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Flumist (Influenza Virus Vaccine Live Intranasal) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Influenza Virus Vaccine Live, Intranasal (FluMist™) is a live trivalent nasally administered vaccine intended for active immunization for the prevention of influenza.

Each 0.5 mL dose is formulated to contain 106.5-7.5 TCID50(median tissue culture infectious dose) of live attenuated influenza virus reassortants of the strains recommended by the U.S. Public Health Service (USPHS) for the 2004-2005 season: A/New Caledonia/20/99 (H1N1), A/Wyoming/3/2003 (H3N2) (A/Fujian/411/2002-like), and B/Jilin/20/2003 (B/Shanghai/361/2002-like) [1]. These strains are (a) antigenically representative of influenza viruses that may circulate in humans during the 2004-2005 influenza season; (b) cold-adapted (ca) (i.e., they replicate efficiently at 25°C, a temperature that is restrictive for replication of many wild-type viruses); (c) temperature-sensitive (ts) (i.e., they are restricted in replication at 37°C (Type B strains) or 39°C (Type A strains), temperatures at which many wild-type influenza viruses grow efficiently); and (d) attenuated (att) so as not to produce classic influenza-like illness in the ferret model of human influenza infection. The cumulative effect of the antigenic properties and the ca, ts, and att phenotype is that the attenuated vaccine viruses replicate in the nasopharynx to induce protective immunity.

Each of the three influenza virus strains contained in FluMist is a genetic reassortant of a Master Donor Virus (MDV) and a wild-type influenza virus. The MDVs (A/Ann Arbor/6/60 and B/Ann Arbor/1/66) were developed by serial passage at sequentially lower temperatures in specific pathogen-free (SPF) primary chick kidney cells [2]. During this process, the MDVs acquired the ca, ts, and att phenotype and multiple mutations in the gene segments that encode viral proteins other than the surface glycoproteins. The individual contribution of the genetic sequences of the six non-glycoprotein MDV genes ("internal gene segments") to the ca, ts, and att phenotype is not completely understood. However, for the Type A MDV, at least five genetic loci in three different internal gene segments contribute to the ts and att phenotype. For the Type B MDV, at least three genetic loci in two different internal gene segments contribute to both the ts and att properties; two additional genetic loci in a third gene segment also contribute to the att property. No evidence of reversion has been observed in the recovered vaccine strains that have been tested (135 of possible 250 recovered isolates) (see TRANSMISSION) [3, 4]. For each of the three strains in FluMist, the six internal gene segments responsible for ca, ts, and att phenotypes are derived from the MDV, and the two segments that encode the two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), are derived from the corresponding antigenically relevant wild-type influenza viruses that have been recommended by the USPHS for inclusion in the annual vaccine formulation. Thus, the three viruses contained in FluMist maintain the replication characteristics and phenotypic properties of the MDV and express the HA and NA of wild-type viruses that are related to strains expected to circulate during the 2004-2005 influenza season.

Viral harvests used in the production of FluMist are produced by inoculating each of the three reassortant viruses into specific pathogen-free (SPF) eggs that are incubated to allow for vaccine virus replication. The allantoic fluid of these eggs is harvested, clarified by centrifugation, and stabilized with buffer containing sucrose, potassium phosphate, and monosodium glutamate (0.47 mg/dose). Viral harvests from the three strains (H1N1, H3N2, and B) are subsequently blended and diluted to desired potency with allantoic fluid derived from uninfected SPF eggs to produce trivalent bulk vaccine. Each lot of viral harvest is tested for ca, ts, and att and is also tested extensively by in vitro and in vivo methods to detect adventitious agents. The bulk vaccine is then filled directly into individual sprayers for nasal administration. These sprayers are labeled and stored at </=-15°C.

Gentamicin sulfate is added early in the manufacturing process during preparation of reassortant viruses at a calculated concentration of approximately 1 µg/mL. Later steps of the manufacturing process do not use gentamicin, resulting in a diluted residual concentration in the final product of <0.015 µg/mL (limit of detection of the assay). FluMist does not contain any preservatives.

Each pre-filled FluMist sprayer contains a single 0.5 mL dose. The teflon tip attached to the sprayer is equipped with a one-way valve that produces a fine mist that is primarily deposited in the nose and nasopharynx. When thawed for administration, FluMist is a colorless to pale yellow liquid and is clear to slightly cloudy (see DOSAGE AND ADMINISTRATION).

CLINICAL PHARMACOLOGY

Influenza is a highly infectious respiratory viral infection that causes recurrent winter epidemics of acute disease in persons of all ages. Highest rates of illness are generally reported among 5-14 year-olds [5, 6]. Influenza-associated deaths have been reported in previously healthy children and young adults. Among healthy individuals 15-44 years of age, the average rate of excess hospitalizations attributable to influenza is 23-25 per 100,000 per year [7], with an annual influenza-associated mortality rate of 0.2-1.5 per 100,000 person-years [8].

Types A and B influenza viruses are the principal causes of influenza in humans. Type A influenza viruses are divided into subtypes on the basis of the two surface antigens, he-magglutinin (HA) and neuraminidase (NA), while influenza virus B is classified as a single subtype. Continuous mutation of the influenza virus genome leads to an accumulation of genetic and accompanying antigenic changes that result in the evolution of viruses into recognizable antigenic lineages or strains within a subtype. Protective immune responses following natural infection result in population-based immunity to circulating strains. However, this immune barrier eventually results in the emergence of strains that have undergone antigenic change, or "drift." Because these "drifted" strains can escape immunity to HA and NA antigens of previously circulating strains, vaccines may require annual updating to match the contemporary strains.

Vaccination is the principal means of prevention of influenza and influenza-associated complications [1].

MECHANISM OF ACTION

Immune mechanisms conferring protection against influenza following receipt of FluMist vaccine are not fully understood. Likewise, naturally acquired immunity to wild-type influenza has not been completely elucidated. Serum antibodies, mucosal antibodies and influenza-specific T cells may play a role in prevention and recovery from infection [9, 10]. Vaccination with FluMist has been demonstrated to induce influenza strain-specific serum antibodies [11, 12].

CLINICAL STUDIES

FluMist was administered to 20,228 subjects in clinical studies. The population evaluated included 10,297 healthy children 5-17 years of age (14,058 doses of FluMist received) and 3297 healthy adults 18-49 years of age (3335 doses of FluMist received) who received at least one dose of vaccine. Second and third annual doses have been given to 1766 and 128 children 5-17 years of age, respectively. In randomized, placebo-controlled trials, 4719 healthy children 5-17 years of age and 2864 healthy adults 18-49 years of age received FluMist.

The efficacy of FluMist against culture-confirmed influenza disease for Types A/H3N2 and B was assessed in a field trial in children. The effectiveness of FluMist against Types A/H3N2 and B, defined as a reduction in influenza-like illness and illness-associated health care utilization, was assessed in a field trial in adults. Type A/H1N1 did not circulate during either trial, and no field efficacy data against this strain are available.

PEDIATRIC STUDY

The Pediatric Efficacy Study was a multi-center, randomized, double-blind, placebo-controlled trial performed in healthy U.S. children to evaluate the efficacy of FluMist against culture-confirmed influenza over two successive seasons [13, 14]. The primary endpoint for the first year of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza in healthy children who received two doses of vaccine. During the first year of the study a subset of 312 children 60-71 months of age were randomized 2:1 (vaccine:placebo). All children with culture-confirmed influenza experienced respiratory symptoms (cough, runny nose, or sore throat) and most experienced fever (68%), health care provider visits (68%), and missed school days (74%).

As shown in Table 1, when compared with placebo recipients, FluMist recipients 60-71 months of age who received two doses of vaccine (n=238) experienced a significant reduction in the incidence of culture-confirmed influenza (efficacy 87.4%, 95% CI: 59.4, 97.9). In the 60-71 month old age group, children who received one dose of FluMist when compared to one dose of placebo experienced a significant reduction in the incidence of culture-confirmed influenza (0 of 54 FluMist recipients vs 3 of 20 placebo recipients; efficacy 100%, 95% CI: 47.0, 100).

Approximately 85% of the participants in the first year returned for the second year of the Pediatric Efficacy Study, including a subset of 544 children 60-84 months of age [15]. During the second year of the trial, the H3N2 strain included in the vaccine was A/Wuhan/359/95, which was antigenically distinct from the A/Sydney/05/97 H3N2 strain that was the primary circulating strain. Type A/Wuhan/359/95 (H3N2) also circulated as did Type B strains. Children remained in the same treatment group as in year one and received a single dose of FluMist or placebo. The primary endpoint of the trial was the prevention of culture-confirmed influenza illness due to antigenically matched wild-type influenza after a single annual revaccination dose of FluMist.

In the subset of 544 children 60-84 months of age, illness associated with culture-confirmed illness in the second year was similar in scope and severity to that in the first year.

The overall efficacy of FluMist against culture-confirmed wild-type influenza, regardless of antigenic match, was 86.9% (95% CI: 70.8, 94.1).

Table 1
Efficacy of FluMist Against Culture-Confirmed
Influenza in Children >/=60 Months of Age
Endpoint Cases Efficacy (%) (95% CI)
FluMist Placebo
N=163 N=75
Year One (60-71 mo of age) n (%) n (%)
Culture-confirmed influenza a 3 (1.8) 11 (14.7) 87.4 (59.4, 97.9) *
   N=375    N=169
Year Two (60-84 mo of age) n (%) n (%)
Culture-confirmed influenza a , b 7 (1.9) 24 (14.2) 86.9 (70.8, 94.1) *
* Denotes statistically significant, p</=0.05.
a Overall efficacy against Type A (H3N2) and Type B wild-type viruses. Field efficacy against wild Type A (H1N1) viruses could not be determined because those strains did not circulate during the study period.
b Includes illness caused by A/Sydney/05/97 (H3N2), an antigenic variant not included in the vaccine.

STUDIES IN ADULTS

The Adult Effectiveness Study was a multi-center, randomized, double-blind, placebo-controlled trial in which healthy adults were enrolled, including 3920 adults 18-49 years of age (2150 women and 1770 men). Participants were randomized 2:1, vaccine:placebo. The trial was designed to evaluate the effectiveness of FluMist in the reduction of influenza-like illness during the peak influenza outbreak period at each site, based on community surveillance [16]. Cultures for influenza virus were not obtained from subjects in the trial, so that the efficacy against culture-confirmed influenza was not assessed. The A/Wuhan/359/95 (H3N2) strain, which was contained in FluMist, was antigenically distinct from the predominant circulating strain of influenza virus during the trial period, A/Sydney/05/97 (H3N2). Type A/Wuhan (H3N2) and Type B strains also circulated in the U.S. during the study period. The primary endpoint of the trial was the reduction in the proportion of participants with one or more episodes of any febrile illness (AFI). Two other, more specific febrile influenza-like illness definitions were also prospectively assessed: severe febrile illness (SFI), and febrile upper respiratory illness (FURI). Adults were characterized as having AFI if they had symptoms for at least two consecutive days with fever on at least one day and if they had two or more symptoms (fever, chills, headache, runny nose, sore throat, cough, muscle aches, tiredness/weakness) on at least one day. SFI was defined as having at least three consecutive days of symptoms, at least one day of fever, and two or more symptoms on at least three days. FURI was defined as at least two consecutive days of upper respiratory infection (URI) symptoms (runny nose, sore throat, or cough), fever on at least one day, and at least two URI symptoms on at least one day. Adults meeting the three illness definitions often had associated health care provider visits (25-31%), used antibiotics (28-32%), and missed at least one day of work (51-58%).

During the seven-week site-specific outbreak period, in the subset of subjects age 18-49 years, FluMist recipients did not experience a significant reduction in AFI; significant reductions were observed for SFI and FURI (Table 2). An additional measure of the severity of disease was illness-associated days of health care provider visits; FluMist recipients experienced significant reductions in days of health care provider visits associated with SFI (17.8%, 95% CI: 2.0, 31.0), and FURI (36.9%, 95% CI: 24.4, 47.3) when compared to placebo recipients. However, no significant reduction in days of health care provider visits associated with AFI was observed among FluMist recipients when compared to placebo recipients.

Table 2
Effectiveness of FluMist in Adults 18-49 Years of Age
During the 7-week Site-Specific Outbreak Period
Endpoint FluMist
N=2411 a
n (%)
Placebo
N=1226 a
n (%)
Percent Reduction (95% CI)
Participants with one or more events of: b
   Any febrile illness 331 (13.73) 189 (15.42) 10.9 (-5.1, 24.4) 
   Severe febrile illness 250 (10.37) 158 (12.89) 19.5 (3.0, 33.2) *
   Febrile upper respiratory illness 213   (8.83) 142 (11.58) 23.7 (6.7, 37.5) *
* Denotes p-value </=0.05.
Note: The proportion of participants with any febrile illness (AFI) was the primary study endpoint; effectiveness was not demonstrated for this endpoint (p-value >0.05).
a Number of evaluable subjects (92.7% and 93.0% of FluMist and placebo recipients, respectively).
b The predominantly circulating virus during the trial period was A/Syndey/05/97 (H3N2), an antigenic variant not included in the vaccine.

CHALLENGE STUDY

The ability of FluMist to protect adults from influenza illness after challenge with wild-type influenza was assessed in a multi-center, randomized, double-blind, placebo-controlled trial in healthy adults 18-41 years of age who were serosusceptible to at least one strain included in the vaccine [12]. Adults were randomized to receive FluMist (n=29) or placebo (n=31). Each subject was challenged intranasally with only a single strain of wild-type virus (Type A/H3N2, Type A/H1N1 or Type B) to which he/she was serosusceptible, and the results were pooled for all three strains combined within each treatment group. Laboratory-documented influenza illness due to all three strains combined was reduced compared to placebo by 85% (95% CI: 28, 100) in FluMist recipients.

TRANSMISSION

FluMist contains live attenuated influenza viruses that must infect and replicate in cells lining the nasopharynx of the recipient to induce immunity. Vaccine viruses capable of infection and replication can be cultured from nasal secretions obtained from vaccine recipients. The relationship of viral replication in a vaccine recipient and transmission of vaccine viruses to other individuals has not been established.

A prospective, randomized, double-blind, placebo-controlled trial in a daycare setting in children less than three years of age was performed with the primary objective of assessing the probability that vaccine viruses will be transmitted from a vaccinated individual to a non-vaccinated individual [17]. Children enrolled in the study attended daycare at least three days per week for four hours per day, and were in a playroom with at least four children, at least one of whom was vaccinated with FluMist. A total of 197 children 8-36 months of age were randomized to receive one dose of FluMist (n=98) or placebo (n=99). Virus shedding was evaluated for 21 days by culture of nasal swab specimens obtained from each subject approximately three times per week. Wild-type A (H3N2) influenza virus was documented to have circulated in the community and in the study population during the trial, whereas Type A (H1N1) and Type B strains did not.

At least one vaccine strain was isolated from 80% of FluMist recipients. Viruses were recovered from specimens obtained over a range of 1-21 days (mean duration of 7.6 days ± 3.4 days). The cold-adapted (ca) and temperature-sensitive (ts) phenotypes were preserved in all recovered viruses tested (n=135 tested of 250 strains isolated at the local laboratory). Ten influenza isolates were cultured from a total of seven placebo subjects. One placebo subject became infected with a Type B virus confirmed as a transmitted vaccine virus by a FluMist recipient in the same playgroup. Of the 11 nasal swabs obtained from the subject on Days 0-21, vaccine virus was cultured only from the Day 15 specimen. This Type B isolate retained the ca, ts, and att phenotypes of the vaccine strain, and had the same genetic sequence when compared to a Type B virus cultured from a vaccine recipient within the same playgroup. This placebo recipient experienced cough, coryza, and irritability similar to the symptoms observed among some FluMist vaccinees in the trial. No viruses were cultured from any of the other placebo recipients in this playgroup. Nine isolates identified as Type A were cultured from six placebo subjects; two of these subjects had two cultures that grew Type A strains (four isolates) confirmed as wild-type A/Panama (H3N2). Type A isolates that could not be further characterized were cultured from the four remaining placebo subjects; because the isolates could not be further characterized, the possibility that they were vaccine strains could not be excluded.

Assuming that a single transmission event occurred (isolation of the Type B vaccine strain), the probability of a young child acquiring vaccine virus following close contact with a single FluMist vaccinee in this daycare setting was 0.58% (95% CI: 0, 1.7) based on the Reed Frost model [18]. With documented transmission of one Type B in one placebo subject and possible transmission of Type A viruses in four placebo subjects, the probability of acquiring a transmitted vaccine virus was estimated to be 2.4% (95% CI: 0.13, 4.6), using the Reed Frost model.

The duration of FluMist vaccine virus replication and the potential for transmission of vaccine viruses by recipients 5-49 years of age have not been established.

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