Vaccine failure and serologic response to live attenuated and inactivated influenza vaccines in children during the 2013-2014 season.

BACKGROUND: Recent observational studies in the United States indicated live attenuated influenza vaccine (LAIV) was less effective in children against clinical influenza infection caused by A(H1N1)pdm09 relative to inactivated influenza vaccine (IIV). During the 2013-2014 influenza season, we conducted an observational study among children aged 5-17 years to compare serologic responses to LAIV and IIV and explore factors associated with vaccine failure. METHODS: One hundred and sixty-one children received one dose of trivalent IIV or quadrivalent LAIV according to parental preference. Baseline and postvaccination serum samples were tested with hemagglutination inhibition (HI) assays against vaccine reference strains. Geometric mean titers (GMT), geometric mean fold rise (GMFR), seroconversion, and seroprotection (HI titer ≥ 40) were used to assess response to vaccine. Active surveillance for acute respiratory illness was conducted during the influenza season and influenza cases were confirmed by reverse transcription polymerase chain reaction (RT-PCR). Logistic regression was used to examine the association between vaccine type and vaccine failure. RESULTS: LAIV and IIV recipients were similar with respect to demographics and baseline GMT for each vaccine strain. RT-PCR confirmed influenza (vaccine failure) occurred in 8 (13%) of 62 LAIV recipients and 3 (3%) of 99 IIV recipients (p = .02). Postvaccination GMFR for A(H1N1)pdm09 was higher for IIV vs LAIV receipt (GMFR 3.3 vs. 0.8, p < .0001). Postvaccination titers against A(H1N1)pdm09 were ≥40 for 91% and 44% of IIV and LAIV recipients, respectively (p < .0001). Among 13 IIV and 18 LAIV recipients with seronegative baseline titer against A(H1N1pdm09), 54% and 0% seroconverted, respectively. LAIV receipt was the only factor associated with A(H1N1)pdm09 vaccine failure in the age-adjusted multivariable model (odds ratio 4.5, 95% CI 1.1-18.2). CONCLUSION: Receipt of LAIV generated minimal HI antibody response in children, including among those seronegative at baseline. LAIV recipients had significant increased risk of A(H1N1)pdm09 infection compared to IIV recipients.

Seasonal Influenza Vaccination of Children Induces Humoral and Cell-Mediated Immunity Beyond the Current Season: Cross-reactivity With Past and Future Strains.

BACKGROUND: Influenza viruses gradually accumulate point mutations, reducing the effectiveness of prior immune protection. METHODS: Children aged 9-14 years received 2010-2011 trivalent inactivated influenza vaccine (TIV). Vaccination history, hemagglutination-inhibition (HI) titers, and cell-mediated immune responses were assessed to investigate the cross-reactivity with past and future influenza virus strains. RESULTS: 2010-2011 TIV induced significant T-cell responses and HI titers of ≥160, with a fold-rise of ≥4 and titers of ≥100 maintained for >7 months in the majority of children. Pre-existing memory B cells in these children differentiated quickly to antibody-secreting cells to the new vaccine antigens. Children vaccinated in the previous year maintained high HI titers well into 2010, demonstrating elevated HI titers against A/Perth/16/2009, the future (in 2010-2011) H3N2 component. Prior vaccination enhanced CD8+ T-cell responses to A/Perth/16/2009. Children vaccinated with the prior 2009-2010 seasonal vaccine also demonstrated higher preexisting levels of interferon γ-secreting CD4+CD69+ T cells to 2009 pandemic influenza A(H1N1). Children previously vaccinated with 2009-2010 seasonal influenza vaccine also showed greater expansion of tumor necrosis factor α-secreting CD8+CD69+ T cells to 2009 pandemic influenza A(H1N1) upon vaccination in the 2010-2011 season than those who were not previously vaccinated. CONCLUSIONS: Seasonal influenza viruses continuously drift, which allows them to circumvent protective immunity, but conserved epitopes provide immunological cross-reactivity in children through either vaccination directly or through prime/boost in the prior influenza season.

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.

Age, serum 25-hydroxyvitamin D and vitamin D receptor (VDR) expression and function in peripheral blood mononuclear cells.

The relationship between age, vitamin D status, expression and functionality of the vitamin D receptor (VDR), and key genes in the vitamin D pathway in immune cells is unclear. We enrolled adults 50 to 69 years old (20 subjects) and 70+ (20 subjects) and measured: 1) 25(OH)D levels by liquid chromatography/mass spectrometry; and 2) mRNA expression of VDR, 1α-OHase, 1,25D3-MARRS, TREM-1, cathelicidin, RIG-I, and interferon-ß by qRT-PCR. Mean serum 25(OH)D was 30 ± 4 ng/mL and was not associated with age. Baseline expression of VDR, 1α-OHase, 1,25D3-MARRS, TREM-1, and RIG-I also did not differ by age; IFN-ß expression, however, was higher in the 70+ year old group. 25(OH)D3- and 1,25(OH)2D3-induced VDR, TREM-1 and cathelicidin expression were similar between age groups, as was LPS-induced expression of VDR and of 1α-OHase. Ligand-induced 1,25D3-MARRS expression was higher in subjects ≥ 70 years. Serum 25(OH)D was inversely associated with LPS-stimulated VDR expression and with baseline or vitamin D-induced TREM-1 expression, adjusting for age, self-rated health, and functional status. In healthy adults ≥ 50 years, the expression and functionality of the VDR, 1α-OHase and key vitamin D pathway genes were not consistently associated with age.

Effects of Repeated Annual Inactivated Influenza Vaccination among Healthcare Personnel on Serum Hemagglutinin Inhibition Antibody Response to A/Perth/16/2009 (H3N2)-like virus during 2010-11.

BACKGROUND: Recently, lower estimates of influenza vaccine effectiveness (VE) against A(H3N2) virus illness among those vaccinated during the previous season or multiple seasons have been reported; however, it is unclear whether these effects are due to differences in immunogenicity. METHODS: We performed hemagglutination inhibition antibody (HI) assays on serum collected at preseason, ∼ 30 days post-vaccination, and postseason from a prospective cohort of healthcare personnel (HCP). Eligible participants had medical and vaccination records for at least four years (since July, 2006), including 578 HCP who received 2010-11 trivalent inactivated influenza vaccine [IIV3, containing A/Perth/16/2009-like A(H3N2)] and 209 HCP who declined vaccination. Estimates of the percentage with high titers (≥ 40 and>100) and geometric mean fold change ratios (GMRs) to A/Perth/16/2009-like virus by number of prior vaccinations were adjusted for age, sex, race, education, household size, hospital care responsibilities, and study site. RESULTS: Post-vaccination GMRs were inversely associated with the number of prior vaccinations, increasing from 2.3 among those with 4 prior vaccinations to 6.2 among HCP with zero prior vaccinations (F[4,567]=9.97, p<.0005). Thirty-two percent of HCP with 1 prior vaccination achieved titers >100 compared to only 11% of HCP with 4 prior vaccinations (adjusted odds ratio=6.8, 95% CI=3.1 - 15.3). CONCLUSION: Our findings point to an exposure-response association between repeated IIV3 vaccination and HI for A(H3N2) and are consistent with recent VE observations. Ultimately, better vaccines and vaccine strategies may be needed in order to optimize immunogenicity and VE for HCP and other repeated vaccinees.

Comparison of serum hemagglutinin and neuraminidase inhibition antibodies after 2010-2011 trivalent inactivated influenza vaccination in healthcare personnel.

Background. Most inactivated influenza vaccines contain purified and standardized hemagglutinin (HA) and residual neuraminidase (NA) antigens. Vaccine-associated HA antibody responses (hemagglutination inhibition [HAI]) are well described, but less is known about the immune response to the NA. Methods. Serum of 1349 healthcare personnel (HCP) electing or declining the 2010-2011 trivalent-inactivated influenza vaccine ([IIV3], containing A/California/7/2009 p(H1N1), A/Perth/16/2009 [H3N2], B/Brisbane/60/2008 strains) were tested for NA-inhibiting (NAI) antibody by a modified lectin-based assay using pseudotyped N1 and N2 influenza A viruses with an irrelevant (H5) HA. Neuraminidase-inhibiting and HAI antibody titers were evaluated approximately 30 days after vaccination and end-of-season for those with polymerase chain reaction (PCR)-confirmed influenza infection. Results. In 916 HCP (68%) receiving IIV3, a 2-fold increase in N1 and N2 NAI antibody occurred in 63.7% and 47.3%, respectively. Smaller responses occurred in HCP age >50 years and those without prior 2009-2010 IIV3 nor monovalent A(H1N1)pdm09 influenza vaccinations. Forty-four PCR-confirmed influenza infections were observed, primarily affecting those with lower pre-exposure HAI and NAI antibodies. Higher pre-NAI titers correlated with shorter duration of illness for A(H1N1)pdm09 virus infections. Conclusions. Trivalent-inactivated influenza vaccine is modestly immunogenic for N1 and N2 antigens in HCP. Vaccines eliciting robust NA immune responses may improve efficacy and reduce influenza-associated morbidity.

Results of a pilot study using self-collected mid-turbinate nasal swabs for detection of influenza virus infection among pregnant women.

BACKGROUND: We evaluated the feasibility of asking pregnant women to self-collect and ship respiratory specimens. METHODS: In a preliminary laboratory study, we compared the RT-PCR cycle threshold (CT) values of influenza A and B viruses incubated at 4 storage temperatures (from 4 to 35°C) for 6 time periods (8, 24, 48, 72, and 168 hours and 30 days), resulting in 24 conditions that were compared to an aliquot tested after standard freezing (-20°C) (baseline condition). In a subsequent pilot study, during January-February, 2014, we delivered respiratory specimen collection kits to 53 pregnant women with a medically attended acute respiratory illness using three delivery methods. RESULTS: CT values were stable after storage at temperatures <27°C for up to 72 hours for influenza A viruses and 48 hours for influenza B viruses. Of 53 women who received kits during the pilot, 89% collected and shipped nasal swabs as requested. However, 30% (14/47) of the women took over 2 days to collect and ship their specimen. The human control gene, ribonuclease P (RNase P), was detected in 100% of nasal swab specimens. However, the mean CT values for RNase P (26.5, 95% confidence interval [CI] = 26.0-27.1) and for the 8 influenza A virus positives in our pilot (32.2, 95% CI = 28.9-35.5) were significantly higher than the CTs observed in our 2010-2012 study using staff-collected nasal pharyngeal swabs (P-values < 0.01). DISCUSSION: Self-collection of respiratory specimens is a promising research method, but further research is needed to quantify the sensitivity and specificity of the approach.

Influenza vaccine effectiveness in the United States during 2012-2013: variable protection by age and virus type.

BACKGROUND: During the 2012-2013 influenza season, there was cocirculation of influenza A(H3N2) and 2 influenza B lineage viruses in the United States. METHODS: Patients with acute cough illness for ≤7 days were prospectively enrolled and had swab samples obtained at outpatient clinics in 5 states. Influenza vaccination dates were confirmed by medical records. The vaccine effectiveness (VE) was estimated as [100% × (1 - adjusted odds ratio)] for vaccination in cases versus test-negative controls. RESULTS: Influenza was detected in 2307 of 6452 patients (36%); 1292 (56%) had influenza A(H3N2), 582 (25%) had influenza B/Yamagata, and 303 (13%) had influenza B/Victoria. VE was 49% (95% confidence interval [CI], 43%-55%) overall, 39% (95% CI, 29%-47%) against influenza A(H3N2), 66% (95% CI, 58%-73%) against influenza B/Yamagata (vaccine lineage), and 51% (95% CI, 36%-63%) against influenza B/Victoria. VE against influenza A(H3N2) was highest among persons aged 50-64 years (52%; 95% CI, 33%-65%) and persons aged 6 months-8 years (51%; 95% CI, 32%-64%) and lowest among persons aged ≥65 years (11%; 95% CI, -41% to 43%). In younger age groups, there was evidence of residual protection from receipt of the 2011-2012 vaccine 1 year earlier. CONCLUSIONS: The 2012-2013 vaccines were moderately effective in most age groups. Cross-lineage protection and residual effects from prior vaccination were observed and warrant further investigation.

Influence of pre-existing hemagglutination inhibition titers against historical influenza strains on antibody response to inactivated trivalent influenza vaccine in adults 50-80 years of age.

BACKGROUND: Concerns about influenza vaccine effectiveness in older adults and the role of influenza strains encountered earlier in life led to this study. METHODS: Antibody responses against antigens in the 2011-2012 influenza vaccine at 21 days post vaccination were analyzed in 264 individuals aged 50-80 years. At Days 0 and 21, sera were tested for hemagglutination-inhibition titers against these vaccine strains and at Day 0 against a panel of 15 historical seasonal strains.: RESULTS: The proportions of participants with seroprotective titers ≥1:40 to the vaccine strains at Days 0 and 21, respectively, were 37% and 66% for A(H1N1) and 28% and 63% for A(H3N2). An increasing number of responses ≥1:40 against historical strains was associated with seroprotective responses after vaccination among participants with a titer<1:40 at Day 0 for A(H1N1) and A(H3N2) vaccine strains (P<0.01). In multivariable regression analyses among those with Day 0 titer<1:40, after controlling for age, sex, race, site and diabetes, Day 21 titers ≥ 1:40 for the vaccine A strains were significantly more likely as the number of seroprotective responses against historical strains increased (A(H1N1) odds ratio [OR] = 1.41, 95% confidence interval [CI] = 1.09-1.82 and A(H3N2) OR = 1.32, 95% CI = 1.07-1.62). The likelihood of seroconversion was significantly higher with an increasing number of responses to historical strains for A(H3N2) only (OR = 1.24, 95% CI = 1.01-1.52). Seroconversion was significantly less likely as Day 0 vaccine strain titers increased. CONCLUSIONS: Seroprotective titers after influenza vaccination increased as the number of responses to historical strains increased.

Influenza vaccine effectiveness in the 2011-2012 season: protection against each circulating virus and the effect of prior vaccination on estimates.

BACKGROUND: Each year, the US Influenza Vaccine Effectiveness Network examines the effectiveness of influenza vaccines in preventing medically attended acute respiratory illnesses caused by influenza. METHODS: Patients with acute respiratory illnesses of ≤ 7 days' duration were enrolled at ambulatory care facilities in 5 communities. Specimens were collected and tested for influenza by real-time reverse-transcriptase polymerase chain reaction. Receipt of influenza vaccine was defined based on documented evidence of vaccination in medical records or immunization registries. Vaccine effectiveness was estimated in adjusted logistic regression models by comparing the vaccination coverage in those who tested positive for influenza with those who tested negative. RESULTS: The 2011-2012 season was mild and peaked late, with circulation of both type A viruses and both lineages of type B. Overall adjusted vaccine effectiveness was 47% (95% confidence interval [CI], 36-56) in preventing medically attended influenza; vaccine effectiveness was 65% (95% CI, 44-79) against type A (H1N1) pdm09 but only 39% (95% CI, 23-52) against type A (H3N2). Estimates of vaccine effectiveness against both type B lineages were similar (overall, 58%; 95% CI, 35-73). An apparent negative effect of prior year vaccination on current year effectiveness estimates was noted, particularly for A (H3N2) outcomes. CONCLUSIONS: Vaccine effectiveness in the 2011-2012 season was modest overall, with lower effectiveness against the predominant A (H3N2) virus. This may be related to antigenic drift, but past history of vaccination might also play a role.