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Background The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines. Methods We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK. Approximately, the first 400 participants meeting the main study entry criteria—with no contraindications to influenza vaccination—were invited to join the substudy. Participants of the main study were randomly assigned (1:1) to receive two intramuscular injections of either NVX-CoV2373 (5 μg) or placebo (normal saline) 21 days apart; participants enrolled into the substudy were co-vaccinated with a single (0·5 mL) intramuscular, age-appropriate (quadrivalent influenza cell-based vaccine [Flucelvax Quadrivalent; Seqirus UK, Maidenhead] for those aged 18–64 years and adjuvanted trivalent influenza vaccine [Fluad; Seqirus UK, Maidenhead] for those ≥65 years), licensed, influenza vaccine on the opposite deltoid to that of the first study vaccine dose or placebo. The influenza vaccine was administered in an open-label manner and at the same time as the first study injection. Reactogenicity was evaluated via an electronic diary for 7 days after vaccination in addition to monitoring for unsolicited adverse events, medically attended adverse events, and serious adverse events. Immunogenicity was assessed with influenza haemagglutination inhibition and SARS-CoV-2 anti-spike protein IgG assays. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed in participants who were seronegative at baseline, received both doses of study vaccine or placebo, had no major protocol deviations affecting the primary endpoint, and had no confirmed cases of symptomatic COVID-19 from the first dose until 6 days after the second dose (per-protocol efficacy population). Immunogenicity was assessed in participants who received scheduled two doses of study vaccine, had a baseline sample and at least one post-vaccination sample, and had no major protocol violations before unmasking (per-protocol immunogenicity population). Reactogenicity was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo and had data collected for reactogenicity events. Safety was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo. Comparisons were made between participants of the substudy and the main study (who were not co-vaccinated for influenza). This study is registered with ClinicalTrials.gov, number NCT04583995. Findings Between Sept 28, 2020, and Nov 28, 2020, a total of 15 187 participants were randomised into the main phase 3 trial, of whom 15 139 received treatment (7569 received dose one of NVX-CoV2373 and 7570 received dose one of placebo). 431 participants were co-vaccinated with a seasonal influenza vaccine in the substudy (217 received NVX-CoV2373 plus the influenza vaccine and 214 received placebo plus the influenza vaccine). In general, the substudy participants were younger, more racially diverse, and had fewer comorbid conditions than those in the main study. Reactogenicity events were more common in the co-administration group than in the NVX-CoV2373 alone group: tenderness (113 [64·9%] of 174 vs 592 [53·3%] of 1111) or pain (69 [39·7%] vs 325 [29·3%]) at injection site, fatigue (48 [27·7%] vs 215 [19·4%]), and muscle pain (49 [28·3%] vs 237 [21·4%]). Incidences of unsolicited adverse events, treatment-related medically attended adverse events, and serious adverse events were low and balanced between the co-administration group and the NVX-CoV2373 alone group. No episodes of anaphylaxis or deaths were reported within the substudy. Co-administration resulted in no change to influenza vaccine immune response although a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. NVX-CoV2373 vaccine efficacy in the substudy (ie, participants aged 18 to

Individuals with type 2 diabetes mellitus experience high rates of influenza virus infection and complications. We compared the magnitude and duration of serologic response to trivalent influenza vaccine in adults aged 50-80 with and without type 2 diabetes mellitus. Serologic response to influenza vaccination was similar in both groups: greater fold-increases in antibody titer occurred among individuals with lower pre-vaccination antibody titers. Waning of antibody titers was not influenced by diabetes status.

Background Although influenza vaccines provide protection against influenza viruses, concern has been raised that they may increase susceptibility to non-influenza respiratory viruses. As pandemic lockdowns end, temporal overlap of circulation of seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expected. Understanding the impact of influenza vaccination on risk of coronavirus infection is therefore of considerable public health importance. Methods We performed a secondary analysis of a randomized trial where children and adolescents in Canadian Hutterite colonies were randomly assigned by colony to receive the 2008-2009 seasonal inactivated trivalent influenza vaccine (TIV) or a control hepatitis A (HepA) vaccine. All 3273 colony members (vaccinated children and nonvaccine recipients) were followed for the primary outcome of RT-PCR confirmed seasonal coronavirus infection. Serum collected pre- and post-vaccination was analyzed for titers of IgG antibodies towards human coronaviruses (HCoV). Results The incidence of coronavirus infection was 0·18/1000 person-days in the colonies that received TIV vs 0.36/1000 person-days in the control group, hazard ratio (HR) 0.49 [0.21-1.17]. The risk reduction among non-vaccine recipients in the TIV group compared to the control group was HR 0.55 [0.24-1.23]. There was an increase in the geometric mean fold change of HCoV-OC43 antibody titers following TIV compared to HepA vaccine (mean difference 1.2 [0.38-2.06], p = 0.007), and an increase in geometric mean HCoV-NL63 antibody titers post-TIV (262.9 vs 342.9, p = 0.03). Conclusion The influenza vaccine does not increase the risk of a coronavirus infection. Instead, the influenza vaccine may reduce the rate of coronavirus infections by inducing cross-reactive anti-coronavirus IgG antibodies.

OBJECTIVES: To summarize reports to the national adverse event following immunization surveillance system (NAEFISS) following inactivated quadrivalent influenza vaccine (QIV) in Zhejiang province from 2018 to 2020. METHODS: We analyzed adverse events following immunization (AEFI) reports following QIV, with a comparison, with the AEFI reports following inactivated trivalent influenza vaccine (TIV). Reporting rates of AEFI were calculated by age, severity of AEFI, categories of AEFI, and reaction categories. The data mining algorithm used in this study was reporting odds ratio (ROR). A value of ROR‑1.96SE >1 (standard error [SE]) was considered as positive signal. These reporting rates between vaccine types were compared through chi-square tests. RESULTS: NAEFISS received 514 AEFI reports following QIV and 536 reports following TIV, with a reporting rate of 13.66/100,000 100,000 doses/100,000 doses (χ(2) = 7.11, P> .05). Of the 514 reports following QIV, 410 were vaccine product-related reactions and 51 were severe AEFI. Fever/redness/induration was the most frequent clinical diagnosis of the QIV AEFI, with a reporting rate of 12.42/100,000 doses in the age group of 3–17 years, and 12.44/100,000 doses in the age group of ≥18 years. The positive signal of QIV AEFI was observed for the allergic rash and asthma/wheezing. CONCLUSION: The present analysis did not identify any new/unexpected safety concerns. We suggested that NAEFISS continue to monitor the safety of QIV.

AIM Pneumococcal and influenza infections can cause serious morbidity and mortality in patients with cardiovascular diseases. The purpose of this study was to investigate the safety and efficacy of simultaneous inoculations of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and trivalent influenza vaccine (TIV) in patients with coronary artery disease (CAD). METHODS This was a prospective, randomized, single-blind, placebo-controlled study. A total of 40 patients with CAD were randomly assigned to the TIV＋PPSV23 (simultaneous inoculations of TIV and PPSV23) and TIV＋Placebo (inoculations of TIV and placebo) groups. Primary outcomes were the safety of simultaneous vaccinations and the changing of circulating cardiovascular biomarkers before, at 4-, and at 12-weeks after vaccinations. RESULTS The baseline characteristics between the two groups were identical. The prevalence of injection-site pain, swelling, and reddening were 47%, 37%, and 37% in the TIV＋PPSV23 group, and 10%, 5%, and 0% in the TIV＋Placebo group, respectively. All reactions were self-limited. Body temperature ＞37.0℃ or serious injection-related reaction was not observed. The levels of white blood cells, high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, pentraxin-3, and malondialdehide-modified low-density lipoprotein (LDL), were not significantly different between the two groups before and after vaccinations. The levels of anti-oxidized LDL were significantly and step-wisely decreased from baseline, to 4-, and 12-weeks vaccinations in the both groups. No significant changes of other markers were observed in both groups at each time point. CONCLUSION Simultaneous inoculations of TIV and PPSV23 were safety in patients with CAD, suggesting that dual vaccinations can be considered even in patients with CAD.

Background Seasonal influenza is an acute respiratory infection mostly caused by type A and B influenza viruses. The severe form of the infection can be life-threatening and lead to a significant burden. Vaccination is the most efficient way of preventing influenza infections and limit this burden. Objectives To assess the cost-effectiveness of switching from a trivalent influenza vaccine (TIV) to a quadrivalent influenza vaccine (QIV) in the vaccination programme in Peru, and to evaluate the health and economic impact of reaching the vaccination coverage rate targeted by the Ministry of Health. Methods A decision-analytic static cost-effectiveness model, was adapted to the Peruvian setting under both payer and societal perspectives. Results A switch from TIV to QIV would prevent 29,126 additional cases (including 12,815 consultations), 54 hospitalisations, and 23 deaths related to influenza, mostly in the population 60 years-old. This would lead to a saving of US $505,206 under the payer perspective, that would partially offset the investment necessary to introduce QIV into the immunisation programme. The resulting incremental cost-effectiveness ratio (ICER) is $16,649 per QALYs gained. The main drivers of the model results were vaccine efficacy against influenza B viruses, degree of match, vaccines prices and proportion of cases attributable to influenza B. The robustness of the results seems satisfactory as QIV has the probability of being a cost-effective strategy of 83.8% (considering a threshold of three GDP per capita). Reaching the coverage targeted by the Ministry of Health would result in health benefits and disease management savings, and lower ICERs. Conclusion Introducing QIV instead of TIV in the Peruvian immunisation programme is expected to be a cost-effective strategy, especially in younger children and the elderly. The benefit of QIV would be even more important if the coverage targeted by the Ministry of Health would be reached in the most vulnerable groups.

Background Seasonal Influenza is still considered associated with seasonal morbidity and hospitalization in the elderly population. The World Health Organization (WHO) recommended seasonal quadrivalent influenza vaccine (QIV) to reduce burden of two currently circulating influenza B lineages. Until 2019 Korean National Immunization Program (NIP) recommended trivalent influenza vaccine (TIV) after ongoing debates on cost effectiveness of QIV for elderly population. Although influenza vaccine only showed modest effect on reducing influenza in elderly, this study aimed to evaluate the immunogenicity and safety of inactivated QIV in healthy participants ≥ 65 years of age. Methods A total of 274 healthy participants aged ≥ 65 years received a QIV. Seroconversion-based vaccine efficacy of 4 strains of seasonal influenza was assessed 21 days after vaccination and adverse events were monitored until 180 days after vaccination. Results The percentages of participants seroconverted after vaccination on HI antibody against each strain were 36.5% (99/271) to A/H1N1, 47.6% (129/271) to A/H3N2, 40.6% (110/271) to B Yamagata, and 49.1% (133/271) to B Victoria. The percentages of participants seroprotected after vaccination on HI antibody against each strain were 81.2% (220/271) to A/H1N1, 98.5% (267/271) to A/H3N2, 95.2% (258/271) to B Yamagata, and 93.7% (254/271) to B Victoria. There was no serious adverse event (SAE) related with the study vaccine. Conclusion The quadrivalent split influenza vaccine is expected to offer seroprotection against influenza A and both influenza B lineages even in the elderly population.

Purpose Severe adverse events (AEs), such as Guillain‐Barré syndrome (GBS) occur rarely after influenza vaccination. We identify highly associated AEs with GBS and develop prediction models for GBS using the US Vaccine Adverse Event Reporting System (VAERS) reports following trivalent influenza vaccination (FLU3). Methods This study analyzed 80 059 reports from the US VAERS between 1990 and 2017. Several AEs were identified as highly associated with GBS and were used to develop the prediction model. Some common and mild AEs that were suspected to be underreported when GBS occurred simultaneously were removed from the final model. The analyses were validated using European influenza vaccine AEs data from EudraVigilance. Results Of the 80 059 reports, 1185 (1.5%) were annotated as GBS related. Twenty‐four AEs were identified as having strong association with GBS. The full prediction model, using age, sex, and all 24 AEs achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 85.4% (90% CI: [83.8%, 86.9%]). After excluding the nine (e.g., pruritus, rash, injection site pain) likely underreported AEs, the final AUC became 77.5% (90% CI: [75.5%, 79.6%]). Two hundred and one (0.25%) reports were predicted as of high risk of GBS (predicted probability >25%) and 84 actually developed GBS. Conclusion The prediction performance demonstrated the potential of developing risk‐prediction models utilizing the VAERS cohort. Excluding the likely underreported AEs sacrificed some prediction power but made the model more interpretable and feasible. The high absolute risk of even a small number of AE combinations suggests the promise of GBS prediction within the VAERS dataset.

Background The effectiveness of standard, egg-derived quadrivalent influenza vaccines (IIV4) may be reduced in adults ≥65 years of age, largely because of immunosenescence. An MF59-adjuvanted trivalent influenza vaccine (aIIV3) and a high-dose trivalent influenza vaccine (HD-IIV3) offer older adults enhanced protection versus standard vaccines. This study compared the relative effectiveness of aIIV3 with IIV4 and HD-IIV3 in preventing influenza-related medical encounters over 2 US influenza seasons. Methods This retrospective cohort study included US patients ≥65 years vaccinated with aIIV3, IIV4, or HD-IIV3. The outcome of interest was the occurrence of influenza-related medical encounters. Data were derived from a large dataset comprising primary and specialty care electronic medical records linked with pharmacy and medical claims. Adjusted odds ratios (OR) were derived from an inverse probability of treatment-weighted sample adjusted for age, sex, race, ethnicity, geographic region, vaccination week, and health status. Relative vaccine effectiveness (rVE) was determined using the formula (% VE = 1 – ORadjusted) × 100. Results In 2017–2018, cohorts included: aIIV3, n = 524 223; IIV4, n = 917 609; and HD-IIV3, n = 3 377 860. After adjustment, 2017–2018 rVE of aIIV3 versus IIV4 was 18.2 (95% confidence interval [CI], 15.8–20.5); aIIV3 vs. HD-IIV3 was 7.7 (95% CI, 2.3–12.8). In 2018–2019, cohorts included: aIIV3, n = 1 031 145; IIV4, n = 915 380; HD-IIV3, n = 3 809 601, with adjusted rVEs of aIIV3 versus IIV4 of 27.8 (95% CI, 25.7–29.9) and vs. HD-IIV3 of 6.9 (95% CI, 3.1–10.6). Conclusion In the 2017–2018 and 2018–2019 influenza seasons in the United States, aIIV3 demonstrated greater reduction in influenza-related medical encounters than IIV4 and HD-IIV3 in adults ≥65 years., During the 2017–2018 and 2018–2019 US influenza seasons, the adjuvanted trivalent inactivated influenza vaccine (aIIV3) demonstrated statistically significantly greater effectiveness in reducing influenza-related medical encounters versus standard, egg-derived quadrivalent influenza vaccines (IIV4) and the high-dose trivalent inactivated influenza vaccine (HD-IIV3).

Background There is good evidence of vaccine effectiveness in healthy individuals but less robust evidence for vaccine effectiveness in the populations targeted for influenza vaccination. The live attenuated influenza vaccine (LAIV) has recently been recommended for children in the UK. The trivalent influenza vaccine (TIV) is recommended for all people aged ≥ 65 years and for those aged Objective To examine the vaccine effectiveness of LAIV and TIV. Design Cohort study and test-negative designs to estimate vaccine effectiveness. A self-case series study to ascertain adverse events associated with vaccination. Setting A national linkage of patient-level general practice (GP) data from 230 Scottish GPs to the Scottish Immunisation & Recall Service, Health Protection Scotland virology database, admissions to Scottish hospitals and the Scottish death register. Participants A total of 1,250,000 people. Interventions LAIV for 2- to 11-year-olds and TIV for older people (aged ≥ 65 years) and those aged Main outcome measures The main outcome measures include vaccine effectiveness against laboratory-confirmed influenza using real-time reverse-transcription polymerase chain reaction (RT-PCR), influenza-related morbidity and mortality, and adverse events associated with vaccination. Results Two-fifths (40%) of preschool-aged children and three-fifths (60%) of primary school-aged children registered in study practices were vaccinated. Uptake varied among groups [e.g. most affluent vs. most deprived in 2- to 4-year-olds, odds ratio 1.76, 95% confidence interval (CI) 1.70 to 1.82]. LAIV-adjusted vaccine effectiveness among children (aged 2–11 years) for preventing RT-PCR laboratory-confirmed influenza was 21% (95% CI –19% to 47%) in 2014/15 and 58% (95% CI 39% to 71%) in 2015/16. No significant adverse events were associated with LAIV. Among at-risk 18- to 64-year-olds, significant trivalent influenza vaccine effectiveness was found for four of the six seasons, with the highest vaccine effectiveness in 2010/11 (53%, 95% CI 21% to 72%). The seasons with non-significant vaccine effectiveness had low levels of circulating influenza virus (2011/12, 5%; 2013/14, 9%). Among those people aged ≥ 65 years, TIV effectiveness was positive in all six seasons, but in only one of the six seasons (2013/14) was significance achieved (57%, 95% CI 20% to 76%). Conclusions The study found that LAIV was safe and effective in decreasing RT-PCR-confirmed influenza in children. TIV was safe and significantly effective in most seasons for 18- to 64-year-olds, with positive vaccine effectiveness in most seasons for those people aged ≥ 65 years (although this was significant in only one season). Future work The UK Joint Committee on Vaccination and Immunisation has recommended the use of adjuvanted injectable vaccine for those people aged ≥ 65 years from season 2018/19 onwards. A future study will be required to evaluate this vaccine. Trial registration Current Controlled Trials ISRCTN88072400. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 67. See the NIHR Journals Library website for further project information.

Background The 2017–2018 influenza season in Israel was characterized by the predominance of influenza B Yamagata, with a lesser circulation of influenza A(H1N1)pdm09 and influenza A(H3N2). We estimated vaccine effectiveness (VE) of the inactivated influenza vaccine which was selected for use that season. Methods End-of-season VE and 95% confidence intervals (CI) against laboratory-confirmed influenza-like illness (ILI) were estimated by means of the test-negative design. Age-specific VE analysis was carried out using a moving age interval. Results Specimen were obtained from 1,453 community ILI patients; 610 (42.0%) were influenza-positive, among which 69.7% were B, 17.2% A(H1N1)pdm09 and 13.4% A(H3N2). A 98.6% of molecularly characterized influenza B belonged to the Yamagata lineage. Of the sampled individuals, 1320 were suitable for VE analysis. Of those vaccinated, 90.6% received the inactivated trivalent influenza vaccine (TIV) containing a Victoria lineage influenza B-like virus. VE against influenza A differed by age, with the highest VE of 72.9% (95%CI 31.9–89.2%) observed in children 0.5–14 years old, while all ages VE was 46.6% (95%CI 10.4–68.2%). All ages VE against influenza B was 23.2% (95%CI −10.1–46.4%) with age-specific analysis showing non-significant VE estimates. Utilizing a moving age interval of 15 years, afforded a detailed age-specific insight into influenza VE against the influenza viruses circulating during the 2017–2018 season. Conclusions The moderate-high 2017–2018 influenza A VE among children and adolescents, supports seasonal influenza vaccination at a young age. The low VE against influenza B in Israel, is most likely the result of influenza B/TIV-mismatch.

Inactivated quadrivalent influenza vaccine (IIV4) containing two influenza A strains (H1N1 and H3N2) and one strain from each B lineage (Victoria and Yamagata) may offer broader protection against seasonal influenza. This study examined the immunogenicity and safety of a candidate IIV4. A randomized, double-blind, controlled phase III clinical trial was conducted in healthy subjects aged ≥3 years. Subjects were randomly assigned into three groups in a 2:1:1 ratio, receiving single dose of IIV4 or inactivated trivalent influenza vaccine (IIV3) which contains either B/Victoria strain (BV) or B/Yamagata strain (BY). Blood samples were collected before and 28 days after vaccination to test hemagglutination inhibition (HI) antibodies of the four influenza strains. Safety information was collected for 28 days after vaccination. A total of 2320 subjects (IIV4: 1160, IIV3-BV: 580, IIV3-BY: 580) were enrolled in this study. After vaccination, the seroconversion rates of IIV4 against H1N1, H3N2, BV and BY strains were 77.15%, 81.93%, 60.14% and 64.57%, respectively. Geometric mean titers (GMTs) against the four influenza strains were 523.91, 274.13, 115.35 and 257.81, respectively. The investigational IIV4 was non-inferiority to IIV3 for the four strains, meanwhile superior to IIV3 for additional B strains (B/BV, B/BY). For safety, there had no significant difference in the incidence of the adverse reactions among the three groups (P = 0.5986). No serious adverse events related to vaccination occurred. The IIV4 had good immunogenicity and safety, which added an influenza B protection with no increased safety concerns. (ClinicalTrials.gov number: NCT03853993)

Background Influenza causes severe complications in at-risk populations, resulting in significant morbidity and mortality. Vaccination is the most effective measure to prevent infection and complications caused by seasonal influenza. However, no study has analyzed the cost-effectiveness of influenza vaccines in 50- to 64-year-olds in South Korea. Objective We examined the application of the National Immunization Program (NIP) in 50- to 64-year-olds and compared the cost-effectiveness of quadrivalent influenza vaccine (QIV) with that of trivalent influenza vaccine (TIV) in South Korea. Methods One-year static model was assumed by constructing separate decision trees for age subgroups: 50–54, 55–59, and 60–64. Each subgroup was divided into at-risk and not-at-risk groups. Using circulation data from previous studies and Korea Centers for Disease Control and Prevention, we estimated the probabilities of influenza infection, outpatient treatment, hospitalization, and deaths. Medical cost was estimated from 2015 to 2017 National Health Insurance Sharing Service claim data, while productivity losses from work absenteeism or death were estimated from labor and economic surveys of Korean government. Disutility was estimated based on previous studies. Results Compared with non-vaccination, incremental cost-effectiveness ratios (ICERs) for the 50–54, 55–59, and 60–64 age groups for TIV were US$2010.90, US$2004.58, and US$1865.55, respectively, while for QIV were US$2187.17, US$2190.89, and US$2074.52, respectively. Compared with TIV, ICERs for QIV were US$4445.66, US$4578.06, and US$4751.93, respectively. All the aforementioned ICER values were lower than the 2017 Korean GDP per capita of US$29,742.839. Conclusion Implementing the NIP in the 50- to 64-year-old age group was found to be cost effective. Since both TIV and QIV were cost effective, we recommend QIV as the preferred option, based on its greater protection against Influenza B.

Introduction Influenza surveillance in Argentina reported influenza-like illness at a rate of 3500/100,000, a hospitalization rate of 15.5/100,000, and a death rate of 0.32/100,000 annually in adults aged over 65 years. The high burden of disease may be due to a combination of immunosenescence and the suboptimal clinical effectiveness of conventional, non-adjuvanted influenza vaccines in this age group. There is a clinical need for more effective influenza vaccines in this population. This study evaluated the cost-effectiveness of an MF59®-adjuvanted trivalent influenza vaccine (aTIV) in adults aged over 65 years in Argentina compared with the non-adjuvanted trivalent influenza vaccine (TIV) used under the current national vaccination policy. Methods A decision tree cost-effectiveness model was developed to estimate the cost-effectiveness of switching from TIV to aTIV in Argentinian older adults. The model compared cost and health benefits of vaccination in one influenza season from the payer perspective. The main predictions included survival, quality-adjusted survival, and costs. Model inputs were sourced from Argentina or internationally where local data was considered inaccurate. Vaccine efficacy assumptions were extracted from recently published, peer-reviewed scientific literature. Results Switching from TIV to aTIV would result in 170 deaths averted and 1310 incremental quality-adjusted life years (QALYs) gained. The incremental cost-effectiveness ratio per QALY was US $2660.59 from the payer perspective. In all sensitivity analyses, aTIV remained highly cost-effective. The probabilistic sensitivity analyses showed a 95% CI per QALY of US $113.74–7721.67. Conclusion Introducing an adjuvanted influenza vaccine in Argentina is potentially beneficial and cost-effective relative to the currently-used TIV through the reduction of disease burden and utilization of healthcare resources.

Growing evidence suggests that sleep plays an important role in immunological memory, including antibody responses to vaccination. However, much of the prior research has been carried out in the laboratory limiting the generalizability of the findings. Furthermore, no study has sought to identify sensitive periods prior to or after vaccination where sleep may have a stronger influence on antibody responses. Eighty-three healthy young adults completed 13 days of sleep diaries and received the trivalent influenza vaccine on day 3 of the study. Measures of self-reported sleep duration, sleep efficiency, and subjective sleep quality were assessed on each day. Antibody levels to the influenza viral strains were quantified at baseline and 1 and 4 months following influenza vaccination. Shorter sleep duration, averaged over the collection period, was associated with fewer antibodies to the A/New Caledonia viral strain 1 and 4 months later, independent of baseline antibodies, age, sex, and cohort year. Analyses focused on nightly sleep on the days preceding and after the vaccination revealed that shorter sleep duration on the two nights before the vaccination predicted fewer antibodies 1 and 4 months later. Measures of self-reported sleep efficiency and subjective quality were unrelated to antibody responses to the influenza vaccination. These findings provide further support for an association between sleep duration and antibody responses to the influenza vaccine and suggest that perhaps sleep on nights prior to vaccination are critical. If replicated, these findings may support sleep as a target for enhancing vaccination efficacy.

Pi-Shan Hsu,1,2 Ie-Bin Lian,3,4 Day-Yu Chao2 1Department of Family Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 2Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan; 3Graduate Institute of Statistics and Information Science, National Changhua University of Education, Changhua, Taiwan; 4Department of Applied Math, National Chung-Hsing University, Taichung, TaiwanCorrespondence: Day-Yu ChaoGraduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung-Hsing University, Taichung 401, TaiwanTel +886-4-22840694Fax +886-4-22852186Email dychao@nchu.edu.twIe-Bin Lian Tel +886-4-7232105 ext. 3222Fax +886-4-7211192Email maiblian@cc.ncue.edu.twBackground: Influenza is a major cause of morbidity and mortality in the elderly worldwide. Influenza vaccination can prevent morbidity/mortality from influenza infection. A gap of 1– 2 years, before an epidemic strain is recommended by the World Health Organization (WHO) to be the vaccine strain in Southeast Asia, has been reported; this results in a high rate of vaccine mismatch and excess influenza-associated morbidity. The aim of the current study was to evaluate the effect of repeated vaccination on vaccine effectiveness (VE) among the elderly in Taiwan, during years with and without early appearance of antigenically drifted strains.Methods: A historical cohort study was conducted to evaluate the impact of repeated vaccination on the reduction of influenza-associated hospitalization among persons older than 64 years over two influenza seasons: 2007– 08, with all circulatingvirus strainsmismatched, and 2008– 09, with all virusstrainsmatched with the vaccine strains, considering four exposure effects, namely current vaccine effect, sequential vaccination effect, residual protection effect and no vaccination effect. Propensity score matching on vaccination status was performed to ensure similar baseline characteristics between the groups that received and did not receive vaccination.Results: Only current-year vaccination in combination with prior history of annual revaccination significantly reduced the risk of hospitalization, with adjusted hazard ratios of 0.68 (95% CI: 0.54, 0.85) and 0.74 (95% CI: 0.57, 0.95) during the 2007– 08 and 2008– 09 influenza seasons, respectively. Further stratification showed that even during the 2007– 08 influenza season, when all vaccinations weremismatched with the circulating strains, sequential vaccinations still significantly reduced influenza-associated hospitalization in thefemale population aged 68– 74 and 75– 84 years, with adjusted VE of 25.2% (95% CI: − 9.6, 49.0%) and 36.9% (95% CI: 17.1, 52.0%), respectively.Conclusion: Our study supports the recommendation of annual revaccination against influenza in theelderly, even though the circulating strain of influenza virus was antigenically mismatched with thevaccine strains.Keywords: vaccine effectiveness, trivalent influenza vaccine, elderly, prior vaccination history, repeated vaccination, propensity score matching

Diabetes mellitus (DM) patients are at an increased risk of complications following influenza-virus infection, seasonal vaccination (SV) is recommended. However, SV with trivalent influenza vaccine (TIV) can induce antibody and type-I interferon (IFN) responses, and the effect of anti-DM treatment on these responses is incompletely understood. We evaluated the antibody response and IFN-α expression in individuals with and without type 2 DM (T2DM) following SV, and examined the effects on anti-DM treatment. TIV elicited sero-protection in all groups, but antibody persistency was <8 months, except for the antibody response to B-antigens in non-DM. T2DM impaired the IgG avidity index, and T2DM showed a significantly decreased response against H1N1 and H3N2, in addition to delaying and reducing haemagglutination-inhibition persistency against influenza B-antigens in DM groups treated with metformin (Met-DM) or glibenclamide (GB-DM). Following TIV, the Met-DM and GB-DM groups exhibited reduced IFN-α expression upon stimulation with whole- and split-virion influenza vaccines. Suppression of IFN-α expression in the Met-DM group was associated with a reduction in the mechanistic target of rapamycin complex-1 pathway and impaired IgG avidity index. Thus, single-dose TIV each year might not be suitable for T2DM. Our data could aid the development of an efficacious influenza vaccine for T2DM.

Background Adults 65 years and older (seniors) experience more complications following influenza infection than younger adults. We estimated the relative vaccine effectiveness (rVE) of a trivalent high dose (HD-IIV3) versus an adjuvanted trivalent influenza vaccine (aIIV3) in seniors for respiratory-related hospitalizations. Methods We conducted a retrospective cohort study using claims data from Optum’s Clinformatics® Data Mart to compare outcome rates between seniors who received HD-IIV3 versus aIIV3 during the 2016/17 and 2017/18, predominantly A/H3N2 respiratory seasons. Rates were adjusted for demographic characteristics, comorbid conditions, previous influenza vaccination, and geography. We used the previous event rate ratio (PERR) approach to address bias by time-fixed unmeasured confounders. Results We identified 842,282 HD-IIV3 and 34,157 aIIV3 recipients for the 2016/17 season and 1,058,638 HD-IIV3 and 189,636 aIIV3 recipients for the 2017/18 season. The pooled rVE of HD-IIV3 versus aIIV3 for respiratory-related hospitalizations over both seasons was 12% (95% confidence interval: 3.3%–20%); 13% (−6.4% to 32%) for the 2016/17 season and 12% (2.1%–21%) for the 2017/18 season. Conclusions Pooled over two predominantly A/H3N2 respiratory seasons, HD-IIV3 was associated with fewer respiratory hospital admissions than aIIV3 in senior members of large national managed health care company in the U.S.

Instituto Butantan is a biomedical research center and vaccine manufacturer affiliated with the Sao Paulo State Secretary of Health in Brazil. In 2013, Instituto Butantan successfully licensed its trivalent influenza vaccine, in order to support the Brazilian National Immunization Program's influenza vaccination strategy, which was introduced in 1999. In order to respond to the increasing influenza vaccine demand worldwide, Instituto Butantan is undergoing prequalification of its trivalent influenza vaccine by the World Health Organization (WHO). A key requirement of the prequalification review was the submission of a pharmacovigilance plan, including an active surveillance evaluation, for the trivalent influenza vaccine, and proof of a functional pharmacovigilance system at Instituto Butantan. The aim of this paper is to describe the capacity strengthening process of the pharmacovigilance system at Instituto Butantan for the WHO prequalification of the trivalent influenza vaccine. This process was supported by PATH and the U.S. Federal Government Biomedical Advanced Research and Development Authority (BARDA). The key strategic axes for this capacity strengthening process included the improvement of organizational structure, human resources training, internal processes and procedures, appropriate documentation, and acquisition of an E2B compliant pharmacovigilance database. The project led to the establishment of a functional pharmacovigilance system compliant with international regulatory requirements.

Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20–21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.

Background Vaccination is the most effective form of prevention of seasonal influenza; the United Kingdom has a national influenza vaccination program to cover targeted population groups. Influenza vaccines are known to be associated with some common minor adverse events of interest (AEIs), but it is not known if the adjuvanted trivalent influenza vaccine (aTIV), first offered in the 2018/2019 season, would be associated with more AEIs than other types of vaccines. Objective We aim to compare the incidence of AEIs associated with different types of seasonal influenza vaccines offered in the 2018/2019 season. Methods We carried out a retrospective cohort study using computerized medical record data from the Royal College of General Practitioners Research and Surveillance Centre sentinel network database. We extracted data on vaccine exposure and consultations for European Medicines Agency–specified AEIs for the 2018/2019 influenza season. We used a self-controlled case series design; computed relative incidence (RI) of AEIs following vaccination; and compared the incidence of AEIs associated with aTIV, the quadrivalent influenza vaccine, and the live attenuated influenza vaccine. We also compared the incidence of AEIs for vaccinations that took place in a practice with those that took place elsewhere. Results A total of 1,024,160 individuals received a seasonal influenza vaccine, of which 165,723 individuals reported a total of 283,355 compatible symptoms in the 2018/2019 season. Most AEIs occurred within 7 days following vaccination, with a seasonal effect observed. Using aTIV as the reference group, the quadrivalent influenza vaccine was associated with a higher incidence of AEIs (RI 1.46, 95% CI 1.41-1.52), whereas the live attenuated influenza vaccine was associated with a lower incidence of AEIs (RI 0.79, 95% CI 0.73-0.83). No effect of vaccination setting on the incidence of AEIs was observed. Conclusions Routine sentinel network data offer an opportunity to make comparisons between safety profiles of different vaccines. Evidence that supports the safety of newer types of vaccines may be reassuring for patients and could help improve uptake in the future.

Background We compared influenza antibody titers among vaccinated and unvaccinated pregnant and non-pregnant women. Methods During 1st June– 30th September 2018, four groups of cohort participants—vaccinated pregnant, unvaccinated pregnant, vaccinated non-pregnant, and unvaccinated non-pregnant women were selected by matching age, gestational age, and the week of vaccination. Serum antibody titers against each strain of 2018 Southern Hemisphere inactivated trivalent influenza vaccine (IIV3) were assessed by hemagglutination inhibition (HI) assay on Day 0 (pre-vaccination) and Day 28 (one month post-vaccination) serum samples. Geometric mean titer (GMT), GMT ratio (GMR), seroconversion (defined as ≥4 fold increase in HI titer), and seroprotection (i.e. HI titer ≥1:40) were compared across the study groups using multilevel regression analyses, controlling for previous year vaccination from medical records and baseline antibody levels. Results A total of 132 participants were enrolled in the study (33 in each of the four study groups). The baseline GMTs for influenza A(H1N1), A(H3N2), and B vaccine strains were not significantly different among all four groups (all p-values >0.05). After one month, both vaccinated groups had significantly higher GMT, GMR, seroconversion, and seroprotection than their unvaccinated controls (all p-values 0.05). Conclusions The 2018 seasonal IIV3 was immunogenic against all three vaccine strains and pregnancy did not seem to alter the immune response to IIV3. These findings support the current influenza vaccination recommendations for pregnant women.

Influenza vaccination is the most effective method for preventing influenza virus infection. The incidence of influenza is higher in schoolchildren than other age groups. This study evaluated the effectiveness of seasonal inactivated influenza vaccination (IIV) in a community population of schoolchildren during two seasons. This study was a cross-sectional survey of public schoolchildren based on data collected in the 2012/2013 and 2014/2015 seasons. The questionnaire was distributed to all public schoolchildren of target grade in a survey area, and 7945 respondents were included in the analysis. The vaccination status and influenza onset were defined based on the self-reported questionnaire by parents or guardians. Generalized linear mixed models were used to adjust clustering within schools and individual covariates and calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between vaccination status and influenza onset. The influenza incidence was higher in the 2015 than the 2013 survey (25% versus 17%), although the vaccination rates were comparable between the two seasons. Receiving one- or two-dose vaccination was more protective against influenza than non-vaccination in both the 2013 (OR, 0.77; 95%CI, 0.65–0.92) and 2015 (OR, 0.88; 95%CI, 0.75–1.02) surveys. Full vaccination was also more protective in both the 2013 (OR, 0.75; 95%CI, 0.62–0.89) and 2015 (OR, 0.86; 95%CI, 0.74–1.00) surveys. Seasonal IIV was protective against influenza for Japanese schoolchildren in a community-based real-world setting. The difference in clinical effectiveness of IIV between the two seasons was likely due to the antigenic mismatch between the circulating and vaccine strains.

Objective: To assess the long-term safety of MF59-adjuvanted trivalent influenza vaccine (aIIV3; Fluad™) in adults ≥65 years of age. Methods: Data from 36 primary vaccination and 7 re-vaccination Phase I through III trials were analyzed; 7532 subjects received aIIV3 and 5198 subjects a nonadjuvanted trivalent inactivated influenza vaccine (IIV3). These trials were evaluated in 2 data poolings: first-dose randomized controlled trials (FD-RCT) and revaccination trials. Spontaneously reported adverse events (AEs) from post-marketing surveillance were also analyzed. Results: The percentages of subjects reporting AEs following vaccination were similar between aIIV3 and IIV3: 24.8% for aIIV3 vs 26.7% for IIV3 (relative risk [RR] 0.94; 95% confidence interval [CI] 0.87–1.01). The percentage of subjects with serious AEs was 6.7% for aIIV3 vs 7.0% for IIV3 (RR 0.95; 95% CI 0.82–1.09). Percentages of subjects with AEs leading to withdrawal, hospitalizations, adverse events of special interest (AESIs), and deaths between vaccination groups were similar. There was no signal of disproportionality for AESIs associated with aIIV3 compared to IIV3 in the post-marketing database. Conclusions: This integrated safety analysis demonstrates an acceptable safety profile for aIIV3 in adults ≥65 years of age. Keywords: Safety, MF59, Adjuvant, Influenza, Vaccine, Elderly

Summary: Background: Paediatric vaccination against influenza can result in indirect protection, by reducing transmission to their unvaccinated contacts. We investigated whether influenza vaccination of children would protect them and their household members in a resource-limited setting. Methods: We did a cluster-randomised, blinded, controlled study in three villages in India. Clusters were defined as households (ie, dwellings that shared a courtyard), and children aged 6 months to 10 years were eligible for vaccination as and when they became age-eligible throughout the study. Households were randomly assigned (1:1) by a computer-based system to intramuscular trivalent inactivated influenza vaccine (IIV3) or a control of inactivated poliovirus vaccine (IPV) in the beginning of the study; vaccination occurred once a year for 3 years. The primary efficacy outcome was laboratory-confirmed influenza in a vaccinated child with febrile acute respiratory illness, analysed in the modified intention-to-treat population (ie, children who received at least one dose of vaccine, were under surveillance, and had not an influenza infection within 15 days of last vaccine dose). The secondary outcome for indirect effectiveness (surveillance study) was febrile acute respiratory illness in an unvaccinated household member of a vaccine study participant. Data from each year (year 1: November, 2009, to October, 2010; year 2: October, 2010, to October, 2011; and year 3: October, 2011, to May, 2012) were analysed separately. Safety was analysed among all participants who were vaccinated with at least one dose of the vaccine. This trial is registered with ClinicalTrials.gov, number NCT00934245. Findings: Between Nov 1, 2009, to May 1, 2012, we enrolled 3208 households, of which 1959 had vaccine-eligible children. 1010 households were assigned to IIV3 and 949 households were assigned to IPV. In 3 years, we vaccinated 4345 children (2132 with IIV3 and 2213 with IPV) from 1868 households (968 with IIV3 and 900 with IPV) with 10 813 unvaccinated household contacts. In year 1, influenza virus was detected in 151 (10%) of 1572 IIV3 recipients and 206 (13%) of 1633 of IPV recipients (total IIV3 vaccine efficacy 25·6% [95% CI 6·8–40·6]; p=0·010). In year 2, 105 (6%) of 1705 IIV3 recipients and 182 (10%) of 1814 IPV recipients had influenza (vaccine efficacy 41·0% [24·1–54·1]; p

Objectives Influenza is a leading cause of avoidable admissions for nursing home (NH) residents. We previously evaluated the effectiveness of a high-dose trivalent influenza vaccine (HD) compared to a standard-dose influenza vaccine (SD) through a cluster-randomized trial of NH residents. Fewer residents from facilities randomized to HD were hospitalized. In this article, we extend our analyses to consider direct medical care costs relative to vaccine costs for HD ($31.82/dose) as compared to SD ($12.04/dose). Design Post hoc, cost-benefit analysis. Setting and participants From the participating NH facilities (n = 817), we identified Medicare fee-for-service enrollees who were long-stay residents (>100 days) at the start of the 2013-2014 influenza season (November 1–May 31). The intervention was residence in a facility randomized to HD or SD influenza vaccine. Methods We summed expenditures from long-stay NH residents' Medicare Part A, B, and D fee-for-service claims and compared person-level expenditures between residents of facilities offering HD vs SD. Expenditures were adjusted for clustering of residents within NHs, person-time, and prespecified covariates using 2-part, generalized linear models with bootstrapped standard errors. We examined the incremental cost-benefit of HD vs SD vaccines from a payer perspective. Results There were 18,605 and 18,658 Medicare fee-for-service long-stay residents in facilities offering HD and SD, respectively. Person- and facility-adjusted total expenditures differed by $546 (P = .006). The $20 incremental cost of HD to SD offset adjusted expenditures for a net benefit of $526 per NH resident and a financial return on investment of 546/20 = 27:1. Conclusions/implications The use of HD influenza vaccine in long-stay NH residents reduced total health care expenditures for a net benefit despite HD being more expensive per dose. These cost offsets applied to Medicare beneficiaries residing in NHs could result in important savings to the Medicare program.

Highlights • Immunisation with MCV during pregnancy resulted in an antibody response. • Maternal immunization with MCV conveyed protective levels of MenA IgG at birth. • Infant antibody levels declined over the first 3 months of life., A prospective, randomised, controlled observer-blind trial measuring the efficacy and immunogenicity of trivalent influenza vaccine (TIV) and the immunogenicity of quadrivalent meningococcal conjugate vaccine (MCV) in pregnant women and their infants up to 6 months of age was conducted in Mali. Here we reported the immunogenicity of MCV, which was used as a comparator vaccine to TIV, in this population. Third-trimester pregnant Malian women were randomized to receive TIV or MCV. Blood samples were collected from women prior to vaccination, 28 days post-vaccination, at delivery and 3 and 6 months post-delivery and from infants at birth and 3 and 6 months of age. Meningococcal-specific serogroup (Men) A, C, Y and W-specific antibodies were measured by enzyme linked immunosorbent assay in a randomly selected subset of 50 mother-infant pairs where the mother had received MCV. At birth, 94.0% (47/50) of infants had MenA specific IgG levels ≥ 2 µg/mL decreasing to 72.9% and 30.4% at 3 and 6 months of age. For MenC, 81.3% (39/48) of infants had MenC specific IgG levels ≥ 2 µg/mL at birth decreasing to 29.4% and 17.8% at 3 and 6 months of age. For MenY, 89.6% (43/48) of infants had MenY specific IgG levels ≥ 2 µg/mL at birth decreasing to 64.6% and 62.5% at 3 and 6 months of age. For MenW, 89.6% (43/48) of infants had MenW specific IgG levels ≥ 2 μg/ml at birth decreasing to 62.5% and 41.7% at 3 and 6 months of age. Maternal immunization with MCV conveyed protective levels of IgG at birth through to 3 months of age in the majority of infants.

Influenza imparts an age-related increase in mortality and morbidity. The most effective countermeasure is vaccination; however, vaccines offer modest protection in older adults. To investigate how ageing impacts the memory B cell response we tracked haemagglutinin specific B cells by indexed flow sorting and single cell RNA sequencing in twenty healthy adults administered the trivalent influenza vaccine. We found age-related skewing in the memory B cell compartment six weeks after vaccination, with younger adults developing haemagglutinin specific memory B cells with an FCRL5+ “atypical” phenotype, showing evidence of somatic hypermutation and positive selection, which happened to a lesser extent in older persons. We confirmed the germinal center ancestry of these FCRL5+ “atypical” memory B cells using scRNASeq from fine needle aspirates of influenza responding human lymph nodes and paired blood samples. Together, this study shows that the aged human germinal center reaction and memory B cell response following vaccination is defective.SummaryImmune responses to vaccination wane with age. Using single cell RNA sequencing of influenza vaccine specific B cells, this study delineates changes in B cell memory generation, antibody mutation and their subsequent selection in older persons.

Objectives: As of 2019, quadrivalent influenza vaccine (QIV) has replaced trivalent influenza vaccine (TIV) in the national immunization program in The Netherlands. Target groups are individuals of 601 years of age and those with chronic diseases. The objective was to estimate the incremental break-even price of QIV over TIV at a threshold of (sic)20 000 per quality-adjusted life-year (QALY).Methods: An age-structured compartmental dynamic model was adapted for The Netherlands to assess health outcomes and associated costs of vaccinating all individuals at higher risk for influenza with QIV instead of TIV over the seasons 2010 to 2018. Influenza incidence rates were derived from a global database. Other parameters (probabilities, QALYs and costs) were extracted from the literature and applied according to Dutch guidelines. A threshold of (sic)20 000 per QALY was applied to estimate the incremental break-even prices of QIV versus TIV. Sensitivity analyses were performed to test the robustness of the model outcomes.Results: Retrospectively, vaccination with QIV instead of TIV could have prevented on average 9500 symptomatic influenza cases, 2130 outpatient visits, 84 hospitalizations, and 38 deaths per year over the seasons 2010 to 2018. This translates into 385 QALYs and 398 life-years potentially gained. On average, totals of (sic)431 527 direct and (sic)2 388 810 indirect costs could have been saved each year.Conclusion: Using QIV over TIV during the influenza seasons 2010 to 2018 would have been cost-effective at an incremental price of maximally (sic)3.81 (95% confidence interval, (sic)3.26-4.31). Sensitivity analysis showed consistent findings on the incremental break-even price in the same range.

RESUMEN Las personas mayores son uno de los colectivos que más sufren los efectos de la gripe estacional. Aunque la vacuna antigripal es efectiva a la hora de prevenir la infección por el virus de la gripe y sus complicaciones, no resulta tan efectiva en personas de edad avanzada debido al fenómeno de inmunosenescencia asociado a la edad. Desde 2009 existe en EE. UU. una vacuna antigripal trivalente de alta dosis aprobada para la inmunización de personas ≥ 65 años con una concentración de antígeno cuatro veces mayor que la vacuna estándar. Múltiples ensayos clínicos llevados a cabo a lo largo de distintas temporadas, y mediante diferentes metodologías, han demostrado que la vacuna antigripal trivalente de alta dosis no solo es más efectiva, sino que además presenta un perfil de seguridad similar y es más inmunogénica que la vacuna de dosis estándar en la prevención de la gripe y sus complicaciones en personas de avanzada edad. En este documento se hace una revisión de la evidencia científica actual sobre la seguridad e inmunogenicidad de la vacuna antigripal de alta dosis en personas ≥ 65 años, y se incluye información de ensayos clínicos aleatorizados, estudios observacionales con datos de práctica clínica real y revisiones sistemáticas y metaanálisis.

BackgroundThe objective of this rapid scoping review was to identify potentially safe and effective dose-sparing strategies for intramuscular administration of seasonal influenza vaccines in healthy individuals of all ages.MethodsComprehensive literature searches were developed and executed in MEDLINE, EMBASE, and the Cochrane library, and grey literature was searched via international clinical trial registries for relevant studies published in English in the last 20 years. References of relevant systematic reviews and included studies were also scanned. Title/abstract and full-text screening were carried out by pairs of reviewers independently and data charting conducted by a single reviewer and verified by a second reviewer. Results were presented narratively.ResultsA total of 13 studies with 10,351 participants were included in the review and all studies were randomized control trials conducted between 2006 and 2019. The most common interventions were the trivalent influenza vaccine (n=10), followed by quadrivalent influenza vaccine (n=4). Nine studies included infants/toddlers 6-36 months old and one of these studies also included children and adolescents. In these nine studies, no clinical effectiveness outcomes were reported and no difference was found in local and systemic reactogenicity between dosing strategies. Of the four adult studies (≥ 18 years), the two studies that reported on effectiveness outcomes found similar results between the half-dose and full-dose vaccination groups and all four studies reported no differences in safety outcomes between groups.ConclusionThe current evidence for the administration of intramuscular influenza vaccines suggests there is no significant difference in safety and clinical effectiveness with the use of low-dose compared to full-dose vaccines, which is promising given the predicted resource constraints in the upcoming influenza season due to the 2019 novel coronavirus. Due to the low number of studies in adults and the lack of studies assessing confirmed influenza and influenza-like illness, there remains a need for further evaluation.EXECUTIVE SUMMARYPURPOSEThe Centre for Immunization and Respiratory Infectious Diseases of the Public Health Agency of Canada (PHAC) submitted a query regarding the safety and effectiveness of fractional dosing of seasonal influenza vaccines through the Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Network (DSEN). They requested that the DSEN Methods and Application Group in Indirect Comparisons (MAGIC) conduct a rapid review on this topic with an approximate 6-week timeline.The overall objective of this rapid review was to identify potentially safe and effective dose-sparing strategies for administration of seasonal influenza vaccines in healthy individuals of all ages that have been evaluated in human trials. In order to limit the scope of the work and ensure the rapid timeline could be met, this review focused only on intramuscular vaccine formulations, thus the research question was as follows:What is the safety and effectiveness of using fractional dosing strategies to deliver intramuscular seasonal influenza vaccines?

Influenza virus infections are a major public health threat. Influenza viruses are associated with high mortality and morbidity worldwide through seasonal epidemics. Vaccination programs are available, but unpredictable antigenic changes in circulating strains require annual modification of seasonal influenza vaccines. Influenza vaccines are given, one of which is a trivalent influenza vaccine (TIV) aimed at the formation of antibodies that are specific to influenza viruses by B cells. In this study TIV vaccination has an effect in the form of decreasing viral replication in ferret that have been tested with H1N1 and H3N2 viruses. The results of this study are data about viral replication obtained from hemagglutination tests (HA test) and ATP6V0C expression with SDS-Page.

Inactivated influenza vaccines efficacy is variable and often poor. We conducted a phase 1 trial (NCT02188810), to assess the safety and immunogenicity of a novel nanoparticle Toll-like receptor 7/8 agonist adjuvant (Papaya Mosaic Virus) at different dose levels combined with trivalent influenza vaccine in healthy persons 18&ndash, 50 years of age. Hemagglutination-inhibition assays, antibody to Influenza A virus nucleoprotein and peripheral blood mononuclear cells for measurement of interferon-gamma ELISPOT response to influenza antigens, Granzyme B and IFN&gamma, IL-10 ratio were measured. The most common adverse events were transient mild to severe injection site pain and no safety signals were observed. A dose-related adjuvant effect was observed. Geometric mean hemagglutination-inhibition titers increased at day 28 in most groups and waned over time, but fold-antibody responses were poor in all groups. Cell mediated immunity results were consistent with humoral responses. The Papaya Mosaic Virus adjuvant in doses of 30 to 240 &micro, g combined with reduced influenza antigen content was safe with no signals up to 3 years after vaccination. A dose-related adjuvant effect was observed and immunogenicity results suggest that efficacy study should be conducted in influenza antigen-na&iuml, ve participants.

Background Limited data are available regarding the immunogenicity of high-dose influenza vaccine among persons with chronic lymphocytic leukemia (CLL) and monoclonal B cell lymphocytosis (MBL). Methods A prospective pilot study of humoral immune responses to 2013–2014 and 2014–2015 high-dose trivalent influenza vaccine (HD IIV; Fluzone® High-Dose; Sanofi Pasteur) was conducted among individuals with MBL and previously untreated CLL. Serum hemagglutination inhibition (HAI) antibody titers were measured at baseline and Day 28 after vaccination; seroprotection and seroconversion rates were determined. Memory B cell responses were assessed by B-cell enzyme-linked immune absorbent spot assays. Results Thirty subjects (17 CLL and 13 MBL) were included. Median age was 69.5 years. Day 28 seroprotection rates for the cohort were 19/30 (63.3%) for A/H1N1; 21/23 (91.3%) for A/H3N2; and 13/30 (43.3%) for influenza B. Those with MBL achieved higher day 28 HAI geometric mean titers (54.1 [4.9, 600.1] vs. 12.1 [1.3, 110.1]; p = 0.01) and higher Day 28 seroprotection rates (76.9% vs. 17.6%; p = 0.002) against the influenza B-vaccine strain virus than those with CLL. Conclusions Immunogenicity of the HD IIV3 in patients with CLL and MBL is lower than reported in healthy adults. Immunogenicity to influenza B was greater in those with MBL than CLL.

Background Despite the current recommendation for influenza vaccination in cancer patients with active oncological therapy, limited data are available on the efficacy of vaccination in cancer patients receiving targeted therapies. We aimed to investigate the immunogenicity and tolerability of influenza vaccination in breast cancer patients treated with trastuzumab in adjuvant setting. Methods A prospective open-label multicenter study was performed including patients with breast cancer during trastuzumab treatment in adjuvant setting and healthy controls. Blood samples were taken before, 4 weeks after, and 12 weeks after a single dose of trivalent influenza vaccine containing inactivated A/California/7/2009 (H1N1) pdm09, A/Hongkong4801/2014 (H3N2), and B/Brisbane/60/2008. Levels of serum antibody titers to hemagglutinin for H1N1 and influenza B strains were measured. Results Twenty breast cancer patients and 37 controls were included in the study. No difference in seroprotection rate between trastuzumab-treated patients and controls was observed for either H1N1 (100% in both groups) or B strain (78.9% vs. 89.2%, p value = 0.423). A statistically significant increase in geometric mean titers from baseline was seen in both groups and was evident both 4 weeks and 12 weeks after vaccination. Adverse events in the trastuzumab-treated group were uncommon and mild with only one serious adverse event not related to vaccination. Conclusion Breast cancer patients treated with trastuzumab in adjuvant setting seem to benefit from influenza vaccination in terms of immunogenicity without increasing the risk for adverse events. The current data support the recommendation to offer influenza vaccination in breast cancer patients treated with this type of targeted therapy.

International audience; Purpose: Quadrivalent influenza vaccine (QIV) includes the same strains as trivalent influenza vaccine (TIV) plus an additional B strain of the other B lineage. The aim of the study was to analyse the public health and economic impact of replacing TIV with QIV in different scenarios in Spain.Methods: A dynamic transmission model was developed to estimate the number of influenza B cases prevented under TIV and QIV strategies (

The influenza is a common viral infection that can be fatal, especially in high-risk groups such as children, pregnant women, elderly, and immune-deficient individuals. Vaccination is the most efficient approach to prevent the spreading of viral infection and promote individual and public health. In contrast, exposure to environmental pollutants such as cigarette smoke reduces the efficacy of vaccination. We investigated whether chronic exposure to hydroquinone (HQ), the most abundant compound of the tobacco particulate phase, could impair the adaptive immune responses elicited by influenza vaccination. For this, adult male C57BL/6 mice were daily exposed to either nebulized HQ or PBS for 1 h for a total of eight weeks. At weeks 6 and 8, the mice were primed and boosted with the trivalent influenza vaccine via IM respectively. Although the HQ exposure did not alter the body weight of the mice and the biochemical and hematological parameters, the pollutant increased the oxidative stress in splenocytes of immunized animals, modified the morphology of spleen follicles, and augmented the size of their lymph nodes. The lymphoid organs of HQ-exposed mice presented a similar number of vaccine-specific IgG-secreting cells, titers of vaccine-specific total IgG, and respective subclasses. Transcriptome studies with HQ, benzene, or cigarette smoke exposure were also analyzed. The genes up-regulated upon pollutant exposure were associated with neutrophil migration and were shown to be co-expressed with antibody-secreting cell genes. Therefore, these findings suggest that HQ exposure may trigger an immune-compensatory mechanism that enhances the humoral responses induced by influenza vaccination.

Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals. ispartof: ELIFE vol:9 ispartof: location:England status: published

The effectiveness of current influenza vaccines is considered suboptimal, and 1 way to improve the vaccines is using adjuvants. However, the current pool of adjuvants used in influenza vaccination is limited due to safety concerns. Aloe vera, or aloe, has been shown to have immunomodulatory functions and to be safe for oral intake. In this study, we explored the potential of orally administered processed Aloe vera gel (PAG) as an adjuvant for influenza vaccines in C57BL/6 mice. We first evaluated its adjuvanticity with a split-type pandemic H1N1 (pH1N1) Ag by subjecting the mice to lethal homologous influenza challenge. Oral PAG administration with the pH1N1 Ag increased survival rates in mice to levels similar to those of alum and MF59, which are currently used as adjuvants in influenza vaccine formulations. Similarly, oral PAG administration improved the survival of mice immunized with a commercial trivalent influenza vaccine against lethal homologous and heterologous virus challenge. PAG also increased hemagglutination inhibition and virus neutralization Ab titers against homologous and heterologous influenza strains following immunization with the split-type pH1N1 Ag or the commercial trivalent vaccine. Therefore, this study demonstrates that PAG may potentially be used as an adjuvant for influenza vaccines.

Annual vaccination with influenza vaccines is recommended for protection against influenza in the United States. Past clinical studies and meta-analysis, however, have reported conflicting results on the benefits of annual vaccination. B-cell responses elicited following repeat influenza vaccinations over multiple seasons have not been examined in detail. We analyzed the B-cell and antibody (Ab) responses in volunteers vaccinated yearly, from 2010 or 2011 through 2014, with seasonal trivalent inactivated influenza vaccines. Statistical analyses were designed to help correct for possible bias due to reduced sample size in the later years of the study. We show that, after the second annual vaccination, the frequency of vaccine-specific plasmablasts and the binding reactivity of plasmablast-derived polyclonal Abs are reduced and do not increase in subsequent years. Similar trends are observed with the serum hemagglutination inhibition Ab response after each annual vaccination, as well as the binding reactivity of plasmablast-derived polyclonal Abs to the hemagglutinin of influenza A virus vaccine components, even with changes in the seasonal vaccine components during the study. Our findings indicate a diminished B-cell response to annual vaccination with seasonal trivalent influenza vaccine. These results emphasize the need for developing improved strategies to enhance the immunogenicity and efficacy of annual influenza vaccination.

Two antigenically distinct influenza B lineage viruses (Yamagata/Victoria) have been co-circulating globally since the mid-1980s. The quadrivalent influenza vaccine (QIV) may provide better protection against unpredictable B strains. We conducted a randomized, double-blind, phase III trial to evaluate the immunogenicity and safety of an egg-based inactivated, split-virion QIV (GC3110A). Subjects aged ≥ 19 years were randomized 2:1:1 to be vaccinated with QIV- GC3110A, trivalent influenza vaccine (TIV) containing the Yamagata lineage strain (TIV-Yamagata), or TIV containing the Victoria lineage strain (TIV-Victoria). Hemagglutination inhibition assays were performed 21 days post-vaccination. Solicited/unsolicited adverse events (AEs) were assessed within 21 days after vaccination, while serious AEs were reported up to six months after vaccination. A total of 1,299 were randomized to receive QIV-GC3110A (648 subjects), TIV-Yamagata (325 subjects), or TIV-Victoria (326 subjects). Compared to the TIVs, the QIV-GC3110A met the non-inferiority criteria for all four subtype/lineage strains with respect to the geometric mean titer (GMT) ratio and the difference of seroconversion rate. The safety profiles of QIV-GC3110A were consistent with those of TIV. In conclusion, QIV-GC3110A is safe, immunogenic, and comparable to strain-matched TIV.

Background and objectives High-dose influenza vaccine, which contains fourfold more antigen than standard dose, is associated with fewer cases of influenza and less influenza-related morbidity in the elderly general population. Whether the high-dose influenza vaccine benefits patients on dialysis, whose immune response to vaccination is less robust than that of healthy patients, is uncertain. Design, setting, participants, & measurements We compared hospitalizations and deaths during the 2015–2016 and 2016–2017 influenza seasons by vaccine type (standard trivalent, standard quadrivalent, and high-dose trivalent influenza vaccine) administered within a national dialysis organization. The association of vaccine type with outcomes was estimated using Cox proportional hazards regression with adjustment for patient factors and “center effect.” Analyses were stratified by age and dialysis modality. Results Between September 1 and December 31, 2015, standard dose trivalent, standard dose quadrivalent, and high-dose trivalent influenza vaccines were administered to 3057 (31%), 5981 (61%), and 805 (8%) patients, respectively. The adjusted rates of first hospitalizations by vaccine type during the influenza season were 8.43, 7.88, and 7.99 per 100 patient-months, respectively, and the adjusted rates of death were 1.00, 0.97, and 1.04, respectively. These differences were not significant. In 2016, 3614 (39%) received quadrivalent vaccine, and 5700 (61%) received high-dose trivalent vaccine. The adjusted rates of first hospitalization by vaccine type were 8.71 and 8.04 per 100 patient-months, respectively, and the adjusted rates of death were 0.98 and 1.02, respectively. Receipt of high dose was associated with a significant reduction in hospitalization (hazard ratio, 0.93; 95% confidence interval, 0.86 to 1.00; P=0.04); there was no significant association with death. There was no significant heterogeneity of either association by age group or dialysis modality. Conclusions Receipt of high-dose compared with standard dose influenza vaccine in 2016–2017 was associated with lower rates of hospitalization in patients on dialysis, although that was not seen in 2015–2016.

Vaccine effectiveness (VE) against influenza B was derived separately for Victoria and Yamagata lineages across 8 seasons (2010–2011 to 2017–2018) in Canada when trivalent influenza vaccine was predominantly used. VE was ≥50% regardless of lineage match to circulating viruses, except when the vaccine strain was unchanged from the prior season.