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Objective: To assess the validity of electronic health record (EHR)-based influenza vaccination data among adults in a multistate network., Methods: Following the 2018-2019 and 2019-2020 influenza seasons, surveys were conducted among a random sample of adults who did or did not appear influenza-vaccinated (per EHR data) during the influenza season. Participants were asked to report their influenza vaccination status; self-report was treated as the criterion standard. Results were combined across survey years., Results: Survey response rate was 44.7% (777 of 1740) for the 2018-2019 influenza season and 40.5% (505 of 1246) for the 2019-2020 influenza season. The sensitivity of EHR-based influenza vaccination data was 75.0% (95% confidence interval [CI] 68.1, 81.1), specificity 98.4% (95% CI 92.9, 99.9), and negative predictive value 73.9% (95% CI 68.0, 79.3)., Conclusions: In a multistate research network across two recent influenza seasons, there was moderate concordance between EHR-based vaccination data and self-report., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Epidemics of seasonal influenza vary in intensity annually, and influenza vaccine effectiveness (VE) fluctuates based in part on antigenic match to circulating viruses. We estimated the incidence of influenza and influenza cases averted by vaccination in four ambulatory care sites in the United States, during seasons when overall influenza VE ranged from 29% to 40%., Methods: We conducted active surveillance for influenza at ambulatory care settings at four sites within the United States Influenza Vaccine Effectiveness Network. We extrapolated the total number of influenza cases in the source populations served by these organizations based on incidence of medically attended acute respiratory illness in the source population and influenza test results in those actively tested for influenza. We estimated the number of medically attended influenza cases averted based on incidence, vaccine coverage, and VE., Results: From 2016/17 through 2018/19, incidence of ambulatory visits for laboratory-confirmed influenza ranged from 31 to 51 per 1,000 population. Incidence was highest in children aged 9-17 years (range, 56 to 81 per 1,000) and lowest in adults aged 18-49 years (range, 23-32 per 1,000). Medically attended cases averted by vaccination ranged from a high of 46.6 (95 % CI, 12.1- 91.9) per 1,000 vaccinees in children aged 6 months to 8 years, to a low of 6.9 (95 % CI, -5.1- 27.3) per 1,000 vaccinees in adults aged ≥ 65 years., Discussion: Even in seasons with low vaccine effectiveness for a particular virus subtype, influenza vaccines can still lead to clinically meaningful reductions in ambulatory care visits for influenza., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Influenza vaccines can mitigate illness severity, including reduced risk of ICU admission and death, in people with breakthrough infection. Less is known about vaccine attenuation of mild/moderate influenza illness. We compared subjective severity scores in vaccinated and unvaccinated persons with medically attended illness and laboratory-confirmed influenza. Participants were prospectively recruited when presenting for care at five US sites over nine seasons. Participants aged ≥ 16 years completed the EQ-5D-5L visual analog scale (VAS) at enrollment. After controlling for potential confounders in a multivariable model, including age and general health status, VAS scores were significantly higher among 2,830 vaccinated participants compared with 3,459 unvaccinated participants, indicating vaccinated participants felt better at the time of presentation for care. No differences in VAS scores were observed by the type of vaccine received among persons aged ≥ 65 years. Our findings suggest vaccine-associated attenuation of milder influenza illness is possible., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Dr. Gaglani reports grants from CDC outside the submitted work. Dr. McLean reports grants from Seqirus outside the submitted work. Dr. Nowalk reports grants from Merck & Co outside the submitted work. Dr. Zimmerman reports grants from Sanofi Pasteur outside the submitted work. Dr. L. Jackson reports grants from Novavax outside the submitted work. Dr. Martin reports personal fees from Pfizer outside the submitted work. All other authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.’, (Published by Elsevier Ltd.)

Background: The effects of sequential vaccination with enhanced influenza vaccines are poorly understood. We conducted an exploratory open-label study to assess serologic response to sequential vaccination in older adults., Methods: 160 adults aged 65 through 74 years were randomized (1:1:1) to receive trivalent inactivated standard dose (SD), high-dose (HD), or MF59-adjuvanted (AD) vaccine in 2016/17. In 2017/18, HD and AD recipients received the same vaccine; SD recipients were re-randomized to HD or AD. Hemagglutination inhibition assays were performed using turkey erythrocytes against A/California/7/2009(H1N1)-like and B/Brisbane/60/2008(B/Victoria)-like in both seasons, and A/Michigan/45/2015(H1N1)-like in season 2. Microneutralization assays were performed against cell-propagated A/Hong Kong/4801/2014(H3N2)-like using MDCK-SIAT1 cells. Postvaccination geometric mean titer (GMT), percent with titer ≥ 40, and mean fold rise (MFR, ratio of postvaccination versus prevaccination titer) in season 2 were compared across groups, and ratio of MFR in season 2 versus season 1 was assessed for each strain., Results: Analysis included 152 participants (55 HD → HD, 58 AD → AD, 19 SD → HD, and 20 SD → AD). Season 2 postvaccination GMTs and percent with titer ≥ 40 did not differ between HD → HD and AD → AD recipients for vaccine strains examined. However, a higher percent of HD → HD and AD → AD recipients had postvaccination titer ≥ 40 than SD → AD recipients for A/H1N1 (86%-89% versus 60%) and SD → AD and SD → HD recipients for A/H3N2 (83%-87% versus 40%-53%). GMTs were higher in AD → AD versus SD → AD recipients for A/H1N1 (p = .01) and A/H3N2 (p = .002). MFRs in season 2 were low in all groups for A/H3N2 (1.5-2.2) and B/Victoria (1.7-2.3). MFR was lower in season 2 versus 1 for HD → HD and AD → AD recipients for all vaccine strains (1.6-3.7 versus 2.6-6.2)., Conclusions: Sequential vaccination with enhanced vaccines did not reduce immunogenicity in adults aged 65 through 74 years. Serologic response to cell-propagated A/H3N2 was suboptimal for all vaccines. ClinicalTrials.gov identifier. NCT02872311., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention and funding agency. HQM receives research funding from Seqirus unrelated to the present work. All other authors have no conflicts to report., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Mid-season influenza vaccine effectiveness (VE) estimates are a useful tool to help guide annual influenza vaccine strain selection, vaccine policy, and public health messaging. We propose using a sample size-driven approach with data-driven inputs for publication of mid-season influenza VE., Methods: We used pooled inputs for VE by (sub)type and average vaccine coverage by age groups using data from eight seasons of the US Influenza VE Network to calculate sample sizes needed to estimate mid-season VE., Results: We estimate that 135 influenza-positive cases would be needed to detect an overall VE of 40% with 55% vaccine coverage among test-negative controls. Larger sample sizes would be required to produce reliable estimates specifically against influenza A/H3N2 and for older age groups., Conclusion: Using an existing network, most of the recent influenza seasons in the US would facilitate valid mid-season VE estimates using the proposed sample sizes for broad age groupings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: In the United States (U.S.), annual influenza vaccination has been recommended for all persons aged ≥6 months with the Healthy People 2020 coverage target of 70%. However, vaccination coverage has remained around 42-49% during the past eight influenza seasons. We sought to quantify influenza vaccination coverage and factors associated with vaccination in persons seeking outpatient medical care for an acute respiratory illness (ARI)., Methods: We enrolled outpatients aged ≥6 months with ARI from >50 U.S. clinics from 2011 to 2012 through 2018-2019 influenza seasons and tested for influenza with molecular assays. Vaccination status was based on documented receipt of the current season's influenza vaccine. We estimated vaccination coverage among influenza-negative study participants by study site, age, and season, and compared to state-level influenza coverage estimates in the general population based on annual immunization surveys. We used multivariable logistic regression to examine factors independently associated with receipt of influenza vaccines., Results: We enrolled 45,424 study participants with ARI who tested negative for influenza during the study period. Annual vaccination coverage among influenza-negative ARI patients and the general population in the participating states averaged 55% (range: 47-62%), and 52% (range: 46-54%), respectively. Among enrollees, coverage was highest among adults aged ≥65 years (82%; range, 80-85%) and lowest among adolescents aged 13-17 years (38%; range, 35-41%). Factors significantly associated with non-vaccination included non-White race, no college degree, exposure to cigarette smoke, absence of high-risk conditions, and not receiving prior season influenza vaccine., Conclusions: Influenza vaccination coverage over eight seasons among outpatients with non-influenza respiratory illness was slightly higher than coverage in the general population but 15% lower than national targets. Increased efforts to promote vaccination especially in groups with lower coverage are warranted to attain optimal health benefits of influenza vaccine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: New influenza vaccine formulations are designed to improve vaccine effectiveness and protect those most vulnerable to infection. High dose trivalent inactivated influenza vaccine (HD-IIV3), licensed for ages ≥65 years, produces greater antibody responses and efficacy in clinical trials, but post-licensure vaccine effectiveness (VE) compared to standard dose (SD-IIV3/4) vaccine remains an open question., Methods: Using a test-negative, case control design and propensity analyses to adjust for confounding, US Influenza VE Network data from the 2015-2016 through 2018-2019 seasons were analyzed to determine relative VE (rVE) between HD-IIV3 and SD-IIV3/4 among outpatients ≥65 years old presenting with acute respiratory illness. Influenza vaccination status was derived from electronic medical records and immunization registries., Results: Among 3861 enrollees, 2993 (78%) were vaccinated; 1573 (53%) received HD-IIV3 and 1420 (47%) received SD-IIV3/4. HD-IIV3 recipients differed from SD-IIV3/4 recipients by race, previous vaccination, number of outpatient visits in the previous year and timing of vaccination, and were balanced in the propensity model except the timing of vaccination. Compared with no vaccination, significant protection against any influenza A was observed from both HD-IIV3 (VE = 29%; 95%CI = 10%, 44%) and SD-IIV3/4 (VE = 24%; 95%CI = 5%, 39%); rVE = 18% (95%CI = 0%, 33%, SD as referent). When stratified by virus type, against A/H1N1, HD-IIV3 VE was 30% (95%CI = -7%, 54%), SD-IIV3/4 VE was 40% (95%CI = 10%, 61%), and rVE = -32%; (95%CI = -94%, 11%); Against A/H3N2, HD-IIV3 VE was 31% (95%CI = 9%, 47%), SD-IIV3/4 VE was 19% (95%CI = -5%, 37%), and rVE = 27%; (95% CI = 9%, 42%)., Conclusions: Among adults ≥65 years of age, recipients of standard and high dose influenza vaccines differed significantly in their characteristics. After adjusting for these differences, high dose vaccine offered more protection against A/H3N2 and borderline significant protection against all influenza A requiring outpatient care during the 2015-2018 influenza seasons., Competing Interests: Declaration of Competing Interest RKZ has/had a research grant from Sanofi Pasteur, Inc. RKZ and MPN have/had research grant funding from Merck & Co, Inc. MLG has received institutional research grant from AstraZeneca-MedImmune. MLJ reports research funding from Sanofi Pasteur, unrelated to the present work. ASM reports consulting fees from Sanofi, Seqirus and Roche. ETM reports consulting fees from Pfizer. HQM reports research funding from Seqirus unrelated to the present work. The other authors have no conflicts to report., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Licensed inactivated influenza vaccines (IIV) are recommended for persons aged ≥65 years, including trivalent high-dose IIV (HD-IIV3) and adjuvanted IIV (aIIV3); both are manufactured in eggs. Quadrivalent recombinant vaccine (RIV4) is produced without eggs. We conducted an exploratory study to compare immunogenicity of HD-IIV3, aIIV3 and RIV4 against cell-grown vaccine and circulating A(H3N2) viruses in 2017-18., Methods: Eighty-nine adults aged 65-74 years participating in a 2-year, open-label immunogenicity trial (ClinicalTrails.gov: NCT02872311) were randomized 1:1:1 to receive HD-IIV3, aIIV3, or RIV4 after receipt of standard dose IIV3 in 2016-17. Serum was obtained at baseline and day 28 post vaccination. Microneutralization titers were determined using four cell-propagated A(H3N2) viruses: 2017-18 vaccine strain (clade 3C.2a), circulating viruses from clades 3C.2a1 and 3C.2a2, and 'antigenically advanced' clade 3C.3a (2019-20 vaccine strain). Active surveillance was conducted to identify influenza illnesses., Results: Post vaccination geometric mean titer (GMT) against the vaccine strain was <1:60 in each group and <15% seroconverted. RIV4 generated a greater fold-rise (2.0, 95% CI 1.7-2.5) compared to HD-IIV3 (1.6, 95% CI 1.3-1.8). RIV4 generated higher post vaccination titers against 3C.2a1 and 3C.2a2 viruses, and the mean fold-rise after RIV4 was twice as high (3.3 and 3.5, respectively) relative to HD-IIV3 (1.4 and 1.6) and aIIV3 (1.7 and 1.6). Against the antigenically advanced 3C.3a virus, RIV4 generated a greater mean fold-rise (2.9, 95% CI 2.0-4.3) vs HD-IIV3 (1.3, 95% CI 1.1-1.6) and aIIV3 (1.7, 95% CI 1.3-2.1). Postvaccination titers against 3C.2a2 were ≥1:40 in 5 of 7 participants with PCR-confirmed A(H3N2) infection during the ensuing influenza season., Conclusion: High-dose, adjuvanted, and recombinant vaccines generated suboptimal neutralizing antibody responses to the cell-grown vaccine strain, but RIV4 generated a greater cross-protective response against circulating and antigenically advanced viruses. Recombinant technology may contribute to more broadly protective influenza vaccines, and comparative effectiveness studies are needed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Huong McLean receives research support from Seqirus. The other authors declare no competing interests.]., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Seasonal influenza vaccines aim to induce strain-specific neutralizing antibodies. Non-neutralizing antibodies may be more broadly cross-reactive and still protect through mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC). Influenza vaccines may stimulate ADCC antibodies in adults, but whether they do so in children is unknown. Here we examined how vaccination affects cross-reactive ADCC antibody responses in children after receipt of inactivated trivalent vaccine (IIV3) or quadrivalent live-attenuated vaccine (LAIV4)., Methods: Children aged 5-17 were recruited in fall 2014 to provide pre- and post-vaccination serum samples. Children aged 5-9 received LAIV4 based on then-current recommendation, and older children were randomly assigned to IIV3 or LAIV4. We used microtiter-plate-based flow cytometry with an NK cell line to examine ADCC antibody responses to the 2014-15 H3N2 vaccine component (A/Texas/50/2012 [TX12]) and a drifted strain, A/Switzerland/9715293/2013 (SW13). Responses were stratified by two-season (2013-14 and 2014-15) vaccine sequence., Results: Eighty-five children received LAIV4 and 45 received IIV3. Prevaccination ADCC activity was highest in children who had received any vaccine in the prior season. Increase in ADCC antibody responses against the vaccine strain TX12 following vaccination was greatest for participants who received IIV3 in 2014-15 and LAIV4 in the prior season (geometric mean fold rise [MFR] = 1.6, 95% CI. 1.23-2.11). This group also had a detectable ADCC response to the drifted SW13 strain. There was a modest ADCC response against SW13 in LAIV4 recipients who were unvaccinated in the previous season (MFR = 1.18, 95% CI 1.10-1.25). There were no significant changes in 2014-15 ADCC response to vaccination among children who had received IIV3 in 2013-14., Conclusions: Vaccinating children with IIV3 after prior receipt of LAIV4 generated a modest increase in ADCC antibodies, including some cross-reactivity with an emerging drift variant. Other vaccine-induced ADCC responses were minimal and not affected by vaccine type or sequence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: We evaluate safety of routine vaccination among adults infected with human immunodeficiency virus (HIV) in five healthcare organizations in the United States., Methods: We conducted a retrospective cohort study of HIV-infected adults who received inactivated influenza vaccines, hepatitis B vaccines, pneumococcal vaccines, or tetanus, diphtheria, and acellular pertussis vaccines between 2002 and 2013. We conducted self-controlled case series analysis to estimate the relative risk (RR) for 11 pre-specified adverse events (AEs) requiring medical attention., Results: Among 20,417 HIV-infected adults (90.2% male), a total of 137,674 vaccine doses were administered. Based on ICD-9 codes, we detected an increased risk of cellulitis and infection (RR: 1.18, 95% CI: 1.03-1.35) among all patients, and an increased risk of stroke/cerebrovascular diseases among patients with an HIV viral load >10,000 copies/ml (adjusted RR: 3.94, 95% CI: 1.32-11.72). Further analyses on chart confirmed cases of stroke/cerebrovascular diseases indicated no statistically significant increased risk (adjusted RR: 1.72, 95% CI: 0.41-7.24). There was no evidence of increased risk for other AEs following routine vaccination in HIV-infected adults., Conclusions: Routinely administered vaccines are generally safe for HIV-infected adults., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Febrile seizures are associated with the first dose of measles-containing vaccines and the risk increases with chronologic age during the second year of life. We used the Vaccine Safety Datalink (VSD) to determine if the relative increase in risk of seizures following receipt of measles-containing vaccine differs by gestational age at birth., Methods: Children were eligible if they received their first dose of measles-containing vaccine at age 12 through 23 months from January 2003 through September 2015. Children were excluded if they had a history of seizure or conditions strongly related to seizure prior to 12 months of age. Seizures were identified by diagnostic codes in the inpatient or emergency department settings. Using risk-interval analysis, we estimated the incidence rate ratio (IRR) for seizures in the 7 through 10 days (risk period) vs 15 through 42 days (control period) following receipt of measles-containing vaccines in children born preterm (<37 weeks gestation age) and those born full-term (≥37 weeks)., Results: There were 532,375 children (45,343 preterm and 487,032 full-term) who received their first dose of measles-containing vaccine at age 12 through 23 months. The IRRs of febrile seizures 7 through 10 days compared with 15 through 42 days after receipt of measles-containing vaccine were 3.9 (95% CI: 2.5-6.0) in preterm children and 3.2 (2.7-3.7) in full-term children; the ratio of IRRs: was 1.2 (0.76-1.9), p = 0.41. IRRs were also similar across gestational age groups, by vaccine type received (measles-mumps-rubella [MMR] or measles-mumps-rubella-varicella [MMRV]) and age at vaccination (12-15 or 16-23 months)., Conclusion: Vaccination with a measles-containing vaccine in the second year of life is associated with a similar relative risk of a first seizure in children born preterm as in those who were born full-term., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Annual influenza vaccination has been recommended for persons with high-risk conditions since the 1960s. However, few estimates of influenza vaccine effectiveness (VE) for persons with high-risk conditions are available., Methods: Data from the U.S. Influenza Vaccine Effectiveness Network from 2012 to 2016 were analyzed to compare VE of standard-dose inactivated vaccines against medically-attended influenza among patients aged ≥6 months with and without high-risk medical conditions. Patients with acute respiratory illness were tested for influenza by RT-PCR. Presence of high-risk conditions and vaccination status were obtained from medical records. VE by influenza virus type/subtype and age group was calculated for patients with and without high-risk conditions using the test-negative design. Interaction terms were used to test for differences in VE by high-risk conditions., Results: Overall, 9643 (38%) of 25,369 patients enrolled during four influenza seasons had high-risk conditions; 2213 (23%) tested positive for influenza infection. For all ages, VE against any influenza was lower among patients with high-risk conditions (41%, 95% CI: 35-47%) than those without (48%, 95% CI: 43-52%; P-for-interaction = 0.02). For children aged <18 years, VE against any influenza was 51% (95% CI: 39-61%) and 52% (95% CI: 39-61%) among those with and without high-risk conditions, respectively (P-for-interaction = 0.54). For adults aged ≥18 years, VE against any influenza was 38% (95% CI: 30-45%) and 44% (95% CI: 38-50%) among those with and without high-risk conditions, respectively (P-for-interaction = 0.21). For both children aged <18 and adults aged ≥18 years, VEs against illness related to influenza A(H3N2), A(H1N1)pdm09, and influenza B virus infection were similar among those with and without high-risk conditions., Conclusions: Influenza vaccination provided protection against medically-attended influenza among patients with high-risk conditions, at levels approaching those observed among patients without high-risk conditions. Results from our analysis support recommendations of annual vaccination for patients with high-risk conditions., (Published by Elsevier Ltd.)

Background: Third doses of measles-mumps-rubella (MMR) vaccine have been administered during mumps outbreaks and in various non-outbreak settings. The immunogenicity of the rubella component has not been evaluated following receipt of a third dose of MMR vaccine., Methods: Young adults aged 18-31 years with documented two doses of MMR vaccine received a third dose of MMR vaccine between July 2009 and October 2010. Rubella neutralizing antibody titers were assessed before, 1 month, and 1 year after receipt of a third dose of MMR vaccine., Results: Among 679 participants, 1.8% had rubella antibody titers less than 10 U/ml, immediately before vaccination, approximately 15 years after receipt of a second dose of MMR vaccine. One month after receipt of a third dose of MMR vaccine, average titers were 4.5 times higher and >50% of participants had a 4-fold boost. Response was highest among those with titers less than 10 U/ml prior to vaccination (geometric mean titer ratio = 18.8; 92% seroconversion) and decreased with increasing pre-vaccination titers. Average titers declined 1 year postvaccination but remained significantly higher than pre-vaccination levels. The proportion classified as low-positive antibody levels increased from 3% 1 month postvaccination to 24% 1 year postvaccination., Conclusions: Vaccination with a third dose of MMR vaccine resulted in a robust boosting of rubella neutralizing antibody response that remained elevated 1 year later. Young adults with low rubella titers are more likely to benefit from a third dose of MMR vaccine., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: There have been inconsistent reports of decreased vaccine effectiveness (VE) against influenza viruses among older adults (aged ≥ 65 years) compared with younger adults in the United States. A direct comparison of VE over multiple seasons is needed to assess the consistency of these observations., Methods: We performed a pooled analysis of VE over 5 seasons among adults aged ≥ 18 years who were systematically enrolled in the U.S. Flu VE Network. Outpatients with medically-attended acute respiratory illness (cough with illness onset ≤ 7 days prior to enrollment) were tested for influenza by reverse transcription polymerase chain reaction. We compared differences in VE and vaccine failures among older adult age group (65-74, ≥75, and ≥ 65 years) to adults aged 18-49 years by influenza type and subtype using interaction terms to test for statistical significance and stratified by prior season vaccination status., Results: Analysis included 20,022 adults aged ≥ 18 years enrolled during the 2011-12 through 2015-16 influenza seasons; 4,785 (24%) tested positive for influenza. VE among patients aged ≥ 65 years was not significantly lower than VE among patients aged 18-49 years against any subtype with no significant interaction of age and vaccination. VE against A(H3N2) viruses was 14% (95% confidence interval [CI] -14% to 36%) for adults ≥ 65 years and 21% (CI 9-32%) for adults 18-49 years. VE against A(H1N1)pdm09 was 49% (95% CI 22-66%) for adults ≥ 65 years and 48% (95% CI 41-54%) for adults 18-49 years and against B viruses was 62% (95% CI 44-74%) for adults ≥ 65 years and 55% (95% CI 45-63%) for adults 18-49 years. There was no significant interaction of age and vaccination for separate strata of prior vaccination status., Conclusions: Over 5 seasons, influenza vaccination provided similar levels of protection among older and younger adults, with lower levels of protection against influenza A(H3N2) in all ages., (Published by Elsevier Ltd.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Antibodies to measles, mumps, and rubella decline 3% per year on average, and have a high degree of individual variation. Yet, individual variations and differences across antigens are not well understood. To better understand potential implications on individual and population susceptibility, we reanalyzed longitudinal data to identify patterns of seropositivity and persistence., Methods: Children vaccinated with the second dose of measles, mumps, rubella vaccine (MMR2) at 4-6 years of age were followed up to 12 years post-vaccination. The rates of antibody decline were assessed using regression models, accounting for differences between and within subjects., Results: Most of the 302 participants were seropositive throughout follow-up (96% measles, 88% mumps, 79% rubella). The rate of antibody decline was associated with MMR2 response and baseline titer for measles and age at first dose of MMR (MMR1) for rubella. No demographic or clinical factors were associated with mumps rate of decline. One month post-MMR2, geometric mean titer (GMT) to measles was high (3892 mIU/mL), but declined on average 9.7% per year among those with the same baseline titer and <2-fold increase post-MMR2. Subjects with ≥2-fold experienced a slower decline (≤7.4%). GMT to rubella was 149 one month post-MMR2, declining 2.6% and 5.9% per year among those who received MMR1 at 12-15 months and >15 months, respectively. GMT to mumps one month post-MMR2 was 151, declining 9.2% per year. Only 14% of subjects had the same persistence trends for all antigens., Conclusions: The rate of antibody decay varied substantially among individuals and the 3 antigen groups. A fast rate of decline coupled with high variation was observed for mumps, yet no predictors were identified. Future research should focus on better understanding waning titers to mumps and its impacts on community protection and individual susceptibility, in light of recent outbreaks in vaccinated populations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Influenza vaccination may provide a "back-boost" to antibodies against previously encountered strains. If the back-boost effect is common, this could allow more aggressive vaccine updates, as emerging variants would be expected to both elicit de-novo responses and boost pre-existing responses against recently circulating strains. Here we used the emergence of an antigenically novel A(H3N2) strain to determine whether an antigenically updated vaccine boosted antibodies against historical strains., Methods: We performed hemagglutination-inhibition (HI) assays on pre- and post-vaccination sera from 124 children 5-17 years old who received 2015-2016 inactivated influenza vaccine, containing an antigenically updated A(H3N2) strain. We evaluated the mean fold increase in HI titer against both the 2015-2016 vaccine strain and representative strains from two prior antigenic clusters. Factors associated with post-vaccination titers against historical strains were evaluated using linear regression, adjusting for baseline titer., Results: Geometric mean titers against each antigen examined increased significantly after vaccination (P < .0001). Mean fold increase was 3.29 against the vaccine strain and 1.22-1.46 against historical strains. Response to vaccine strain was associated with increased post-vaccination titers against historical strains., Conclusions: A vaccine containing an antigenically novel A(H3N2) strain modestly boosted antibody responses against historical influenza strains in children., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: In addition to preventing hospitalizations and deaths due to influenza, influenza vaccination programs can reduce the burden of outpatient visits for influenza. We estimated the incidence of medically-attended influenza at three geographically diverse sites in the United States, and the cases averted by vaccination, for the 2013/14 through 2015/16 influenza seasons., Methods: We defined surveillance populations at three sites from the United States Influenza Vaccine Effectiveness Network. Among these populations, we identified outpatient visits laboratory-confirmed influenza via active surveillance, and identified all outpatient visits for acute respiratory illness from healthcare databases. We extrapolated the total number of outpatient visits for influenza from the proportion of surveillance visits with a positive influenza test. We combined estimates of incidence, vaccine coverage, and vaccine effectiveness to estimate outpatient visits averted by vaccination., Results: Across the three sites and seasons, incidence of medically attended influenza ranged from 14 to 54 per 1000 population. Incidence was highest in children aged 6 months to 9 years (33 to 70 per 1000) and lowest in adults aged 18-49 years (21 to 27 per 1000). Cases averted ranged from 9 per 1000 vaccinees (Washington, 2014/15) to 28 per 1000 (Wisconsin, 2013/14)., Discussion: Seasonal influenza epidemics cause a considerable burden of outpatient medical visits. The United States influenza vaccination program has caused meaningful reductions in outpatient visits for influenza, even in years when the vaccine is not well-matched to the dominant circulating influenza strain., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: A clinical study found that live attenuated influenza vaccine (LAIV) was superior to inactivated influenza vaccine (IIV) against drifted A(H3N2) viruses in children. During the 2014-2015 influenza season, widespread circulation of antigenically and genetically drifted A(H3N2) viruses provided an opportunity to evaluate subtype-specific vaccine effectiveness (VE) of quadrivalent LAIV (LAIV4) and IIV in children., Methods: Children (2-17years) with febrile acute respiratory illness <5days' duration were enrolled at 4 outpatient sites in the United States during the 2014-2015 influenza season. Nasal swabs were tested for influenza by reverse transcription polymerase chain reaction; vaccination dates were obtained from medical records or immunization registries. VE was estimated using a test-negative design comparing odds of vaccination among influenza cases and test-negative controls with adjustment for potential confounders., Results: Among 1696 children enrolled, 1511 (89%) were included in the analysis. Influenza was detected in 427 (28%) children; 317 had influenza A(H3N2) and 110 had influenza B. Most influenza isolates were characterized as a drifted strain of influenza A(H3N2) or a drifted strain of B/Yamagata. For LAIV4, adjusted VE was 50% (95% confidence interval [CI], 27-66%) against any influenza, 30% (95% CI, -6% to 54%) against influenza A(H3N2), and 87% (95% CI, 63-96%) against type B. For IIV, adjusted VE was 39% (95% CI, 18-54%) against any influenza, 40% (95% CI, 16-58%) against A(H3N2), and 29% (95% CI, -15% to 56%) against type B. Odds of influenza for LAIV4 versus IIV recipients were similar against influenza A(H3N2) (odds ratio [OR], 1.17; 95% CI, 0.73-1.86) and lower against influenza B (OR, 0.18; 95% CI, 0.06-0.55)., Conclusions: LAIV4 and IIV provided similar protection against a new antigenic variant A(H3N2). LAIV4 provided significantly greater protection than IIV against a drifted influenza B strain. ClinicalTrials.gov identifier: NCT01997450., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To address public concern about the safety of the childhood immunization schedule, the Institute of Medicine recommended observational studies comparing adverse health outcomes of fully vaccinated children to children under-vaccinated due to parental choice. Misclassification of vaccination status could bias such studies., Objective: To assess risk of misclassification of vaccination status within the Vaccine Safety Datalink (VSD)., Design/methods: A retrospective cohort study was conducted in three phases. In phase 1, electronic health record (EHR) data were used to identify patterns of under-vaccination during the first 24months of life potentially due to parental choice. In phase 2, a random sample of records of under-vaccinated children was manually reviewed. In phase 3, a separate sample of parents were surveyed to assess whether EHR data accurately reflected their child's vaccination status. Phases 1 and 2 were conducted at 6 VSD sites, phase 3 at 1 site., Results: The study cohort included 361,901 children born 2004 through 2012. By 24months of age, 198,249 (54.8%) were fully vaccinated with no delays, 84,698 (23.4%) experienced delays but were fully vaccinated by 24months of age, 4865 (1.3%) received no vaccines, 3789 (1.0%) delayed starting vaccination until ≥4months of age, 4781 (1.3%) had consistent vaccine-limiting (≤2 vaccines per visit), and the remaining 65,519 (18.1%) were missing vaccine series or doses. When a diagnosis code for vaccine refusal was present in EHR data, encounter notes confirmed vaccine refusal as the reason for under-vaccination for nearly 100% of sampled records. Parent surveys confirmed these findings. Parents of under-vaccinated children were more likely to report visiting an alternative medical provider than parents of fully vaccinated children., Conclusions: Specific groups of children, under-vaccinated due to parental choice, can be identified with relatively low likelihood of misclassification of vaccination status using EHR-based vaccine data and diagnosis codes., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: A postmarketing observational study was initiated to evaluate quadrivalent live attenuated influenza vaccine (LAIV) effectiveness in children aged 2-17 years in the United States., Methods: Children and adolescents aged 2-17 years seeking outpatient care for febrile acute respiratory illness <5 days duration were enrolled at 4 geographically diverse sites during the 2013-2014 influenza season. Nasal swabs were tested for influenza using reverse transcription polymerase chain reaction. Vaccination status was documented from medical records or immunization registries. Children who received ≥1 dose of influenza vaccine ≥14 days before study visit were considered vaccinated. Vaccine effectiveness (VE) was estimated as 100×(1-adjusted odds ratio), where the odds of interest are the odds of vaccine exposure among influenza cases and test-negative controls., Results: In total, 1033 children and adolescents were included in the analysis. Influenza was detected in 14% (145/1033) of all children, with 74% (108/145) of the influenza cases due to A/H1N1pdm09 strains, 21% (31) to influenza B, and 4% (6) to influenza H3N2. LAIV did not show significant effectiveness against A/H1N1pdm09 (VE 13% [95% CI: -55 to 51]) but was effective against B/Yamagata strains (82% [95% CI: 12-96]). Inactivated influenza vaccine was effective against A/H1N1pdm09 (74% [95% CI: 50-86]) and B/Yamagata (70% [95% CI: 18-89])., Conclusions: LAIV provided significant protection against B/Yamagata influenza but not against A/H1N1pdm09 in children aged 2-17 years in 2013-2014, resulting in a proposed change of the 2015-2016 formulation with a new and more heat-stable A/H1N1pdm09 LAIV strain., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Influenza vaccine is moderately effective for preventing influenza illness. It is not known if vaccination reduces the risk of subsequent hospital admission among patients with vaccine failure and laboratory confirmed influenza illness., Methods: Patients in a community cohort presenting with acute respiratory illness were prospectively enrolled and tested for influenza during 8 seasons to estimate seasonal vaccine effectiveness. Hospital admissions within 14 days after illness onset were identified for all participants aged ≥20 years with laboratory confirmed influenza. The association between vaccination and hospital admission was examined in a propensity score adjusted logistic regression model. The model was validated by examining the association between vaccination and hospital admission in participants without influenza., Results: Influenza was identified in 1393 (28%) of 4996 participants. Sixty-two (6%) of 1020 with influenza A and 17 (5%) of 369 with influenza B were hospitalized. Vaccination was not associated with a reduced risk of hospital admission among all participants with influenza [adjusted odds ratio (aOR)=1.08; 95% CI: 0.62, 1.88]; or among those with influenza A (aOR=1.35; 95% CI: 0.71, 2.57) or influenza B (aOR=0.67; 95% CI: 0.21, 2.15). Influenza vaccination was not associated with hospitalization after non-influenza respiratory illness (aOR=1.14; 95% CI: 0.84, 1.54)., Conclusions: Influenza vaccination did not reduce the risk of subsequent hospital admission among patients with vaccine failure. These findings do not support the hypothesis that vaccination mitigates influenza illness severity., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)