Development of a broadly active influenza intranasal vaccine adjuvanted with self-assembled particles composed of mastoparan-7 and CpG

Currently licensed vaccine adjuvants offer limited mucosal immunity, which is needed to better combat respiratory infections such as influenza. Mast cells (MCs) are emerging as a target for a new class of mucosal vaccine adjuvants. Here, we developed and characterized a nanoparticulate adjuvant composed of an MC activator [mastoparan-7 (M7)] and a TLR ligand (CpG). This novel nanoparticle (NP) adjuvant was co-formulated with a computationally optimized broadly reactive antigen (COBRA) for hemagglutinin (HA), which is broadly reactive against influenza strains. M7 was combined at different ratios with CpG and tested for in vitro immune responses and cytotoxicity. We observed significantly higher cytokine production in dendritic cells and MCs with the lowest cytotoxicity at a charge-neutralizing ratio of nitrogen/phosphate = 1 for M7 and CpG. This combination formed spherical NPs approximately 200 nm in diameter with self-assembling capacity. Mice were vaccinated intranasally with COBRA HA and M7-CpG NPs in a prime–boost–boost schedule. Vaccinated mice had significantly higher antigen-specific antibody responses (IgG and IgA) in serum and mucosa compared with controls. Splenocytes from vaccinated mice had significantly increased cytokine production upon antigen recall and the presence of central and effector memory T cells in draining lymph nodes. Finally, co-immunization with NPs and COBRA HA induced influenza H3N2-specific HA inhibition antibody titers across multiple strains and partially protected mice from a challenge against an H3N2 virus. These results illustrate that the M7-CpG NP adjuvant combination can induce a protective immune response with a broadly reactive influenza antigen via mucosal vaccination

A computationally optimized broadly reactive hemagglutinin vaccine elicits neutralizing antibodies against influenza B viruses from both lineages

Abstract Influenza B viruses (IBV) can cause severe disease and death much like influenza A viruses (IAV), with a disproportionate number of infections in children. Despite moving to a quadrivalent vaccine to include strains from both the B/Victoria and B/Yamagata lineages, vaccine effectiveness rates continue to be variable and low in many past seasons. To develop more effective influenza B virus vaccines, three novel IBV hemagglutinin (HA) vaccines were designed using a computationally optimized broadly reactive antigen (COBRA) methodology. These IBV HA proteins were expressed on the surface of a virus-like particle (VLP) and used to vaccinate ferrets that were pre-immune to historical B/Victoria or B/Yamagata lineage viruses. Ferrets vaccinated with B-COBRA HA vaccines had neutralizing antibodies with high titer HAI titer against all influenza B viruses regardless of pre-immunization history. Conversely, VLPs expressing wild-type IBV HA antigens preferentially boosted titers against viruses from the same lineage and there was little-to-no seroprotective antibodies detected in ferrets with mismatched IBV pre-immune infections. Overall, a single IBV HA developed using the COBRA methodology elicited protective broadly-reactive antibodies against current and future drifted IBVs from both lineages

Urine Metabolome Dynamics Discriminate Influenza Vaccination Response

Influenza represents a major and ongoing public health hazard. Current collaborative efforts are aimed toward creating a universal flu vaccine with the goals of both improving responses to vaccination and increasing the breadth of protection against multiple strains and clades from a single vaccine. As an intermediate step toward these goals, the current work is focused on evaluating the systemic host response to vaccination in both normal and high-risk populations, such as the obese and geriatric populations, which have been linked to poor responses to vaccination. We therefore employed a metabolomics approach using a time-course (n = 5 time points) of the response to human vaccination against influenza from the time before vaccination (pre) to 90 days following vaccination. We analyzed the urinary profiles of a cohort of subjects (n = 179) designed to evenly sample across age, sex, BMI, and other demographic factors, stratifying their responses to vaccination as “High”, “Low”, or “None” based on the seroconversion measured by hemagglutination inhibition assay (HAI) from plasma samples at day 28 post-vaccination. Overall, we putatively identified 15,903 distinct, named, small-molecule structures (4473 at 10% FDR) among the 895 samples analyzed, with the aim of identifying metabolite correlates of the vaccine response, as well as prognostic and diagnostic markers from the periods before and after vaccination, respectively. Notably, we found that the metabolic profiles could unbiasedly separate the high-risk High-responders from the high-risk None-responders (obese/geriatric) within 3 days post-vaccination. The purine metabolites Guanine and Hypoxanthine were negatively associated with high seroconversion (p = 0.0032, p < 0.0001, respectively), while Acetyl-Leucine and 5-Aminovaleric acid were positively associated. Further changes in Cystine, Glutamic acid, Kynurenine and other metabolites implicated early oxidative stress (3 days) after vaccination as a hallmark of the High-responders. Ongoing efforts are aimed toward validating these putative markers using a ferret model of influenza infection, as well as an independent cohort of human seasonal vaccination and human challenge studies with live virus

Relationship of Maximum Strength to Weightlifting Performance

Purpose: The primary objective was to assess the relationship of maximum strength to weightlifting ability using established scaling methods. The secondary objective was to compare men and women weightlifters on strength and weightlifting ability. Methods: Two correlational observations were carried out using Pearson\u27s r. In the first observation (N = 65) the relationship of dynamic maximum strength (one-repetition maximum (IRM) squat) was compared with weightlifting ability; in the second observation (N = 16), isometric maximum strength (midthigh pull) was studied. Scaling methods for equating maximum strength and weightlifting results were used (load * (Ht2 I6)- . load * kg-\u27, load * lbm-\u27, allometric, and Sinclair formula) to assess the association between measures of maximum strength and weightlifting performance. Results: Using scaled values; correlations betweeh maximum strength and weightlifting results were generally strong in both observations (e.g., using allometric scaling for the IRM squat vs the IRM snatch: r = 0.84, N = 65). Men were stronger than women (e.g., IRM squat, N = 65: men = 188.1 ± 48.6 kg; women = 126.7 + 28.3 kg); differences generally held when scaling was applied (e.g., IRM squat scaled with the Sinclair formula: men = 224.7 ± 36.5 kg; women = 144.2 ± 25.4 kg). Conclusions: When collectively considering scaling methods, maximum strength is strongly related to weightlifting performance independent of body mass and height differences. Furthermore, men are stronger than women even when body mass and height are obviated by scaling methods

Relationship of maximum strength to weightlifting performance

Purpose: The primary objective was to assess the relationship of maximum strength to weightlifting ability using established scaling methods. The secondary objective was to compare men and women weightlifters on strength and weightlifting ability. Methods: Two correlational observations were carried out using Pearson\u27s r. In the first observation (N = 65) the relationship of dynamic maximum strength (one-repetition maximum (IRM) squat) was compared with weightlifting ability; in the second observation (N = 16), isometric maximum strength (midthigh pull) was studied. Scaling methods for equating maximum strength and weightlifting results were used (load * (Ht2 I6)- . load * kg-\u27, load * lbm-\u27, allometric, and Sinclair formula) to assess the association between measures of maximum strength and weightlifting performance. Results: Using scaled values; correlations betweeh maximum strength and weightlifting results were generally strong in both observations (e.g., using allometric scaling for the IRM squat vs the IRM snatch: r = 0.84, N = 65). Men were stronger than women (e.g., IRM squat, N = 65: men = 188.1 ± 48.6 kg; women = 126.7 + 28.3 kg); differences generally held when scaling was applied (e.g., IRM squat scaled with the Sinclair formula: men = 224.7 ± 36.5 kg; women = 144.2 ± 25.4 kg). Conclusions: When collectively considering scaling methods, maximum strength is strongly related to weightlifting performance independent of body mass and height differences. Furthermore, men are stronger than women even when body mass and height are obviated by scaling methods

Maximum Strength and Strength Training---A Relationship to Endurance?

Endurance can be defined as the ability to maintain or to repeat a given force or power output. The sport performance-endurance relationship is a multi-factorial concept. However, evidence indicates that maximum strength is a major component. Conceptually, endurance is a continuum. The literature indicates that (a) maximum strength is moderately to strongly related to endurance capabilities and associated factors, a relationship that is likely stronger for high intensity exercise endurance (HIEE) activities than for low intensity exercise endurance (LIEE); (b) strength training can increase both HIEE and LIEE, the effect being greater for HIEE; (c) the volume of strength training plays a role in endurance adaptation; and (d) mechanical specificity and training program variables also play a role in the degree of adaptation.

Maximum strength and strength training - A relationship to endurance?

Endurance can be defined as the ability to maintain or to repeat a given force or power output. The sport performance-endurance relationship is a multi-factorial concept. However, evidence indicates that maximum strength is a major component. Conceptually, endurance is a continuum. The literature indicates that (a) maximum strength is moderately to strongly related to endurance capabilities and associated factors, a relationship that is likely stronger for high intensity exercise endurance (HIEE) activities than for low intensity exercise endurance (LIEE); (b) strength training can increase both HIEE and LIEE, the effect being greater for HIEE; (c) the volume of strength training plays a role in endurance adaptation; and (d) mechanical specificity and training program variables also play a role in the degree of adaptation

Maximum Strength and Strength Training - A Relationship to Endurance?

Endurance can be defined as the ability to maintain or to repeat a given force or power output. The sport performance-endurance relationship is a multi-factorial concept. However, evidence indicates that maximum strength is a major component. Conceptually, endurance is a continuum. The literature indicates that (a) maximum strength is moderately to strongly related to endurance capabilities and associated factors, a relationship that is likely stronger for high intensity exercise endurance (HIEE) activities than for low intensity exercise endurance (LIEE); (b) strength training can increase both HIEE and LIEE, the effect being greater for HIEE; (c) the volume of strength training plays a role in endurance adaptation; and (d) mechanical specificity and training program variables also play a role in the degree of adaptation