Can individuals with low antibody responses to vaccines against other viruses acquire adequate SARS-CoV-2 antibody after vaccination with the BNT162b2 mRNA vaccine?

Objective In Japan, healthcare workers (HCWs) are vaccinated against coronavirus disease (COVID-19) and other contagious viruses (measles, rubella, chickenpox, mumps, and hepatitis B) to prevent nosocomial infection. However, some do not produce sufficient antibodies after vaccination (low responders). This study investigated changes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels among HCWs after SARS-CoV-2 vaccination and assessed whether low responders produced adequate SARS-CoV-2 anti-spike and neutralizing antibodies. Methods We conducted a prospective cohort study of HCWs before and after vaccination with the BNT162b2 mRNA vaccine in a hospital in Tokyo, Japan. The HCWs received two doses of BNT162b2 vaccine, 3 weeks apart. Those whose antibody levels against previous antiviral vaccines did not reach protective antibody levels after receiving two doses were defined as low responders, whereas those who produced adequate antibodies were defined as normal responders. SARS-CoV-2 anti-spike antibodies were measured 11 times from before the first BNT162b2 vaccination to 5 months after the second vaccination. SARS-CoV-2 neutralizing antibody activity was measured twice in low responders, 1 week to 1 month and 5 months after the second vaccination. Results Fifty HCWs were included in the analytic cohort. After vaccination, SARS-CoV-2 anti-spike antibody was detectable in the samples from both responders at each timepoint, but the level was lower at 5 months than at 1 week after the second vaccination. Low responders had SARS-CoV-2 neutralizing antibody activity 1 week to 1 month after the second vaccination, which exceeded the positive threshold after 5 months. Conclusion After BNT162b2 vaccination, low responders acquired adequate SARS-CoV-2 anti-spike and SARS-CoV-2 neutralizing antibodies to prevent SARS-CoV-2. However, SARS-CoV-2 anti-spike antibody levels were lower at 5 months than at 1 week after the second dose of BNT162b2 vaccine in low and normal responders. Therefore, low responders should also receive a third dose of BNT162b2 vaccine.

TGF-β Induction of miR-143/145 Is Associated to Exercise Response by Influencing Differentiation and Insulin Signaling Molecules in Human Skeletal Muscle

Physical training improves insulin sensitivity and can prevent type 2 diabetes (T2D). However, approximately 20% of individuals lack a beneficial outcome in glycemic control. TGF-β, identified as a possible upstream regulator involved in this low response, is also a potent regulator of microRNAs (miRNAs). The aim of this study was to elucidate the potential impact of TGF-β-driven miRNAs on individual exercise response. Non-targeted long and sncRNA sequencing analyses of TGF-β1-treated human skeletal muscle cells corroborated the effects of TGF-β1 on muscle cell differentiation, the induction of extracellular matrix components, and identified several TGF-β1-regulated miRNAs. qPCR validated a potent upregulation of miR-143-3p/145-5p and miR-181a2-5p by TGF-β1 in both human myoblasts and differentiated myotubes. Healthy subjects who were overweight or obese participated in a supervised 8-week endurance training intervention (n = 40) and were categorized as responder or low responder in glycemic control based on fold change ISIMats (≥+1.1 or <+1.1, respectively). In skeletal muscle biopsies of low responders, TGF-β signaling and miR-143/145 cluster levels were induced by training at much higher rates than among responders. Target-mining revealed HDACs, MYHs, and insulin signaling components INSR and IRS1 as potential miR-143/145 cluster targets. All these targets were down-regulated in TGF-β1-treated myotubes. Transfection of miR-143-3p/145-5p mimics in differentiated myotubes validated MYH1, MYH4, and IRS1 as miR-143/145 cluster targets. Elevated TGF-β signaling and miR-143/145 cluster induction in skeletal muscle of low responders might obstruct improvements in insulin sensitivity by training in two ways: by a negative impact of miR-143-3p on muscle cell fusion and myofiber functionality and by directly impairing insulin signaling via a reduction in INSR by TGF-β and finetuned IRS1 suppression by miR-143-3p.

Preliminary Evidence of Endotoxin Tolerance in Dairy Cows during the Transition Period

The blastogenic response of bovine peripheral blood mononuclear cells (PBMCs) to lipopolysaccharides (LPS) has been investigated for a long time in our laboratories. In particular, a possible correlation between the blastogenic response to LPS and the disease resistance of dairy cows has been suggested in previous studies. Isolated PBMCs from eight cows at three different time points during the transition period (T0 = 15 days before calving; T1 = 7 days post-calving; T2 = 21 days post-calving) were cultured in the presence or absence of LPS, and the blastogenic response was assayed 72 h after in vitro stimulation. Moreover, the gene expression of proinflammatory cytokines and kynurenine pathway molecules was investigated by real-time RT-PCR on both unstimulated and stimulated PBMCs. The cows were retrospectively divided into healthy and diseased, based on the development of peripartum diseases (subclinical ketosis and placenta retention). The comparison between healthy and diseased cows suggested that healthy animals seemed to better control the response to LPS. On the contrary, diseased animals showed a much higher inflammatory response to LPS. Moreover, cows were retrospectively classified as high and low responders based on the in vitro proliferative response of PBMCs to LPS, using the median value as a threshold. Unstimulated PBMCs of low responders showed higher expression of the proinflammatory cytokines Interleukin 1-β (IL-1β), Interleukin 6 (IL-6) and Tumor Necrosis Factor-α (TNF-α), compared to high responders. Our preliminary data suggest that, during the peripartum period, high responders seem to be more tolerant to endotoxins and develop a lower inflammatory response to different stressors. Instead, low responders could be more prone to the development of unwanted inflammatory conditions in response to mild/moderate stressors.

SARS-CoV-2 Antibody Response is Associated with Age in Convalescent Outpatients

COVID-19 has had an unprecedented global impact on human health. Understanding the antibody memory responses to infection is one tool needed to effectively control the pandemic. Among 173 outpatients who had virologically confirmed SARS-CoV-2 infection, we evaluated serum antibody concentrations, microneutralization activity, and enumerated SARS-CoV-2 specific B cells in convalescent blood specimens. Serum antibody concentrations were variable, allowing for stratification of the cohort into high and low responders. Serum antibody concentration was associated with microneutralization activity and participant age, with participants under the age of 30 showing the lowest antibody level. Neither participant sex, the timing of blood sampling following the onset of illness, nor the number of SARS-CoV-2 spike protein specific B cells correlated with serum antibody concentration. These data suggest that young adult outpatients did not generate as robust antibody memory, compared with older adults. Further, serum antibody concentration or neutralizing activity trended but did not significantly correlate with the number of SARS-CoV-2 memory B cells. These findings have direct implications for public health policy and current vaccine efforts. Knowledge gained regarding antibody memory following infection will inform the need for vaccination in those previously infected and allow for a better approximation of population-wide protective immunity.

Comparison of High and Low Responders to a Cross-Country Skiing Talent Transfer Program: A Coach’s Perspective

Purpose: To examine how coaches differentiate athletes with successful and non-successful development during a cross-country (XC) skiing talent transfer (TT) program. Methods: We conducted qualitative, semi-structured interviews with seven Norwegian coaches working with a group of 23 Chinese summer endurance athletes transferring from running, rowing, and kayaking to the winter endurance sport XC skiing over a six-month training period. The athletes were grouped as either high (n = 9), moderate (n = 3), or low responders (n = 11) based on objective performance development, quantified using laboratory testing. The interview guide contained six sections: physiological development, technical development, psychological characteristics, training and recovery routines, athlete background, and considerations about the effectiveness of TT initiatives in general. Results: The assessments of the coaches revealed that greater development of both physiological and technical capacities among the high-responding TT athletes were associated with higher motivation, as well as superior ability to deal with adversity in the development process. Conclusion: The coaches considered the TT program to be effective; however, successful transfer of athletes to a world class level in a complex sport such as XC skiing requires a multidisciplinary selection process and a longer time frame than the six-month period used in the current project.

Multi-parameter phenotyping of platelet reactivity for stratification of human cohorts

Accurate and comprehensive assessment of platelet function across cohorts of donors may be key to understanding the risk of thrombotic events associated with cardiovascular disease, and hence help personalise the application of antiplatelet drugs. However, platelet function tests can be difficult to perform and analyse, unreliable or uninformative and poorly standardised across studies. The Platelet Phenomic Analysis (PPAnalysis) assay and associated open-source software platform was developed in response to these challenges. PPAnalysis utilises pre-prepared freeze-dried microtitre plates to provide a detailed characterisation of platelet function. The automated analysis of the high-dimensional data enables the identification of sub-populations of donors with distinct platelet function phenotypes. Using this approach we identified that the Sensitivity of a donor's platelets to an agonist and their Capacity to generate a functional response are distinct independent metrics of platelet reactivity. Hierarchical clustering of these metrics identified six subgroups with distinct platelet phenotypes within healthy cohorts, indicating that platelet reactivity does not fit into the traditional simple categories of 'high' and 'low' responders. These platelet phenotypes were found to exist in two independent cohorts of healthy donors and were stable on recall. PPAnalysis is a powerful tool for stratification of cohorts on the basis of platelet reactivity which will enable investigation of the causes and consequences of differences in platelet function and drive progress towards precision medicine.

Physiological Effects and Inter-Individual Variability to 12 Weeks of High Intensity-Interval Training and Dietary Energy Restriction in Overweight/Obese Adult Women

Background: Human adaptive response to exercise interventions is often described as group average and SD to represent the typical response for most individuals, but studies reporting individual responses to exercise show a wide range of responses.Objective: To characterize the physiological effects and inter-individual variability on fat mass and other health-related and physical performance outcomes after 12 weeks of high-intensity interval training (HIIT) and dietary energy restriction in overweight/obese adult women.Methods: Thirty untrained adult overweight and obese women (age = 27.4 ± 7.9 years; BMI = 29.9 ± 3.3 kg/m2) successfully completed a 12-week supervised HIIT program and an individually prescribed home hypocaloric diet (75% of daily energy requirements) throughout the whole intervention. High and low responders to the intervention were those individuals who were able to lose ≥ 10 and &lt; 10% of initial absolute fat mass (i.e., kilograms), respectively.Results: The prevalence for high and low responders was 33% (n = 11) and 66% (n = 19), respectively. At the whole group level, the intervention was effective to reduce the absolute fat mass (30.9 ± 7.2 vs. 28.5 ± 7.2 kg; p &lt; 0.0001), body fat percentage (39.8 ± 4.3 vs. 37.8 ± 4.9%; p &lt; 0.0001), and total body mass (76.7 ± 10.1 vs. 74.4 ± 9.9 kg; p &lt; 0.0001). In addition, there were improvements in systolic blood pressure (SBP; Δ% = −5.1%), diastolic blood pressure (DBP; Δ% = −6.4%), absolute VO2peak (Δ% = +14.0%), relative VO2peak (Δ% = +13.8%), peak power output (PPO; Δ% = +19.8%), anaerobic threshold (AT; Δ% = +16.7%), maximal ventilation (VE; Δ% = +14.1%), and peak oxygen pulse (O2 pulse; Δ% = +10.4%). However, at the individual level, a wide range of effects were appreciated on all variables, and the magnitude of the fat mass changes did not correlate with baseline body mass or fat mass.Conclusion: A 12-week supervised HIIT program added to a slight dietary energy restriction effectively improved fat mass, body mass, blood pressure, and cardiorespiratory fitness (CRF). However, a wide range of inter-individual variability was observed in the adaptative response to the intervention. Furthermore, subjects classified as low responders for fat mass reduction could be high responders (HiRes) in many other health-related and physical performance outcomes. Thus, the beneficial effects of exercise in obese and overweight women go further beyond the adaptive response to a single outcome variable such as fat mass or total body mass reduction.