Trivalent Inactivated Influenza Vaccine Recipients Research Articles

Effect of seasonal influenza vaccination on influenza symptom severity among children in Hutterite communities: Follow-up study of a randomized trial.

BackgroundWe investigated whether influenza vaccination reduces symptom severity among children who develop laboratory‐confirmed influenza, and whether this association differed between influenza vaccine formulations.MethodsWe performed a retrospective cohort study using data from two blinded cluster randomized control trials of influenza vaccines in Hutterite colonies. In trial 1, children received trivalent inactivated influenza vaccine (TIV) or hepatitis A vaccine. In trial 2, children received trivalent live attenuated (TLAIV) or TIV. We assessed four outcomes (total number of symptoms, number of respiratory symptoms, number of systemic symptoms, and duration of symptoms) among children with PCR‐confirmed influenza. We utilized two‐sample t tests to quantify the relationship between vaccine group and outcome. We performed multivariable strain‐specific analyses, controlling for age and season.Results TIV vs. Hep A vaccine: Among vaccinated children, 200 confirmed influenza infections were observed across 3014 person‐seasons. Vaccine type (TIV vs. Hep A vaccine) did not significantly affect the number of respiratory or systemic symptoms, nor duration of symptoms (P > .05). TLAIV vs. TIV: Among 1186 children who received a study vaccine, 166 confirmed influenza infections were observed. TLAIV recipients experienced fewer total, respiratory, and systemic symptoms compared to TIV recipients (P < .05 for all). TLAIV‐associated attenuation of symptom severity was observed in influenza B or A/H1N1 infections, but not H3.ConclusionsSeasonal influenza vaccine did not consistently attenuate symptom severity in the context of vaccine failure; however, TLAIV offered superior severity attenuation compared to TIV. Our results challenge the dictum that influenza vaccine reduces the severity of symptoms even when the vaccine fails to prevent influenza.

Health-related behaviors and effectiveness of trivalent inactivated versus live attenuated influenza vaccine in preventing influenza-like illness among young adults.

BackgroundVaccination is the preferred preventive strategy against influenza. Though health behaviors are known to affect immunity and vaccine delivery modes utilize different immune processes, data regarding the preferred influenza vaccine type among adults endorsing specific health-related behaviors (alcohol use, tobacco use, and exercise level) are limited.MethodsThe relative effectiveness of two currently available influenza vaccines were compared for prevention of influenza-like illness during 2 well-matched influenza seasons (2006/2007, 2008/2009) among US military personnel aged 18–49 years. Relative vaccine effectiveness was compared between those self-reporting and not reporting recent smoking history and potential alcohol problem, and by exercise level using Cox proportional hazard modeling adjusted for sociodemographic and military factors, geographic area, and other health behaviors.Results28,929 vaccination events and 3936 influenza-like illness events over both influenza seasons were studied. Of subjects, 27.5% were smokers, 7.7% had a potential alcohol-related problem, 10.5% reported minimal exercise, and 4.4% reported high exercise levels. Overall, the risk of influenza-like illness did not significantly differ between live attenuated and trivalent inactivated influenza vaccine recipients (hazard ratio, 0.98; 95% confidence interval, 0.90–1.06). In the final adjusted model, the relative effectiveness of the 2 vaccine types did not differ by smoking status (p = 0.10), alcohol status (p = 0.21), or activity level (p = 0.11).ConclusionsLive attenuated and trivalent inactivated influenza vaccines were similarly effective in preventing influenza-like illness among young adults and did not differ by health-related behavior status. Influenza vaccine efforts should continue to focus simply on delivering vaccine.

Transient decrease in human peripheral blood myeloid dendritic cells following influenza vaccination correlates with induction of serum antibody

Dendritic cells (DC) are critical inducers of the adaptive immune response. Extensive characterization of tissue-resident and monocyte-derived DC has revealed diverse stimulatory and regulatory actions, although the role of peripheral blood dendritic cells (PBDC) in maintaining homeostasis remains unclear. Examination of various myeloid (CD11c+CD303-) and plasmacytoid (CD11c-CD303+) DC populations in the peripheral blood of seasonal trivalent inactivated influenza vaccine recipients revealed a transient decrease in the frequency of CD11c+CD1c- myeloid DC subsets 5-10 days following vaccination, including both CD141+ and CD141- myeloid DC subsets of this population. These populations rebounded by 1 month, while plasmacytoid DC remained stable. The magnitude of the decrease in the CD141+ myeloid DC subset at d5-7 significantly correlated with the induction of influenza specific serum antibodies measured at 1 month following vaccination. These results demonstrate a mobilization of peripheral blood myeloid DC following vaccination and indicate these cells are potential biomarkers of immune response.

Guillain-Barré Syndrome, Influenza Vaccination, and Antecedent Respiratory and Gastrointestinal Infections: A Case-Centered Analysis in the Vaccine Safety Datalink, 2009-2011.

BackgroundGuillain-Barré Syndrome (GBS) can be triggered by gastrointestinal or respiratory infections, including influenza. During the 2009 influenza A (H1N1) pandemic in the United States, monovalent inactivated influenza vaccine (MIV) availability coincided with high rates of wildtype influenza infections. Several prior studies suggested an elevated GBS risk following MIV, but adjustment for antecedent infection was limited.MethodsWe identified patients enrolled in health plans participating in the Vaccine Safety Datalink and diagnosed with GBS from July 2009 through June 2011. Medical records of GBS cases with 2009–10 MIV, 2010–11 trivalent inactivated influenza vaccine (TIV), and/or a medically-attended respiratory or gastrointestinal infection in the 1 through 141 days prior to GBS diagnosis were reviewed and classified according to Brighton Collaboration criteria for diagnostic certainty. Using a case-centered design, logistic regression models adjusted for patient-level time-varying sources of confounding, including seasonal vaccinations and infections in GBS cases and population-level controls.ResultsEighteen confirmed GBS cases received vaccination in the 6 weeks preceding onset, among 1.27 million 2009–10 MIV recipients and 2.80 million 2010–11 TIV recipients. Forty-four confirmed GBS cases had infection in the 6 weeks preceding onset, among 3.77 million patients diagnosed with medically-attended infection. The observed-versus-expected odds that 2009–10 MIV/2010–11 TIV was received in the 6 weeks preceding GBS onset was odds ratio = 1.54, 95% confidence interval (CI), 0.59–3.99; risk difference = 0.93 per million doses, 95% CI, −0.71–5.16. The association between GBS and medically-attended infection was: odds ratio = 7.73, 95% CI, 3.60–16.61; risk difference = 11.62 per million infected patients, 95% CI, 4.49–26.94. These findings were consistent in sensitivity analyses using alternative infection definitions and risk intervals for prior vaccination shorter than 6 weeks.ConclusionsAfter adjusting for antecedent infections, we found no evidence for an elevated GBS risk following 2009–10 MIV/2010–11 TIV influenza vaccines. However, the association between GBS and antecedent infection was strongly elevated.

Efficacy and immunogenicity of influenza vaccine in HIV-infected children

HIV-infected children are at heightened risk for severe influenza illness; however, there is no study on the efficacy or effectiveness of influenza vaccine in these children. We evaluated the safety, immunogenicity, and efficacy of nonadjuvanted, trivalent inactivated influenza vaccine (TIV) against confirmed seasonal influenza virus illness in HIV-infected children. A double-blind, placebo-controlled trial was undertaken in Johannesburg in 2009. Four hundred and ten children were randomized to two doses of TIV or placebo 1 month apart. Nasopharyngeal aspirates obtained at respiratory illness visits were tested by influenza-specific reverse transcriptase-PCR (RT-PCR). Vaccine immunogenicity was evaluated by hemagglutinin inhibition (HAI) assay. Influenza isolates were sequenced and evaluated in maximum likelihood phylogenetic analysis. Overall, the median age of participants was 23.8 months and their median CD4% was 33.5. Ninety-two percent of enrolees were on antiretroviral therapy. Among children receiving both doses of vaccine/placebo, confirmed seasonal influenza illness occurred in 13 (all H3N2) of 205 TIV recipients and 17 (15 H3N2 and two influenza B) of 200 placebo recipients with vaccine efficacy of 17.7% (95% confidence interval <0-62.4%). The proportion of TIV recipients who seroconverted after second dose against vaccine strains of H1N1, H3N2, and influenza B were 47.5, 50.0, and 40.0%, compared to 4.7, 11.6, and 0%, respectively among placebo recipients. There were no TIV-related serious adverse events. Sequence analysis of wild-type H3N2 strains indicated drift from the H3N2 vaccine strain. Poor immunogenicity of TIV, coupled with drift of circulating H3N2 wild-type compared to vaccine strain, may explain the lack of efficacy of TIV in young HIV-infected children. Alternate TIV vaccine schedules or formulations warrant evaluation for efficacy in HIV-infected children.

The safety and efficacy of live attenuated influenza vaccine in young children with asthma or prior wheezing

In the European Union and Canada, an Ann Arbor strain live attenuated influenza vaccine (LAIV) is approved for use in children aged 2–17 years, including those with mild to moderate asthma or prior wheezing. The safety and efficacy of LAIV versus trivalent inactivated influenza vaccine (TIV) in children with asthma aged 6–17 years have been demonstrated. However, few data are available for children younger than 6 years of age with asthma or prior wheezing. Safety and efficacy data were collected for children aged 2–5 years with asthma or prior wheezing from two randomized, multinational trials of LAIV and TIV (N = 1,940). Wheezing, lower respiratory illness, and hospitalization were not significantly increased among children receiving LAIV compared with TIV. Increased upper respiratory symptoms and irritability were observed among LAIV recipients (p < 0.05). Relative efficacies were consistent with the results observed in the overall study populations, which demonstrated fewer cases of culture-confirmed influenza illness in LAIV compared with TIV recipients. Study results support the safety and efficacy of LAIV among children aged 2–17 years with mild to moderate asthma or a history of wheezing. Data regarding LAIV use are limited among individuals with severe asthma or active wheezing within the 7 days before vaccination.

The Efficacy of Live Attenuated Influenza Vaccine Against Influenza-associated Acute Otitis Media in Children

Acute otitis media (AOM) is a frequent complication of influenza in young children. Influenza vaccination is known to protect against AOM by preventing influenza illness. We sought to determine the efficacy of the live attenuated influenza vaccine (LAIV) against influenza-associated AOM compared with placebo and trivalent inactivated influenza vaccine (TIV). LAIV is approved for eligible children aged ≥ 2 years in the United States and in several other countries. AOM incidence data from 6 randomized, double-blind, placebo-controlled trials and 2 randomized, double-blind, TIV-controlled trials in children 6 to 83 months of age were pooled and analyzed. A total of 290 cases of AOM were identified in 24,046 study subjects. LAIV efficacy against influenza-associated AOM was 85.0% (95% confidence interval [CI], 78.3%-89.8%) compared with placebo and 54.0% (95% CI, 27.0%-71.7%) compared with TIV. Efficacy trended higher in those ≥ 24 months of age compared with those aged 6 to 23 months. In placebo-controlled trials, among children who acquired influenza despite vaccination, AOM was diagnosed in 10.3% of LAIV recipients and 16.8% of placebo recipients, representing a 38.2% (95% CI, 11.0%-58.2%) relative reduction in the development of AOM. In TIV-controlled studies, among subjects with breakthrough influenza illness, the proportions of LAIV and TIV recipients who developed AOM were similar. Children receiving LAIV had a high level of protection against influenza-associated AOM when compared with placebo or TIV. This was most evident in children older than 2 years, for whom LAIV is indicated. LAIV recipients who contracted breakthrough influenza illness despite vaccination developed AOM at a significantly lower rate than did unvaccinated children who developed influenza.

Trivalent Inactivated Influenza Vaccine in African Adults Infected With Human Immunodeficient Virus: Double Blind, Randomized Clinical Trial of Efficacy, Immunogenicity, and Safety

Data on the efficacy of trivalent, inactivated influenza vaccine (TIV) in HIV-infected adults, particularly in Africa, are limited. This study evaluated the safety, immunogenicity, and efficacy of TIV in HIV-infected adults. In Johannesburg, South Africa, we undertook a randomized, double-blind, placebo-controlled trial involving 506 HIV-infected adults. Subjects included 157 individuals who were antiretroviral treatment (ART) naive and 349 on stable-ART. Participants were randomly assigned to receive TIV or normal saline intramuscularly. Oropharyngeal swabs were obtained at illness visits during the influenza season and tested by shell vial culture and RT PCR assay for influenza virus. Immune response was evaluated by hemagglutinin antibody inhibition assay (HAI) in a nested cohort. The primary study outcome involved vaccine efficacy against influenza confirmed illness. This trial is registered with ClinicalTrials.gov, number NCT00757900. The efficacy of TIV against confirmed influenza illness was 75.5% (95% CI: 9.2%-95.6%); with a risk difference of 0.18 per 100 person-weeks in TIV recipients. Among TIV recipients, seroconversion, measured by HAI titers, was evident in 52.6% for H1N1, 60.8% for H3N2, and 53.6% for influenza B virus. This compared with 2.2%, 2.2%, and 4.4% of placebo recipients (P < .0001). The frequency of local and systemic adverse events post-immunization was similar between study groups. TIV immunization is safe and efficacious in African HIV-infected adults without underlying co-morbidities. Further evaluation of effectiveness is warranted in severely immunocompromized HIV-infected adults and those with co-morbidities such as tuberculosis.

538 Severity of Breakthrough Influenza Illness Among Children and Adults Receiving Live Attenuated Influenza Vaccine and Trivalent Inactivated Influenza Vaccine

Aims: The efficacies of live attenuated influenza vaccine (LAIV) and trivalent inactivated influenza vaccine (TIV) have been evaluated in children and adults in multiple studies; however, vaccine impact on illness severity has not been examined. This analysis compared illness severity among LAIV and TIV recipients who developed influenza illness using data from existing randomized studies. LAIV is approved for eligible individuals 2-49 years of age in the United States, Israel, Hong Kong, Macau, and South Korea. Methods: Three studies in children, one wild-type challenge study in adults 18-45 years, and one study in adults ≥60 years compared LAIV and TIV efficacy and collected symptom duration and severity. Results: In 2 studies of children < 6 years, a higher proportion of LAIV versus TIV breakthroughs were afebrile: 22% vs. 12% (P=0.001) and 28% vs. 5% (P=0.005). In one study, LAIV breakthroughs missed 1.6 (95% CI: 2.9, 0.2) fewer days of school/daycare and had less antibiotic use (17% LAIV vs. 33% TIV, P=0.11). No differences were seen in a study of children 6-17 years. In the adult challenge study, LAIV vaccinees tended to have lower mean symptom scores versus TIV and placebo recipients (2.7, 5.7, 9.2, respectively, P=NS except LAIV vs placebo). In the older adult study, LAIV breakthroughs had less feverishness (14% LAIV vs 46% TIV, P=0.05). Conclusions: Among younger children, LAIV recipients who develop breakthrough influenza have less severe illness than TIV recipients. The same may be true among adults; however, more research is needed. Sponsored by MedImmune.

537 Relative Efficacy of Live Attenuated and Inactivated Influenza Vaccines in Children as a Function of Time Postvaccination

Aims: To examine the relative efficacy of live attenuated influenza vaccine (LAIV) and trivalent inactivated influenza vaccine (TIV) as a function of time post-vaccination from three large randomized studies that compared the efficacy of LAIV and TIV in children. LAIV is approved for use in eligible individuals 2 to 49 years of age in the U.S., Israel, Hong Kong, Macau, and South Korea.Methods: Relative efficacy of LAIV vs. TIV against culture-confirmed influenza was calculated by timeinterval (0-4 and >4-8 months postvaccination) for matched strains, the studies' primary endpoint. Match for B viruses in Study 1 was based on genetic sequence as serology was less reliable.Results: In each study, LAIV recipients had less influenza than TIV recipients in both time intervals and the relative efficacy of LAIV vs. TIV increased from 0-4 months to 4-8 months. Table Table Full size table Conclusions: For matched strains, the available data suggest that the relative efficacy of LAIV vs. TIV in children increases over time. Further research is needed to confirm these findings and to characterize the duration of protection provided by TIV in children. Sponsored by MedImmune.

The Efficacy of Live Attenuated and Inactivated Influenza Vaccines in Children as a Function of Time Postvaccination

In the United States, more children are being vaccinated against influenza in August and September, months before peak influenza activity. Sustained vaccine efficacy through 12 months postvaccination has been demonstrated in children for live attenuated influenza vaccine (LAIV) but not trivalent inactivated influenza vaccine (TIV). Three large, randomized studies compared LAIV and TIV efficacy in children, providing the opportunity to examine the impact of time on the relative efficacy of the 2 vaccines. For each study, the relative efficacy of LAIV versus TIV was analyzed by time interval (0-4 and >4-8 months postvaccination) for matched and mismatched strains. LAIV recipients had less influenza than TIV recipients during both intervals; the relative efficacy of LAIV versus TIV for matched strains in each study increased from 0 to 4 months (range, 25%-60%) to >4 to 8 months (range, 49%-89%). Analysis of the incidence of individual types/subtypes revealed the same pattern for the predominant matched strain in each study; no consistent pattern was seen for lower-incidence matched strains. For mismatched strains, similar relative efficacy was seen in each time interval. For matched strains, data suggest that the relative efficacy of LAIV versus TIV in young children increases over time. Consistent with previous studies of TIV-induced immunity, this analysis suggests that the absolute efficacy of TIV against matched strains in children may be lower at >4 to 8 versus 0 to 4 months postvaccination. Relative efficacy against mismatched strains was similar over time, consistent with previous estimates of the absolute efficacies of the vaccines against mismatched strains. Further research is needed to confirm these findings and to characterize the duration of protection provided by TIV in children.

Genetic sequence analysis of influenza viruses and illness severity in ill children previously vaccinated with live attenuated or inactivated influenza vaccine

In a large comparative study in 2004–2005, children aged 6–59 months vaccinated with live attenuated influenza vaccine (LAIV) experienced 55% fewer cases of culture-confirmed influenza illness compared with trivalent inactivated influenza vaccine (TIV) recipients. To better understand the characteristics of the breakthrough influenza illnesses, we analyzed the HA1 genetic sequence for all available samples and examined disease severity by strain and treatment group. All 48 A/H1N1 viruses were well-matched to the vaccine, whereas all 276 A/H3N2 viruses and 349 (96%) influenza B viruses were mismatched to the vaccine. The incidence of fever or lower respiratory illness did not differ by strain; however, LAIV recipients had less febrile disease and fewer lower respiratory illnesses than TIV recipients. Viruses of each influenza B lineage caused more illnesses than A/H1N1 viruses; strategies to enhance protection against multiple influenza B lineages should be pursued.

Influence of Prior Influenza Vaccination on Antibody and B-Cell Responses

Currently two vaccines, trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV), are licensed in the USA. Despite previous studies on immune responses induced by these two vaccines, a comparative study of the influence of prior influenza vaccination on serum antibody and B-cell responses to new LAIV or TIV vaccination has not been reported. During the 2005/6 influenza season, we quantified the serum antibody and B-cell responses to LAIV or TIV in adults with differing influenza vaccination histories in the prior year: LAIV, TIV, or neither. Blood samples were collected on days 0, 7–9 and 21–35 after immunization and used for serum HAI assay and B-cell assays. Total and influenza-specific circulating IgG and IgA antibody secreting cells (ASC) in PBMC were detected by direct ELISPOT assay. Memory B cells were also tested by ELISPOT after polyclonal stimulation of PBMC in vitro. Serum antibody, effector, and memory B-cell responses were greater in TIV recipients than LAIV recipients. Prior year TIV recipients had significantly higher baseline HAI titers, but lower HAI response after vaccination with either TIV or LAIV, and lower IgA ASC response after vaccination with TIV than prior year LAIV or no vaccination recipients. Lower levels of baseline HAI titer were associated with a greater fold-increase of HAI titer and ASC number after vaccination, which also differed by type of vaccine. Our findings suggest that the type of vaccine received in the prior year affects the serum antibody and the B-cell responses to subsequent vaccination. In particular, prior year TIV vaccination is associated with sustained higher HAI titer one year later but lower antibody response to new LAIV or TIV vaccination, and a lower effector B-cell response to new TIV but not LAIV vaccination.

Safety and efficacy of live attenuated influenza vaccine in children 2–7 years of age

Three pivotal trials supported the licensure of live attenuated influenza vaccine (LAIV) for children ≥2 years of age: 2 placebo-controlled studies each conducted over 2 seasons, and a 1-year trial comparing LAIV with trivalent inactivated influenza vaccine (TIV). Analyses were conducted to evaluate the safety and efficacy of LAIV in the subgroup of children ≥2 years of age from these trials. Efficacy was demonstrated compared with placebo in children aged 2–7 years in seasons with matched strains (69.2% [95% CI: 52.7, 80.4] and 94.6% [95% CI: 88.6, 97.5]), seasons with primarily mismatched strains (87% [95% CI: 77.0, 92.6]), and during late season epidemics (73.8% [95% CI: 40.4, 89.4]). Compared with TIV recipients, LAIV recipients aged 2–5 years had 52.5% (95% CI: 26.7, 68.7) and 54.4% (95% CI: 41.8, 64.5) fewer cases of influenza illness against matched and mismatched strains, respectively. No unusual or unexpected adverse reactions were noted. The adverse reactions most commonly associated with LAIV were runny nose/nasal congestion and low-grade fever. Hospitalizations and medically significant wheezing were increased in children 6–11 and 6–23 months of age who received LAIV, respectively, but were not increased in children 2–5 years of age.

Superior Relative Efficacy of Live Attenuated Influenza Vaccine Compared With Inactivated Influenza Vaccine in Young Children With Recurrent Respiratory Tract Infections

Young children have a high incidence of influenza and influenza-related complications. This study compared the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) with trivalent inactivated influenza vaccine (TIV) in young children with a history of recurrent respiratory tract infections (RTIs). Children 6 to 71 months of age were randomized to receive 2 doses of CAIV-T (n = 1101) or TIV (n = 1086), 35 +/- 7 days apart before the start of the 2002-2003 influenza season and were followed up for culture-confirmed influenza, effectiveness outcomes, reactogenicity, and adverse events. Overall, 52.7% (95% confidence interval [CI] = 21.6%-72.2%) fewer cases of influenza caused by virus strains antigenically similar to vaccine were observed in CAIV-T than in TIV recipients. Greater relative efficacy for CAIV-T was observed for the antigenically similar A/H1N1 (100.0%; 95% CI = 42.3%-100.0%) and B (68.0%; 95% CI = 37.3%-84.8%) strains but not for the antigenically similar A/H3N2 strains (-97.1%; 95% CI = -540.2% to 31.5%). Relative to TIV, CAIV-T reduced the number of RTI-related healthcare provider visits by 8.9% (90% CI = 1.5%-15.8%) and missed days of school, kindergarten, or day care by 16.2% (90% CI = 10.4%-21.6%). Rhinitis and rhinorrhea, otitis media, and decreased appetite were the only events that were reported more frequently in CAIV-T subjects. There was no difference between groups in the incidence of wheezing after vaccination. CAIV-T was well tolerated in these children with RTIs and demonstrated superior relative efficacy compared with TIV in preventing influenza illness.

Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses

Trivalent, live, cold-adapted influenza vaccine (CAIV-T) is highly effective in the prevention of influenza in children, and a variety of monovalent and bivalent cold-adapted influenza vaccines have been efficacious in adults. In order to determine the efficacy of CAIV-T in healthy adults, we administered CAIV-T, trivalent inactivated influenza vaccine (TIV) or placebo to 103 adults in randomized double-blind fashion, and then challenged those subjects who had pre-screening serum hemagglutination-inhibition antibody titers of 1:8 or less with wild-type influenza viruses corresponding to the strains contained in the vaccine. CAIV-T was well tolerated. Upon challenge with wild-type influenza virus, laboratory documented influenza illness (respiratory symptoms with either isolation of wild-type influenza virus from nasal secretions or 4-fold and/or greater HAI antibody response to challenge) occurred in 14/31 (45%) placebo recipients, 4/32 (13%) TIV recipients, and 2/29 (7%) CAIV-T recipients. The estimated protective efficacy of CAIV-T was therefore 85% and of TIV was 71%. These results are consistent with those of previous studies using monovalent preparations of cold-adapted influenza vaccine in this model, and indicate that CAIV-T will be an effective means to prevent influenza illness in adults.