Robert E. Walker

Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents

Objective. To determine the safety of cold-adapted trivalent intranasal influenza virus vaccine (CAIV) in children and adolescents. Study design. A randomized, double blind, placebo-controlled safety trial in healthy children age 12 months to 17 years given CAIV (FluMist; MedImmune Vaccines, Inc.) or placebo (randomization, 2:1). Children <9 years of age received a second dose of CAIV or placebo 28 to 42 days after the first dose. Enrolled children were then followed for 42 days after each vaccination for all medically attended events. Prespecified outcomes included 4 prespecified diagnostic groups and 170 observed individual diagnostic categories. The relative risk and the 2-sided 90% confidence interval were calculated for each diagnostic group and individual category by clinical setting, dose and age. More than 1500 relative risk analyses were performed. Results. A total of 9689 evaluable children were enrolled in the study. Of the 4 prespecified diagnostic categories (acute respiratory tract events, systemic bacterial infection, acute gastrointestinal tract events and rare events potentially associated with wild-type influenza), none was associated with vaccine. Of the biologically plausible individual diagnostic categories, 3, acute gastrointestinal events, acute respiratory events and abdominal pain, had different analyses that demonstrated increased and decreased relative risks, making their association with the vaccine unlikely. For reactive airway disease a significant increased relative risk was observed in children 18 to 35 months of age with a relative risk of 4.06 (90% confidence interval, 1.29 to 17.86) in this age group. The individual diagnostic categories of upper respiratory infection, musculoskeletal pain, otitis media with effusion and adenitis/adenopathy had at least one analysis that achieved a significant increased risk ratio. All of these events were infrequent. Conclusion. CAIV was generally safe in children and adolescents. The observation of an increased risk of asthma/reactive airway disease in children <36 months of age is of potential concern. Further studies are planned to evaluate the risk of asthma/reactive airway disease after vaccine.

Safety, immunogenicity and efficacy of intranasal, live attenuated influenza vaccine

Data supporting the use of the live attenuated influenza vaccine (LAIV) in children and adults is reviewed, and the development and characteristics of the vaccine are summarized. The vaccine is highly effective and well tolerated in children and adults from 5 to 49 years of age. Correlates of immune protection include serum hemagglutination-inhibition antibody and secretory immunoglobulin A. Efficacy against antigenically well-matched epidemic influenza strains was high at 92%. In 1 year, despite a significant antigenic change in the epidemic influenza virus that did not match the vaccine, LAIV conferred 86% protection against culture-confirmed illness in children. In the future it is expected that additional studies will support a broadening of the age range for use with the LAIV to prevent influenza in children and adults.

Shedding and immunogenicity of live attenuated influenza vaccine virus in subjects 5-49 years of age

BACKGROUNDnLive attenuated influenza vaccine (LAIV) is indicated for influenza prevention in persons 2-49 years of age. This study describes the incidence and duration of vaccine virus shedding and serum immune responses after receipt of LAIV.nnnMETHODSnA single open-label dose of trivalent LAIV was administered intranasally to 344 subjects in 3 age cohorts: 5-8, 9-17, and 18-49 years of age. Shedding was determined by culture of nasal swabs (on days 1-7, daily; days 9-25, every other day; and day 28). Immunogenicity was measured as serum strain-specific hemagglutinin inhibition (HAI) titers (days 0, 28).nnnRESULTSnAmong subjects aged 5-8 years, 9-17 years, and 18-49 years, 44%, 27%, and 17% of subjects, respectively, shed vaccine virus after vaccination, and the mean number of positive samples per subject was 2.2, 1.8, and 1.5, respectively. Shedding occurred on days 1-11 postvaccination. Shedding incidence peaked on day 2, and maximum observed titers were highest on days 2-3 (<5, <4, and <3 log(10)TCID(50)/mL, respectively, by age group). Despite positive cultures, all titers were <1 log(10)TCID(50)/mL after days 10, 6, and 6, respectively, by age group. Shedding incidence was inversely correlated to age and baseline serum HAI titer. The seroresponse rate (4-fold rise in HAI) to at least 1 strain was 59% (68%, 64%, and 47%, respectively, by age group), and strain-specific rates were higher in baseline seronegative/serosusceptible subjects. Reactogenicity, most commonly runny nose, headache, and sore throat, was not associated with shedding or seroresponse.nnnCONCLUSIONSnThis is the first study to comprehensively evaluate nasal shedding of LAIV in individuals 5-49 years of age. Shedding was generally of short duration and at low titers. Study findings support the current recommendation of the Advisory Committee on Immunization Practices that LAIV recipients should only avoid contact with severely immunosuppressed persons (e.g., hematopoietic stem cell transplant recipients) for 7 days after vaccination.

Shedding of Live Vaccine Virus, Comparative Safety, and Influenza-Specific Antibody Responses after Administration of Live Attenuated and Inactivated Trivalent Influenza Vaccines to HIV-Infected Children

HIV-infected children (N=243), >or=5 to <18 years old, receiving stable antiretroviral therapy, were stratified by immunologic status and randomly assigned to receive intranasal live attenuated influenza vaccine (LAIV) or intramuscular trivalent inactivated influenza vaccine (TIV). The safety profile after LAIV or TIV closely resembled the previously reported tolerability to these vaccines in children without HIV infection. Post-vaccination hemagglutination inhibition (HAI) antibody responses and shedding of LAIV virus were also similar, regardless of immunological stratum, to antibody responses and shedding previously reported for children without HIV infection. LAIV should be further evaluated for a role in immunizing HIV-infected children.

Safety and tolerability of cold-adapted influenza virus vaccine in children and adolescents with asthma

Background. Influenza infections can cause severe respiratory disease in high risk persons such as those with asthma, but immunization rates for high risk groups remain suboptimal. An investigational influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) administered by intranasal spray was shown previously to be effective in healthy adults and healthy children. Purpose. To assess the safety and tolerability of CAIV-T in subjects 9 years of age and older with moderate to severe asthma. Methods. In this randomized, double blind, placebo-controlled study, spirometry was performed twice before vaccination to establish a baseline forced expiratory volume at 1 s (FEV1) and once 2 to 5 days thereafter. The primary outcome index was the percent change in percent predicted FEV1 before and after vaccination. Peak flows, clinical asthma symptom scores and nighttime awakening scores were measured daily from 7 days pre- to 28 days postvaccination. Results. The primary outcome index (percentage change in percent predicted FEV1) was not different between the two groups (0.2%vs. 0.4% for the treatment and placebo groups, respectively;P = 0.78). Secondary outcomes did not differ between the two groups; these included the number of subjects with a decrease in FEV1 ≥15% from baseline, reductions in peak flows ≥15%, ≥30% or ≥2 sd below baseline, use of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma symptom scores before and after vaccination. The same proportion of subjects in each group experienced postvaccination symptoms within 10 days (92% and 91%, respectively;P = 1.0). No serious adverse event occurred. Conclusion. CAIV-T was generally safe and well-tolerated in children and adolescents with moderate to severe asthma.

Development of a PIV-vectored RSV vaccine: Preclinical evaluation of safety, toxicity, and enhanced disease and initial clinical testing in healthy adults

MEDI-534 is a bivalent live attenuated vaccine candidate against human respiratory syncytial virus (hRSV) and human parainfluenza virus type 3 (hPIV3) that was previously shown to be immunogenic and to protect rodents and African green monkeys from wild-type (wt) hRSV challenge. We performed further preclinical evaluations to address the safety of MEDI-534 prior to human testing. MEDI-534 did not predispose rodents to enhanced RSV disease following wt-RSV challenge, and the tissue tropism of the chimeric virus was confined to the respiratory tract. Representative clinical trial material did not produce toxicity in rats. In adults, MEDI-534 was highly restricted in replication, did not boost RSV and PIV3 antibody titers, and produced no medically significant vaccine-related adverse events thereby warranting further evaluation in pediatric populations.

Measuring antibody responses to a live attenuated influenza vaccine in children

Background: Hemagglutination inhibition (HAI) assay is the standard method for evaluating inactivated influenza vaccines, but no standard assay has been established for evaluating live attenuated influenza vaccines (LAIV). LAIV containing A/Beijing/262/95(H1N1) induced low serum HAI antibody responses to the antigenic variant, A/New Caledonia/20/99(H1N1) in a serologic study but provided protection against the A/New Caledonia-like viruses in a community study. Neutralization and HAI assays were compared by measuring H1N1 cross-reactive antibody responses to the LAIV in children. Methods: Sera were collected from 50 children 1–8 years of age before vaccination and 4–6 weeks after each dose of the LAIV. Antibody titers to the 3 vaccine viruses were measured by the HAI assay, whereas antibody titers against the H1N1 vaccine virus (A/Beijing/262/95) and 2 H1N1 antigenic variants (A/Shenzhen/227/95 and A/New Caledonia/20/99) were measured by the HAI and neutralization assays. Results: Initially seronegative participants were more likely to develop HAI seroconversion responses to the 3 vaccine viruses than the baseline seropositive participants (77% versus 14% for H1N1, 100% versus 20% for H3N2, 100% versus 19% for B, P < 0.01, Fishers exact test). For the H1N1 cross-reactive antibody responses, seroconversion rates measured by the neutralization assay were significantly higher than those measured by the HAI assay (95% versus 78%, P = 0.0485 for A/Beijing/262/95; 75% versus 24%, P < 0.0001 for A/Shenzhen/227/95; 51% versus 5%, P < 0.0001 for A/New Caledonia/20/99). Conclusions: The neutralization assay was more sensitive than the HAI assay for measuring H1N1 antibody responses after vaccination of children with the LAIV and may provide a better correlate of clinical protection provided by the LAIV.

Safety and immunogenicity of a live-attenuated influenza vaccine blended and filled at two manufacturing facilities

This study was designed to compare the safety and immunogenicity of a trivalent live-attenuated, cold-adapted influenza vaccine (CAIV-T) blended and filled at two different manufacturing facilities (Medeva and Aviron-PA). The vaccines contained approximately 10(7) TCID(50) (median tissue culture infectious dose) of each of the three recommended 1997-1998 influenza vaccine components, A/Shenzhen/227/95 (H1N1) (A/Bayern/7/95 (H1N1)-like strain), A/Wuhan/359/95 (H3N2), and B/Ann Arbor/1/94 (B/Beijing/184/93-like strain). Two hundred and twenty-five healthy Australian children aged 12-42 months were enrolled and randomized in a 3:2 ratio to receive CAIV-T blended and filled either at Medeva or at Aviron-PA. Two doses of CAIV-T were given 4-6 weeks apart as an intranasal spray. Three blood specimens were collected (immediately before doses one and two, and 28 +/- 5 days following dose two) for measuring hemagglutination inhibition (HAI) antibody responses. Adverse events occurring within 10 days and serious adverse events occurring within 42 days were collected. Serum HAI antibody levels were measured against the three vaccine strains. Equivalent immunogenicity between the two vaccine groups was pre-specified as: (1) within 20% difference in seroconversion rates (HAI titers > or =4-fold rise); and (2) within 4-fold difference in the 90% confidence interval of geometric mean titer ratio. Among 10 pre-specified adverse events, only vomiting had significantly different incidence rates in the two vaccine groups following dose one (3% versus 13%, P = 0.01) but the difference disappeared following dose two (4% versus 4%). Differences in seroconversion rates following dose two between the two vaccine groups in pre-vaccination seronegative children were all <20% for the three vaccine strains (16% for H1N1, 0% for H3N2, and 0% for B). The results indicate that CAIV-T blended and filled in the two facilities had equivalent profiles of safety and immunogenicity.

Medical Burden of Respiratory Syncytial Virus and Parainfluenza Virus Type 3 Infection Among US Children: Implications for Design of Vaccine Trials

Respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are two leading causes of lower respiratory illness (LRI) in infants. Many efforts have been directed to develop vaccines against these two viruses. Licensure of new vaccines includes three phases of clinical trials to evaluate safety, immunogenicity, and efficacy. To design an efficacy trial, age-specific incidence rates of suitable clinical endpoints need to be available. In this review, historical data are summarized to estimate the age-specific rates of acute respiratory illness (ARI), LRI, and hospitalization caused by RSV and PIV3 among US children

A Bovine Parainfluenza Virus Type 3 Vaccine Is Safe and Immunogenic in Early Infancy

BACKGROUNDnA phase 2 trial was conducted to assess in young infants the safety, tolerability, infectivity, and immunogenicity of multiple doses of an intranasal vaccine using bovine parainfluenza virus type 3 (bPIV3).nnnMETHODSnOne hundred ninety-two healthy 2-month-old infants were randomized 1 : 1 : 1 to receive 1x10(5) median tissue culture infective dose (TCID(50)) bPIV3 vaccine, 1x10(6) TCID(50) bPIV3 vaccine, or placebo at 2, 4, 6, and 12-15 months of age. Safety information was collected by use of diary sheets and telephone interviews. Nasal wash and serum specimens were collected for assessment of infectivity and immunogenicity.nnnRESULTSnThe safety profiles of both dosages of bPIV3 were similar to that of placebo, with the exception of fever with temperature of >/=38.1 degrees C after dose 2 only, occurring in 34% of the 1x10(5) TCID(50) group, 35% of the 1x10(6) TCID(50) group, and 12% of the placebo group (P<.01). No vaccine-related serious adverse events were reported. The cumulative vaccine infectivity (isolation of bPIV3 and/or bPIV3 seroconversion) after dose 3 was similar in the 2 vaccine groups (87% in the 1x10(5) TCID(50) group and 77% in the 1x10(6) TCID(50) group) (P=.46). Seroconversion rates after dose 3, assessed by means of hemagglutination inhibition assay, after adjustment for decrease in maternal antibody titers, were 67% in the 1x10(5) TCID(50) group, 57% in the 1x10(6) TCID(50) group, and 12% in the placebo group (P<.01). Isolation of bPIV3 was common after dose 1, dose 2, or dose 3, but only 1 of 51 participants in the vaccine groups had bPIV3 isolated after dose 4.nnnCONCLUSIONSnMultiple doses of bPIV3 vaccine were well tolerated and immunogenic in young infants.