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Despite vaccine availability, influenza remains a substantial global public health concern. Here, we report interim findings on the primary and secondary objectives of the safety, reactogenicity, and humoral immunogenicity of a quadrivalent messenger RNA (mRNA) vaccine against seasonal influenza, mRNA-1010, from the first 2 parts of a 3-part, first-in-human, phase 1/2 clinical trial in healthy adults aged ≥18 years (NCT04956575). In the placebo-controlled Part 1, a single dose of mRNA-1010 (50 µg, 100 µg, or 200 µg) elicited hemagglutination inhibition (HAI) titers against vaccine-matched strains. In the active-comparator-controlled Part 2, mRNA-1010 (25 µg, 50 µg, or 100 µg) elicited higher HAI titers than a standard dose, inactivated seasonal influenza vaccine for influenza A strains and comparable HAI titers for influenza B strains. No safety concerns were identified; solicited adverse reactions were dose-dependent and more frequent after receipt of mRNA-1010 than the active comparator. These interim data support continued development of mRNA-1010. Here the authors report initial findings of a phase 1 clinical trial, showing that an investigational, mRNA-based vaccine for seasonal influenza (mRNA-1010) has no safety concerns and produces immune responses in adults that are similar or higher than a licensed comparator vaccine.

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.

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.

Background.Staphylococcal menstrual toxic shock syndrome depends on vaginal production of exotoxins. Glycerol monolaurate (GML) inhibits Staphylococcus aureus exotoxin production in vitro. The purpose of this study was to determine whether GML, as a tampon fiber finish, inhibits production of exotoxins and the cytokine interleukin 8 (IL-8) during normal tampon use. Methods.On day 2 of menstruation, when vaginal S. aureus counts are high in colonized women, study participants exchanged their own preferred tampons, after wearing them for 2–6 h, for study tampons with or without GML (assigned randomly and blindly), which they then wore for 4–6 h. The women's own tampons and the study tampons with or without GML were assayed for S. aureus, the exotoxins toxic shock syndrome toxin 1 and α-toxin, and IL-8. Results.A total of 225 women completed the study. S. aureus was present in the tampons of 41 women (18%). Lower numbers of S. aureus and the exotoxins were detected in study tampons with or without GML than in women's own tampons; lower amounts of the exotoxins were present in study tampons with GML than study tampons without GML. The IL-8 level was lower in tampons from women without vaginal S. aureus compared with women with S. aureus and was lower in study tampons with GML than in study tampons without GML. Conclusions.Tampons that contain GML reduce S. aureus exotoxin production. S. aureus increases vaginal IL-8 levels, and GML reduces production of this proinflammatory cytokine. These results suggest that GML added to tampons provides additional safety relative to menstrual toxic shock syndrome as well as benefits for vaginal health generally, thus supporting the addition of GML to tampons.

Staphylococcus aureus is a major cause of infective endocarditis (IE) and sepsis. Both methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) strains cause these illnesses. Common S. aureus strains include pulsed-field gel electrophoresis (PFGE) types USA200, 300, and 400 types where we hypothesize that secreted virulence factors contribute to both IE and sepsis. Rabbit cardiac physiology is considered similar to humans, and rabbits exhibit susceptibility to S. aureus superantigens (SAgs) and cytolysins. As such, rabbits are an excellent model for studying IE and sepsis, which over the course of four days develop IE vegetations and/or fatal septicemia. We examined the ability of MRSA and MSSA strains (4 USA200, 2 USA300, 2 USA400, and three additional common strains, FRI1169, Newman, and COL) to cause vegetations and lethal sepsis in rabbits. USA200, TSST-1(+) strains that produce only low amounts of α-toxin, exhibited modest LD(50) in sepsis (1 × 10(8) - 5 × 10(8)) colony-forming units (CFUs), and 3/4 caused significant IE. USA200 strain MNPE, which produces high-levels of α-toxin, was both highly lethal (LD(50) 5 × 10(6) CFUs) and effective in causing IE. In contrast, USA300 strains were highly effective in causing lethal sepsis (LD(50)s 1 × 10(6) and 5 × 10(7) CFUs) but were minimally capable of causing IE. Strain Newman, which is phylogenetically related to USA300 strains, was not highly lethal (LD(50) of 2 × 10(9) CFUs) and was effective in causing IE. USA400 strains were both highly lethal (LD(50)s of 1 × 10(7) and 5 × 10(7) CFUs) and highly effective causes of IE. The menstrual TSS isolate FRI1169, that is TSST-1(+), produces high-levels of α-toxin, but is not USA200, was both highly lethal and effective in causing IE. Additional studies showed that phenol soluble modulins (PSMs) produced by FRI1169 were important for sepsis but did not contribute to IE. Our studies show that these clonal groups of S. aureus differ in abilities to cause IE and lethal sepsis and suggest that secreted virulence factors, including SAgs and cytolysins, account for some of these differences.

Staphylococcus aureus is a major cause of infective endocarditis (IE) and sepsis. In addition, 50% of IE survivors develop strokes and metastatic abscesses due to the release of emboli from infected valves. Both methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) strains cause IE and sepsis, and they may be categorized by pulsed-field gel electrophoresis, for example clonal types USA200, 300, and 400. We hypothesize that secreted virulence factors contribute to their differential ability to cause IE and/or sepsis. Rabbits are an excellent model for studying IE, which over the course of 4 days are monitored for development of vegetations (the hallmark signs of IE), and sepsis, as S. aureus are administered intravenously. Rabbit cardiac physiology is similar to humans, and rabbits exhibit susceptibility to superantigens and cytolysins produced by these clonal types of S. aureus. We examined the differential ability of community-associated MRSA and MSSA strains (5 USA200 or related strain FRI1169, 3 USA300, and 2 USA400) to cause vegetations versus lethal sepsis in rabbits. USA200 and related strain FRI1169 exhibited intermediate LD50s in sepsis (5x106-5x108) colony-forming units (CFUs), and 4/5 caused significant IE. In contrast, USA300 strains were highly effective in causing lethal sepsis (LD50s of 1 x 106-5 x 107 CFUs) but were minimally capable of causing IE. USA300 variant strain Newman was not highly lethal (LD50 of 2 x 109 CFUs) but was highly effective in causing IE. USA400 strains were both highly lethal (LD50s of 1 x 107-5 x 107 CFUs) and highly effective causes of IE. Additional studies showed that phenol soluble modulins produced by FRI1169 were important for sepsis but did not contribute to IE. Our studies show that these clonal groups of S. aureus have differential abilities to cause IE and lethal sepsis and suggest that secreted virulence factors, including superantigens and cytolysins, account for these differences.