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Several vaccines are approved in the United States for seasonal influenza vaccination every year. Here we compare the impact of repeat influenza vaccination on hemagglutination inhibition (HI) titers, antibody binding and affinity maturation to individual hemagglutinin (HA) domains, HA1 and HA2, across vaccine platforms. Fold change in HI and antibody binding to HA1 trends higher for H1N1pdm09 and H3N2 but not against B strains in groups vaccinated with FluBlok compared with FluCelvax and Fluzone. Antibody-affinity maturation occurs against HA1 domain of H1N1pdm09, H3N2 and B following vaccination with all vaccine platforms, but not against H1N1pdm09-HA2. Importantly, prior year vaccination of subjects receiving repeat vaccinations demonstrated reduced antibody-affinity maturation to HA1 of all three influenza virus strains irrespective of the vaccine platform. This study identifies an important impact of repeat vaccination on antibody-affinity maturation following vaccination, which may contribute to lower vaccine effectiveness of seasonal influenza vaccines in humans Here, Khurana et al. report the results of a phase 4 clinical trial with three FDA approved influenza vaccines and show that repeat influenza vaccination results in reduced antibody affinity maturation to hemagglutinin domain 1 irrespective of vaccine platform.

High-dose inactivated influenza vaccine has been shown to provide protection against influenza that is superior to that with the standard dose. However, data from individually randomized trials on the effectiveness of the high-dose vaccine against severe outcomes are limited. In this pragmatic, open-label, randomized, controlled trial conducted in Denmark during the 2022-2023, 2023-2024, and 2024-2025 influenza seasons, we assigned older adults (≥65 years of age) to receive the high dose of the inactivated influenza vaccine or the standard dose. Data collection relied on nationwide administrative health registries. The primary end point was hospitalization for influenza or pneumonia that occurred from 14 days after vaccination through May 31 of the following year. Of the 332,438 participants who underwent randomization, 166,218 were assigned to receive the high-dose vaccine and 166,220 to receive the standard-dose vaccine. The mean (±SD) age of the participants was 73.7±5.8 years, and 161,538 participants (48.6%) were women. A primary end-point event occurred in 1138 participants (0.68%) in the high-dose group and in 1210 (0.73%) in the standard-dose group (relative vaccine effectiveness, 5.9%; 95.2% confidence interval [CI], -2.1 to 13.4; P = 0.14). Hospitalization for influenza occurred in 0.06% of the participants in the high-dose group and in 0.11% of those in the standard-dose group (relative vaccine effectiveness, 43.6%; 95.2% CI, 27.5 to 56.3); hospitalization for pneumonia occurred in 0.63% and 0.63%, respectively (relative effectiveness, 0.5%; 95.2% CI, -8.6 to 8.8); hospitalization for cardiorespiratory disease in 2.25% and 2.38% (relative effectiveness, 5.7%; 95.2% CI, 1.4 to 9.9); hospitalization for any cause in 9.38% and 9.58% (relative effectiveness, 2.1%; 95.2% CI, -0.1 to 4.3), and death from any cause in 0.67% and 0.66% (relative effectiveness, -2.5%; 95.2% CI, -11.6 to 5.9). The incidence of serious adverse events was similar in the two groups. In this trial, a high-dose inactivated influenza vaccine did not result in a significantly lower incidence of hospitalization for influenza or pneumonia than a standard dose among older adults. (Funded by Sanofi; DANFLU-2 ClinicalTrials.gov number, NCT05517174; EU Clinical Trials Register number, 2022-500657-17-00.).

Influenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses. We did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime–boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050. Between Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2–5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis. The tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed. Bill & Melinda Gates Foundation.

In adults 65 to 79 years of age, there appeared to be fewer hospitalizations for influenza or pneumonia with high-dose influenza vaccine than with the standard dose, with a similar incidence of serious adverse events.

In a randomized, double-blind trial that treated household contacts of patients with influenza with a single dose of baloxavir or placebo, participants taking baloxavir had a lower risk of influenza (1.9%) than placebo controls (13.6%). Adverse events were similar in the two groups.

In phase 2 and 3 randomized, controlled trials, baloxavir — an inhibitor of influenza cap-dependent endonuclease — showed evidence of clinical symptom relief and antiviral activity against influenza. However, influenza-resistant variants appeared to develop with treatment.

Current influenza vaccines induce immune responses to hemagglutinin (HA), a surface glycoprotein of seasonal influenza viruses, but have suboptimal effectiveness. mRNA vaccines may improve protection by targeting additional antigens such as neuraminidase (NA), for which immune responses independently correlate with protection. In this phase 1/2 trial (NCT05333289), healthy adults 18–75 years were randomly assigned to receive different doses of mRNA-1020 or mRNA-1030 (encoding HA and NA at different ratios), mRNA-1010 (encoding HA), or a licensed active comparator (recombinant HA). Primary endpoints were safety and reactogenicity, and HA and NA antibody responses against vaccine-matched influenza strains. Most common local and systemic solicited ARs were injection site pain and fatigue. There were no vaccine-related serious adverse events nor significant associated safety concerns through 181 days. mRNA-1020 and mRNA-1030 elicited high HA-specific immune responses and induced NA-specific immune responses with no additional reactogenicity at equivalent dose levels beyond an mRNA-based, HA-only–containing vaccine. Improving neuraminidase content of influenza vaccines is a major focus of vaccine development. Here the authors present safety and immunogenicity of seasonal influenza mRNA vaccine candidates simultaneously encoding hemagglutinin and neuraminidase antigens in a first in-human study.

Influenza A viruses are believed to spread between humans through contact, large respiratory droplets and small particle droplet nuclei (aerosols), but the relative importance of each of these modes of transmission is unclear. Volunteer studies suggest that infections via aerosol transmission may have a higher risk of febrile illness. Here we apply a mathematical model to data from randomized controlled trials of hand hygiene and surgical face masks in Hong Kong and Bangkok households. In these particular environments, inferences on the relative importance of modes of transmission are facilitated by information on the timing of secondary infections and apparent differences in clinical presentation of secondary infections resulting from aerosol transmission. We find that aerosol transmission accounts for approximately half of all transmission events. This implies that measures to reduce transmission by contact or large droplets may not be sufficient to control influenza A virus transmission in households. Influenza A viruses spread through contact, large and small respiratory droplets (aerosols), but the relative importance of these modes of transmission is unclear. Cowling et al . model data from community trials of face masks and hand hygiene and find that aerosol transmission accounts for half of influenza occurrences.

Background The effect of corticosteroids on influenza A(H1N1)pdm09 viral pneumonia patients remains controversial, and the impact of dosage has never been studied. Methods Using data of hospitalized adolescent and adult patients with influenza A(H1N1)pdm09 viral pneumonia, prospectively collected from 407 hospitals in mainland China, the effects of low‐to‐moderate‐dose (25‐150 mg d−1) and high‐dose (>150 mg d−1) corticosteroids on 30‐day mortality, 60‐day mortality, and nosocomial infection were assessed with multivariate Cox regression and propensity score‐matched case–control analysis. Results In total, 2141 patients (median age: 34 years; morality rate: 15.9%) were included. Among them, 1160 (54.2%) had PaO2/FiO2<300 mm Hg on admission, and 1055 (49.3%) received corticosteroids therapy. Corticosteroids, without consideration of dose, did not influence either 30‐day or 60‐day mortality. Further analysis revealed that, as compared with the no‐corticosteroid group, low‐to‐moderate‐dose corticosteroids were related to reduced 30‐day mortality (adjusted hazard ratio [aHR] 0.64 [95% CI 0.43‐0.96, P=.033]). In the subgroup analysis among patients with PaO2/FiO2<300 mm Hg, low‐to‐moderate‐dose corticosteroid treatment significantly reduced both 30‐day mortality (aHR 0.49 [95% CI 0.32‐0.77]) and 60‐day mortality (aHR 0.51 [95% CI 0.33‐0.78]), while high‐dose corticosteroid therapy yielded no difference. For patients with PaO2/FiO2 ≥300 mm Hg, corticosteroids (irrespective of dose) showed no benefit and even increased 60‐day mortality (aHR 3.02 [95% CI 1.06‐8.58]). Results were similar in the propensity model analysis. Conclusions Low‐to‐moderate‐dose corticosteroids might reduce mortality of influenza A(H1N1)pdm09 viral pneumonia patients with PaO2/FiO2<300 mm Hg. Mild patients with PaO2/FiO2 ≥300 mm Hg could not benefit from corticosteroid therapy.

Background. Experience from treating patients with Spanish influenza and influenza A(H5N1) suggested that convalescent plasma therapy might be beneficial. However, its efficacy in patients with severe pandemic influenza A(H1N1) 2009 virus (H1N1 2009) infection remained unknown. Methods. During the period from 1 September 2009 through 30 June 2010, we conducted a prospective cohort study by recruiting patients aged ≥ 18 years with severe H1N1 2009 infection requiring intensive care. Patients were offered treatment with convalescent plasma with a neutralizing antibody titer of ≥1:160, harvested by apheresis from patients recovering from H1N1 2009 infection. Clinical outcome was compared with that of patients who declined plasma treatment as the untreated controls. Results. Ninety-three patients with severe H1N1 2009 infection requiring intensive care were recruited. Twenty patients (21.5%) received plasma treatment. The treatment and control groups were matched by age, sex, and disease severity scores. Mortality in the treatment group was significantly lower than in the nontreatment group (20.0% vs 54.8%; P = .01). Multivariate analysis showed that plasma treatment reduced mortality (odds ratio [OR], .20; 95% confidence interval [CI], .06-.69; P = .011), whereas complication of acute renal failure was independently associated with death (OR, 3.79; 95% CI, 1.15-12.4; P = .028). Subgroup analysis of 44 patients with serial respiratory tract viral load and cytokine level demonstrated that plasma treatment was associated with significantly lower day 3, 5, and 7 viral load, compared with the control group (P < .05). The corresponding temporal levels of interleukin 6, interleukin 10, and tumor necrosis factor α (P < .05) were also lower in the treatment group. Conclusions. Treatment of severe H1N1 2009 infection with convalescent plasma reduced respiratory tract viral load, serum cytokine response, and mortality.