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Quadrivalent recombinant influenza vaccine (RIV4) is indicated for active immunization against influenza virus in adults (≥18 years) in countries where it is currently registered. This Phase III, parallel, randomized, modified double-blind, active controlled, multi-center study was designed to compare the immunogenicity and safety of single dose intramuscular RIV4 with a locally–licensed quadrivalent–inactivated influenza vaccine (IIV4, Fluarix® quadrivalent) in participants aged ≥18 years during 2021–22 Northern Hemisphere influenza season at three tertiary care centers in South Korea. Participants were randomized (1:1) to receive single dose intramuscular RIV4 or IIV4. All participants were centrally assigned to randomized study intervention using an interactive response technology (IRT). Participants, investigators, and the staff in-charge of the sampling, safety assessment and immunogenicity assays were blinded. The overall mean age of 300 participants who completed the study was 46.1 years. The post-vaccination geometric mean fold-rise of HAI antibodies were 32.0, 13.2, 6.1, and 5.3 in RIV4 group, and 22.3, 8.0, 4.7, and 3.4 in IIV4 group for the A/H1N1, A/H3N2, B/Victoria lineage, and B/Yamagata lineage strains, respectively. Seroconversion in RIV4 was comparable or higher than IIV4. Neither immediate unsolicited AEs were reported within 30 min of vaccination nor SAEs, AESIs nor deaths were reported during the 6-month follow-up. Clinical Trial Registration:ClinicalTrials.gov number – NCT05144945.

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.

Background. Influenza vaccine effectiveness is not optimal in solid organ transplant recipients (SOTR). We hypothesized that a booster dose might increase it. Methods. TRANSGRIPE 1–2 is a phase 3, randomized, controlled, multicenter, open-label clinical trial. Patients were randomly assigned (1:1 stratified by study site, type of organ, and time since transplantation) to receive 1 dose (control group) or 2 doses (booster group) of the influenza vaccine 5 weeks apart. Results. A total of 499 SOTR were enrolled. Although seroconversion at 10 weeks did not meet significance in the modified intention-to-treat population, seroconversion rates were significantly higher in the booster arm for the per-protocol population (53.8% vs 37.6% for influenza A(H1N1)pdm; 48.1% vs 32.3% for influenza A(H3N2); and 90.7% vs 75% for influenza B; P < .05). Furthermore, seroprotection at 10 weeks was higher in the booster group: 54% vs 43.2% for A(H1N1)pdm; 56.9% vs 45.5% for A(H3N2); and 83.4% vs 71.8% for influenza B (P < .05). The number needed to treat to seroprotect 1 patient was <10. The clinical efficacy (99.2% vs 98.8%) and serious adverse events (6.4% vs 7.5%) were similar for both groups. Conclusions. In SOTR, a booster strategy 5 weeks after standard influenza vaccination is safe and effective and induces an increased antibody response compared with standard influenza vaccination consisting of a single dose. Clinical Trials Registration. EudraCT (2011-003243-21).

•aQIV-associated GMTs and seroconversion rates are noninferior to those of aTIV.•aQIV immunogenicity is superior for B strains not included in aTIV.•aQIV was well tolerated in adults aged ≥65 years.•aQIV is suitable for vaccination of adults aged ≥65 years. Evaluate whether adjuvanted quadrivalent influenza vaccine (aQIV) elicits a noninferior immune response compared with a licensed adjuvanted trivalent influenza vaccine (aTIV-1; Fluad™) and aTIV-2 containing an alternate B strain, examine whether aQIV had immunological superiority for the B strain absent from aTIV comparators, and evaluate reactogenicity and safety among adults ≥65 years. In a multicenter, double-blind, randomized controlled trial, adults ≥65 years were randomized 2:1:1 to vaccination with aQIV (n = 889), aTIV-1 (n = 445), or aTIV-2 (n = 444) during the 2017-2018 influenza season. Immunogenicity was assessed by hemagglutination inhibition (HI) assay conducted on serum samples collected before vaccination and 21 days after vaccination for homologous influenza strains. aQIV met non-inferiority criteria for geometric mean titer ratios (GMT ratios) and seroconversion rate (SCR) differences against aTIV. The upper bounds of the 2-sided 95% confidence interval (CI) for GMT ratios were <1.5 for all 4 strains (A/H1N1 = 1.27, A/H3N2 = 1.09, B-Yamagata = 1.08, B-Victoria = 1.08). The upper bounds of the 95% CI of the SCR differences were <10% for all 4 strains (A/H1N1 = 7.76%, A/H3N2 = 4.96%, B-Yamagata = 3.27%, B-Victoria = 2.55%). aQIV also met superiority criteria (upper bound of 95% CI for GMT ratios <1 and SCR differences <0) for B strain absent from aTIV comparators (B-Yamagata GMT ratio = 0.70, SCR difference = −8.81%; B-Victoria GMT ratio = 0.78, SCR difference = −8.11%). aQIV and aTIV vaccines were immunogenic and well-tolerated. The immunological benefit of aQIV was also demonstrated in age subgroups 65–74 years, 75–84 years, and ≥85 years and in those with high comorbidity risk scores. Reactogenicity profiles were generally comparable. aQIV induces a similar immune response as the licensed aTIV vaccine against homologous influenza strains and has a comparable reactogenicity and safety profile. Superior immunogenicity against the additional B strain was observed, indicating that aQIV could provide a broader protection than aTIV against influenza in older adults (NCT03314662).

Recently, the World Health Organization confirmed 120 new human cases of avian H7N9 influenza in China resulting in 37 deaths, highlighting the concern for a potential pandemic and the need for an effective, safe, and high-speed vaccine production platform. Production speed and scale of mRNA-based vaccines make them ideally suited to impede potential pandemic threats. Here we show that lipid nanoparticle (LNP)-formulated, modified mRNA vaccines, encoding hemagglutinin (HA) proteins of H10N8 (A/Jiangxi-Donghu/346/2013) or H7N9 (A/Anhui/1/2013), generated rapid and robust immune responses in mice, ferrets, and nonhuman primates, as measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays. A single dose of H7N9 mRNA protected mice from a lethal challenge and reduced lung viral titers in ferrets. Interim results from a first-in-human, escalating-dose, phase 1 H10N8 study show very high seroconversion rates, demonstrating robust prophylactic immunity in humans. Adverse events (AEs) were mild or moderate with only a few severe and no serious events. These data show that LNP-formulated, modified mRNA vaccines can induce protective immunogenicity with acceptable tolerability profiles. Potential pandemic influenzas and the need for an effective, safe, and high-speed vaccine production platform have been widely discussed in the scientific community. Bahl et al. report the rapid and robust immune responses achieved against H10N8 and H7N9 viruses from modified mRNA vaccines with an acceptable safety profile.

Randomized comparison of immunogenicity and safety of quadrivalent recombinant versus inactivated vaccine in young adults showed overall comparable antibody titers to vaccine strains, including higher responses to influenza A/H3N2 consistent with better efficacy previously reported in adults 50 or older. Abstract Background Seasonal influenza vaccines are transitioning to quadrivalent formulations including the hemagglutinins of influenza A subtypes H1N1 and H3N2 and B lineages Yamagata and Victoria. Methods A new quadrivalent recombinant influenza vaccine (RIV4) was compared directly with a standard-dose, egg-grown, quadrivalent-inactivated influenza vaccine (IIV4) for immunogenicity and safety in adults 18–49 years of age. The coprimary endpoints for noninferiority were hemagglutination inhibition seroconversion rates and postvaccination geometric mean titer ratios for each antigen using US regulatory criteria. Reactogenicity solicited for 7 days, other safety events collected for 28 days, and serious or medically attended adverse events collected for 6 months after vaccination comprised the safety evaluation. Results The immunogenicity of RIV4 was comparable to that of IIV4; the coprimary noninferiority criteria were met for 3 antigens, and the antibody responses to the fourth antigen, influenza B/Brisbane/60/2008, were low in each group, making comparisons uninterpretable. Systemic and injection site reactions were mild, transient, and similar in each group, whereas none of the spontaneously reported adverse events, serious or nonserious, were considered related to study vaccine. Conclusions This first head-to-head comparison of recombinant versus inactivated quadrivalent influenza vaccines in 18–49 year old adults showed comparable immunogenicity, safety, and tolerability for both vaccines.

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.

Messenger RNA (mRNA)-based influenza vaccines have the potential to improve upon limitations of current vaccine approaches to seasonal influenza. Here we report findings on the primary and secondary objectives of the safety, reactogenicity, and humoral immunogenicity of the quadrivalent mRNA vaccine, mRNA-1010, versus licensed standard-dose and high-dose quadrivalent influenza vaccines from a three-part, phase 3 clinical trial in adults aged ≥18 years (Part A), 18–64 years (Part B), and ≥ 65 years (Part C) (NCT05827978). A single 50-μg dose of mRNA-1010 elicited hemagglutination inhibition titers against vaccine-matched strains that were statistically noninferior and superior to licensed standard-dose and high-dose egg-based quadrivalent vaccine comparators. Solicited adverse reactions were more frequent with receipt of mRNA-1010; adverse reactions were lower in frequency and severity among adults aged ≥65 years than younger adults. No safety concerns were identified. These findings support the potential benefit of mRNA-1010 as a seasonal influenza vaccine. •Seasonal influenza viral infections are a global health concern.•mRNA platform may improve upon limitations of current influenza vaccine technology.•mRNA-1010 is an mRNA-based vaccine targeting seasonal influenza A and B strains.•mRNA-1010 elicited strong immune responses in adults of all ages.•No safety concerns were identified with mRNA-1010 in this phase 3 study.

Improving the efficacy of influenza vaccination in older adults is a challenge. In this randomized clinical trial, a high-dose influenza vaccine was shown to be more effective than a standard-dose vaccine in the prevention of laboratory-confirmed influenza. Between 1990 and 1999, seasonal influenza caused an average of 36,000 deaths and 226,000 hospitalizations per year in the United States. 1 – 3 Adults 65 years of age or older are particularly vulnerable to complications associated with influenza and account for most seasonal influenza–related hospitalizations and deaths. 2 , 3 Although vaccination currently represents the most effective intervention against influenza and associated complications, 3 , 4 antibody response and protection elicited by the vaccine are lower among persons 65 years of age or older than among younger adults. 5 – 7 Strategies to improve antibody responses to influenza vaccine in the older population, such as increasing the . . .

Disease caused by Streptococcus pneumoniae is associated with considerable morbidity and mortality in adults. V116 is an approved 21-valent pneumococcal conjugate vaccine with a serotype composition designed to address the majority of residual pneumococcal disease in adults. This phase 3 study evaluated the safety, tolerability, and immunogenicity of V116 when administered concomitantly with quadrivalent influenza vaccine (QIV) in adults. A total of 1080 healthy adults ≥ 50 years of age were randomized 1:1 to receive QIV and V116 concomitantly (n = 540) or QIV followed by V116 30 days later (n = 540). Immunogenicity was evaluated at 30 days postvaccination using opsonophagocytic activity (OPA) geometric mean titers (GMTs) and immunoglobulin G (IgG) geometric mean concentrations (GMCs) for V116, and hemagglutination inhibition (HAI) GMTs for QIV. For V116, the statistical criterion for noninferiority between groups required the lower bound of the 2-sided 95 % confidence interval of the OPA GMT ratio (concomitant/sequential groups) to be > 0.5. For QIV, the statistical criterion for noninferiority required the lower bound of the 2-sided 95 % CI of the HAI GMT ratio (concomitant/sequential groups) to be >0.67. Safety was evaluated by the proportion of participants with adverse events (AEs). The concomitant group met the primary noninferiority immunogenicity endpoints for 20 of 21 serotypes in V116 and for 3 of 4 influenza strains in QIV; noninferiority criteria were narrowly missed for serotype 23B and influenza H3N2. IgG GMCs at 30 days postvaccination were generally comparable between groups for all V116 serotypes. The proportions of participants with injection-site, systemic, vaccine-related, and serious AEs were generally comparable between groups. In adults ≥ 50 years of age, V116 is well tolerated and immunogenic when given concomitantly with QIV. Study results support use of V116 with QIV.