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Importance: Evaluating Iran's national highly pathogenic avian influenza (HPAI) control program can inform vaccine selection, optimize immunization duration, guide exit strategies, and assess hemagglutination inhibition (HI) and serum neutralization (SN) methods. Objective: To establish a serological baseline, assess antibody stability, and compare the efficacy of three HPAI (H5) vaccines. Methods: We analyzed over 9,000 blood samples and 6,420 swabs from approximately 1.5 million birds up to 64 weeks old. HI (ß, a), RT-PCR, and SN tests were conducted, with statistical analysis performed using two-way ANOVA. Conclusions and Relevance: After two vaccinations, Re6+Re8 exhibited the most stable HI ß antibody response, while H5N3 had the highest neutralization index, surpassing Re6+Re8 by 0.2 and the baculovirus vaccine by 0.5. These findings highlight discrepancies between HI ß and SN test results, with SN being a stronger indicator of protective titers due to its in vivo methodology, compared to the in vitro HI assay. [ABSTRACT FROM AUTHOR]

BACKGROUND: Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown. METHODS: This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3-17 years old who were 3-35 months post-allogeneic HCT, with each formulation administered twice, 28-42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28-42 days following each dose, and 138-222 days after the second dose. Using linear mixed effects models, we estimated adjusted geometric mean HAI titer ratios (aGMR: HD-TIV/SD-QIV) to influenza antigens. Early and late periods were defined as 3-5 and 6-35 months post-HCT, respectively. RESULTS: During 3 influenza seasons (2016-2019), 170 participants were randomized to receive HD-TIV (n = 85) or SD-QIV (n = 85). HAI titers maintained significant elevations above baseline for both vaccine formulations, although the relative immunogenic benefit of HD-TIV to SD-QIV waned during the study. A 2-dose series of HD-TIV administered late post-HCT was associated with higher GMTs compared to the early post-HCT period (late group: A/H1N1 aGMR = 2.16, 95% confidence interval [CI] = [1.14-4.08]; A/H3N2 aGMR = 3.20, 95% CI = [1.60-6.39]; B/Victoria aGMR = 1.91, 95% CI = [1.01-3.60]; early group: A/H1N1 aGMR = 1.03, 95% CI = [0.59-1.80]; A/H3N2 aGMR = 1.23, 95% CI = [0.68-2.25]; B/Victoria aGMR = 1.06, 95% CI = [0.56-2.03]). CONCLUSIONS: Two doses of HD-TIV were more immunogenic than SD-QIV, especially when administered ≥6 months post-HCT. Both groups maintained higher titers compared to baseline throughout the season. CLINICAL TRIALS REGISTRATION: NCT02860039.

Cigarette smoking confers additional risk from influenza. This study assessed the effect of smoking on humoral immune response to influenza vaccine. Adults ≥50 y of age were enrolled during the 2011–2016 influenza vaccination seasons in an observational prospective study. Non-fasting whole blood samples for hemagglutination inhibition (HAI) assays were obtained from participants at pre- and 28 d post-clinically administered, trivalent influenza vaccination. Among 273 participants, 133 subjects self-reported as never smokers, 87 as ex-smokers, and 53 as current smokers. Postvaccination geometric mean HAI titers were significantly higher among smokers for A/H1N1 (p = .031) and A/H3N2 (p = .001). Relative to never smokers, smoking was independently related to seroconversion to A/H1N1, A/H3N2 and B. The adjusted odd ratios (ORs) were 5.2 [95% confidence interval (CI), 2.3, 11.5] for seroconversion to A/H1N1, 5.4 (95% CI, 2.4, 12.1) for A/H3N2, and 2.7 (95% CI, 1.3, 5.7) for B. Smoking was also independently related to seroprotection to A/H1N1, A/H3N2 and B. The ORs were 3.6 (95% CI, 1.6, 8.08) for seroprotection to A/H1N1 in smokers, 2.7 (95% CI, 1.14, 6.5) for A/H3N2, and 2.5 (95% CI, 1.1, 5.7) for B. Although the mechanism is unclear, smokers showed a better immune response to influenza vaccination than never smokers and ex-smokers. The results can be used to emphasize the value of influenza vaccination for smokers.

BACKGROUND: In Australia, seasonal inactivated influenza vaccine is typically offered in April. However, the onset, peak and end of a typical influenza season vary, and optimal timing for vaccination remains unclear. Here, we investigated vaccine-induced antibody response kinetics over 6 months in different age groups. METHODS: We conducted a prospective serosurvey among 71 adults aged 18-50 years, 15 community-dwelling (healthy) and 16 aged-care facility resident (frail) older adults aged ≥65 years who received the 2018 southern hemisphere vaccines. Sera were collected at baseline, and 1, 2, 4, and 6 months post-vaccination. Antibody titres were measured by haemagglutination inhibition or microneutralisation assays. Geometric mean titres were estimated using random effects regression modelling and superimposed on 2014-2018 influenza season epidemic curves. RESULTS: Antibody titres peaked 1.2-1.3 months post-vaccination for all viruses, declined by 3 months post-vaccination but, notably, persisted above baseline after 6 months in all age groups by 1.3- to 1.5-fold against A(H1N1)pdm09, 1.7- to 2-fold against A(H3N2), 1.7- to 2.1-fold against B/Yamagata and 1.8-fold against B/Victoria. Antibody kinetics were similar among different age groups. Antibody responses were poor against cell-culture grown compared to egg-grown viruses. CONCLUSIONS: These results suggest subtype-specific antibody-mediated protection persists for at least 6 months, which corresponds to the duration of a typical influenza season.

BACKGROUND: The extent to which influenza recurrence depends upon waning immunity from prior infection is undefined. We used antibody titers of Ha-Nam cohort participants to estimate protection curves and decay trajectories. METHODS: Households (270) participated in influenza-like-illness (ILI) surveillance and provided blood at intervals spanning laboratory-confirmed virus transmission. Sera were tested in hemagglutination inhibition assay. Infection was defined as influenza virus-positive ILI and/or seroconversion. Median protective titers were estimated using scaled-logistic regression to model pretransmission titer against infection status in that season, limiting analysis to households with infection(s). Titers were modelled against month since infection using mixed-effects linear regression to estimate decay and when titers fell below protection thresholds. RESULTS: From December 2008-2012, 295 and 314 participants were infected with H1N1pdm09-like and A/Perth/16/09-like (H3N2Pe09) viruses, respectively. The proportion protected rose more steeply with titer for H1N1pdm09 than for H3N2Pe09, and estimated 50% protection titers were 19.6 and 37.3, respectively. Postinfection titers started higher against H3N2Pe09 but decayed more steeply than against H1N1pdm09. Seroprotection was estimated to be sustained against H1N1pdm09 but to wane by 8-months for H3N2Pe09. CONCLUSIONS: Estimates indicate that infection induces durable seroprotection against H1N1pdm09 but not H3N2Pe09, which could in part account for the younger age of A(H1N1) versus A(H3N2) cases.

Equine influenza is a highly contagious viral disease, specially among 1-5 years old naive horses. Vaccination is considered the best way to control the disease spread and outbreaks. Although foals are the main animal used for evaluation of equine influenza vaccines, guinea pigs were chosen as an alternative model in the present work, as they have a negligible antibody titer against equine influenza virus and are cheaper and easier to handle than foals. Five equine influenza vaccine batches were evaluated in two animal models, foals and guinea pigs, by injection of two doses/animal with 4 weeks apart using 2 mL/animal/dose and evaluation of immune responses by hemagglutination inhibition test and enzyme-linked immunosorbent assay. On the 7th week post vaccination, equine influenza antibodies titers reached maximum values of 9-10.2 and 8.7-10 hemagglutination inhibition units for foals and guinea pigs, respectively; sample/negative ratios were 0.126-0.464 and 0.128-0.445 for both animals, respectively. The use of guinea pigs as an animal model for the evaluation of equine influenza vaccines could be recommended instead of foals.

As with many pathogens, most dengue infections are subclinical and therefore unobserved 1 . Coupled with limited understanding of the dynamic behaviour of potential serological markers of infection, this observational problem has wide-ranging implications, including hampering our understanding of individual- and population-level correlates of infection and disease risk and how these change over time, between assay interpretations and with cohort design. Here we develop a framework that simultaneously characterizes antibody dynamics and identifies subclinical infections via Bayesian augmentation from detailed cohort data (3,451 individuals with blood draws every 91 days, 143,548 haemagglutination inhibition assay titre measurements)2,3. We identify 1,149 infections (95% confidence interval, 1,135-1,163) that were not detected by active surveillance and estimate that 65% of infections are subclinical. After infection, individuals develop a stable set point antibody load after one year that places them within or outside a risk window. Individuals with pre-existing titres of ≤1:40 develop haemorrhagic fever 7.4 (95% confidence interval, 2.5-8.2) times more often than naive individuals compared to 0.0 times for individuals with titres >1:40 (95% confidence interval: 0.0-1.3). Plaque reduction neutralization test titres ≤1:100 were similarly associated with severe disease. Across the population, variability in the size of epidemics results in large-scale temporal changes in infection and disease risk that correlate poorly with age.

Introduction: While it remains impossible to predict the timing of the next influenza pandemic, novel avian influenza A viruses continue to be considered a significant threat., Methods: A Phase II study was conducted in healthy adults aged 18-64 years to assess the safety and immunogenicity of two intramuscular doses of pre-pandemic 2017 influenza A(H7N9) inactivated vaccine administered 21 days apart. Participants were randomized (n = 105 in each of Arms 1-3) to receive 3.75 μg, 7.5 μg or 15 μg of hemagglutinin (HA) with MF59® adjuvant, or 15 μg of HA unadjuvanted vaccine (n = 57, Arm 4)., Results: The three MF59 adjuvanted vaccines and the 15 μg unadjuvanted vaccine were safe and well-tolerated. Little antibody activity was detected against the A(H7N9) vaccine antigen after the first vaccination across study Arms. After second vaccination, the three adjuvanted Arms showed increases in hemagglutination inhibition (HAI), neutralizing (Neut), and neuraminidase inhibition (NAI) geometric mean titers (GMT), peaking at 21 days post second vaccination. The percentage of participants with titer ≥1:40 and seroconversion rates for HAI were 30-43 % and 0 for the adjuvanted Arms and the unadjuvanted Arm, respectively. Antibody responses against antigenically drifted A(H7N9) strains A/Shanghai/2/2013 and A/Guangdong/17SF003/2016 showed similar trends. Exploratory linear modeling of HAI and Neut responses post second vaccination revealed significantly lower log antibody titers among older participants (aged 35-49 and 50-64 years) compared to participants aged 18-34 years after adjusting for study vaccination, BMI, sex, and prior seasonal influenza vaccination. Post second vaccination, participants who received seasonal influenza vaccination in at least one of the two previous seasons had significantly lower log antibody titers than participants who did not., Conclusion: Adjuvanted doses of vaccine provided higher antibody responses, on average, than the 15 μg unadjuvanted vaccine. Proportion of participants achieving seroconversion and antibody titers ≥40 remained below 50 % in all study Arm., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SF: received grant support (paid to the institution) for multiple avian influenza studies. LJ: Kaiser Permanente Washington Health Research Institute received funding from Pfizer for the conduct of a clinical trial of an investigational influenza vaccine; PG: is on a patent for a COVID monoclonal antibody with Aridis Pharmaceuticals. CBC: is a consultant to Moderna, GSK, Sanofi Pasteur, CommenseBio, Debiopham, Premier Healthcare, and TDCowen and receives royalties from UpToDate. GCP: reports grant support (paid to institution) from Pfizer, Moderna and Sanofi. RB, HMES, RLA, GA, RR, AW, JW, PCR have no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

The detection of Highly Pathogenic Avian Influenza (HPAI) A(H5N1) in dairy cattle in the United States has raised concerns about human exposure. This study evaluated the efficacy of various doses of an inactivated H5 AI vaccine in cattle and assessed antibody transfer in milk against a recent bovine isolate of HPAI A(H5N1, clade 2.3.4.4b). Calves were inoculated with different vaccine doses, while lactating cows received the vaccine four weeks later. The humoral immune response was measured using the Hemagglutination Inhibition (HI) test and ELISA. Results showed a dose-dependent immune response, with higher doses producing stronger and more sustained antibody levels. Group 1 maintained a stable HI titer of 6 log 2 , while Groups 2, 3, and 4 peaked at 8, 9, and 9 log 2 , respectively, by the fourth week post-vaccination. Milk antibody transfer was observed, with strong positive responses in milk samples by the second week post-vaccination. The ID Screen ELISA demonstrated higher sensitivity for detecting antibodies in milk compared to serum. The immune response to the AI vaccine differed from responses to other vaccines used in cattle such as Foot and Mouth Disease Virus (FMDV) and Lumpy Skin Disease Virus (LSDV), indicating the need for optimizing vaccine dosage and formulation, including adjuvant and antigen content. Future research should extend the monitoring period, increase sample sizes, and explore different vaccine formulations to develop effective vaccination strategies for cattle. These findings highlight the potential for using inactivated H5 AI vaccines in cattle to enhance immune protection and facilitate antibody transfer through milk., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Consent for publication: Not applicable., (© 2025. The Author(s).)

(1) Background: The administration of a live attenuated influenza vaccine (LAIV) has emerged as a viable option for preventing pediatric infections. The LAIV vaccine is available in China based on efficacy results. However, LAIV immunogenicity in children aged 3-17 years old in China has not yet to be studied and reported broadly. (2) Methods: This is a substudy investigating the immunogenicity and safety of the LAIV under a Phase 3, multicentre, randomized, double-blind, placebo-controlled trial. A total of 3000 participants were enrolled in a randomized, double-blind, placebo-controlled trial, split in half between vaccine and placebo, was conducted to evaluate a single LAIV dose in this age group. Hemagglutination inhibition (HI) antibody titers and incidence of adverse events were used to evaluate immunogenicity and safety, respectively. (3) Results: Although there was no significant difference in frequencies of all solicited or unsolicited AEs, nasal congestion, headache, and muscle pain were statistically significantly more frequent in vaccine recipients as compared to placebo Seroconversions and geometric mean fold increases in HI antibody titers against all strains were significantly higher in the vaccine group than in the placebo group. (4) Conclusions: The LAIV is safe and immunogenic in Chinese children and adolescents., Competing Interests: Declaration of competing interest This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. All study participants provided informed consent, and the study design was approved by the appropriate ethics review board. We have read and understood your journal's policies, and we believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The current situation with H5N1 highly pathogenic avian influenza virus (HPAI) is causing a worldwide concern due to multiple outbreaks in wild birds, poultry, and mammals. Moreover, multiple zoonotic infections in humans have been reported. Importantly, HPAI H5N1 viruses with genetic markers of adaptation to mammals have been detected. Together with HPAI H5N1, avian influenza viruses H7N9 (high and low pathogenic) stand out due to their high mortality rates in humans. This raises the question of how prepared we are serologically and whether seasonal vaccines are capable of inducing protective immunity against these influenza subtypes. An observational study was conducted in which sera from people born between years 1925-1967, 1968-1977, and 1978-1997 were collected before or after 28 days or 6 months post-vaccination with an inactivated seasonal influenza vaccine. Then, hemagglutination inhibition, viral neutralization, and immunoassays were performed to assess the basal protective immunity of the population as well as the ability of seasonal influenza vaccines to induce protective responses. Our results indicate that subtype-specific serological protection against H5N1 and H7N9 in the representative Spanish population evaluated was limited or nonexistent. However, seasonal vaccination was able to increase the antibody titers to protective levels in a moderate percentage of people, probably due to cross-reactive responses. These findings demonstrate the importance of vaccination and suggest that seasonal influenza vaccines could be used as a first line of defense against an eventual pandemic caused by avian influenza viruses, to be followed immediately by the use of more specific pandemic vaccines.IMPORTANCEInfluenza A viruses (IAV) can infect and replicate in multiple mammalian and avian species. Avian influenza virus (AIV) is a highly contagious viral disease that occurs primarily in poultry and wild water birds. Due to the lack of population immunity in humans and ongoing evolution of AIV, there is a continuing risk that new IAV could emerge and rapidly spread worldwide, causing a pandemic, if the ability to transmit efficiently among humans was gained. The aim of this study is to analyze the basal protection and presence of antibodies against IAV H5N1 and H7N9 subtypes in the population from different ages. Moreover, we have evaluated the humoral response after immunization with a seasonal influenza vaccine. This study is strategically important to evaluate the level of population immunity that is a major factor when assessing the impact that an emerging IAV strain would have, and the role of seasonal vaccines to mitigate the effects of a pandemic., Competing Interests: The authors declare no conflict of interest.

Background: Pediatric hematopoietic cell transplant (HCT) recipients are at high risk for morbidity from influenza virus infection. We demonstrated in a primary phase 2 randomized controlled trial that 2 post-HCT doses of high-dose trivalent influenza vaccine (HD-TIV) given 4 weeks apart were more immunogenic than 2 doses of standard-dose quadrivalent influenza vaccine (SD-QIV). Herein, we present the immunogenicity and safety of influenza vaccination in a consecutive season post-HCT using the same dosing regimen., Methods: A subcohort of study participants reenrolled and had hemagglutinin inhibition titers measured at baseline and 4 weeks after each vaccine dose in year 2. We estimated geometric mean fold rise in hemagglutinin inhibition titer from baseline for each group and used linear mixed effects models to estimate adjusted geometric mean ratios (comparing HD-TIV vs SD-QIV) for each antigen at each time point. We described systemic and injection site reactions., Results: A total of 65 subcohort patients participated (33 SD-QIV, 32 HD-TIV). Postvaccine geometric mean fold rise and adjusted geometric mean ratio estimates were higher for both groups following a single influenza vaccine dose in year 2 as compared with 2 doses of the same formulation in year 1. Both groups had similar frequencies of injection site and systemic reactions., Conclusions: A single dose of HD-TIV or SD-QIV was more immunogenic in year 2 than 2 doses of the same formulation in year 1. Reactogenicity was comparable between groups. One dose of influenza vaccine may be sufficient after a 2-dose schedule in the prior year post-HCT., Clinical Trials Registration: NCT02860039 (ClinicalTrials.gov)., Competing Interests: Potential conflicts of interest. N. B. H. received grant support from Sanofi and Quidel and a current grant from Merck. C. E. B. receives grant support from Pfizer and Merck. J. A. E. reports grant support from AstraZeneca, Merck, Pfizer, and GlaxoSmithKline (all paid to institution) and consultant fees for AbbVie, AstraZeneca, Meissa Vaccines, Moderna, Pfizer, Sanofi Pasteur, Shinogi, and Ark Biopharma. G. M. reports research support from Astellas Inc and SymBio Pharmaceuticals. C. L. K. reports payment for participation on an advisory board for Horizon Therapeutics; payment for educational lectures from Medscape, i3Health, Physicians Education Resource, and Dava Oncology; travel support for Global Summit on Hematologic Malignancies from Dava Oncology; and payment from CSL Behring for providing graft-vs-host disease adjudication for a clinical trial. M. I. A. reports institutional research grants from Miravista Diagnostics and Merck, consulting fees from Karius, travel support for meeting attendance from the Pediatric Infectious Diseases Society and the American Academy of Pediatrics, and an unpaid position on the Pediatric Infectious Diseases Society Board of Directors. C. J. H. reports grants or contracts from GlaxoSmithKline, Pfizer, Merck, and Astellas; royalties from UpToDate; payment or honoraria for educational material from Pediatric News; and nonfinancial interests in the American Board of Pediatrics. J. L. F. reports consulting fees and stock options from Massive Bio, Inc. J. E. S. reports institutional grants or contracts from the Centers for Disease Control and Prevention, National Institutes of Health, and Food and Drug Administration; personal consulting fees from the Association of Professionals in Infection Control and Epidemiology and the Association of American Medical Colleges; and honoraria for speaking engagements from the Missouri American Academy of Pediatrics. E. A. M. reports institutional grants or contracts for clinical trials of pediatric coronavirus disease vaccines and therapeutics from Pfizer. G. C. P. reports institutional grants or contracts for COVID-19 clinical trials from Pfizer and Moderna. F. M. M. reports grants or contracts paid to institution from Gilead for antiviral research and from Pfizer for vaccine research; grant support from the National Institutes of Health and the Centers for Disease Control and Prevention; and participation as a data and safety monitoring board member for, and payments to author from, Pfizer and Moderna. A. J. S. reports grant support from the National Institutes of Health. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Epidemiological studies suggest that heterogeneity in influenza vaccine antibody response can be associated with specific host factors, including pre-vaccination immune status, age, gender, and vaccination history. However, the pattern of reported associations varies between studies. To better understand the underlying influences on antibody responses, we combined host factors and vaccine-induced in-host antibody kinetics from a cohort study conducted across multiple seasons with a unified analysis framework. We developed a flexible individual-level Bayesian model to estimate associations and interactions between host factors, including pre-vaccine HAI titre, age, sex, vaccination history and study setting, and vaccine-induced HAI titre antibody boosting and waning. We applied the model to derive population-level and individual effects of post-vaccine antibody kinetics for A(H1N1) and A(H3N2) influenza subtypes. We found that post-vaccine HAI titre dynamics were significantly influenced by pre-vaccination HAI titre and vaccination history and that lower pre-vaccination HAI titre results in longer durations of seroprotection (HAI titre equal to 1:40 or higher). We also observed that the effect of vaccination history on antibody boosting was stronger for egg-grown A(H1N1) vaccinating strains in individuals with higher pre-vaccination HAI titres, whereas this effect diminished for egg-grown A(H3N2) vaccinating strains. Consequently, for cell-grown A(H1N1), our inference finds that the expected duration of seroprotection post-vaccination was 171 (95 % Posterior Predictive Interval[PPI] 128-220) and 159 (95 % PPI 120-200) days longer for those who are infrequently vaccinated (<2 vaccines in last five years) compared to those who are frequently vaccinated (2 or more vaccines in the last five years) at pre-vaccination HAI titre values of 1:10 and 1:20 respectively. In addition, we found significant differences in the empirical distributions that describe the individual-level duration of seroprotection for A(H1N1) cell-grown strains. In future, studies that rely on serological endpoints should include the impact of pre-vaccine HAI titre and prior vaccination status on seropositivity and seroconversion estimates, as these can significantly influence an individual's post-vaccination antibody kinetics., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sheena Sullivan reports a relationship with Seqirus Australia Pty Ltd. that includes: consulting or advisory. Sheena Sullivan reports a relationship with Moderna Inc. that includes: consulting or advisory. Sheena Sullivan reports a relationship with Pfizer Inc. that includes: consulting or advisory. Sheena Sullivan reports a relationship with Evolution Health that includes: consulting or advisory. Annette Fox reports a relationship with Sanofi that includes: consulting or advisory. Annette Fox reports a relationship with Evidera that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Crocodilians are susceptible to a range of virus infection including influenza A virus (IAV). However, little is known about the ecology and epidemiology of IAV in crocodile species. This study aimed to investigate IAV infection in farmed Siamese crocodiles in central Thailand. We collected plasma samples and pharyngeal swab samples from Siamese crocodiles residing in 13 crocodile farms in 9 provinces of central Thailand during 2019. Additional archival plasma samples of Siamese crocodiles collected in 2012 and 2018 were also included in the study. Plasma samples were screened for influenza A antibodies by a hemagglutination inhibition (HI) assay and positive were evaluated by a cytopathic effect/hemagglutination based-microneutralization (MN) assay. Swab samples were tested for influenza viral RNA by a real-time RT-PCR assay targeting the influenza matrix (M) gene. Among 246 tested plasma samples, the overall seroprevalence of antibodies against IAV in farmed Siamese crocodiles was 17.5% (43/246). The most common hemagglutinin (HA) subtype was H2 (46.5%, 20/43) followed by H9 (39.5%, 17/43), human H1 (14%, 6/43) and H1 (7%, 3/43). Multiple HA subtypes were also detected in 7% (3/43) of infected crocodiles with combination of H1 and H2 subtypes. All 126 tested swab samples were negative for influenza viral RNA. In addition, we demonstrated the ability of wild-type IAV subtypes (H1, H2, H9 and human H1) to infect primary Siamese crocodile fibroblast cells. To our knowledge, this is the first report of serological evidences of avian and human IAV infection in Siamese crocodiles. Our findings highlighted the role of crocodile species in the ecology of IAV particularly the potential to serve as the reservoir or mixing vessel for the viruses that significantly threaten both human and animal health., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Thongdee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In recent years, infection cases of H5 subtype highly pathogenic avian influenza viruses (HPAIVs) in wild mammals have increased globally. To obtain recent epidemiological information regarding influenza A virus (IAV) infection in raccoons (Procyon lotor), the prevalence of anti-IAV antibodies in sera was analyzed among raccoons captured in Tokachi District, Hokkaido, Japan, from 2019 to 2023. Screening of serum samples using enzyme-linked immunosorbent assay and agar gel precipitation test detected anti-IAV antibodies in 5 of 114 (4.4 %) raccoons. All positive sera were from raccoons captured from 2022 to 2023. The hemagglutination inhibition test revealed that all five serum samples contained anti-H5 subtype HPAIV antibodies, and one also contained anti-H1 subtype antibodies. The neuraminidase inhibition test revealed that all five sera contained anti-N1 subtype antibodies, and one also contained anti-N8 subtype antibodies. In the virus neutralization test, these five sera showed stronger neutralization activity against the H5 subtype clade 2.3.4.4b HPAIV strain recently circulating worldwide compared to the old H5 HPAIV strain isolated in Japan in 2007. These findings suggested that raccoons could be involved in the circulation of H5 HPAIVs in nature., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The continuous circulation and evolution of the H5N6 subtype highly pathogenic avian influenza virus (HPAIV) challenge the development of the global poultry industry and human public health security. To address the potential threat of the H5N6 virus, a secure and efficacious vaccine is urgent. In our research, a self-assembling nanoparticle vaccine presenting the hemagglutinin of the H5N6 AIV was developed based on the ferritin antigen display platform. The results showed that a single-dose vaccination of this nanoparticle vaccine elicited potent hemagglutination inhibition (HI) antibody responses and neutralizing antibody responses in the chickens. Meanwhile, the fused HA-ferritin nanoparticle vaccine induced significantly higher levels of Th1/Th2 immune responses. After a lethal attack with the H5N6 virus, the fused HA-ferritin nanoparticle vaccine conferred chickens with 100 % (10/10) challenge protection. Importantly, the fused HA-ferritin nanoparticle with only 2 8 hemagglutination units (HAU) provided chickens with immune protection comparable to commercial inactivated vaccines and protected the chickens from severe lung pathological damage. These results in our study support the superiority of ferritin as an antigen display platform and suggest that self-assembled nanoparticle vaccines based on this platform possess the potential as an avian influenza candidate vaccine., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The study design, data collection and analysis, decision to publish, and preparation of the manuscript belong to the authors only., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The objective of the study was to assess the safety and immunogenicity of mRNA-1273 COVID-19 booster vaccination when co-administered with an egg-based standard dose seasonal quadrivalent influenza vaccine (QIV). This was a phase 3, randomized, open-label study. Eligible adults aged ≥ 18 years were randomly assigned (1:1) to receive mRNA-1273 (50 µg) booster vaccination and QIV 2 weeks apart (Seq group) or concomitantly (Coad group). Primary objectives were non-inferiority of haemagglutinin inhibition (HI) and anti-Spike protein antibody responses in the Coad compared to Seq group. 497/498 participants were randomized and vaccinated in the Seq/Coad groups, respectively. The adjusted geometric mean titer/concentration ratios (95% confidence intervals) (Seq/Coad) for HI antibodies were 1.02 (0.89-1.18) for A/H1N1, 0.93 (0.82-1.05) for A/H3N2, 1.00 (0.89-1.14] for B/Victoria, and 1.04 (0.93-1.17) for B/Yamagata; and 0.98 (0.84-1.13) for anti-Spike antibodies, thus meeting the protocol-specified non-inferiority criteria. The most frequently reported adverse events in both groups were pain at the injection site and myalgia. The 2 groups were similar in terms of the overall frequency, intensity, and duration of adverse events. In conclusion, co-administration of mRNA-1273 booster vaccine with QIV in adults was immunologically non-inferior to sequential administration. Safety and reactogenicity profiles were similar in both groups (clinicaltrials.gov NCT05047770).

The immune response to inactivated influenza vaccines (IIV) is influenced by multiple factors, including hemagglutinin content and egg-based manufacturing. Only two US-licensed vaccines are manufactured without egg passage: cell culture-based inactivated vaccine (ccIIV) and recombinant vaccine (RIV). We conducted a randomized open-label trial in central Wisconsin during the 2018-19 and 2019-20 seasons to compare immunogenicity of sequential vaccination. Participants 18-64 years old were randomized 1:1:1 to receive RIV, ccIIV or IIV in strata defined by number of influenza vaccine doses in the prior 3 years. They were revaccinated with the same product in year two. Paired serum samples were tested by hemagglutination inhibition against egg-adapted and cell-grown vaccine viruses. Serologic endpoints included geometric mean titer (GMT), mean fold rise, and percent seroconversion. There were 373 participants randomized and vaccinated in 2018-19; 332 were revaccinated in 2019-20. In 2018-19, RIV and ccIIV were not more immunogenic than IIV against A/H1N1. The post-vaccination GMT against the cell-grown 3C.2a A/H3N2 vaccine virus was higher for RIV vs IIV ( p  = .001) and RIV vs ccIIV ( p  = .001). The antibody response to influenza B viruses was similar across study arms. In 2019-20, GMT against the cell-grown 3C.3a A/H3N2 vaccine virus was higher for RIV vs IIV ( p  = .03) and for RIV vs ccIIV ( p  = .001). RIV revaccination generated significantly greater backboosting to the antigenically distinct 3C.2a A/H3N2 virus (2018-19 vaccine strain) compared to ccIIV or IIV. This study adds to the evidence that RIV elicits a superior immunologic response against A/H3N2 viruses compared to other licensed influenza vaccine products.

The influenza viruses cause seasonal respiratory illness that affect millions of people globally every year. Prophylactic vaccines are the recommended method to prevent the breakout of influenza epidemics. One of the current commercial influenza vaccines consists of inactivated viruses that are selected months prior to the start of a new influenza season. In many seasons, the vaccine effectiveness (VE) of these vaccines can be relatively low. Therefore, there is an urgent need to develop an improved, more universal influenza vaccine (UIV) that can provide broad protection against various drifted strains in all age groups. To meet this need, the computationally optimized broadly reactive antigen (COBRA) methodology was developed to design a hemagglutinin (HA) molecule as a new influenza vaccine. In this study, COBRA HA-based inactivated influenza viruses (IIV) expressing the COBRA HA from H1 or H3 influenza viruses were developed and characterized for the elicitation of immediate and long-term protective immunity in both immunologically naïve or influenza pre-immune animal models. These results were compared to animals vaccinated with IIV vaccines expressing wild-type H1 or H3 HA proteins (WT-IIV). The COBRA-IIV elicited long-lasting broadly reactive antibodies that had hemagglutination-inhibition (HAI) activity against drifted influenza variants.

A half-dose influenza vaccine (7.5 μg hemagglutinin per strain) has been used for children under 3 years of age for a long time. However, several studies indicate that a full-dose influenza vaccine (15 μg hemagglutinin per strain) may bring more benefit to this population without increasing the risk of adverse reactions. We conducted a clinical study in children aged 6-35 months in China. Participants were randomized to receive two doses of full-dose quadrivalent influenza vaccine (F-QIV), half-dose quadrivalent vaccine (H-QIV), and two half-dose trivalent vaccines (H-TIV) in a 2:2:1:1 ratio. The safety and tolerability profile of the vaccine was evaluated for 6 months postvaccination. Hemagglutination inhibition (HI) antibody titers were measured for immunogenicity assessment. The primary objective was to assess whether the results of all vaccines met the criteria. A total of 1,980 participants were enrolled in the study. Both H-QIV and F-QIV were well tolerated after vaccination. Although the geometric mean increase (GMI), seroconversion rate (SCR), and seroprotection rate (SPR) for both H-QIV and F-QIV were achieved by the criteria, superior immunogenicity in terms of geometric mean titer (GMT) ratio was observed in F-QIV to H-QIV for A/H3N2 (GMT ratio (95% CI) of 1.37 (1.11 ~ 1.68)) and B/Yamagata (1.21 (1.05 ~ 1.39)). Antibody responses to the QIV were non-inferior to the response to the TIV for the matched strains. In conclusion, F-QIV and H-QIV were both safe and immunogenic for children. F-QIV induced a stronger immune response to influenza viruses and may provide more protection and benefit by promoting the use of F-QIV in children aged 6-35 months.

Vaccine immunogenicity is affected by a variety of factors. Melatonin has been reported to affect immune responses to vaccines and infection. This was a randomized open-label trial - in which adults scheduled to receive the influenza vaccine were randomized to 5 mg melatonin or control to evaluate the effect of post-vaccination melatonin on humoral (hemagglutination-inhibition assays, HAI) and cellular (FluoroSpot) vaccine-specific cytokine responses 14-21 days post-vaccination. A total of 108 participants (melatonin treatment group: 53; control group: 55) completed the study. The groups were similar in baseline characteristics, including sleep as measured by the Pittsburgh Sleep Quality Index. Seroconversion rates or geometric mean fold rises (GMFR) in HAI titers did not vary by treatment group. There were also no statistically significant differences between pre- and post-vaccination levels of interferon gamma (IFN-γ) or granzyme B (GzB) by treatment; however, there was a significantly higher fold rise in the double secretor (IFN-γ + GzB) peripheral blood mononuclear cells for influenza vaccine in subjects taking daily melatonin (GMFR 1.7; 95% CI 1.3, 2.3) compared to those who did not (GMFR 0.9; 95% CI 0.7, 1.1) ( p  < .001). Daily melatonin for 14 days post-influenza vaccination significantly increased the cellular co-expression of IFN-γ + GzB; however, there were no other differences in the cellular or humoral responses. Future studies of the potential utility of melatonin for enhancing vaccine response with larger sample sizes may help elucidate candidate mechanisms for these limited effects, including any interactions with the circadian system.

Background: Influenza virus remains a threat to human health, but gaps remain in our knowledge of the humoral correlates of protection against influenza virus A/H3N2, limiting our ability to generate effective, broadly protective vaccines. The role of antibodies against the hemagglutinin (HA) stalk, a highly conserved but immunologically subdominant region, has not been established for influenza virus A/H3N2., Methods: Household transmission studies were conducted in Managua, Nicaragua, across 3 influenza seasons. Household contacts were tested for influenza virus infection using reverse-transcription polymerase chain reaction. We compared preexisting antibody levels against full-length HA, HA stalk, and neuraminidase (NA) measured by enzyme-linked immunosorbent assay, along with hemagglutination inhibition assay titers, between infected and uninfected participants., Results: A total of 899 individuals participated in household activation, with 329 infections occurring. A 4-fold increase in initial HA stalk titers was independently associated with an 18% decrease in the risk of infection (adjusted odds ratio [aOR], 0.82 [95% confidence interval {CI}, .68-.98]; P = .04). In adults, anti-HA stalk antibodies were independently associated with protection (aOR, 0.72 [95% CI, .54-.95]; P = .02). However, in 0- to 14-year-olds, anti-NA antibodies (aOR, 0.67 [95% CI, .53-.85]; P < .01) were associated with protection against infection, but anti-HA stalk antibodies were not., Conclusions: The HA stalk is an independent correlate of protection against A/H3N2 infection, though this association is age dependent. Our results support the continued exploration of the HA stalk as a target for broadly protective influenza vaccines but suggest that the relative benefits may depend on age and influenza virus exposure history., Competing Interests: Potential conflicts of interest. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological assays, Newcastle disease virus–based SARS-CoV-2 vaccines, influenza virus vaccines, and influenza virus therapeutics that list F. K. as co-inventor. Some of this intellectual property has been licensed and F. K. receives royalty payments from it. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, Castlevax, to develop SARS-CoV-2 vaccines; F. K. is co-founder and scientific advisory board member of Castlevax. F. K. has consulted for Merck, Curevac, Seqirus, and Pfizer and is currently consulting for 3rd Rock Ventures, GSK, Gritstone, and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development. A. G. has served on a respiratory syncytial virus vaccine advisory board for Janssen. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: We examined the added value of serologic testing for estimating influenza virus infection incidence based on illness surveillance with molecular testing versus periodic serologic testing., Methods: Pregnant persons unvaccinated against influenza at <28 weeks gestation were enrolled before the 2017 and 2018 influenza seasons in Peru and Thailand. Blood specimens were collected at enrollment and ≤14 days postpartum for testing by hemagglutination inhibition assay for antibodies against influenza reference viruses. Seroconversion was defined as a ≥4-fold rise in antibody titers from enrollment to postpartum with the second specimen's titer of ≥40. Throughout pregnancy, participants responded to twice weekly surveillance contacts asking about influenza vaccination and influenza-like symptoms (ILS). A mid-turbinate swab was collected with each ILS episode for influenza real-time reverse transcription polymerase chain reaction (rRT-PCR)., Results: Of 1,466 participants without evidence of influenza vaccination during pregnancy, 296 (20.2%) had evidence of influenza virus infections. Fifteen (5.1%) were detected by rRT-PCR only, 250 (84.4%) by serologic testing only, and 31 (10.5%) by both methods., Conclusions: Influenza virus infections during pregnancy occurred in 20% of cohort participants; >80% were not detected by a broad illness case definition coupled with rRT-PCR., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In this comprehensive large-scale study, conducted from 2015 to 2019, 7,209 wild boars across South Korea were sampled to assess their exposure to influenza A viruses (IAVs). Of these, 250 (3.5%) were found to be IAV-positive by ELISA, and 150 (2.1%) by the hemagglutination inhibition test. Detected subtypes included 23 cases of pandemic 2009 H1N1, six of human seasonal H3N2, three of classical swine H1N1, 13 of triple-reassortant swine H1N2, seven of triple-reassortant swine H3N2, and seven of swine-origin H3N2 variant. Notably, none of the serum samples tested positive for avian IAV subtypes H3N8, H5N3, H7N7, and H9N2 or canine IAV subtype H3N2. This serologic analysis confirmed the exposure of Korean wild boars to various subtypes of swine and human influenza viruses, with some serum samples cross-reacting between swine and human strains, indicating potential infections with multiple IAVs. The results highlight the potential of wild boar as a novel mixing vessel, facilitating the adaptation of IAVs and their spillover to other hosts, including humans. In light of these findings, we recommend regular and frequent surveillance of circulating influenza viruses in the wild boar population as a proactive measure to prevent potential human influenza pandemics and wild boar influenza epizootics., Competing Interests: Declaration. Conflict of Interest: The authors declare that they have no competing interest., (© 2024. EcoHealth Alliance.)

Objectives: Trivalent inactivated influenza vaccine effectiveness was low in a prospective cohort of healthcare personnel (HCP) in Israel from 2016 to 2019. We conducted a randomised immunogenicity trial of quadrivalent recombinant influenza vaccine (RIV4) and standard-dose inactivated influenza vaccine (IIV4) among frequently and infrequently vaccinated previous cohort participants., Methods: From October 2019 to January 2020, we enrolled and randomly allocated HCP from two Israeli hospitals to receive IIV4 or RIV4. Hemagglutination inhibition (HAI) antibody titres against 2019-2020 vaccine reference influenza viruses were compared between vaccine groups using geometric mean titre (GMT) ratios from sera collected one-month post-vaccination and by frequency of vaccination in the past 5 years (>2 vs ≤2)., Results: Among 415 HCP, the GMT ratio comparing RIV4 to IIV4 was 2.0 (95% confidence interval [CI] 1.7-2.7) for A(H1N1)pdm09, 1.6 (95% CI: 1.3-1.9) for A(H3N2), 1.8 (95% CI: 1.4-2.2) for B(Yamagata), and 1.1 (95% CI: 0.9-1.4) for B(Victoria). Similarly, RIV4 elicited higher HAI titres than IIV4 against all 2019-2020 vaccine reference viruses except B(Victoria) among infrequently and frequently vaccinated HCP (lower bound of GMT ratio 95% CIs ≥1.0)., Conclusion: RIV4 had improved immunogenicity for influenza vaccine strains among both infrequent and frequent vaccinees compared to standard-dose IIV4., Clinical Trials Registration: NCT04523324., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Adam Lauring: Roche steering committee for a clinical trial of Baloxivir; grants/contracts from NIAID, CDC, Burroughs Wellcome Fund, Flu Lab. David Greenberg: Received grants from: Merck Sharp & Dohme and Abbvie, Sanofi unrelated to influenza vaccine; Scientific consultant for Pfizer, Abbvie, Beyond Air, Astra Zeneca, Enox Biopharma, GlaxoSmithKline, and Merck Sharp & Dohme, Beyond Air, Beyond Cancer on subjects unrelated to influenza vaccine; Received honoraria as a speaker from Pfizer, Abbvie, Merck Sharp & Dohme, Sanofi, Astra Zeneka unrelated to the area of this influenza vaccine; Shareholder of Beyond Air, Beyond Cancer. Emily T. Martin: grants/contracts from NIH, Merck, US CDC., (Published by Elsevier Ltd.)

Most H1 influenza A viruses (IAVs) of swine are derived from past human viruses. As human population immunity against these IAVs gradually decreases, the risk of reintroduction to humans increases. We examined 549 serum samples from persons 0–97 years of age collected in Belgium during 2017–2018 for hemagglutination inhibiting and virus neutralizing antibodies against 7 major H1 swine IAV (swIAV) clades and 3 human progenitor IAVs. Seroprevalence (titers >40) rates were >50% for classical swine and European human-like swIAVs, >24% for North American human-like δ1a and Asian avian-like swIAVs, and

This investigation elucidated the differences in humoral and H1N1 HA-specific memory B-cells response in participants exhibiting distinct immune response patterns prior to and after vaccination with Fluzone, the quadrivalent split-inactivated seasonal influenza virus vaccine. Participants were categorized into persistent non-responders and persistent responders based on their hemagglutination-inhibition (HAI) antibody titers to the H1N1 component from each vaccine administered between the 2019-2020 to 2023-2024 seasons. Persistent responders had higher fold change in H1N1 HA-specific CD21 expressing B-cells, plasmablasts, and plasma cells. A significant increase in H1N1 HA-specific transitional B-cells in persistent non-responders was observed. The frequency and fold change of H1N1-specific IgM-expressing memory B-cells was higher in persistent non-responders. Dimensionality reduction analysis also demonstrated higher IgM expression for persistent non-responders than persistent responders. Furthermore, persistent non-responders had a significant fold change increase in IgA tissue-like memory, IgG exhausted tissue-like memory, and double negative (DN) activated memory cells. In contrast, persistent responders had increased frequency of IgG-activated memory B-cells, IgG resting B-cells and DN resting B-cells. Correlation analysis revealed a positive correlation between HAI titers and DN memory B-cells and a negative correlation between HAI titers and IgG-expressing memory B-cells in persistent non-responders. Conversely, persistent responders had a positive correlation between HAI titers and IgA resting memory B-cells and a negative correlation between IgG memory B-cells and DN memory B-cells. Overall, this study provided valuable insights into the differential immune memory B-cell responses following influenza virus vaccination and paves the way for future research to further unravel the complexities of vaccine-induced memory B-cells and ultimately improve vaccination strategies against influenza virus infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Reis, Silva-Moraes, Teixeira-Carvalho and Ross.)

Background: We evaluated co-administration of adjuvanted seasonal quadrivalent influenza vaccine (FLU-aQIV) and respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) in ≥65-year-olds., Methods: This phase 3, open-label trial randomized ≥65-year-olds to receive FLU-aQIV and RSVPreF3 OA concomitantly (Co-Ad) or sequentially, 1 month apart (Control). Primary objectives were to demonstrate the non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration in terms of hemagglutination inhibition (HI) titers for each FLU-aQIV strain and RSV-A and RSV-B neutralization titers, 1 month post-vaccination. Reactogenicity and safety were also assessed., Results: Overall, 1045 participants were vaccinated (Co-Ad: 523; Control: 522). Non-inferiority of FLU-aQIV and RSVPreF3 OA co-administration versus sequential administration was demonstrated in terms of HI titers for the A/Victoria(H1N1), B/Victoria, and B/Yamagata influenza strains and RSV-A neutralization titers (upper limits [ULs] of 95% confidence intervals [CIs] for adjusted geometric mean titer [GMT] ratios [Control/Co-Ad] ≤1.50) but not for A/Darwin(H3N2) HI titers (95% CI UL = 1.53). The immune response to A/Darwin(H3N2) was further assessed post-hoc using a microneutralization assay; the post-vaccination adjusted GMT ratio (Control/Co-Ad) was 1.23 (95% CI: 1.06-1.42, ie, UL ≤1.50), suggesting an adequate immune response to A/Darwin(H3N2) following co-administration. RSV-B neutralization titers were comparable between groups (95% CI UL for adjusted GMT ratio ≤1.50). Solicited adverse events were mostly mild or moderate and transient; unsolicited and serious adverse event rates were balanced between groups., Conclusions: Adjuvanted FLU-aQIV and RSVPreF3 OA had acceptable reactogenicity/safety profiles when co-administered in ≥65-year-olds, without clinically relevant interference with the immune responses to either vaccine., Clinical Trials Registration: NCT05568797., Competing Interests: Potential conflicts of interest. R. C. runs RSV studies at her trial site with Moderna and GSK and received NIHR funding to attend the World Vaccine Congress (October 2022) as part of the UK delegation; she is the Deputy Specialty Lead and the Clinical Lead for vaccine research at the North West Coast Clinical Research Network. P. L. received consulting fees from GSK and Pfizer, declares payments or honoraria from Janssen, GSK, Moderna, AstraZeneca, Pfizer, and Sanofi, and financial support for attending meetings and/or travel from AstraZeneca, Pfizer, and Sanofi. J.-F. N., M. R., and I. S.-M. report grants and funding from GSK to their institutions for conducting this clinical trial. N. D., S. G., M.-P. D., A. J., H. A. H., S. K., and N. M. are or were employed by GSK at the time the study was designed, initiated, and/or conducted. N. D., M.-P. D., H. A. H., S. K., and N. M. have stock options or shares from GSK. N. D. also reports stocks from Haleon and patents on vaccination against RSV (numbers 2218080.6 and 2303002.6). M.-P. D. is a co-applicant on a pending patent filed by GSK. S. N. M. declares being a Principal Investigator on the current trial. S. D., J. L., H. M. M., M. P. V., and M. H. R. -R. have no conflicts of interest to declare. The authors declare no other financial or non-financial relationships. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

BackgroundHighly pathogenic avian influenza (HPAI) H5Nx and human H1N1pdm2009 influenza viruses can infect cats. Infections in cats may result in viral adaptations or recombinant viruses, which may facilitate zoonotic transfer.AimWe aimed to investigate the presence of HPAI H5 clade 2.3.4.4 and H1 influenza viruses and antibodies to these viruses in domestic and rural stray cats in the Netherlands and factors associated with exposure.MethodsSera from stray and domestic cats, sampled 2020-2023, were analysed by ELISA and confirmed by hemagglutination inhibition assay (HAI) and pharyngeal swabs and lung tissue for influenza A virus by RT-qPCR.ResultsIn 701 stray cats, 83 (11.8%; 95% confidence interval (CI): 9.5-14.5) sera were positive for HPAI H5 and 65 findings were confirmed. In HAI, two sera were positive for both HPAI H5 and H1. In 871 domestic cats, four (0.46%; 95% CI: 0.13-1.2) sera were HPAI H5 positive and none were confirmed but 40 (4.6%; 95% CI: 3.3-6.2) sera were seropositive for H1 and 26 were confirmed. Stray cats living in nature reserves (odds ratio (OR) = 5.4; 95% CI: 1.5-20.1) and older cats (OR = 3.8; 95% CI: 2.7-7.1) were more likely to be HPAI H5 seropositive. No influenza A virus was detected in 230 cats.ConclusionThe higher HPAI H5 seroprevalence in stray cats compared with domestic cats suggests more frequent viral exposure, most likely due to foraging on wild birds. In contrast, exposure to H1 was more common in domestic cats compared with stray cats.

The emergence of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b viruses and their transmission to dairy cattle and animals, including humans, poses a major global public health threat. Therefore, the development of effective vaccines and therapeutics against H5N1 clade 2.3.4.4b virus is considered a public health priority. In the United States, three H5N1 vaccines derived from earlier strains of HPAI H5N1 (A/Vietnam, clade 1, and A/Indonesia, clade 2.1) virus, with (MF59 or AS03) or without adjuvants, are licensed and stockpiled for pre-pandemic preparedness, but whether they can elicit neutralizing antibodies against circulating H5N1 clade 2.3.4.4b viruses is unknown. In this study, we evaluated the binding, hemagglutination inhibition and neutralizing antibody response generated after vaccination of adults with the three licensed vaccines. Individuals vaccinated with the two adjuvanted licensed H5N1 vaccines generated cross-reactive binding and cross-neutralizing antibodies against the HPAI clade 2.3.4.4b A/Astrakhan/3212/2020 virus. Seroconversion rates of 60-95% against H5 clade 2.3.4.4b were observed after two doses of AS03-adjuvanted-A/Indonesia or three doses of MF59-adjuvanted-A/Vietnam vaccine. These findings suggest that the stockpiled US-licensed adjuvanted H5N1 vaccines generate cross-neutralizing antibodies against circulating HPAI H5N1 clade 2.3.4.4b in humans and may be useful as bridging vaccines until updated H5N1 vaccines become available., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: The World Health Organization considers the values of antibody titers in the hemagglutination inhibition assay as one of the most important criteria for assessing successful vaccination. Mathematical modeling of cross-immunity allows for identification on a real-time basis of new antigenic variants, which is of paramount importance for human health., Materials and Methods: This study uses statistical methods and machine learning techniques from simple to complex: logistic regression model, random forest method, and gradient boosting. The calculations used the AAindex matrices in parallel to the Hamming distance. The calculations were carried out with different types and values of antigenic escape thresholds, on four data sets. The results were compared using common binary classification metrics., Results: Significant differentiation is shown depending on the data sets used. The best results were demonstrated by all three models for the forecast autumn season of 2022, which were preliminary trained on the February season of the same year (Auroc 0.934; 0.958; 0.956, respectively). The lowest results were obtained for the entire forecast year 2023, they were set up on data from two seasons of 2022 (Aucroc 0.614; 0.658; 0.775). The dependence of the results on the types of thresholds used and their values turned out to be insignificant. The additional use of AAindex matrices did not significantly improve the results of the models without introducing significant deterioration., Conclusion: More complex models show better results. When developing cross-immunity models, testing on a variety of data sets is important to make strong claims about their prognostic robustness.

Background: Intranasal administration of respiratory vaccines offers many advantages such as eliciting both systemic and mucosal immunity at the point of viral entry. Immunogenicity of intranasal vaccination can be improved through the use of adjuvants. Bacteria-like particles derived fromLactococcus lactishave the potential to serve as a vaccine adjuvant.This clinical study investigated the safety, reactogenicity and immunogenicity of intranasal seasonal influenza vaccine adjuvanted with gram-positive matrix particles (FluGEM®)., Methods: This was a first-in-human, randomized, double-blind, controlled, dose-escalation study performed at the Centre for Human Drug Research (CHDR), the Netherlands. Participants aged 18-49 were randomized in a 3:1 ratio to receive FluGem® in ascending doses (two-dose regimens) together with a standard trivalent inactivated influenza vaccine or unadjuvanted TIV only. Primary outcomes were safety and tolerability. Secondary outcomes were serum hemagglutination inhibition (HI) antibody titers and mucosal IgA. The most immunogenic dose was used in an additionalelderly cohort (>65 years)., Results: Ninty participants were included. Intranasal FluGem®was safe and well tolerated. The majority of adverse events were mild (97.4 %) with (un)solicited adverse events comparable across all dose levels and control groups. All groups showed geometric mean increases ≥ 2.5-fold. Seroconversion (≥40 % participants) was achieved at both day 21 (single-dose) and 42 (two-dose) for the 1.25 mg dose and on day 42 (two-dose only) for the 2.5 mg dose. Highest geometric mean IgA increases were observed in the 1.25 mg group on day 21. Immunogenicity was less pronounced in elderly., Conclusions: Intranasal vaccination of FluGEM®was safe and tolerable in healthy adult volunteers aged 18-49 years and 65 and older. Highest immunogenicity was observed for 1.25 mg and 2.5 mg doses (compared to 5 mg) suggesting a potential non-linear dose-response relationship.More research is needed to further investigate the capabilities of bacteria-like peptides as adjuvants., Competing Interests: Declaration of competing interest Kees Leenhouts and Bert-Jan Haijema were former employees of Mucosis BV. The study was sponsored by Mucosis BV. For the other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Understanding the molecular mechanisms underpinning diverse vaccination responses is critical for developing efficient vaccines. Molecular subtyping can offer insights into heterogeneous nature of responses and aid in vaccine design. We analyzed multi-omic data from 62 haemagglutinin seasonal influenza vaccine recipients (2019-2020), including transcriptomics, proteomics, glycomics, and metabolomics data collected pre-vaccination. We performed a subtyping analysis on the integrated data revealing five subtypes with distinct molecular signatures. These subtypes differed in the expression of pre-existing adaptive or innate immunity signatures, which were linked to significant variation in baseline immunoglobulin A (IgA) and hemagglutination inhibition (HAI) titer levels. It is worth noting that these differences persisted through day 28 post-vaccination, indicating the effect of initial immune state on vaccination response. These findings highlight the significance of interpersonal variation in baseline immune status as a crucial factor in determining the effectiveness of seasonal vaccines. Ultimately, incorporating molecular profiling could enable personalized vaccine optimization., Competing Interests: Declaration of competing interest The A.G.-S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus, Pfizer and Prosetta, outside of the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott and Astrazeneca. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. All other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Daratumumab-treated myeloma patients may face increased seasonal influenza risk due to weakened postvaccination immune responses, especially with daratumumab treatment. We aimed to assess humoral responses to boosted influenza vaccination in daratumumab-treated or -untreated patients., Methods: In a single-center study, we evaluated humoral responses (hemagglutination-inhibition assay) one month following a two-injection (4-weeks apart) influenza vaccination (standard dose) in 84 patients with multiple myeloma (40 with daratumumab in the past year)., Results: Seroprotection rates (titer ≥1/40) after the second vaccine injection were low across vaccinal subtypes (except for A-H3N2): 71.3% (A-H3N2), 19.7% (A-H1N1pdm09), 9.9% (B-Victoria), 11.3% (B-Yamagata). Only A-H3N2 seroprotection rates significantly increased with the booster in daratumumab-treated patients (30% (12/40) after one injection vs 55% (22/40) after the boost; P = 0.01).After propensity score weighting, daratumumab was not significantly associated with a reduced likelihood of seroprotection against at least one vaccine strain (OR 0.65 [95% CI: 0.22-1.88])., Conclusion: While daratumumab treatment did not lead to a significant reduction in seroprotection rates following influenza vaccination, a booster vaccine injection demonstrated potential benefit for specific strains (A-H3N2) in patients undergoing daratumumab treatment. Nevertheless, the overall low response rates in patients with multiple myeloma necessitates the development of alternative vaccination and prophylaxis strategies., Competing Interests: Declarations of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: F. Lemonnier received research funding from Institut Roche and travel grant from Gilead, G. Melica received honoraria from lectures from Astellas, Pfizer, Gilead, MSD, Janssen. S. Fourati received research grants from Moderna, and consulting fees from Moderna, Astrazeneca, Pfizer, GSK and Cepheid, as well as support for traval from Astellas, Gilead and Pfizer. C. Haioun received research funding and consulting honoraria for lectures from Amgen, Celgen, Gilead, Janssen, Novartis, F.Hoffmann-La Roche, Servier, Takeda, Miltenyi. F. Lemonnier received research funding from La Roche Institute and support for attending meetings from Gilead. F. Le Bras received research funding from Takeda and Celgene BMS, and honoraria from Takeda, Kite Gilead and Novartis. K. Belhadj received nonfinancial research support from AbbVie., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Influenza B/Yamagata viruses exhibited weak antigenic selection in recent years, reducing their prevalence over time and requiring no update of the vaccine component since 2015. To date, no B/Yamagata viruses have been isolated or sequenced since March 2020., Methods: The antibody prevalence against the current B/Yamagata vaccine strain in Italy was investigated: For each influenza season from 2012/2013 to 2021/2022, 100 human serum samples were tested by haemagglutination inhibition (HAI) assay against the vaccine strain B/Phuket/3073/2013. In addition, the sequences of 156 B/Yamagata strains isolated during the influenza surveillance activities were selected for analysis of the haemagglutinin genome segment., Results: About 61.9% of the human samples showed HAI antibodies, and 21.7% had protective antibody levels. The prevalence of antibodies at protective levels in the seasons between the isolation of the strain and its inclusion in the vaccine was between 11% and 25%, with no significant changes observed in subsequent years. A significant increase was observed in the 2020/2021 season, in line with the increase in influenza vaccine uptake during the pandemic. Sequence analysis showed that from 2014/2015 season onward, all B/Yamagata strains circulating in Italy were closely related to the B/Phuket/2013 vaccine strain, showing only limited amino acid variation., Conclusions: A consistent prevalence of antibodies to the current B/Yamagata vaccine strain in the general population was observed. The prolonged use of a well-matched influenza vaccine and a low antigenic diversity of B/Yamagata viruses may have facilitated a strong reduction in B/Yamagata circulation, potentially contributing to the disappearance of this lineage., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Many influenza studies assume that symptomatic and asymptomatic cases have equivalent antibody responses.Methods: This study examines the relationship between influenza symptoms and serological response. Influenza-positive index cases and household members in Managua, Nicaragua, during 2012-2017 were categorized by symptom status.Results: Antibody response was assessed using hemagglutination inhibition assays (HAI). Among 510 cases, 74.5% had ≥4-fold increase in HAI antibodies, and 75.3% had febrile illness. In a logistic regression model, febrile cases had 2.17 times higher odds of a ≥4-fold titer rise compared to asymptomatic cases (95% confidence interval, 1.02-4.64).Conclusions: Studies relying on serological assays may not generalize to asymptomatic infections. [ABSTRACT FROM AUTHOR]

Influenza seasons occur annually, building immune history for individuals, but the influence of this history on subsequent influenza vaccine protection remains unclear. We extracted data from an animal trial to study its potential impact. The trial involved 80 ferrets, each receiving either one type of infection or a placebo before vaccination. We quantified the vaccine protection by evaluating hemagglutination inhibition (HAI) antibody titer responses. We tested whether hosts with different infection histories exhibited similar level of responses when receiving the same vaccine for all homologous and heterologous outcomes. We observed that different pre-existing immunities were generally beneficial to vaccine induced responses, but varied in magnitude. Without pre-immunity, post-vaccination HAI titers after the 1st dose of the vaccine were less likely to be above 1:40, and a booster shot was needed. Our study suggests that pre-existing immunity may strengthen and extend the homologous and heterologous vaccine responses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: This study was to assess the lot-to-lot consistency, immunogenicity and safety of three manufacturing lots of a quadrivalent inactivated influenza vaccine (IIV4)., Methods: A randomized, double-blind, phase IV clinical trial was conducted in healthy children, adolescents and adults aged 9-59 years in Guizhou Province, China. Eligible participants were enrolled and randomized into three groups in a ratio of 1:1:1 to receive a single dose of one of three manufacturing lots of IIV4. Serum samples were collected before and 28 days after vaccination for hemagglutination inhibition (HI) antibody testing. Safety data were collected for up to 28 days after vaccination. The primary objective was to evaluate the lot-to-lot consistency of immune response as assessed by the geometric mean titer (GMT) of HI antibody at 28 days after vaccination., Results: Between November 27, 2022 and December 18, 2022, 1260 eligible participants were enrolled, with similar participant demographics among groups. Immune responses after vaccination were comparable across groups, with the 95% confidence intervals (CIs) of GMT ratios for all 4 strains falling into the equivalence criterion of (0.67, 1.5). The seroconversion rates (SCRs) and seroprotection rates (SPRs) met the US Center or Biologics Evaluation and Research (CBER) criteria for all strains for each lot (lower limit of 95% CI of SCR ≥ 40% and SPR ≥ 70%). The incidences of solicited and unsolicited adverse reactions were similar among three groups, most of which (91.9%) were mild or moderate in severity. A total of 11 serious adverse events were reported during the study, and all were considered unrelated to vaccination., Conclusion: The three manufacturing lots of IIV4 demonstrated consistent immunogenicity. IIV4 can elicit satisfactory immune responses for all four strains and no safety concerns were identified., Clinical Trial Registration: Identifier No. NCT05512494., Competing Interests: Declaration of competing interest Yuwei Li, Danyu and Jieru Wang are employed by Sinovac Biotech Co., Ltd. Xinyi Yang, and Siliang Zhou are employed by Sinovac Life Sciences Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Influenza vaccination may protect through the humoral immune response, cellular immune response, or possibly both. Immunity after vaccination can be mediated through antibodies that may be detected by the rise of serum hemagglutination inhibition (HAI) titers. Our objective was to investigate the proportion of protection against influenza mediated through antibodies by measuring the rise of HAI titer (indirect effect) compared to that induced through other immune mechanisms (direct effect) for influenza A and B., Methods: We analysed data from a cluster randomized trial conducted during the 2008-2009 season in which Canadian Hutterite children were vaccinated against influenza. We used inverse probability weighting to calculate the indirect and direct effect of vaccination against influenza A/H3N2 and influenza B/Brisbane using HAI titres and overall vaccine efficacy., Results: We included data on 617 children from 46 Hutterite colonies, aged between 3 and 15 years who were vaccinated with either inactivated trivalent influenza vaccine or hepatitis A vaccine. Vaccine efficacy was 63 % for influenza A (H3N2) and 28 % for influenza B. The hazard ratio for protection against influenza A/H3N2 due to an indirect effect of vaccination was 0.96 (95 % confidence interval (CI) of 0.00 to 2.89) while for the direct effect it was 0.38 (95 % CI of 0.00 to 5.47). The hazard ratio for influenza B indirect effect was 0.75 (95 % CI of 0.07 to 1) and for the direct effect 0.96 (95 % CI of 0.00 to 12.02). In contrast, repeating the analysis using microneutralization in a subgroup of 488 children revealed that the protective effect for vaccination for A/H3N2 was entirely mediated by antibodies but only for 13 % for influenza B., Conclusions: Although vaccination provided higher protective effectiveness against influenza A than B, most of the influenza A vaccine efficacy likely occurred through antibodies other than what could be detected by HAI titres. In contrast, for influenza B, while the HAI titres appeared to mediate most of the vaccine effectiveness, this was not confirmed by microneutralization analysis., Competing Interests: Declaration of competing interest Dr. Loeb reports grant support from the Canadian Institutes of Health Research and WHO; receipt of an in-kind supply of vaccines from Sanofi; consulting fees for participation on advisory boards for Medicago, Novavax, Janssen, Pfizer, GSK, Merck, Sanofi, and Seqirus; and participation on a data and safety monitoring board for CanSino Biologics., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The aim of the current study was to determine the safety and immunogenicity of trivalent inactivated influenza vaccine (TIV) alone or formulated with Advax delta inulin adjuvant in those who were older (aged >60 years) or had chronic disease., Methods: Over 4 consecutive years from 2008 through 2011, adult participants with chronic disease or >60 years of age were recruited into a randomized controlled study to assess the safety, tolerability and immunogenicity of Advax-adjuvanted TIV (TIV + Adj) versus standard TIV. The per-protocol population with ≥1 postbaseline measurement of influenza antibodies comprised 1297 participants, 447 in the TIV and 850 in the TIV + Adj) group., Results: No safety issues were identified. Variables negatively affecting vaccine responses included obesity and diabetes mellitus. Advax adjuvant had a positive impact on anti-influenza immunoglobulin M responses and on H3N2 and B strain seropositivity as assessed by hemagglutination inhibition., Conclusions: TIV + Adj was safe and well tolerated in individuals with chronic disease. There is an ongoing need for research into improved influenza vaccines for high-risk populations., Clinical Trials Registration: Australia New Zealand Clinical Trial Registry: ACTRN 12608000364370., Competing Interests: Potential conflicts of interest. Y. H. O. and N. P. are affiliated with Vaxine, which holds proprietary rights over Advax adjuvant. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Since influenza and respiratory syncytial virus (RSV) carry significant burden in older adults with overlapping seasonality, vaccines for both pathogens would ideally be coadministered in this population. Here we evaluate the immunogenicity and safety of concomitant administration of Ad26.RSV.preF/RSV preF protein and high-dose seasonal influenza vaccine (Fluzone-HD) in adults ≥65 years old., Methods: Participants were randomized 1:1 to the Coadministration or Control group. The Coadministration group received concomitant Ad26.RSV.preF/RSV preF protein and Fluzone-HD on day 1 and placebo on day 29, while the Control group received Fluzone-HD and placebo on day 1 and Ad26.RSV.preF/RSV preF protein on day 29. Influenza hemagglutination-inhibiting and RSV preF-binding antibody titers were measured postvaccination and tested for noninferiority between both groups. Safety data were collected throughout the study and analyzed descriptively., Results: Coadministered Ad26.RSV.preF/RSV preF protein and Fluzone-HD vaccines induced noninferior immune responses compared to each vaccine administered alone. Seroconversion and seroprotection rates against influenza were similar between groups. Both vaccines remained well tolerated upon concomitant administration., Conclusions: Coadministration of Ad26.RSV.preF/RSV preF protein and Fluzone-HD showed an acceptable safety profile and did not hamper the immunogenicity of either vaccine, thus supporting that both vaccines can be concomitantly administered in adults ≥65 years old., Competing Interests: Potential conflicts of interest. W. W., C. A. C., and E. H. are former employees of Janssen Vaccines and Prevention B.V.; A. R. B., N. L., and B. C. are employees of Janssen Vaccines and Prevention B.V.; A. M. J. and I. S. are employees of Janssen Research and Development; E. D. P. is a former employee of Janssen Infectious Diseases. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Vaccine responsiveness is often reduced in older adults. Yet, our lack of understanding of low vaccine responsiveness hampers the development of effective vaccination strategies to reduce the impact of infectious diseases in the ageing population. Young-adult (25-49 y), middle-aged (50-64 y) and older-adult ( ≥ 65 y) participants of the VITAL clinical trials (n = 315, age-range: 28-98 y), were vaccinated with an annual (2019-2020) quadrivalent influenza (QIV) booster vaccine, followed by a primary 13-valent pneumococcal-conjugate (PCV13) vaccine (summer/autumn 2020) and a primary series of two SARS-CoV-2 mRNA-1273 vaccines (spring 2021). This unique setup allowed investigation of humoral responsiveness towards multiple vaccines within the same individuals over the adult age-range. Booster QIV vaccination induced comparable H3N2 hemagglutination inhibition (HI) titers in all age groups, whereas primary PCV13 and mRNA-1273 vaccination induced lower antibody concentrations in older as compared to younger adults (primary endpoint). The persistence of humoral responses, towards the 6 months timepoint, was shorter in older adults for all vaccines (secondary endpoint). Interestingly, highly variable vaccine responder profiles overarching multiple vaccines were observed. Yet, approximately 10% of participants, mainly comprising of older male adults, were classified as low responders to multiple vaccines. This study aids the identification of risk groups for low vaccine responsiveness and hence supports targeted vaccination strategies. Trial number: NL69701.041.19, EudraCT: 2019-000836-24., (© 2024. The Author(s).)

Influenza exposures early in life are believed to shape future susceptibility to influenza infections by imprinting immunological biases that affect cross-reactivity to future influenza viruses. However, direct serological evidence linked to susceptibility is limited. Here we analysed haemagglutination-inhibition titres in 1,451 cross-sectional samples collected between 1992 and 2020, from individuals born between 1917 and 2008, against influenza B virus (IBV) isolates from 1940 to 2021. We included testing of 'future' isolates that circulated after sample collection. We show that immunological biases are conferred by early life IBV infection and result in lineage-specific cross-reactivity of a birth cohort towards future IBV isolates. This translates into differential estimates of susceptibility between birth cohorts towards the B/Yamagata and B/Victoria lineages, predicting lineage-specific birth-cohort distributions of observed medically attended IBV infections. Our data suggest that immunological measurements of imprinting could be important in modelling and predicting virus epidemiology., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

BackgroundHealthcare personnel (HCP) are at high risk for respiratory infections through occupational exposure to respiratory viruses.AimWe used data from a prospective influenza vaccine effectiveness study in HCP to quantify the incidence of acute respiratory infections (ARI) and their associated presenteeism and absenteeism.MethodsAt the start and end of each season, HCP at two Israeli hospitals provided serum to screen for antibodies to influenza virus using the haemagglutination inhibition assay. During the season, active monitoring for the development of ARI symptoms was conducted twice a week by RT-PCR testing of nasal swabs for influenza and respiratory syncytial virus (RSV). Workplace presenteeism and absenteeism were documented. We calculated incidences of influenza- and RSV-associated ARI and applied sampling weights to make estimates representative of the source population.ResultsThe median age of 2,505 participating HCP was 41 years, and 70% were female. Incidence was 9.1 per 100 person-seasons (95% CI: 5.8-14.2) for RT-PCR-confirmed influenza and 2.5 per 100 person-seasons (95% CI: 0.9-7.1) for RSV illness. Each season, 18-23% of unvaccinated and influenza-negative HCP seroconverted. The incidence of seroconversion or RT-PCR-confirmed influenza was 27.5 per 100 person-seasons (95% CI: 17.8-42.5). Work during illness occurred in 92% (95% CI: 91-93) of ARI episodes, absence from work in 38% (95% CI: 36-40).ConclusionInfluenza virus and RSV infections and associated presenteeism and absenteeism were common among HCP. Improving vaccination uptake among HCP, infection control, and encouraging sick HCP to stay home are important strategies to reduce ARI incidence and decrease the risk of in-hospital transmission.

Background: The hemagglutination inhibition antibody (HAI) titer contributes only a part of vaccine-induced protection against influenza virus infections. Using causal mediation analysis, we quantified the proportion of vaccine efficacy mediated by postvaccination HAI titers., Methods: We conducted causal mediation analyses using data from a randomized, active-comparator controlled, phase III, trial of an inactivated, split-virion seasonal quadrivalent influenza vaccine in children conducted from October 2010 to December 2011 in 8 countries. Vaccine efficacy was estimated using a weighted Cox proportional hazards model. Estimates were decomposed into the direct and indirect effects mediated by postvaccination HAI titers., Results: The proportions of vaccine efficacy mediated by postvaccination HAI titers were estimated to be 22% (95% confidence interval, 18%--47%) for influenza A(H1N1), 20% (16%-39%) for influenza A(H3N2), and 37% (26%-85%) for influenza B/Victoria., Conclusions: HAI titers partially mediate influenza vaccine efficacy against influenza A(H1N1), A(H3N2), and B/Victoria. Our estimates were lower than in previous studies, possibly reflecting expected heterogeneity in antigenic similarity between vaccine and circulating viruses across seasons., Competing Interests: Potential conflicts of interests. B. J. C. consults for AstraZeneca, Fosun Pharma, GlaxoSmithKline, Haleon, Moderna, Novavax, Pfizer, Roche, and Sanofi Pasteur. All other authors report no other potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The aim of this study was to determine the level of anti-hemagglutinin antibodies in blood sera collected from patients during the 2022/2023 epidemic season in Poland. A total of 700 sera samples from patients across the country were tested. The samples were divided into seven groups according to the age of the patients, with 100 samples from each age group. The hemagglutination inhibition test (OZHA) was used to determine the level of anti-hemagglutinin antibodies. The test results have confirmed the presence of anti-hemagglutinin antibodies for antigens A/Victoria/2570/2019 (H1N1)pdm09, A/Darwin/9/2021 (H3N2), B/Austria/1359417/2021 (B/Yamagata lineage) and B/ Phuket/3073/2013 (B/Victoria lineage) present in the influenza vaccine recommended by the World Health Organization (WHO) for the 2022/2023 epidemic season. The highest geometric mean antibody titres (GMT) and protection rate values (%) were recorded for hemagglutinin A/H3N2. In Poland, in the 2022/2023 epidemic season, the percentage of the population vaccinated against influenza was 5.7%. Therefore, the test results can be interpreted as the response of the immune system in patients who have been previously infected with an influenza virus.

H1N1 influenza virus is a significant global public health concern. Monoclonal antibodies (mAbs) targeting specific viral proteins such as hemagglutinin (HA) have become an important therapeutic strategy, offering highly specific targeting to block viral transmission and infection. This study focused on the development of mAbs targeting HA of the A/Victoria/2570/2019 (H1N1pdm09, VIC-19) strain by utilizing hybridoma technology to produce two mAbs with high binding capacity. Notably, mAb 2B2 has demonstrated a strong affinity for HA proteins in recent H1N1 influenza vaccine strains. In vitro assessments showed that both mAbs exhibited broad-spectrum hemagglutination inhibition and potent neutralizing effects against various vaccine strains of H1N1pdm09 viruses. 2B2 was also effective in animal models, offering both preventive and therapeutic protection against infections caused by recent H1N1 strains, highlighting its potential for clinical application. By individually co-cultivating each of the aforementioned mAbs with the virus in chicken embryos, four amino acid substitution sites in HA (H138Q, G140R, A141E/V, and D187E) were identified in escape mutants, three in the antigenic site Ca2, and one in Sb. The identification of such mutations is pivotal, as it compels further investigation into how these alterations could undermine the binding efficacy and neutralization capacity of antibodies, thereby impacting the design and optimization of mAb therapies and influenza vaccines. This research highlights the necessity for continuous exploration into the dynamic interaction between viral evolution and antibody response, which is vital for the formulation of robust therapeutic and preventive strategies against influenza., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Participants between the ages of 10-86 years old were vaccinated with split-inactivated influenza vaccine (Fluzone®) in six consecutive influenza seasons from 2016-2017 to 2021-2022. Vaccine effectiveness varies from season to season as a result of both host immune responses as well as evolutionary changes in the influenza virus surface glycoproteins that provide challenges to vaccine manufacturers to produce more effective annual vaccines. Next generation influenza vaccines are in development and may provide protective immune responses against a broader number of influenza viruses and reduce the need for annual vaccination. An improved understanding how current influenza vaccines are influenced by human host immune responses in people of different ages and co-morbidities is necessary for designing the next-generation of 'universal' or broadly-protective influenza vaccines. Overall, pre-existing immune responses to previous influenza virus exposures, either by past infections or vaccinations, is a critical factor influencing host responses to seasonal influenza vaccination. Participants vaccinated in consecutive seasons had reduced serum hemagglutination-inhibition (HAI) activity against strains included in the vaccine compared to participants that had not been vaccinated in the preceding 1-2 years prior to entering this study. The magnitude and breadth of these antibody responses were also modulated by the age of the participant. Elderly participants over 65 years of age, in general, had lower pre-existing HAI titers each season prior to vaccination with lower post-vaccination titers compared to children or young adults under the age of 35. The administration of higher doses (HD) of the split-inactivated vaccine enhanced the antibody titers in the elderly. This report showcases 6 consecutive years of antibody HAI activity in human subjects receiving seasonal split-inactivated influenza vaccine., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Carlock et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs., Methods: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 μg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed., Results: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval., Conclusions: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807., Competing Interests: Potential conflicts of interest . E. J. A. has consulted for Pfizer, Sanofi Pasteur, GSK, Janssen, Moderna, and Medscape, and his institution has received funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Sanofi-Pasteur, Janssen, and Micron. He has served on a safety monitoring board for Kentucky BioProcessing, Inc. and Sanofi Pasteur. He has served on a data adjudication board for WCG and ACI Clinical. His institution has also received funding from the National Institutes of Health (NIH) to conduct clinical trials of COVID-19 vaccines. He is currently employed by Moderna, Inc. N. R. has consulted for EMMES, Moderna, GSK, Sanofi, Seqirus, and ICON, and her institution receives funds to conduct clinical research unrelated to this manuscript from Pfizer, Sanofi, Quidel, Lilly, Immorna, Vaccine Company, and Merck as well as NIH to conduct translational clinical studies and interventional clinical trials. P. W. has consulted for EMMES and Pfizer and her institution has received funds to conduct clinical research unrelated to this manuscript from Pfizer, Glaxo Smith Kline, Sanofi-Pasteur, and Gilead as well as NIH. C. A. R.'s institution has received funds to conduct clinical research unrelated to this manuscript from the Centers for Disease Control and Prevention, BioFire Inc, GSK, MedImmune, Janssen, Merck, Moderna, Novavax, PaxVax, Pfizer, Regeneron, and Sanofi-Pasteur. She is co-inventor of patented respiratory syncytial virus vaccine technology, which has been licensed to Meissa Vaccines, Inc. C. M. K.'s institution has received funds to conduct clinical research unrelated to this manuscript from the CDC, Pfizer, Merck, and the NIH to conduct clinical trials of the Moderna COVID-19 vaccine. V. R. is currently employed by Pfizer, Inc., and works in vaccine clinical research unrelated to the current manuscript. This material reflects the personal views of the author and may not reflect the views of her current employer. M. J. M. reported these potential competing interests: laboratory research and clinical trials contracts for vaccines or MAB with Lilly, Pfizer, and Sanofi; contract funding from USG/HHS/BARDA for research specimen characterization and repository; research grant funding from USG/HHS/NIH for vaccine and MAB clinical trials; personal fees for Scientific Advisory Board service from Merck, Meissa Vaccines, Inc., and Pfizer. EBW has received funding support from Pfizer, Moderna, Sequiris, Najit Technologies Inc, and Clinetic for the conduct of clinical trials and clinical research. E. B. W. has served as an advisor to Vaxcyte and consultant to ILiAD biotechnologies. A. C. S.'s institution has received funds to conduct clinical research unrelated to this manuscript from NIH, HIV Vaccine Trials Network, COVID Vaccine Prevention Network, International AIDS Vaccine Initiative, Crucell/Janssen, Moderna, Pfizer, and Sanofi-Pasteur. S. K.'s institution has received funds to conduct clinical research and vaccine trials unrelated to this manuscript from the CDC, Pfizer, Meissa, Emergent BioSolutions, and the NIH. I. Y. reported being a member of the NIAID/COVPN mRNA-1273 Study Group and her institution received funding to conduct clinical research from NIH, Gates Foundation, Centers for Disease Control and Prevention, Pfizer, and Moderna outside the submitted work. She has consulted for Merck, Sanofi-Pasteur, and UptoDate. S. E. F. has received funding to conduct research from Novartis, Moderna, Janssen, Pfizer, and Bavarian Nordic and is a member of the HIV Vaccine Trials Network safety monitoring board. G. A. has received funding to conduct research from Bavarian Nordic. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)