Jufu Chen

Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 U.S. communities.

We estimated the effectiveness of four monovalent pandemic influenza A (H1N1) vaccines (three unadjuvanted inactivated, one live attenuated) available in the U.S. during the pandemic. Patients with acute respiratory illness presenting to inpatient and outpatient facilities affiliated with four collaborating institutions were prospectively recruited, consented, and tested for influenza. Analyses were restricted to October 2009 through April 2010, when pandemic vaccine was available. Patients testing positive for pandemic influenza by real-time RT-PCR were cases; those testing negative were controls. Vaccine effectiveness was estimated in logistic regression models adjusted for study community, patient age, timing of illness, insurance status, enrollment site, and presence of high-risk medical conditions. Pandemic virus was detected in 1,011 (15%) of 6,757 enrolled patients. Fifteen (1%) of 1,011 influenza positive cases and 1,042 (18%) of 5,746 test-negative controls had record-verified pandemic vaccination >14 days prior to illness onset. Adjusted effectiveness (95% confidence interval) for pandemic vaccines combined was 56% (23%, 75%). Adjusted effectiveness for inactivated vaccines alone (79% of total) was 62% (25%, 81%) overall and 32% (−92%, 76%), 89% (15%, 99%), and −6% (−231%, 66%) in those aged 0.5 to 9, 10 to 49, and 50+ years, respectively. Effectiveness for the live attenuated vaccine in those aged 2 to 49 years was only demonstrated if vaccination >7 rather than >14 days prior to illness onset was considered (61%∶ 12%, 82%). Inactivated non-adjuvanted pandemic vaccines offered significant protection against confirmed pandemic influenza-associated medical care visits in young adults.

Influenza Vaccine Effectiveness Against Pediatric Deaths: 2010–2014

This study estimates influenza VE against deaths among children with and without underlying high-risk medical conditions by using a case–cohort approach. BACKGROUND AND OBJECTIVES: Surveillance for laboratory-confirmed influenza-associated pediatric deaths since 2004 has shown that most deaths occur in unvaccinated children. We assessed whether influenza vaccination reduced the risk of influenza-associated death in children and adolescents. METHODS: We conducted a case–cohort analysis comparing vaccination uptake among laboratory-confirmed influenza-associated pediatric deaths with estimated vaccination coverage among pediatric cohorts in the United States. Case vaccination and high-risk status were determined by case investigation. Influenza vaccination coverage estimates were obtained from national survey data or a national insurance claims database. We estimated odds ratios from logistic regression comparing odds of vaccination among cases with odds of vaccination in comparison cohorts. We used Bayesian methods to compute 95% credible intervals (CIs) for vaccine effectiveness (VE), calculated as (1 − odds ratio) × 100. RESULTS: From July 2010 through June 2014, 358 laboratory-confirmed influenza-associated pediatric deaths were reported among children aged 6 months through 17 years. Vaccination status was determined for 291 deaths; 75 (26%) received vaccine before illness onset. Average vaccination coverage in survey cohorts was 48%. Overall VE against death was 65% (95% CI, 54% to 74%). Among 153 deaths in children with underlying high-risk medical conditions, 47 (31%) were vaccinated. VE among children with high-risk conditions was 51% (95% CI, 31% to 67%), compared with 65% (95% CI, 47% to 78%) among children without high-risk conditions. CONCLUSIONS: Influenza vaccination was associated with reduced risk of laboratory-confirmed influenza-associated pediatric death. Increasing influenza vaccination could prevent influenza-associated deaths among children and adolescents.

Preexisting Immunity, More Than Aging, Influences Influenza Vaccine Responses

Background. Influenza disproportionately impacts older adults while current vaccines have reduced effectiveness in the older population. Methods. We conducted a comprehensive evaluation of cellular and humoral immune responses of adults aged 50 years and older to the 2008–2009 seasonal trivalent inactivated influenza vaccine and assessed factors influencing vaccine response. Results. Vaccination increased hemagglutination inhibition and neutralizing antibody; however, 66.3% of subjects did not reach hemagglutination inhibition titers ≥ 40 for H1N1, compared with 22.5% for H3N2. Increasing age had a minor negative impact on antibody responses, whereas prevaccination titers were the best predictors of postvaccination antibody levels. Preexisting memory B cells declined with age, especially for H3N2. However, older adults still demonstrated a significant increase in antigen-specific IgG+ and IgA+ memory B cells postvaccination. Despite reduced frequency of preexisting memory B cells associated with advanced age, fold-rise in memory B cell frequency in subjects 60+ was comparable to subjects age 50–59. Conclusions. Older adults mounted statistically significant humoral and cell-mediated immune responses, but many failed to reach hemagglutination inhibition titers ≥40, especially for H1N1. Although age had a modest negative effect on vaccine responses, prevaccination titers were the best predictor of postvaccination antibody levels, irrespective of age.

Hospitalizations for Severe Lower Respiratory Tract Infections

BACKGROUND: Hospitalization for lower respiratory tract infections (LRTIs) among children have been well characterized. We characterized hospitalizations for severe LRTI among children. METHODS: We analyzed claims data from commercial and Medicaid insurance enrollees (MarketScan) ages 0 to 18 years from 2007 to 2011. LRTI hospitalizations were identified by the first 2 listed International Classification of Diseases, Ninth Revision discharge codes; those with ICU admission and/or receiving mechanical ventilation were defined as severe LRTI. Underlying conditions were determined from out- and inpatient discharge codes in the preceding year. We report insurance specific and combined rates that used both commercial and Medicaid rates and adjusted for age and insurance status. RESULTS: During 2007–2011, we identified 16 797 and 12 053 severe LRTI hospitalizations among commercial and Medicaid enrollees, respectively. The rates of severe LRTI hospitalizations per 100 000 person-years were highest in children aged <1 year (commercial: 244; Medicaid: 372, respectively), and decreased with age. Among commercial enrollees, ≥1 condition increased the risk for severe LRTI (1 condition: adjusted relative risk, 2.68; 95% confidence interval, 2.58–2.78; 3 conditions: adjusted relative risk, 4.85; 95% confidence interval, 4.65–5.07) compared with children with no medical conditions. Using commercial/Medicaid combined rates, an estimated 31 289 hospitalizations for severe LRTI occurred each year in children in the United States. CONCLUSIONS: Among children, the burden of hospitalization for severe LRTI is greatest among children aged <1 year. Children with underlying medical conditions are at greatest risk for severe LRTI hospitalization.

High-dose influenza vaccine favors acute plasmablast responses rather than long-term cellular responses.

UNLABELLED High-dose (HD) influenza vaccine shows improved relative efficacy against influenza disease compared to standard-dose (SD) vaccine in individuals ⩾65years. This has been partially credited to superior serological responses, but a comprehensive understanding of cell-mediated immunity (CMI) of HD vaccine remains lacking. In the current study, a total of 105 participants were randomly administered HD or SD vaccine and were evaluated for serological responses. Subsets of the group (n=12-26 per group) were evaluated for B and T cell responses at days 0, 7, 14 and 28 post-vaccination by flow cytometry or ELISPOT assay. HD vaccine elicited significantly higher hemagglutination inhibition (HI) titers than SD vaccine at d28, but comparable titers at d365 post-vaccination. HD vaccine also elicited higher vaccine-specific plasmablast responses at d7 post-vaccination than SD vaccine. However, long-lived memory B cell induction, cytokine-secreting T cell responses and persistence of serological memory were comparable regardless of vaccine dose. More strategies other than increased Ag amount may be needed to improve CMI in older adults. TRIAL REGISTRATION ClinicalTrials.gov NCT 01189123.

Extensive T cell cross-reactivity between diverse seasonal influenza strains in the ferret model

Influenza virus causes widespread, yearly epidemics by accumulating surface protein mutations to escape neutralizing antibodies established from prior exposure. In contrast to antibody epitopes, T cell mediated immunity targets influenza epitopes that are more highly conserved and have potential for cross-protection. The extent of T cell cross-reactivity between a diverse array of contemporary and historical influenza strains was investigated in ferrets challenged with 2009 pandemic H1N1 influenza or the seasonal H3N2 strain, A/Perth/16/2009. Post-challenge cell-mediated immune responses demonstrated extensive cross-reactivity with a wide variety of contemporary and historical influenza A strains as well as influenza B. Responses in peripheral blood were undetectable by 36d post-challenge, but cross-reactivity persisted in spleen. The strongest responses targeted peptides from the NP protein and demonstrated cross-reactivity in both the CD4+ and CD8+ T cell populations. Cross-reactive CD4+ T cells also targeted HA and NA epitopes, while cross-reactive CD8+ T cells targeted internal M1, NS2, and PA. T cell epitopes demonstrated extensive cross-reactivity between diverse influenza strains in outbred animals, with NP implicated as a significant antigenic target demonstrating extensive cross-reactivity for both CD4+ and CD8+ T cells.

Hospitalizations within 14 days of vaccination among pediatric recipients of the live attenuated influenza vaccine, United States 2010–2012

BACKGROUND Live attenuated influenza vaccine (LAIV) is safe in healthy children ⩾2years. The original clinical trials excluded individuals with underlying conditions; however, post-marketing data suggest LAIV may be safe for these populations. METHODS We analyzed MarketScan Commercial Claims Databases from 2010 to 2012 to describe hospitalizations within 14days of vaccination among LAIV recipients. We evaluated LAIV recipients aged 2-18years and defined underlying conditions by presence of inpatient or outpatient ICD-9 code during the previous calendar year. We excluded asthma and immunocompromising conditions. We defined risk windows as 1-7days and 8-14days after vaccination; the control period was 12-4days prior to and 15-23days after vaccination. We conducted a self-controlled case series analysis using a conditional Poisson regression model to estimate incidence-rate ratios (IRR). RESULTS 1,216,123 children aged 2-18years received LAIV from 2010 to 2012. 634 children met our inclusion criteria and were hospitalized during the observation period (12days prior to vaccination to 23days after vaccination). Of those hospitalized, 72 (11.4%) had non-asthma, non-immunocompromising underlying conditions. Children with non-asthma, non-immunocompromising underlying conditions had an all-cause hospitalization IRR of 1.1 (95% CI 0.6-2.0, p=0.83) in the 1-7day risk period and 0.9 (95% CI 0.4-1.7, p=0.67) in the 8-14day risk period. Children with no underlying conditions had an all-cause hospitalization IRR of 0.9 (0.8-1.2, p=0.60) in the 1-7day risk period and 1.1 (95% CI 0.9-1.3, p=0.53) in the 8-14day risk period. There were no differences in all-cause hospitalization risk in individuals with non-asthma, non-immunocompromising underlying conditions compared to those without underlying conditions in the 1-7day (p=0.88) or 8-14day (p=0.24) risk period. CONCLUSIONS We found no evidence of differences in post-LAIV hospitalization risk among children with non-asthma, non-immunocompromising underlying conditions compared to healthy children.