Quadrivalent Influenza Vaccine Research Articles

1719. Duration of antibodies after immunization with the quadrivalent influenza vaccine in children after hematopoietic stem cell transplantation or chemotherapy compared to healthy children

Abstract Background Children that have undergone hematopoietic stem cell transplantation (HSCT) are at a higher risk for severe influenza. The purpose of this study was to compare the duration of antibodies after immunization with the quadrivalent influenza vaccine (QIV) in children after hematopoietic stem cell transplantation or chemotherapy compared to healthy children. Methods This was a prospective study of children below 18 years old that received the QIV influenza vaccine during the 2021-2022 influenza vaccination season. Children were divided into 3 groups as follows: a) post-HSCT, b) post-chemotherapy, and c) immunocompetent children as a healthy control. Blood samples were taken immediately before immunization, at 1 month, 3 months, 6 months, and 12 months after immunization. Hemagglutination Inhibition (HI) assays were performed. Seropositive rate was defined by the percentage of patients with HI titer ≥1:40. Seroconversion rate (SCR) was defined as follows: 1) in patients with a pre-vaccination HI titer < 1:10, rise in post-vaccination HI titers ≥1:40, or in patients with pre-vaccination HI titers ≥1:40, a 4-fold increase. Results A total of 60 children were included in the preliminary analyses, n=20 in each of the three groups. The SPR at post-vaccination 1 month for both A/H1N1 and H3N2 exceeded 80% in all three groups. The SPR remained above 60% at 3 months post-immunization for both A antigens. However, by 6 months post-vaccination, the SPR dropped to 50% in the post-chemotherapy group for the A/H1N1 antigen, and the geometric mean titers (GMTs) were 26.39. For B/Victoria and B/Yamagata, the SPR was below 40% in the post-HSCT and post chemotherapy group at 1 months and below 20% by 3 months. The GMTs were also below 1:40 for both antigens. In the normal control group, the SPR for B/Victoria was 50% at 1 months and 45% at 3 months post-immunization, and for B/Yamagata, 50% at 1 months and 55% at 3 months post-immunization. However, the GMTs were below 1:40 by 3 months post-immunization. Conclusion For A/H1N1, the SPR and GMTs at 6 months in the post-chemotherapy was low. In both the post-HSCT and chemotherapy group, HI titers were low for both B antigens at 1-month post-vaccination, and GMTs showed < 1:40. B antigens contained within QIV need to illicit better protection against Influenza in children. Disclosures All Authors: No reported disclosures

1168. Cost-effectiveness of high-dose quadrivalent influenza vaccine versus standard-dose quadrivalent influenza vaccine for older people in a country with high influenza vaccination rate

Abstract Background The high-dose quadrivalent formulation (QIV-HD) has shown improved protection against influenza and its complications in older adults. We aimed to evaluate the cost-effectiveness of QIV-HD compared with QIV-SD among Korean adults aged ≥ 65 years in reducing influenza-related disease burden. Methods We evaluated the 2016/2017 and 2017/2018 seasons and their average values using a static decision tree model. For the main analysis, hospitalization was defined as cardiorespiratory disease-related. The difference in efficacy between standard-dose (SD) and high-dose (HD) was calculated based on the results of a clinical trial comparing Fluzone® High-Dose Vaccine and Fluzone® Vaccine in older adults. Incremental cost-effectiveness ratios (ICERs) were assessed from the healthcare system perspective. A discount rate of 4.5% was applied to life-year-gained (LYG) values and utilities. We performed deterministic and probabilistic sensitivity analyses to account for both epidemiological and economic sources of uncertainty. Results In the analysis of the 2017/2018 season, the QIV-HD strategy generated an excess of 0.003953 quality-adjusted life-years (QALYs) compared with QIV-SD. The ICER was 6,467.56 USD/QALY. For the 2016/2017 season, QIV-HD caused an excess of 0.003272 QALYs and ICER was 7,902.46 USD /QALY. From the average data of the two seasons, an excess of 0.003561 QALYs were generated and the ICER was 7,190.44 USD/QALY. In the one-way sensitivity analysis, the parameters with the greatest impact on the results were the relative VE of QIV-HD vs. QIV-SD against influenza-associated hospitalization. PSAs were conducted for the 2016/2017 and 2017/2018 seasons, with the cost of the QIV-HD vaccine fixed at 50,000 KRW (40.48 USD) or 65,000 KRW (52.62 USD). The results showed that for a WTP threshold of 24,692.36 USD/QALY, the probability that QIV-HD is a cost-effective option for the Korean health system is 100% in all seasons and QIV-HD vaccine costs considered. Conclusion From the healthcare system perspective, QIV-HD was a more cost-effective vaccination option in reducing influenza-related disease burden and healthcare costs in Koreans aged ≥ 65 years compared with QIV-SD. Disclosures Hee Jin Cheong, M.D., Ph.D., Sequiris: Advisor/Consultant Jung-Min Lee, n/a, Sanofi Korea: Stocks/Bonds

1147. A study of high-dose influenza vaccination responses compared to standard-dose in lupus patients: an open- labeled, randomized controlled study

Abstract Background Annual influenza vaccination at standard dosing in the general population is suggested. However, there may be more suitable for lupus patients. Objectives To assess the immune responses among lupus patients receiving high dose (HD) and standard (SD) quadrivalent inactivated influenza vaccine, evaluate the adverse events of the HD, and monitor the incidence of influenza infection. Methods A randomized parallel design, controlled trial was conducted from March 2021 to May 2022 at Ramathibodi Hospital. All lupus patients were stratified into two groups depending on the depth of immunosuppressive therapy received and randomized to receive either HD or SD in a 1:1 ratio. Patient demographics data and relevant information were retrieved. Blood samples were obtained for hemagglutination inhibition assay (HAI) before vaccination and 4-12 weeks after completion of the vaccination series to determine seroprotection and seroconversion rates. Results One hundred twenty-eight lupus patients were enrolled, and 109 individuals completed the HAI analysis. 54/109 patients were in the high- (HI) with mean age (mean ± SD) of 34.3 (25.2-43.4) years, and 55/109 were in the low-immunosuppressive (LI) groups with mean age (mean ± SD) of 38.2 (30.2-46.2) (p=0.018). The majority of patients had a SLEDAI-2K score of 4. The seroprotection rates against H1N1, H3N2/Hongkong, H3N2/Cambodia, B/Victoria, and B/Yamagata strains in HI and LI groups at baseline after the first and second injections were outlined as follows 1.) HI; 74.1%, 82.1%, 76.9%, 75.9%, 79.6%; 85.2%, 89.3%, 88.5%, 85.2%, 88.9%; 89.5%, 89.3%, 88.5%, 93.9%, 88.9%, and 2.) LI; 76.4%, 84.6%, 93.1%, 74.5%, 89.1%; 92.7%, 100%, 100%, 94.5%, 96.4%; 92.7%, 100%, 100%, 94.5%, 94.5%. There was one documented influenza infection during the 9-month follow-up period. The patient was in the LI group and received the SD vaccine. 19/109 (17.4%) patients had grade 1 adverse events with no difference between SD and HD. Conclusion Lupus patients’ immune response, especially those taking HI, may not be similar to healthy individuals. A higher dosage of influenza vaccination may provide a better seroprotection rate. However, real-world clinical effectiveness is yet to demonstrate, and further studies are required. Disclosures All Authors: No reported disclosures

Summary of the National Advisory Committee on Immunization (NACI) Seasonal Influenza Vaccine Statement for 2023-2024.

The National Advisory Committee on Immunization (NACI) reviews the evolving evidence on influenza immunization and provides annual recommendations regarding the use of seasonal influenza vaccines. The NACI Statement on Seasonal Influenza Vaccine for 2023-2024 updates the 2022-2023 NACI recommendations. To summarize the 2023-2024 NACI seasonal influenza vaccine recommendations and to highlight new and updated information. In the preparation of the Statement on Seasonal Influenza Vaccine for 2023-2024, the NACI Influenza Working Group applied the NACI evidence-based process to critically appraise the available evidence and to propose recommendations. The recommendations were then considered and approved by NACI in light of the available evidence. Key changes for the 2023-2024 season include: 1) incorporation of updated information/guidance on influenza vaccination in the context of the coronavirus disease 2019 (COVID-19); 2) new recommendations for Flucelvax® Quad and Influvac® Tetra, the two quadrivalent inactivated influenza vaccines with expanded paediatric age indications; and 3) an update to the format of the Statement. Overall, NACI continues to recommend that an age-appropriate influenza vaccine should be offered annually to all individuals aged six months and older who do not have a contraindication to the vaccine, with particular focus on the groups for whom influenza vaccination is particularly recommended.

Immunogenicity and Safety of Alternative Influenza Vaccination Strategies in Repeated Seasons in Pediatric Hematopoietic-Cell Transplant Recipients

Abstract Background Pediatric hematopoietic cell transplant (HCT) recipients are at increased risk for morbidity and mortality from influenza infection. Annual influenza vaccination is recommended; however, HCT recipients have diminished immune responses to vaccination. Our recent trial demonstrated that two doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart post-HCT were more immunogenic than two doses of standard dose quadrivalent influenza vaccine (SD-QIV). We assessed the impact of this strategy in a consecutive season post-HCT. Methods The initial trial was a multi-center double-blinded phase II randomized controlled trial comparing two doses of HD-TIV to two doses of SD-QIV in children 3-17 years old given 3-35 months post-allogeneic HCT. Participants completing the initial trial could re-enroll the subsequent influenza season to receive the same two-dose vaccine formulation. Hemagglutinin inhibition (HAI) titers were measured at baseline and 28-42 days following each dose. Injection-site and systemic adverse events were assessed. The immunogenicity endpoints were the post-dose 1 and post-dose 2 geometric mean HAI titers (GMTs) in the second year of participation. Results A total of 170 participants were enrolled in the initial trial, with 65 re-enrolling for a second year (n=33 SD-QIV and n=32 HD-TIV). Post-dose 1 and 2 GMTs were higher for both the SD-QIV and HD-TIV groups in the second year compared the first year (Table 1). In year two, the adjusted geometric mean ratio (aGMR) comparing HD-TIV to SD-QIV was higher post-dose 1 for A/H1N1 (aGMR=1.99, 95% CI:[1.07, 3.68]). The HD-TIV group demonstrated a higher frequency of four-fold titer rise after a single dose compared to two doses of SD-QIV for A/H3N2 (61% vs. 48%) and B/Victoria (77% vs. 65%). Frequency of injection site and systemic reactions were similar between the HD-TIV and SD-QIV groups in year two. Conclusions The post-dose 1 and 2 GMTs were consistently higher for HD-TIV compared to SD-QIV in year two, and aGMR reached statistical significance after a single dose of HD-TIV for A/H1N1. Year two reactogenicity was comparable for both vaccination strategies. Further studies with larger numbers of participants are needed to demonstrate if one or two doses of HD-TIV are needed in subsequent influenza seasons post-HCT when a two-dose vaccination series is given in the first post-HCT season. Table 1. Point estimates and 95% CIs for geometric mean HAI titer, titer ≥1:40, and proportion with ≥4-fold rise from baseline for each vaccine regimen, stratified for each antigen. Also included is the ratio of the observed values (n) to the number of evaluable subjects (N) at each visit. Baseline titers are measured prior to first vaccine dose, post-dose 1 titers are measured 28-42 days following first dose (prior to the second dose), post-dose 2 titers are measured 28-42 days following second dose. Table 1 Note: If 100% achieved seroprotection or seroconversion, “n/a” was entered as a two-sided 95% CI could not be calculated.

Cost-effectiveness of high-dose quadrivalent influenza vaccine versus standard-dose quadrivalent influenza vaccine for older people in a country with high influenza vaccination rate

ABSTRACT The highdose quadrivalent influenza vaccine (QIVHD) has shown improved protection against influenza and its complications in older adults. We aimed to evaluate the costeffectiveness of QIVHD compared with QIVSD among Korean adults aged ≥ 65 years in reducing influenzarelated disease burden. We evaluated the 2016/2017 and 2017/2018 seasons and their average values using a static decision tree model. The difference in efficacy between standard-dose (SD) and high-dose (HD) was calculated based on the results of a clinical trial comparing Fluzone® High-Dose Vaccine and Fluzone® Vaccine in older adults. Incremental cost-effectiveness ratios (ICERs) were assessed from the healthcare system perspective. A discount rate of 4.5% was applied to life-year-gained (LYG) values and utilities. We performed deterministic and probabilistic sensitivity analyses to account for both epidemiological and economic sources of uncertainty. In the analysis of the 2017/2018 season, the QIV-HD strategy generated an excess of 0.00182 life-years (Lys)/person and 0.003953 quality-adjusted life-years (QALYs)/person compared with QIV-SD. The ICER was 6,467.56 United States Dollars (USD)/QALY. In the analysis from the 2016/2017 season, QIV-HD caused a surplus of 0.00117 Lys/person and 0.003272 QALYs/person compared with QIV-SD. ICER was 7,902.46 USD /QALY. From the average data of the 2016/2017 and 2017/2018 seasons, an excess of 0.00147 Lys/person and 0.003561 QALYs/person were generated using QIV-HD compared with QIV-SD, while the ICER was 7,190.44 USD /QALY. From the healthcare system perspective, QIV-HD was a more cost-effective vaccination option in reducing influenza-related disease burden and healthcare costs in Koreans aged ≥ 65 years compared with QIV-SD.

Cost-effectiveness for high dose quadrivalent versus the adjuvanted quadrivalent influenza vaccine in the Italian older adult population.

To assess the cost-effectiveness of switching from adjuvanted quadrivalent vaccine (aQIV) to high-dose quadrivalent influenza vaccine (HD-QIV) in those aged ≥65 years from the Italian National Health Service perspective. We developed a decision tree model over a 1-year time-horizon to assess influenza-related costs and health outcomes. Two hospitalization approaches were considered: "hospitalization conditional on developing influenza" and "hospitalization possibly related to Influenza." The first approach considered only hospitalizations with influenza ICD-9-CM diagnosis codes. The second included hospitalizations for cardiorespiratory events possibly related to influenza to better capture the "hidden burden". Since comparative efficacy of high-dose quadrivalent influenza vaccine versus adjuvanted quadrivalent vaccine was lacking, we assumed relative efficacy versus a common comparator, standard-dose influenza quadrivalent vaccines (SD-QIV). We assumed the relative efficacy of HD-QIV vs. SD-QIV was 24.2 and 18.2% for the first and second hospitalization approaches, respectively, based on published information. Due to lack of comparative efficacy data for aQIV vs. SD-QIV, we assumed three different scenarios: 0, 6, and 12% relative efficacy in scenarios 1, 2, and 3, respectively. For the first hospitalization approach, HD-QIV was a cost-effective alternative to aQIV in all scenarios at a willingness-to-pay threshold of €30,000 per Quality Adjusted Life Years. The incremental cost-effectiveness ratios across the scenarios were €7,301, €9,805, and €14,733, respectively, much lower than the willingness-to-pay per Quality Adjusted Life Years threshold. For the second hospitalization approach, HD-QIV was a dominant alternative to aQIV across all scenarios. The robustness of the results was confirmed in one-way and probabilistic sensitivity analyses. Switching to HD-QIV from aQIV for the older adult in Italy would improve health-related outcomes, and would be cost-effective or cost saving.

Cost effectiveness of quadrivalent influenza vaccines in the elderly population of Malaysia

The economic burden of influenza is a significant issue within healthcare system, related to higher medical costs particularly among the elderly. Yet, influenza vaccination rates in the elderly in Malaysia were considerably low as it is not part of Malaysia’s national immunization program, with substantial mortality and morbidity consequences. Therefore, we conducted a cost-effectiveness analysis of quadrivalent influenza vaccine (QIV) for the elderly in Malaysia compared with the current no-vaccination policy. A static cost-utility model, with a lifetime horizon based on age, was used for the analysis to assess the cost-effectiveness and health outcomes associated with QIV. Univariate and probabilistic sensitivity analyses were performed to test the effects of variations in the parameters. The use of QIV in Malaysia’s elderly population would prevent 66,326 potential influenza cases and 888 potential deaths among the elderly, leading to 10,048 potential quality-adjusted life years (QALYs) gained. The QIV would also save over USD 4.4 million currently spent on influenza-related hospitalizations and reduce productivity losses by approximately USD 21.6 million. The ICER per QALY gained from a third-party payer’s perspective would be USD 2216, which is lower than the country’s gross domestic product per capita. A QIV-based vaccination program in the elderly was found to be highly cost-effective, therefore would reduce the financial burden of managing influenza and reduce pre-mature death related to this disease.

Immunogenicity of Co-Administered Omicron BA.4/BA.5 Bivalent COVID-19 and Quadrivalent Seasonal Influenza Vaccines in Israel during the 2022-2023 Winter Season.

Vaccination against COVID-19 and influenza provides the best defense against morbidity and mortality. Administering both vaccines concurrently may increase vaccination rates and reduce the burden on the healthcare system. This study evaluated the immunogenicity of healthcare workers in Israel who were co-administered with the Omicron BA.4/BA.5 bivalent COVID-19 vaccine and the 2022-2023 quadrivalent influenza vaccine. SARS-CoV-2 neutralizing antibody titers were measured via microneutralization while influenza antibody titers were measured via hemagglutination inhibition. No immunogenic interference was observed by either vaccine when co-administered. Antibody titers against SARS-CoV-2 variants increased significantly in the cohort receiving the COVID-19 vaccine alone and in combination with the influenza vaccine. Antibody titers against the A/H1N1 influenza strain increased significantly in the cohort receiving the influenza vaccine alone and in combination with the COVID-19 vaccine. Antibody titers against B/Victoria increased significantly in the cohort that received both vaccines. This study has important public health implications for the 2023-2024 winter season, and supports co-administration of both vaccines as a viable immunization strategy.

Effectiveness of Cell-Based Quadrivalent Seasonal Influenza Vaccine: A Systematic Review and Meta-Analysis.

Cell-based seasonal influenza vaccine viruses may more closely match recommended vaccine strains than egg-based options. We sought to evaluate the effectiveness of seasonal cell-based quadrivalent influenza vaccine (QIVc), as reported in the published literature. A systematic literature review was conducted (PROSPERO CRD42020160851) to identify publications reporting on the effectiveness of QIVc in persons aged ≥6 months relative to no vaccination or to standard-dose, egg-based quadrivalent or trivalent influenza vaccines (QIVe/TIVe). Publications from between 1 January 2016 and 25 February 2022 were considered. The review identified 18 relevant publications spanning three influenza seasons from the 2017-2020 period, with an overall pooled relative vaccine effectiveness (rVE) of 8.4% (95% CI, 6.5-10.2%) for QIVc vs. QIVe/TIVe. Among persons aged 4-64 years, the pooled rVE was 16.2% (95% CI, 7.6-24.8%) for 2017-2018, 6.1% (4.9-7.3%) for 2018-2019, and 10.1% (6.3-14.0%) for 2019-2020. For adults aged ≥65 years, the pooled rVE was 9.9% (95% CI, 6.9-12.9%) in the egg-adapted 2017-2018 season, whereas there was no significant difference in 2018-2019. For persons aged 4-64 years, QIVc was consistently more effective than QIVe/TIVe over the three influenza seasons. For persons aged ≥65 years, protection with QIVc was greater than QIVe or TIVe during the 2017-2018 season and comparable in 2018-2019.

Vaccine Effectiveness of Cell-Based Quadrivalent Influenza Vaccine in Children: A Narrative Review.

Cell-based manufacturing of seasonal influenza vaccines eliminates the risk of egg-adaptation of candidate vaccine viruses, potentially increasing vaccine effectiveness (VE). We present an overview of published data reporting the VE and cost-effectiveness of a cell-based quadrivalent influenza vaccine (QIVc) in preventing influenza-related outcomes in the pediatric population. We identified 16 clinical studies that included data on the VE of a QIVc or the relative VE (rVE) of a QIVc versus an egg-based QIV (QIVe) in children and/or adolescents, 11 of which presented estimates specifically for the pediatric age group. Of these, two studies reported rVE against hospitalizations. Point estimates of rVE varied from 2.1% to 33.0%, with studies reporting significant benefits of using a QIVc against influenza-related, pneumonia, asthma, and all-cause hospitalization. Four studies reported rVE against influenza-related medical encounters, with point estimates against non-strain specific encounters ranging from 3.9% to 18.8% across seasons. One study evaluated rVE against any influenza, with variable results by strain. The other four studies presented VE data against laboratory-confirmed influenza. Three health economics studies focusing on a pediatric population also found the use of QIVc to be cost-effective or cost-saving. Overall, using a QIVc is effective in pediatric patients, with evidence of incremental benefits over using a QIVe in preventing hospitalizations and influenza-related medical encounters in nearly all published studies.

Expression of Toll-like Receptors on the Immune Cells in Patients with Common Variable Immune Deficiency after Different Schemes of Influenza Vaccination.

for the first time, the effect of one and two doses of adjuvanted influenza vaccines on toll-like receptors (TLRs) in patients with common variable immunodeficiency (CVID) was studied and compared (primary vaccination with one vs. two doses, primary vs. repeated vaccination). Six patients received one dose of quadrivalent adjuvanted influenza vaccine during the 2018-2019 and 2019-2020 influenza seasons, and nine patients with CVID received two doses of trivalent inactivated influenza vaccine during 2019-2020. Expression of TLRs was measured by flow cytometry. The expression of toll-like receptors in patients with CVID was noted both with repeated (annual) administration of the influenza vaccine and in most cases was accompanied by an increase in the proportion of granulocytes (TLR3 and TLR9), lymphocytes (TLR3 and TLR8), and monocytes (TLR3 and TLR9). When carried out for the first time as a simultaneous vaccination with two doses it was accompanied by an increase in the proportion of granulocytes, lymphocytes expressing TLR9, and on monocytes-TLR3 and TLR9. in CVID patients, the use of adjuvanted vaccines is promising, and research on the influence of the innate immunity and more effective regimens should be continued.

Technical guidelines for seasonal influenza vaccination in China (2023-2024)

Technical guidelines for seasonal influenza vaccination in China (2023-2024)

Self-amplifying mRNA seasonal influenza vaccines elicit mouse neutralizing antibody and cell-mediated immunity and protect ferrets

Currently licensed influenza vaccines focus immune responses on viral hemagglutinin (HA), while the other major surface glycoprotein neuraminidase (NA) is not tightly controlled in inactivated vaccine formulations despite evidence that anti-NA antibodies reduce clinical disease. We utilized a bicistronic self-amplifying mRNA (sa-mRNA) platform encoding both HA and NA from four seasonal influenza strains, creating a quadrivalent influenza vaccine. sa-mRNA vaccines encoding an NA component induced the production of NA-inhibiting antibodies and CD4+ T-cell responses in both monovalent and quadrivalent formulations. Including NA in the vaccine enabled cross-neutralization against antigenically drifted strains and provided greater protection than HA alone upon A(H3N2) challenge in ferrets. These results demonstrate that next-generation bicistronic sa-mRNA vaccines expressing HA and NA induce potent antibodies against both viral coat proteins, as well as vaccine-specific cell-mediated immunity. When formulated as a quadrivalent seasonal influenza vaccine, the sa-mRNA platform provides an opportunity to increase the breadth of protection through cross-neutralizing anti-NA antibodies.

Immunogenicity and Safety of MF59-Adjuvanted Quadrivalent Influenza Vaccine Compared with a Nonadjuvanted, Quadrivalent Influenza Vaccine in Adults 50-64 Years of Age.

Adults aged 50-64 years have a high incidence of symptomatic influenza associated with substantial disease and economic burden each year. We conducted a randomized, controlled trial to compare the immunogenicity and safety of an adjuvanted quadrivalent inactivated influenza vaccine (aIIV4; n = 1027) with a nonadjuvanted standard dose IIV4 (n = 1017) in this population. Immunogenicity was evaluated on Days 22, 181, and 271. On Day 22, upper limits (UL) of 95% confidence intervals (CI) for geometric mean titer (GMT) ratios (IIV4/aIIV4) were <1.5 and 95% CI ULs for the difference in seroconversion rate (SCR IIV4 - aIIV4) were <10% for all four vaccine strains, meeting primary endpoint noninferiority criteria. Protocol-defined superiority criteria (95% CI ULs < 1.0) were also met for A(H1N1) and A(H3N2). Immune responses following aIIV4 vaccination were more pronounced in persons with medical comorbidities and those not recently vaccinated against influenza. Safety data were consistent with previous studies of MF59 adjuvanted seasonal and pandemic influenza vaccines. These findings support the immunological benefit of aIIV4 for persons aged 50-64 years, especially those with comorbidities.

The Impact of Adjuvanted Influenza Vaccine on Disease Severity in the US: A Stochastic Model.

Influenza can exacerbate underlying medical conditions. In this study, we modelled the potential impact of an egg-based quadrivalent influenza vaccine (QIVe) or adjuvanted QIV (aQIV) on hospitalizations and mortality from influenza-related cardiovascular disease (CVD), respiratory, and other complications in adults ≥65 years of age in the US with underlying chronic conditions. We used a stochastic decision-tree model, with 1000 simulations varying input across predicted ranges. Due to the variable nature of influenza across seasons and differences in published estimates for input parameters, data are presented as 95% confidence intervals. Compared with no vaccination, use of aQIV would prevent 135,450-564,360 hospitalizations and 1612-29,226 deaths across outcomes evaluated. Overall, aQIV prevented 1071-18,388 more hospitalizations and 85-1944 more deaths than QIVe. By routine seasonal vaccination against influenza, a substantial number of severe influenza-associated complications and deaths, caused by direct influenza symptoms or by exacerbation of chronic conditions, can be prevented in high-risk adults ≥65 years of age in the US.

Dialysis Patients Respond Adequately to Influenza Vaccination Irrespective of Dialysis Modality and Chronic Inflammation.

(1) Background: Chronic inflammation and suboptimal immune responses to vaccinations are considered to be aspects of immune dysregulation in patients that are undergoing dialysis. The present study aimed to evaluate immune responses in hemodialysis (HD) and online hemodiafiltration (OL-HDF) patients to a seasonal inactivated quadrivalent influenza vaccine (IQIV). (2) Methods: We enrolled 172 chronic dialysis patients (87 on HD and 85 on OL-HDF) and 18 control subjects without chronic kidney disease in a prospective, cross-sectional cohort study. Participants were vaccinated with a seasonal IQIV, and antibody titers using the hemagglutination inhibition (HI) assay were determined before vaccination (month 0) and 1, 3, and 6 months thereafter. Demographics and inflammatory markers (CRP, IL-6, IL-1β) were recorded at month 0. The primary endpoints were the rates of seroresponse (SR), defined as a four-fold increase in the HI titer, and seroprotection (SP), defined as HI titer ≥ 1/40 throughout the study period. Statistical analyses were conducted in R (version 3.6.3) statistical software. The differences between groups were analyzed using chi-square and t-test analyses for dichotomous and continuous variables, respectively. To identify independent determinants of SR and SP, generalized linear models were built with response or protection per virus strain as the dependent variable and group, age, sex, time (month 0, 1, 3, 6), diabetes, IL-6, dialysis vintage, HD access, and HDF volume as independent explanatory variables. (3) Results: SR and SP rates were similar between control subjects, and dialysis patients were not affected by dialysis modality. SP rates were high (> 70%) at the beginning of the study and practically reached 100% after vaccination in all study groups. These results applied to all four virus strains that were included in the IQIV. IL-6 levels significantly differed between study groups, with HD patients displaying the highest values, but this did not affect SP rates. (4) Conclusions: Dialysis patients respond to influenza immunization adequately and similarly to the general population. Thus, annual vaccination policies should be encouraged in dialysis units. OL-HDF reduces chronic inflammation; however, this has no impact on SR rates.

Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease

Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial. To evaluate whether high-dose trivalent influenza vaccination is associated with benefit over standard-dose quadrivalent vaccination in reducing CP events during periods of high, local influenza activity. This study was a prespecified secondary analysis of INVESTED, a multicenter, double-blind, active comparator randomized clinical trial conducted over 3 consecutive influenza seasons from September 2016 to July 2019. Follow-up was completed in July 2019, and data were analyzed from September 21, 2016, to July 31, 2019. Weekly Centers for Disease Control and Prevention (CDC)-reported, state-level ILI activity was ascertained to assess the weekly odds of the primary outcome. The study population included 3094 patients with high-risk CV disease from participating centers in the US. Participants were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to 3 seasons. The primary outcome was the time to composite of all-cause death or CP hospitalization within each season. Additional measures included weekly CDC-reported ILI activity data by state. Among 3094 participants (mean [SD] age, 65 [12] years; 2309 male [75%]), we analyzed 129 285 person-weeks of enrollment, including 1396 composite primary outcome events (1278 CP hospitalization, 118 deaths). A 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P < .001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P < .001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001), after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors. Increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P > .99). High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43). Traditionally warmer months in the US were associated with lower CV risk independent of local ILI activity. In this secondary analysis of a randomized clinical trial, ILI activity was temporally associated with increased CP events in patients with high-risk CV disease, and a higher influenza vaccine dose did not significantly reduce temporal CV risk. Other seasonal factors may play a role in the coincident high rates of ILI and CV events. ClinicalTrials.gov Identifier: NCT02787044.

Cross-reactive MHC class I T cell epitopes may dictate heterologous immune responses between respiratory viruses and food allergens

Respiratory virus infections play a major role in asthma, while there is a close correlation between asthma and food allergy. We hypothesized that T cell-mediated heterologous immunity may induce asthma symptoms among sensitized individuals and used two independent in silico pipelines for the identification of cross-reactive virus- and food allergen- derived T cell epitopes, considering individual peptide sequence similarity, MHC binding affinity and immunogenicity. We assessed the proteomes of human rhinovirus (RV1b), respiratory syncytial virus (RSVA2) and influenza-strains contained in the seasonal quadrivalent influenza vaccine 2019/2020 (QIV 2019/2020), as well as SARS-CoV-2 for human HLA alleles, in addition to more than 200 most common food allergen protein sequences. All resulting allergen-derived peptide candidates were subjected to an elaborate scoring system considering multiple criteria, including clinical relevance. In both bioinformatics approaches, we found that shortlisted peptide pairs that are potentially binding to MHC class II molecules scored up to 10 × lower compared to MHC class I candidate epitopes. For MHC class I food allergen epitopes, several potentially cross-reactive peptides from shrimp, kiwi, apple, soybean and chicken were identified. The shortlisted set of peptide pairs may be implicated in heterologous immune responses and translated to peptide immunization strategies with immunomodulatory properties.

A mosaic influenza virus-like particles vaccine provides broad humoral and cellular immune responses against influenza A viruses

The development of a universal influenza vaccine to elicit broad immune responses is essential in reducing disease burden and pandemic impact. In this study, the mosaic vaccine design strategy and genetic algorithms were utilized to optimize the seasonal influenza A virus (H1N1, H3N2) hemagglutinin (HA) and neuraminidase (NA) antigens, which also contain most potential T-cell epitopes. These mosaic immunogens were then expressed as virus-like particles (VLPs) using the baculovirus expression system. The immunogenicity and protection effectiveness of the mosaic VLPs were compared to the commercial quadrivalent inactivated influenza vaccine (QIV) in the mice model. Strong cross-reactive antibody responses were observed in mice following two doses of vaccination with the mosaic VLPs, with HI titers higher than 40 in 15 of 16 tested strains as opposed to limited cross HI antibody levels with QIV vaccination. After a single vaccination, mice also show a stronger level of cross-reactive antibody responses than the QIV. The QIV vaccinations only elicited NI antibodies to a small number of vaccine strains, and not even strong NI antibodies to its corresponding vaccine components. In contrast, the mosaic VLPs caused robust NI antibodies to all tested seasonal influenza virus vaccine strains. Here, we demonstrated the mosaic vaccines induces stronger cross-reactive antibodies and robust more T-cell responses compared to the QIV. The mosaic VLPs also provided protection against challenges with ancestral influenza A viruses of both H1 and H3 subtypes. These findings indicated that the mosaic VLPs were a promising strategy for developing a broad influenza vaccine in future.