Influenza

This is a randomized, blinded, controlled phase I clinical trial with a total of 120 participants aged ≥ 60 years. Experimental group: Influenza virus split vaccine (0.7mL/vial), control group 1: Influenza virus split vaccine, control group 2: placebo group. The three groups were recruited at a ratio of 1:1:1, and 40 individuals were randomly vaccinated in each group. Each person was injected with one dose of the vaccine into the deltoid muscle of the upper arm. Participants in each study group are required to undergo laboratory indicator tests before and on the 4th day after vaccination.

Several influenza antivirals are licensed, differing in availability and routes of administration. Direct comparisons of antiviral and clinical efficacy between the multiple available antivirals are lacking. This comparative information is important for guideline development and for aiding purchasing and prioritisation decisions with several options available. The platform trial will assess the following interventions: * Licensed influenza antiviral interventions: oseltamivir (TAMIFLU®), peramivir (RAPIVAB®), zanamivir (RELENZA®), laninamivir (INAVIR®), baloxavir (XOFLUZA®) and favipiravir alone and in combination. The interventions will be chosen in order of priority as well as local feasibility at sites (availability of drugs, local ethics committee and regulatory approvals) * Interventions with antiviral activity against influenza demonstrated in pre-clinical studies: molnupiravir Randomisation to the no antiviral treatment control arm (no intervention) will be fixed at a minimum of 20% throughout the study. The randomisation ratios will be uniform for all available interventions.

The purpose of this study is to evaluate humoral immunogenicity after 2 doses of mRNA-1018-H5, and to evaluate the safety and reactogenicity of mRNA-1018-H5 in adults ≥18 years of age.

This study consists of two parts: Part A Surveillance and Part B Transmission. The main purpose of Part A is to evaluate the prevalence of pre-dose and treatment-emergent amino acid substitutions in pediatric participants' susceptibility \<12 years with influenza treated with baloxavir marboxil. Part B will include a subset of Part A participants who have household contacts (HHCs) recruited to the study. Part B will evaluate the incidence of onward influenza transmission from pediatric index participants (IPs) under 5 years of age and those aged 5 to under 12 years, treated with baloxavir marboxil, to their HHCs.

Influenza A continues to circulate widely in the human population and causes significant morbidity and mortality. Current vaccines have variable effectiveness year-to-year, with observable breakthrough infections each season, and have limited effectiveness in certain at-risk members of the population. Although basic and clinical influenza research has broadened our understanding of viral immunology, transmission, and pathogenesis, important questions, particularly concerning correlates of protection, viral evolution, and transmission, remain unanswered. Many of these questions can only be approached through studies in humans. As more broadly protective vaccines are developed, efficient and comprehensive methods of determining their value will be imperative. One of the key components and gap-filling measures in the National Institute of Allergy and Infectious Diseases (NIAID) strategic plan for universal influenza vaccines is to expand our capacity to conduct human challenge studies with relevant influenza challenge viruses to facilitate early evaluation of new vaccines and to further our understanding of flu pathogenesis and immunity. The goal of this study is to conduct a human challenge study to build upon our success at establishing the influenza challenge model at Emory to better understand influenza pathogenesis, immunity, transmission, and evolution using an H3N2 challenge stock. Human challenge studies for influenza are a particularly attractive modality for the development of a universal influenza vaccine. As outlined by NIAID's strategic plan, a universal flu vaccine would be at least 75% effective, maintain protection for at least one year, protect against group I (e.g., H1, H5) and II (e.g., H3, H7) influenza A virus strains, and be effective for all age groups. ix The strategic plan also states that a human challenge model could offer unique benefits to better understand the concept of imprinting, determine correlates of protection against influenza, and evaluate different universal influenza vaccine candidates. The development of universal vaccine strategies that reduce transmission potential and can protect from infection by aerosolized viruses will be a strategic advantage for reducing the public health burden from influenza viruses.

In patients with positive airway sample for respiratory viruses, the investigators hypothesize that discontinuation of antibiotic therapy is safe and non-inferior to continuation of antibiotic therapy. More specifically, the investigators hypothesize that the early clinical response assessed at 120 hours after randomization, defined as survival with symptom improvement without receipt of rescue antibacterial therapy, will be similar between patients who discontinue and continue antibiotic therapy. Furthermore, the investigators hypothesize that discontinuation of antibiotic therapy is associated with similar mortality rates, duration of hospital admission and reduced number of defined daily doses of antibiotics. The primary aim is to assess whether discontinuation of antibiotic therapy in patients with positive airway sample for respiratory viruses is safe and associated with early clinical response assessed at 120 hours after randomization that is comparable to patients who continue antibiotic therapy. The secondary aims are to assess whether discontinuation of antibiotic therapy in patients with positive airway sample for respiratory viruses is associated comparable (1) mortality rates, (2) duration of hospital admission, (3) defined daily doses of antibiotic therapy. Specific objectives In patients with positive airway sample for respiratory viruses, assess the impact of discontinuing antibiotic therapy on early clinical response quantified as survival with symptom improvement without receipt of rescue antibacterial therapy. Early clinical response is defined as improvement of one or more levels relative to baseline in two or more symptoms of the investigator's assessment of symptoms of community-acquired bacterial pneumonia and no worsening of one or more levels in other symptoms.

This study is particularly focused on studying antibodies, a protein in blood that react with foreign substances (such as bacteria and viruses) to help eliminate them. This study will examine antibodies and the cells that they are produced by, B cells that develop in response to the influenza vaccine. The majority of antibodies that develop following seasonal influenza vaccine are highly specific for particular influenza strain that comprises the influenza vaccine, necessitating the annual reformulation of the influenza vaccine to match strains expected to be in circulation for the upcoming season. This is problematic, and strategies to develop an influenza vaccine that can promote the robust and persistent development of antibodies that are effective against a wide range of influenza strains are needed. One potential strategy is to promote antibody responses targeting the neuraminidase (NA) protein of influenza. NA is more highly conserved across influenza viruses as compared to the hemagglutinin (HA) protein which is the major component of the influenza vaccine. Thus understanding how differences in seasonal influenza vaccines may influence the quality and breadth of HA and NA specific antibodies is of importance in the development of more effective influenza vaccines. There are several FDA-approved seasonal inactivated influenza vaccines (IIVs) and it remains unknown the extent to which they may induce HA and NA-specific B cells and antibodies, and particularly those that may have broad protective activity against influenza. Differences in the various seasonal IIVs, such as how they were produced, their dose, and the immune stimulating components (adjuvant) they contain may influence the HA and NA-specific response. The two major types of seasonal IIV approved for adults are IIV that is comprised of inactivated influenza virus that was grown in chicken eggs (e.g. Sanofi Fluzone, IIV), and the other comprised of inactivated influenza virus that was grown in cell culture (e.g. Seqirus Flucelvax, cc-IIV). Additionally, for adults 65 years and older, High Dose Fluzone (HD-IIV3), and Sequris Fluad IIV, which includes an adjuvant (a-IIV3). This study will evaluate the relative induction of HA and NA-specific antibodies and B cells from adults immunized with these various seasonal influenza vaccines, and how these responses may change after each year, and differ in older adults who may have a different past exposure history to influenza compared to younger adults. The seasonal influenza vaccines will be given as standard of care, in populations they are approved for, and administered in approved dose and route.

PRIMARY OBJECTIVE: I. To compare the efficacy of baloxavir marboxil (baloxavir) in combination with oseltamivir to oseltamivir monotherapy as measured by changes in influenza viral loads at day 1 from baseline for treatment of severe influenza infections in immunocompromised hosts (such as hematopoietic cell transplant \[HCT\] recipients and hematological malignancy \[HM\] patients) and compare the main clinical outcome, complicated hospital stay between the intervention arm and control arm. SECONDARY OBJECTIVES: I. To compare the efficacy of baloxavir in combination with oseltamivir to oseltamivir monotherapy as measured by changes in influenza viral loads at day 3, 7, 14 and 30 from baseline. II. To measure the incidence of baloxavir and oseltamivir resistance, development of lower respiratory tract infections (LRTI), oxygen requirement, respiratory failure, changes in microbiome of the upper airway, length of hospital stay and all-cause mortality at day 30 while on baloxavir and/or oseltamivir in these immunocompromised hosts. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive oseltamivir orally (PO) twice daily (BID) for up to 10 days and baloxavir marboxil PO every 72 hours for a total of 3 doses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive oseltamivir PO BID for up to 10 days in the absence of disease progression or unacceptable toxicity. After completion of study, patients are followed up at 30 days.

The purpose of this study is to evaluate the immune response of the killed flu vaccine in healthy subjects. Participants in this study are considered to be healthy volunteers. Influenza ("Flu") infection carries a risk of serious illness. The immune system is the body's defense against all kinds of infections and foreign invaders. The flu vaccine is a dose of killed (inactivated) flu virus. The immune system then builds protective responses against the flu virus. These responses help attack and kill the virus. One may not get sick at all, or may have a much shorter or milder illness. The killed flu vaccine is made from a killed influenza virus that has been split apart and modified in such a way as to not be able to grow at all in humans. The killed flu vaccine is given via an injection into your arm. The purpose of this research study is to test the immune response to a vaccination for influenza (the "flu"). Participants will be given one dose of an FDA-approved influenza vaccine. The flu vaccine used in this study is the same seasonal flu vaccine that is approved by the government for this year. The study will measure immune response to the seasonal flu vaccine by measuring the immune response in the blood and bone marrow over a period of time, for up to 1 year post (after) vaccination. Researchers expect to see a change in the immune system in response to the flu vaccination. This response will be evaluated by comparing data obtained before flu vaccination to data collected at specified time points (0, 7, 28, 90, and 365 days) after the administration of the flu vaccine. It is possible that by measuring these differences, especially in the bone marrow, clinicians can better understand how the body responds to flu vaccination and how long the immunity lasts. This is important because it could help lead to the creation of more effective flu vaccines in the future. Up to 90 healthy volunteers will be enrolled into the study. Subjects chosen to participate in this study will be healthy volunteers who are eligible to receive the flu vaccine. An individual's study participation will last for up to 365 days, or 1 year. Subjects who complete the study will be given the option to re-enroll if they meet enrollment criteria. The duration for this study is seven years. This single site study will take place at Emory University. As this is a healthy volunteers study, flyers, social media posts, and electronic newsletter advertisements will be used to recruit participants for this study. Interested individuals can contact the study team to determine eligibility. We will not request any waivers of consent. Participants will be asked, as part of the informed consent process, whether or not they agree to have their specimens used only for future research. This decision can be changed at any time by the participant without penalty. Participants who agree to take part in this study will have specimens collected for antibody determination and viral typing. Each specimen will be labeled only with a unique tracking number to protect participant's confidentiality. These samples will not be used for genetic (DNA) studies and will be stored in a coded manner indefinitely.

Study Description: This is a randomized, double-blinded, placebo-controlled, multicenter, phase 2 clinical trial of beta-propiolactone (BPL)-inactivated quadruple influenza virus cocktail vaccine (BPL-1357) administered intramuscularly (IM) or intranasally (IN) in 2 doses 28 days apart. The study has 2 phases: a vaccination phase (Phase A) and a challenge phase (Phase B). In phase A participants will be randomized to 1 of 3 groups for treatment assignment: group A IM BPL-1357 plus IN placebo, group B IM placebo plus IN BPL-1357, or group C IM placebo and IN placebo. In phase B, participants will undergo influenza challenge as inpatients. The primary hypothesis is that IN and IM BPL-1357 will be safe and offer protection against mild-moderate influenza disease (MMID) caused by H1N1 influenza challenge compared to placebo. Objectives: Primary Objective: 1. To measure the efficacy of BPL-1357, given IM or IN, in preventing MMID compared to placebo. 2. To assess the safety of BPL-1357, given IM or IN as 2 doses 28 days apart, including after H1N1 influenza challenge. Secondary Objective: 1. To measure the efficacy of BPL-1357, given IM or IN, in reducing total InFLUenza Patient Reported Outcome (FLUPRO) scores compared to placebo. 2. To measure the efficacy of BPL-1357, given IM or IN, in preventing shedding measured by quantitative real-time polymerase chain reaction (rtPCR) compared to placebo. 3. To measure the efficacy of BPL-1357, given IM or IN, in reducing shedding duration measured by rtPCR compared to placebo. 4. To assess the immunogenicity of BPL-1357 given IM or IN. Tertiary Objective: 1. To assess the correlates of protection associated with BPL-1357 against H1N1 influenza challenge. 2. To characterize the systemic and mucosal humoral immune responses induced by BPL-1357 at multiple timepoints before and after influenza challenge. 3. To further characterize the immune response induced by BPL-1357 and subsequent influenza challenge through variable, diversity, and joining (VDJ) gene repertoire analysis, cytokine analysis, cytometry, transcriptomics, and further assessment of B- and T-cell responses. 4. To examine whether clinical outcomes and immune responses vary according to time elapsed since vaccination to clinical outcome. 5. To characterize how specific HLA types influence the magnitude and type of immune response. 6. To assess BPL-1357 vaccine efficacy against any community-acquired influenza during the study. Endpoints: Primary Endpoints: 1. Efficacy: Rate of MMID, defined as a positive US Food and Drug Administration (FDA) - approved clinical test for influenza plus 1 or more influenza symptoms, in the 7 days after challenge. 2. Safety: 1. Solicited adverse events (AEs) occurring within 7 days of each vaccination dose recorded through questionnaires. 2. Unsolicited AEs occurring within 28 days of each vaccination dose. 3. Serious adverse events (SAEs) occurring through study completion or withdrawal from study. Secondary Endpoints: 3. Total FLU-PRO questionnaire scores after influenza challenge. 4. Proportion of patients who shed virus after influenza challenge as measured by rtPCR. 5. Mean duration (days) of shedding as measured by rtPCR. 6. Immunogenicity at 28 days after vaccine dose 2 (PAD56): 1. Antibodies against H1, H3, H5, and H7 head and stalk as measured by hemagglutination inhibition (HAI) or enzyme-linked immunosorbent assay (ELISA) from blood and mucosal samples at PAD56. 2. Antibodies against N1, N3, N8, and N9 as measured by neuraminidase inhibition (NAI) or ELISA from blood and mucosal samples at PAD56. 3. Neutralizing antibodies in blood at PAD56. 4. Mucosal response and seroresponse rate after vaccination, defined to be the proportion of patients having a 2.5-fold increase from baseline (PAD0) in ELISA titer and a 4-fold increase from baseline in neutralizing, HAI, or NAI titer. Tertiary Endpoints: 7. Association between pre-challenge immune markers and the occurrence of MMID. 8. Additional antibody titer characterization via: 1. Antibodies against H1, H3, H5, and H7 head and stalk as measured by HAI or ELISA from blood and mucosal samples at all timepoints. 2. Antibodies against N1, N3, N8, and N9 as measured by NAI or ELISA from blood and mucosal samples at all timepoints. 3. Neutralizing antibodies in blood at all timepoints. 4. Mucosal response and seroresponse rate after vaccination. 9. Additional immune response characterization through: 1. VDJ gene repertoire analysis. 2. Cytokine analysis. 3. Flow cytometric phenotyping of lymphocytes. 4. Transcriptomic gene expression. 5. B- and T-cell responses. 10. Associations between time-from-vaccination to clinical outcome and immune responses. 11. Associations between HLA types and immune response. 12. Association of clinical endpoints such as MMID and community acquired influenza diagnosed while on study.