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In a multinational trial in children, a quadrivalent influenza vaccine (with both Victoria and Yamagata influenza B lineages, only one of which is included in the current trivalent vaccine) had about 59% efficacy. The incidence of influenza among children is high, and the illness is associated with substantial increases in outpatient visits and hospitalizations during the influenza season. 1 – 4 Routine vaccination of children against influenza is recommended in the United States 5 and some other countries, despite limited evidence of the efficacy of inactivated influenza vaccine from randomized, controlled trials involving children. 6 When trivalent influenza vaccines (TIVs) are used, there is a possibility of a mismatch between circulating and vaccine B strains, which results in inadequate protection from the vaccine. 7 – 10 A quadrivalent vaccine containing both B lineages would eliminate B-lineage mismatch. This may . . .

Inclusion of additional influenza A/H3N2 strains in seasonal influenza vaccines could expand coverage against multiple, antigenically distinct, cocirculating A/H3N2 clades and potentially replace the no longer circulating B/Yamagata strain. We aimed to evaluate the safety and immunogenicity of three next-generation seasonal influenza mRNA vaccines with different compositions that encode for haemagglutinins of multiple A/H3N2 strains, with or without the B/Yamagata strain, in adults. This randomised, open-label, phase 1/2 trial enrolled healthy adults aged 50–75 years across 22 sites in the USA. Participants were randomly assigned (1:1:1:1:1:1:1) via interactive response technology to receive a single dose of mRNA-1011.1 (pentavalent; containing one additional A/H3N2 strain [Newcastle]), mRNA-1011.2 (quadrivalent; B/Yamagata replaced with one additional A/H3N2 strain [Newcastle]), mRNA-1012 at one of two dose levels (pentavalent; B/Yamagata replaced with two additional A/H3N2 strains [Newcastle and Hong Kong]), or one of three quadrivalent mRNA-1010 controls each encoding one of the A/H3N2 study strains. The primary outcomes were safety, evaluated in all randomly assigned participants who received a study vaccination (safety population), and reactogenicity, evaluated in all participants from the safety population who contributed any solicited adverse reaction data (solicited safety population). The secondary outcome was humoral immunogenicity of investigational mRNA vaccines at day 29 versus mRNA-1010 control vaccines based on haemagglutination inhibition antibody (HAI) assay in the per-protocol population. Here, we summarise findings from the planned interim analysis after participants had completed day 29. The study is registered with ClinicalTrials.gov, NCT05827068, and is ongoing. Between March 27 and May 9, 2023, 1183 participants were screened for eligibility, 699 (59·1%) were randomly assigned, and 696 (58·8%) received vaccination (safety population, n=696; solicited safety population, n=694; per-protocol population, n=646). 382 (55%) of the 696 participants in the safety population self-reported as female and 314 (45%) as male. Frequencies of solicited adverse reactions were similar across vaccine groups; 551 (79%) of 694 participants reported at least one solicited adverse reaction within 7 days after vaccination and 83 (12%) of 696 participants reported at least one unsolicited adverse event within 28 days after vaccination. No vaccine-related serious adverse events or deaths were reported. All three next-generation influenza vaccines elicited robust antibody responses against vaccine-matched influenza A and B strains at day 29 that were generally similar to mRNA-1010 controls, and higher responses against additional A/H3N2 strains that were not included within respective mRNA-1010 controls. Day 29 geometric mean fold rises in HAI titres from day 1 against vaccine-matched A/H3N2 strains were 3·0 (95% CI 2·6–3·6; Darwin) and 3·1 (2·6–3·8; Newcastle) for mRNA-1011.1; 3·3 (2·7–4·1; Darwin) and 4·2 (3·4–5·2; Newcastle) for mRNA-1011.2; 3·4 (2·9–4·0; Darwin), 4·5 (3·6–5·5; Newcastle), and 5·1 (4·2–6·2; Hong Kong) for mRNA-1012 50·0 μg; and 2·6 (2·2–3·1; Darwin), 3·7 (3·0–4·6; Newcastle), and 4·1 (3·3–5·1; Hong Kong) for mRNA-1012 62·5 μg. Inclusion of additional A/H3N2 strains did not reduce responses against influenza A/H1N1 or influenza B strains, and removal of B/Yamagata did not affect responses to B/Victoria. These data support the continued clinical development of mRNA-based next-generation seasonal influenza vaccines with broadened influenza A/H3N2 strain coverage. Moderna.

Influenza epidemics cause substantial morbidity. The seasonal vaccine, an important control measure, is not completely efficacious. This trial assessed the efficacy of a recombinant seasonal vaccine (made in a cell culture rather than with viruses grown in eggs). Reducing the burden of influenza disease requires improved vaccines, and a recombinant influenza vaccine may contribute to this public-health goal. 1 This vaccine contains recombinant hemagglutinin (HA) proteins produced in a serum-free medium by expres SF+ cells. These cells contain recombinant baculovirus vectors carrying genes that code for HA. The process yields recombinant HA that is genetically identical to the selected influenza strains without extraneous egg proteins, formaldehyde, antibiotics, or preservatives. Influenza viruses are grown in eggs to produce the inactivated influenza vaccine (IIV); these viruses typically contain mutations in the genes that code for HA that may reduce vaccine effectiveness. . . .

In this randomized trial conducted over the 2019–2024 influenza seasons, baloxavir resulted in a significantly lower incidence of transmission of influenza virus from patients to household contacts than placebo.

We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. We did a randomised trial in 15 countries worldwide during the 2008–09 (year 1) and 2009–10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65–74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT00753272. We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 [1·27%, 95% CI 1·12–1·43] of 21 573 vs 310 [1·44%, 1·29–1·61] of 21 482; relative efficacy 12·11%, 95% CI −3·40 to 25·29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 [1·04%, 95% CI 0·91–1·18] vs 270 [1·26, 1·11–1·41]; relative efficacy 17·53%, 95% CI 1·55–30·92) and influenza A H3N2 (170 [0·79, 0·67–0·92] vs 205 [0·95, 0·83–1·09]; post-hoc analysis relative efficacy 22·0%, 95% CI 5·68–35·49). AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints. GlaxoSmithKline Biologicals SA.

Vaccine effectiveness estimates for 2015–2016 seasonal influenza vaccine are reported from Canada. Findings suggest that agent-host and immuno-epidemiologic factors beyond antigenic match—including viral genomic variation, birth (immunological) cohort effects, repeat vaccination, and potential within-season waning immunity—may influence vaccine performance. Abstract Background Vaccine effectiveness (VE) estimates for 2015–2016 seasonal influenza vaccine are reported from Canada’s Sentinel Practitioner Surveillance Network (SPSN). This season was characterized by a delayed 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) epidemic and concurrent influenza B(Victoria) virus activity. Potential influences on VE beyond antigenic match are explored, including viral genomic variation, birth cohort effects, prior vaccination, and epidemic period. Methods VE was estimated by a test-negative design comparing the adjusted odds ratio for influenza test positivity among vaccinated compared to unvaccinated participants. Vaccine-virus relatedness was assessed by gene sequencing and hemagglutination inhibition assay. Results Analyses included 596 influenza A(H1N1)pdm09 and 305 B(Victoria) cases and 926 test-negative controls. A(H1N1)pdm09 viruses were considered antigenically related to vaccine (unchanged since 2009), despite phylogenetic clustering within emerging clade 6B.1. The adjusted VE against A(H1N1)pdm09 was 43% (95% confidence interval [CI], 25%–57%). Compared to other age groups, VE against A(H1N1)pdm09 was lower for adults born during 1957–1976 (25%; 95% CI, −16%–51%). The VE against A(H1N1)pdm09 was also lower for participants consecutively vaccinated during both the current and prior seasons (41%; 95% CI, 18%–57%) than for those vaccinated during the current season only (75%; 95% CI, 45%–88%), and the VE among participants presenting in March–April 2016 (19%; 95% CI, −15%–44%) was lower than that among those presenting during January–February 2016 (62%; 95% CI, 44%–74%). The adjusted VE for B(Victoria) viruses was 54% (95% CI, 32%–68%), despite lineage-level mismatch to B(Yamagata) vaccine. The further variation in VE as observed for A(H1N1)pdm09 was not observed for B(Victoria). Conclusions Influenza VE findings may require consideration of other agent-host and immuno-epidemiologic influences on vaccine performance beyond antigenic match, including viral genomic variation, repeat vaccination, birth (immunological) cohort effects, and potential within-season waning of vaccine protection.

Background. Data on the efficacy of trivalent, inactivated influenza vaccine (TIV) in HIV-infected adults, particularly in Africa, are limited. This study evaluated the safety, immunogenicity, and efficacy of TIV in HIV-infected adults. Methods. In Johannesburg, South Africa, we undertook a randomized, double-blind, placebo-controlled trial involving 506 HIV-infected adults. Subjects included 157 individuals who were antiretroviral treatment (ART) naive and 349 on stable-ART. Participants were randomly assigned to receive TIV or normal saline intramuscularly. Oropharyngeal swabs were obtained at illness visits during the influenza season and tested by shell vial culture and RT PCR assay for influenza virus. Immune response was evaluated by hemagglutinin antibody inhibition assay (HAI) in a nested cohort. The primary study outcome involved vaccine efficacy against influenza confirmed illness. This trial is registered with ClinicalTrials.gov, number NCT00757900. Results. The efficacy of TIV against confirmed influenza illness was 75.5% (95% CI: 9.2%—95.6%); with a risk difference of 0.18 per 100 person-weeks in TIV recipients. Among TIV recipients, seroconversion, measured by HAI titers, was evident in 52.6% for H1N1, 60.8% for H3N2, and 53.6% for influenza B virus. This compared with 2.2%, 2.2%, and 4.4% of placebo recipients (P < .0001). The frequency of local and systemic adverse events postimmunization was similar between study groups. Conclusions. TIV immunization is safe and efficacious in African HIV-infected adults without underlying comorbidities. Further evaluation of effectiveness is warranted in severely immunocompromized HIV-infected adults and those with co-morbidities such as tuberculosis.

We describe the epidemiological characteristics, pattern of circulation, and geographical distribution of influenza B viruses and its lineages using data from the Global Influenza B Study. We included over 1.8 million influenza cases occurred in thirty-one countries during 2000-2018. We calculated the proportion of cases caused by influenza B and its lineages; determined the timing of influenza A and B epidemics; compared the age distribution of B/Victoria and B/Yamagata cases; and evaluated the frequency of lineage-level mismatch for the trivalent vaccine. The median proportion of influenza cases caused by influenza B virus was 23.4%, with a tendency (borderline statistical significance, p = 0.060) to be higher in tropical vs. temperate countries. Influenza B was the dominant virus type in about one every seven seasons. In temperate countries, influenza B epidemics occurred on average three weeks later than influenza A epidemics; no consistent pattern emerged in the tropics. The two B lineages caused a comparable proportion of influenza B cases globally, however the B/Yamagata was more frequent in temperate countries, and the B/Victoria in the tropics (p = 0.048). B/Yamagata patients were significantly older than B/Victoria patients in almost all countries. A lineage-level vaccine mismatch was observed in over 40% of seasons in temperate countries and in 30% of seasons in the tropics. The type B virus caused a substantial proportion of influenza infections globally in the 21st century, and its two virus lineages differed in terms of age and geographical distribution of patients. These findings will help inform health policy decisions aiming to reduce disease burden associated with seasonal influenza.

Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift 1 and suboptimal immune responses 2 . Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses. The neuraminidase-targeting monoclonal antibody FNI9 potently inhibits the enzymatic activity of influenza A and B viruses via receptor mimicry.

Influenza viruses undergo continual antigenic evolution allowing mutant viruses to evade host immunity acquired to previous virus strains. Antigenic phenotype is often assessed through pairwise measurement of cross-reactivity between influenza strains using the hemagglutination inhibition (HI) assay. Here, we extend previous approaches to antigenic cartography, and simultaneously characterize antigenic and genetic evolution by modeling the diffusion of antigenic phenotype over a shared virus phylogeny. Using HI data from influenza lineages A/H3N2, A/H1N1, B/Victoria and B/Yamagata, we determine patterns of antigenic drift across viral lineages, showing that A/H3N2 evolves faster and in a more punctuated fashion than other influenza lineages. We also show that year-to-year antigenic drift appears to drive incidence patterns within each influenza lineage. This work makes possible substantial future advances in investigating the dynamics of influenza and other antigenically-variable pathogens by providing a model that intimately combines molecular and antigenic evolution. Every year, seasonal influenza, commonly called flu, infects up to one in five people around the world, and causes up to half a million deaths. Even though the human immune system can detect and destroy the virus that causes influenza, people can catch flu many times throughout their lifetimes because the virus keeps evolving in an effort to avoid the immune system. This antigenic drift—so-called because the antigens displayed by the virus keep changing—also explains why influenza vaccines become less effective over time and need to be reformulated every year. It is possible to determine which antigens are displayed by a new strain of the virus by observing how blood samples that respond to known strains respond to the new strain. This information about the “antigenic phenotype” of the virus can be plotted on an antigenic map in which strains with similar antigens cluster together. Gene sequencing has shown that there are four subtypes of the flu virus that commonly infect people; but the relationship between changes in antigenic phenotype and changes in gene sequences of the influenza virus is poorly understood. Bedford et al. have now developed an approach to combine antigenic maps with genetic information about the four subtypes of the human flu virus. This revealed that the antigenic phenotype of H3N2—a subtype that is becoming increasingly common—evolved faster than the other three subtypes. Further, a correlation was observed between antigenic drift and the number of new influenza cases per year for each flu strain. This suggests that knowing which antigenic phenotypes are present at the start of flu season could help predict which strains of the virus will predominate later on. The work of Bedford et al. provides a useful framework to study influenza, and could help to pinpoint which changes in viral genes cause the changes in antigens. This information could potentially speed up the development of new flu vaccines for each flu season.