.
    *        Effectiveness refers to all illnesses reported, regardless of culture result (not limited to the subset of influenza culture-positive cases). Vaccine antigens were the same as in Table 15-5.

    †        P < 0.05. Abx, antibiotics; OM, otitis media.


    LAIV was also shown to be highly efficacious for preventing culture positive illness in 2 additional multicenter, randomized, placebo controlled trials in children ≤35 months of age. In one study conducted in Asia, subjects 12 to 35 months were randomized in Year 1 to receive two doses of study vaccine 28–56 days apart, followed by re-randomization and administration of a single dose of study vaccine in Year 2 of the study. Efficacy against matched strains and all strains regardless of match was significantly increased in both years of the study.[137a] In Year 1, LAIV efficacy against matched strains was 73%, with significant efficacy demonstrated against H1N1, H3N2, and B, and efficacy against all strains regardless of match was 70%. In Year 2, annual vaccination during 2 successive years (LAIV in Year 1 and in Year 2) demonstrated 84% efficacy against antigenically matched strains and 64% efficacy against all strains regardless of match, compared with no vaccination (placebo in both years). In subjects receiving vaccine in year 1 and placebo in year 2, vaccine efficacy was 56% in year 2 indicating signifi-cant protection lasted for at least 2 years. In a second study conducted in Europe and Israel, subjects 6 to 35 months were randomized in Year 1 to receive two doses of study vaccine 28–42 days part, followed by administration of a single dose of the same study vaccine in Year 2. In Year 1, LAIV efficacy was 85% with significant efficacy for H1N1 and B. In Year 2, LAIV efficacy (revaccination) was 89%, with significant efficacy demonstrated for all 3 strains.[137b,137c]
    Indirect protection and herd immunity
    For several decades, public health policy to reduce the burden of influenza in the U.S. has focused on vaccinating the elderly and persons at high risk for complications of influenza. Despite substantial increases in vaccine coverage for elderly and high-risk adults, appropriately age-adjusted estimated annual influenza-associated deaths have risen at the population level.[153a] For example, the number of influenza-associated deaths rose from 2,265 in 1976–1977 to 14,628 in 1997–1998; 90% of the influenza-associated deaths occurred in persons ≤65 years of age from 1990–1999.[153b] Estimated vaccine coverage for adults aged ≤65 years is 66%, and 23% and 44% for high-risk adults 18–49 years and 50–64 years, respectively.[153c] Moreover, recent data from a well-controlled nested case control study demonstrated that controlling for poor functional status substantially reduces crude vaccine efficacy estimation in the elderly population, suggesting that functional status has been an important confounder in many cohort studies, which presumably led to the overstatement of vaccine efficacy in the elderly.[153d]
    These observations have stimulated explorations of alternate or complementary immunization strategies, including the routine vaccination of children, to prevent transmission to high-risk individuals. ‘Herd immunity’ is the phenomenon wherein immunization of a high percentage of a population results in protection for those who are not vaccinated, as well as those who are vaccinated.[153e] Numerous studies have demonstrated that children amplify transmission and are principally responsible for the introduction and spread of influenza infection to households and subsequently into the community, suggesting that vaccinating children could modulate community spread.[153f,153g] Based on a mathematical model of influenza transmission, a vaccine coverage rate of 70% in children would effectively abort a community outbreak of influenza, but lower rates of vaccination coverage of children could also reduce the magnitude and impact of outbreaks.[153h]
    The concept of herd immunity deriving from influenza vaccination of schoolchildren was first empirically tested in a controlled study of two Michigan communities. An intervention community (Tecumseh) in which 86% of schoolchildren were vaccinated with an injectable monovalent influenza A vaccine was compared to a similar control town (Adrian). Although only children were vaccinated in Tecumseh, community-wide surveillance showed ∼60% reduction of acute respiratory illnesses in the entire community compared with the control town.[153i] The specificity of this intervention was noted when an influenza B outbreak occurred later in the same season and no difference was seen in acute respiratory illness rates in the two communities (since the vaccine did not include the B-strain).
    An association between vaccination of school-aged children and reduced deaths in the entire population was seen in Japan between 1977 and 1987 when influenza vaccination was made mandatory for Japanese schoolchildren.[153j] This ecological study was conducted retrospectively. During this interval, the country experienced an annual reduction of 10,000–12,000 deaths from influenza and pneumonia, despite the limitation of the vaccination program to children and the absence of a national program for elderly vaccination. Since most influenza deaths occur in the elderly, the study authors concluded that universal vaccination of schoolchildren reduced influenza-associated mortality in the older population by preventing spread of the infection to that susceptible group.
    Data were recently reported from a large community intervention study using LAIV.[153k] This was an open-labeled, non-randomized trial in children to determine the degree to which vaccine coverage of children at the community level could reduce spread of influenza in the community. Age-specific baseline rates of medically attended acute respiratory illness (MAARI) for Scott and White Health Plan (SWHP) members at intervention (Temple and Belton) and comparison communities (Waco, Bryan, and College Station) were obtained in 1997–1998. During three subsequent vaccination years, children (4,298, 5,251 and 5,150, respectively) received one dose per season of LAIV. Vaccinees represented 20–25% of the age-eligible children within Temple-Belton. Age-specific MAARI rates were compared for SWHP members in the intervention and comparison sites during the influenza outbreaks. Baseline age-specific MAARI rates per 100 persons for the influenza season were comparable between the intervention and comparison communities. In the subsequent three influenza seasons, adults experienced reductions in MAARI rates in the intervention communities relative to the control communities. In adults >35 years of age, significant reductions in MAARI of 8% (95% CI: 4%, 13%), 18% (95% CI: 14%, 22%) and 15% (95% CI: 12%, 19%), were observed in the influenza seasons for vaccination years 1, 2 and 3, respectively. This small effect may translate into a substantial effect when multiplied up to the population level. Moreover this effect size may be diluted from use of clinical rather than laboratory endpoints. The investigators concluded that ‘vaccination of approximately 20–25% of children, 1.5–18 years of age in the intervention communities resulted in an indirect protection (herd immunity) of 8–18% against MAARI in adults >35 years of age.’
    Recently a small scale pilot study followed by a larger multi-state school-based immunization intervention study using LAIV demonstrated the direct and indirect effectiveness of this approach. In the small pilot study, 40% of pupils in one elementary school in Maryland were vaccinated with LAIV during regular school hours. Two similar schools served as controls. All families from the three study schools were surveyed during the peak influenza outbreak period. Intervention school households were compared with control school households as the analytical framework (Table 16-9). Significant (45–70%) relative reductions in fever or respiratory illness-related outcomes including physician visits by adults, physician visits by children, prescription or other medicines purchased by household members, reported family schooldays and workdays missed were observed for intervention (‘target’) school households compared with control school households.[153l] This evidence of both direct and indirect effectiveness was observed despite intraepidemic vaccination during a year of vaccine mismatch. Following on this proof of concept, a larger randomized cluster trial was conducted in 28 schools grouped into 11 clusters (each with 1 target and 1–2 comparable control schools). LAIV (FluMist® was offered to all eligible pupils in the target schools, and 46% of target school students received LAIV. During the peak influenza week, target school households reported significantly fewer influenza-like illness (ILI)-related doctor/clinic visits in children, lower ILI-related prescription and nonprescription use, lower absence rates for elementary and high school students, and fewer missed adult workdays. Relative reductions across these outcomes ranged from 25–40%, again confirming indirect as well as direct benefit.[153m,153n]

    Table 16-9   -- LAIV Community or School-based Intervention Studies
    Study        Objective        Design        Results
    Piedra et al, Texas community intervention study[153k]
    To compare rates of medically attended acute respiratory illness (MAARI) between intervention and control community.        Open-label, non-randomized, longitudinal, community-intervention trial.        Vaccination of 20–25% of children 1.5–18 years of age in a community resulted in an indirect protection of 8–18% against MAARI in adults ≥35 years of age.
    King et al, SchoolMist Pilot[153l]
    To compare measures of influenza-like illness between family members of children who attended an elementary school where an immunization program was implemented and control schools.        Open-label, non-randomized, small (one intervention school, two control schools) pilot school-based intervention trial.        Vaccination of 40% of intervention school pupils age ≥5 years of age was associated with 45–70% relative reductions in ILI-related outcomes.
    King et al, SchoolMist Study[132a]
    To describe the impact of a school-based intervention on healthcare utilization outcomes associated with influenza-like illness within households.        Open-label, multi-site, randomized cluster design involving eleven intervention schools and seventeen control schools.        Vaccination of 46% of intervention school pupils was associated with significant reductions in ILI-related healthcare utilization outcomes among household members, including older siblings and adults.

    In summary, increasing the number of children vaccinated for influenza may result in broader protection of the population via herd immunity. Studies of various designs have shown that vaccination of school-aged children can result in lower influenza illness rates in the school, the household, the community, and the general population, presumably due to herd immunity.
    Comparative protection of LAIV with TIV
    Three head-to-head comparative trials have been conducted with the refrigerated formulation of LAIV and trivalent inactivated vaccine (Table 16-7).[174a,156a,156b] The general characteristics of LAIV and TIV are summarized in Table 16-8.

    Table 16-7   -- Comparison of Influenza Attack Rates After LAIV (refrigerator stable formulation) or TIV in Children
    Study        Age        Risk Factors        Vaccine        Number Vaccinated        Attack Rate of Influenza        Relative Reduction by LAIV (CI)
    1        6–71 Mos        Recurrent resp. disease        LAIV        1101        2.3%        52.7 (21.6, 72.2)
                              TIV        1086        4.8%         
    2        6–17 Years        Asthma        LAIV        1118        4.1%        34.7 (3.9, 56.0)
                              TIV        1115        6.4%         
    3        6–59 Mos        Age        LAIV        4243        3.9%        54.7 (45.2, 62.7)
                              TIV        4232        8.6%         


    Table 16-8   -- Comparison of LAIV with TIV
            LAIV        TIV
    Route of Administration        Intranasal spray        Intramuscular injection
    Type of vaccine        Live virus        Killed virus
    Number of included virus strains        3 (2 influenza A, 1 influenza B)        3 (2 influenza A, 1 influenza B)
    Vaccine virus strains updated        Annually        Annually
    Frequency of administration        Annual        Annual
    Can be administered to children and adults at high risk
  • from complications due to influenza        No        Yes
    Can be simultaneously administered with other vaccines        Yes[§]
    Yes[‡]

    If not simultaneously administered, can be administered within 4 weeks of another live vaccine        Yes Prudent to space 4 weeks        Yes
    If not simultaneously administered, can be administered within weeks of an inactivated vaccine        Yes        Yes
    *        Populations at high risk from complications of influenza infection include persons aged ≥65 years; residents of nursing homes and other chronic-care facilities that house persons with chronic medical conditions; adults and children with chronic disorders of the pulmonary or cardiovascular systems; adults and children with chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression; children and adolescents receiving long-term aspirin therapy (at risk for developing Reye syndrome after wild-type influenza infection); and women who will be in the second or third trimester of pregnancy during influenza season.
    ‡        TIV coadministration has been evaluated systematically only in adults with pneumococcal polysaccharide vaccine.
    §        No data exist regarding effect on efficacy LAIV coadministration has been evaluated systematically only in children with MMRII® and VARIVAX® vaccines.

    All three trials were conducted in children. The design of the three trials was similar in that subjects were randomized 1:1 to receive either LAIV or TIV. Children received either one or two doses depending on their age: two doses for the initial immunization for children under 9, one dose for children under 9 being revaccinated, or a single dose if children were 9–17 years of age being vaccinated for the first or repeat times. Culture confirmed influenza was the endpoint used in each of the trials. By the nature of the trials (placebo groups were not included), the data obtained are attack rates of culture confirmed influenza in the two different vaccine groups. Because placebo groups were not included, efficacy calculations were not done; data were obtained on the relative protective effect of one vaccine compared with the other. In all three studies, the live attenuated vaccine resulted in significantly greater protection of 34.7%, 52.7% and 54.7% as indicated by significantly lower attack rates of culture confirmed influenza (Table 16-7).
    Although it is not possible to calculate actual efficacy rates from the data, the data are highly instructive at indicating the degree of benefit compared with TIV that one would receive from using live attenuated vaccine in the populations studied. In every instance use of the live attenuated vaccine would result in significantly better protective effect than use of TIV.
    Multinational studies in young children with a refrigerator stable formulation have been conducted which confirm the high efficacy of LAIV (see also Table 16-10).[137a,137b,137c]

    Table 16-10   -- Heterotypic Immunity Studies of LAIV
    Study Population (Reference)        Findings
    Children 15–71 m ([131, 132])
    In samples obtained during year one (1996–97), cross-reactive serum HAI immunity to a variety of H3N2 drift strains was demonstrated for LAIV recipients.
            In year 2 (1997–98), vaccine efficacy was 86% against the A/Sydney (H3N2) drift strain in children who received LAIV containing A/Wuhan (H3N2).
    Adults 18–64 y ([133])
    During the 1997–98 season, when the circulating A/Sydney drift strain was not well-matched to the A/Wuhan vaccine strain, adults vaccinated with LAIV vs. placebo had significant reductions in a variety of effectiveness outcomes including days of work loss.
    Children 6–35 m ([136a])
    Serum HAI antibody titers and seroconversion rates were significantly higher in children who received LAIV vs. TIV to two mismatched strains (A/California [H3N2] and B/Florida) that circulated during the 2004–05 season.
    Children 6–59 months ([156b])
    During the 2004–05 season, when the circulating A/California (H3N2) was not well-matched to the A/Wyoming (H3N2) vaccine strain, children vaccinated with LAIV had statistically greater reductions in influenza attack rates vs. TIV recipients
    Safety of LAIV
    Prior to licensure of the frozen formulation, LAIV was evaluated in at least 20 clinical trials in which more than 20,000 subjects received more than 28,000 doses of vaccine, including more than 15,000 healthy children 1 to 17 years of age and more than 3,700 healthy adults 18 to 64 years of age. In randomized, placebo-controlled trials, over 8,100 healthy children and over 3,200 healthy adults received LAIV and over 3,900 healthy children and over 1,600 healthy adults received placebo. In the placebo-controlled trials, the incidence of adverse reactions that may be complications of influenza (such as pneumonia, bronchitis, bronchiolitis, stomatitis, and central nervous system events) was similar in LAIV and placebo groups (data on file, MedImmune Vaccines, Inc.). LAIV has been well-tolerated in clinical trials with 19 different 6:2 reassortant vaccine virus strains (7 H1N1, 9 H3N2, and 3 type B) conducted prior to those by MedImmune Vaccines and with at least 14 different 6:2 reassortants (4 H1N1, 5 H3N2, and 5 type B) in studies conducted by MedImmune Vaccines.
    No serious adverse events were associated with vaccination of children in the 2-year efficacy trial.[131,132] Transient, minor symptoms of respiratory illness were present after dose 1 of year 1, when more vaccinated children, relative to placebo children, exhibited mild upper respiratory symptoms (rhinorrhea or nasal congestion on days 2, 3, 8, and 9 postvaccine), low-grade fever (on day 2 postvaccine), or decreased activity (on day 2 postvaccine).[131,132] After revaccination, no significant differences in rhinorrhea, fever, or decreased activity were present.[132,154]
    Significant additional safety data were reported from a large, randomized, double-blind, placebo-controlled trial that evaluated medically attended events in the 42 days following vaccination in more than 9,000 healthy children 1 to 17 years of age randomized 2:1 vaccine to placebo and concluded that LAIV appeared to be well tolerated.[155,156] These data are particularly helpful in regard to medically attended lower respiratory events; pneumonia, bronchiolitis, bronchitis, and croup were not significantly increased in vaccine recipients compared to placebo recipients. However, asthma events were modestly increased in children 12 to 59 months of age but were not temporally clustered during the 42-day follow-up period.
    The refrigerator stable formulation of LAIV was also well tolerated in the comparative study of 2,187 children 6 to 71 months of age with a history of recurrent respiratory tract infections who received either LAIV or TIV. Similar rates of wheezing occurred within 10 days and within 42 days after receipt of either vaccine, and no increase in respiratory serious adverse events (SAEs) was observed in LAIV recipients compared to TIV recipients.[156a,156b]
    LAIV in children less than 5 years old
    In the comparative efficacy study that enrolled 8,475 children 6 to 59 months of age, the refrigerator stable formulation of LAIV was also well tolerated with a similar safety profile to that described in previous studies with the frozen formulation of LAIV. A small but significant increase in the incidence of medically significant wheezing, a prospectively defined endpoint that included practitioner documented wheezing plus daily bronchodilator treatment, respiratory distress, and/or hypoxemia, was found after the first dose in subjects primarily under 2 years of age not previously vaccinated against influenza (2.3% LAIV, 1.5% TIV).[156b]
    Risk benefit analysis found that for subjects over 2 years of age, LAIV provided significant health benefits to children relative to TIV. Among children 12–23 months old wheezing events were more common in LAIV recipients compared with TIV recipients. Within 6 months of vaccination, all cause hospitalizations were significantly higher in 6–11 month old infants after LAIV compared to TIV. Use of LAIV in children ≥24 months old without a history of wheezing; has the potential to control influenza in this highly susceptible age. Strategies to prevent influenza in infants will be an active area of research.
    Safety in adults
    In adults, LAIV is associated with minor upper respiratory symptoms, runny nose, and/or sore throat in approximately 10% of subjects. These symptoms are generally well tolerated.[133] A recent study by researchers from the Food and Drug Administration evaluating the safety of the frozen formulation LAIV after 2.5 million doses were distributed in the first two influenza seasons following licensure concluded that there were no unexpected risks associated with vaccination.[133b]
    LAIV in high-risk populations
    The safety and tolerability of 2 doses of LAIV compared to placebo in 120 children less than 6 months of age has been assessed.[133c] Overall, there were no significant differences between treatment groups in the incidence of post-vaccination adverse events following each dose. LAIV was well tolerated in young infants 6 to 24 weeks of age.[133c] LAIV in 48 children and adolescents 9 to 17 years of age with moderate to severe asthma has been evaluated.[157] Asthma stability following vaccination, measured by the percent change from baseline in forced expiratory volume at 1 second, change from baseline in peak expiratory flow rates, asthma symptom scores, nighttime awakening scores, and daily use of rescue medication, was similar in both LAIV and placebo groups. Mild exacerbations of asthma occurred in 2 of 24 LAIV recipients and 0 of 24 placebo recipients.
    Additional safety and tolerability data come from a study conducted in advance of the 2002–03 influenza season, in which 2,229 children and adolescents 6 to 17 years of age with a history of asthma were randomized to receive either LAIV or TIV.[174a] At the time of enrollment, 70.4% of participants were taking inhaled or oral short acting beta-agonists, 31.8% were taking inhaled or oral long acting beta-agonists, 68.6% were taking inhaled corticosteroids, 15.3% were taking leukotriene receptor antagonists, and 1.6% were taking systemic corticosteroids. In the 15 days post-vaccination, wheezing reported by the subject or parent/guardian was significantly decreased in LAIV recipients compared to TIV recipients (-4.3% rate difference), although no significant differences in peak expiratory flow rate (PEFR) reductions or in frequency of nighttime awakenings were observed between the two groups. Continuous asthma symptoms were also reported by significantly more TIV than LAIV recipients from Days 8–14 post-vaccination, but were not significantly different for the Days 0–7 or Days 0–14 observation periods. Asthma exacerbations, analyzed as hospitalizations, unscheduled clinic visits, and medication use occurred at comparable rates between the two groups during the entire study period as well as during the 42-day post-vaccination period.
    Genetic stability of LAIV during replication in humans
    Clinical studies of 6:2 LAIV strains demonstrated genetic stability of the vaccine during replication in humans. Vaccine virus isolates recovered from susceptible adults and seronegative children retain the vaccine phenotypes, indicating that reversion to virulence did not occur during replication of LAIV in humans.[163] It is likely that the observed stable attenuation is due to attenuating genetic sequences contained in multiple genes of LAIV vaccine strains.
    Pandemic influenza and LAIV
    To avoid contributing novel H and N genes to the environment, LAIV would not be used for vaccination against novel pandemic viruses until the virus was already widespread. Reassortants have been produced.[163a] LAIV has many of the characteristics that are desirable in a pandemic influenza vaccine, i.e., single dose immunogenicity, induction of broadly cross reactive antibodies, and highly efficient manufacturing. Clinical trials were underway in an isolation unit in 2006.
    Transmission of LAIV
    LAIV strains replicate in the nasopharynx of the recipient and are shed in the respiratory secretions. Data in the published literature failed to detect transmission of vaccine viruses derived from the passaged cold-adapted master donor viruses in multiple age groups and settings.[164–173] In an evaluation of direct transmissibility in a day care setting in children 8 to 36 months of age, 80% of the 98 FluMist recipients shed one or more vaccine strains, with a mean shedding duration of 7.6 days. One possible transmission event was observed among the 99 placebo recipients that was confirmed by phenotype and genotype analysis. The safety profile for this child following transmission was similar to that of the other children in the study who received vaccine or placebo, and the child was not ill and did not experience a serious adverse event.[174]
    In the year after initial FDA approval, the clinical use of LAIV was restricted in some institutions due to the theoretical concern that live attenuated virus might transmit from vaccinated hospital employees to unvaccinated patient contacts. After several years of experience this concern proved to be unfounded and person to person transmission of LAIV has not been a problem. Izurieta, et al[133b] summarized vaccine adverse event reporting regarding LAIV and no instances of recognized transmission were identified. In the one case in which transmission was suspected, and in which viral cultures were obtained, it turned out that a wild-type influenza virus was involved in transmission and not vaccine virus. The Advisory Committee on Immunization Practices (ACIP) has modified its initial recommendation to reflect the practicalities of vaccine usage within hospitals. At the present time the only concern that remains is a theoretical one. Employees who are vaccinated should not have contact within 7 days with immunosuppressed patients while in reverse isolation (such as bone marrow transplant patients while in the hospital in reverse isolation). All other situations are considered acceptable for using LAIV.
    Indications for use of LAIV to prevent influenza
    On June 17, 2003, LAIV was approved for use by the Food and Drug Administration for active immunization to prevent disease caused by influenza A and B viruses in healthy children, adolescents and adults 5–49 years of age. LAIV is an important new option as a vaccine to prevent influenza (Table 16-10). The ACIP developed draft guidelines for use of LAIV. Children 5–8 years of age should receive two doses 60 ± 14 days apart the first year of influenza vaccination; individuals 9–49 years of age should receive a single dose annually prior to exposure to influenza. In contrast to inactivated influenza vaccine which has been used largely in populations at high risk for death or other complications of influenza, LAIV is currently indicated to prevent influenza in persons without underlying high risk conditions. LAIV and TIV are compared and contrasted in Table 16-8.
    The age range 5 to 49 years was selected for initial clinical use in healthy persons due to the adequacy of safety and efficacy data within that age range. Provisional data in the age group less than 5 years of age raised concerns that LAIV might trigger or exacerbate reactive airway disease in the youngest cohort.[155,157] Although several lines of evidence do not support a causal link, it was widely recognized at the time of initial licensure of LAIV that further studies were needed within this age group. To address these concerns, a large multinational safety and efficacy trial in more than 8,000 children 6 to 59 months of age comparing LAIV with TIV was conducted. In addition, the effectiveness trial in 4,561 healthy working adults was specifically designed to examine the clinical benefits of LAIV compared to placebo in all persons 18–64 years old but there were limited effectiveness data in the subgroup of 50–64 years old, a population universally recommended to receive trivalent inactivated vaccine.[133] Post hoc analysis among persons age 50–64 years (641 of the 4,561 adults) did not reveal statistically significant reductions in illness measures (proportion, episodes or days of illness) in this subgroup, but there were significant reductions in illness associated missed work days and illness associated visits to their healthcare provider. In a similarly designed effectiveness study conducted by the Centers for Disease Control with the TIV compared to placebo in the same season in more than 1,000 adults 18–64 years of age there were no reductions in any illness measures in any age group.[133a] While LAIV appeared to reduce more severe disease in older healthy adults, more data are needed before the live vaccine can be indicated for >50 year olds.
    New contraindications
    Persons who should not be vaccinated with LAIV
              •            LAIV is not indicated for persons aged <2 years
              •            LAIV is not indicated for persons aged ≥50 years
              •            LAIV is contraindicated for individuals with a history of hypersensitivity, especially anaphylaxis, to any component in LAIV, including eggs.
              •            LAIV is contraindicated for children or adolescents receiving aspirin or other salicylates (because of the association of Reye syndrome with wild-type influenza infection).
              •            Persons with a history of Guillain–Barré syndrome should not receive LAIV
              •            Pregnant women should not receive LAIV
              •            Persons with asthma, reactive airways disease or other chronic disorders of the pulmonary or cardiovascular systems; persons with other underlying medical conditions, including metabolic diseases such as diabetes, renal dysfunction, and hemoglobinopathies; or persons with known or suspected immune deficiency diseases or receiving immunosuppressive therapies should not receive LAIV
    Close contacts of severely immunosuppressed individuals (e.g., bone marrow transplant patients during the period in which they are in a protected environment), if given LAIV, should avoid close contact with the immunosuppressed patient for 7 days.
    For vaccination of healthy persons aged 5–49 years in close contact with all other immunocompetent high risk groups (e.g., persons with heart disease, lung disease, or diabetes), either TIV or LAIV are acceptable vaccination options.
    Timing of LAIV administration
    Vaccination with LAIV can begin as soon as vaccine is available for that season. Children aged <9 years receiving LAIV for the first time should begin in October or earlier because those persons need a second dose 6–10 weeks after the initial dose. The safety and immunogenicity of concurrent administration of LAIV with MMRII® and VARIVAX® vaccines has been evaluated in 1,251 children 12 to 15 months of age.[175] Concurrent administration was safe and well tolerated and the immune responses to the relevant viral antigens were similar when the vaccines were given concurrently or separately. In the absence of specific data indicating lack of interference with other vaccines, it is prudent to follow the ACIP General Recommendations on Immunization. Inactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines. An inactivated vaccine can be administered either simultaneously or at any time before or after LAIV. A live vaccine not administered on the same day should be administered ≥4 weeks apart when possible.
    Administration of LAIV and influenza antiviral use
    It is unknown whether administering influenza antiviral medications affects the safety or efficacy of LAIV; LAIV should not be administered until 48 hours following cessation of influenza antiviral therapy, and influenza antiviral medications should not be administered for two weeks following receipt of LAIV.
    Conclusions
    LAIV has the potential to significantly contribute to the control of influenza and influenza-associated illnesses. LAIV has significant advantages in convenience of administration. The high efficacy of LAIV compared to the TIV against matched strains and drifted strains are compelling reasons to use the vaccine in children. Effectiveness of LAIV in adults has also been demonstrated.
    Acknowledgment
    Contributors to this chapter in prior editions were Louise Herlocher, Marty Bryant, Michael Shaw, Carol Heilman, John LaMontagne and Dan DeBorde.
    References
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