Age, not growth, explains larger body size of Pacific cod larvae during recent marine heatwaves.

Marine heatwaves (MHWs) are often associated with physiological changes throughout biological communities but can also result in biomass declines that correspond with shifts in phenology. We examined the response of larval Pacific cod (Gadus macrocephalus) to MHWs in the Gulf of Alaska across seven years to evaluate the effects of MHWs on hatch phenology, size-at-age, and daily growth and identify potential regulatory mechanisms. Hatch dates were, on average, 19 days earlier since the onset of MHWs, shifting a mean of 15 days earlier per 1 â„ƒ increase. Size-at-capture was larger during & between MHWs but, contrary to expectations, larvae grew slower and were smaller in size-at-age. The larger size during & between MHWs can be entirely explained by older ages due to earlier hatching. Daily growth variation was well-explained by an interaction among age, temperature, and hatch date. Under cool conditions, early growth was fastest for the latest hatchers. However, this variation converged at warmer temperatures, due to faster growth of earlier hatchers. Stage-specific growth did not vary with temperature, remaining relatively similar from 4 to 8 â„ƒ. Temperature-related demographic changes were more predictable based on phenological shifts rather than changes in growth, which could affect population productivity after MHWs.

PAK3 Exacerbates Cardiac Lipotoxicity via SREBP1c in Obesity Cardiomyopathy.

Obesity-induced lipid overload in cardiomyocytes contributes to profound oxidative stress and cardiomyopathy, culminating in heart failure. In this study, we investigate a novel mechanism whereby lipids accumulate in cardiomyocytes and seek the relevant treatment strategies. P21-activated kinase 3 (PAK3) was elevated in obese human myocardium, and the murine hearts and cardiomyocytes upon diet- or fatty acid-induced stress, respectively. Mice with cardiac-specific overexpression of PAK3 were more susceptible to the development of cardiac dysfunction upon diet stress, at least partially, due to increased deposition of toxic lipids within the myocardium. Mechanistically, PAK3 promoted the nuclear expression of sterol regulatory element binding protein 1c (SREBP1c) through activation of mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase beta-1 (S6K1) pathway in cardiomyocytes, resulting in abnormal lipid genes profile, accumulation of excessive lipids, and oxidative stress. More importantly, PAK3 knockdown attenuated fatty acid-induced lipotoxicity and cell death in rat and human cardiomyocytes. More importantly, the S6K1 or SREBP1c inhibitor alleviated PAK3-triggered intracellular lipid overload and cardiac dysfunction under obese stress. Collectively, we have demonstrated that PAK3 impairs myocardial lipid homeostasis, while inhibition of cardiac lipotoxicity mitigates cardiac dysfunction. Our study provides a promising therapeutic strategy for ameliorating obesity cardiomyopathy.

Effect of corn silage inclusion with different corn processing on finishing steer performance and carcass characteristics.

Objectives were to determine the effect of corn silage inclusion within dry-rolled corn (DRC) or steam-flaked corn (SFC) finishing diets on cattle growth performance and carcass characteristics. The experiment used British and continental crossbred steers (n = 480; initial body weight [BW] = 389 ±â€…17 kg) in a 4 × 2 factorial arrangement of treatments with six replications per treatment. Treatments consist of four inclusions of corn silage (0%, 15%, 30%, or 45%; dry matter [DM] basis) within either a DRC or SFC diet. A corn silage by corn processing interaction was observed for dry-matter intake (DMI; P = 0.05). As corn silage inclusion increased in the diet, DMI increased linearly (P < 0.01) for both corn processing methods. DM intake was not different between SFC and DRC-fed cattle at 0% (P = 0.33), 30% (P = 0.90), or 45% (P = 0.31) corn silage inclusion. The interaction was due to the DMI of cattle fed 15% silage, as cattle-fed DRC consumed 0.5 kg/d less (P < 0.01) than cattle on the SFC diet. Quadratic effects were observed for final BW, hot carcass weight (HCW), average daily gain (ADG), feed efficiency (G:F), marbling, and fat depth (P < 0.01), regardless of corn processing. Cattle fed 15% or 30% corn silage gained faster (P < 0.01) than those fed 0% or 45% corn silage. Feed efficiency decreased quadratically (P < 0.01) as silage inclusion increased in the diet with G:F similar for cattle fed 0% and 15% silage and decreased curvilinearly for cattle fed 30% and 45% silage. The incidence of liver abscesses was greater (P = 0.03) in cattle fed 0% corn silage than for steers fed 15%, 30%, or 45% corn silage. Corn processing method, independent of silage, had no effect (P = 0.42) on liver abscess incidence. Feeding SFC increased (P < 0.01) steer final BW and HCW when compared to cattle-fed DRC, regardless of silage inclusion. Corn silage inclusion had similar effects on performance in both DRC diets and SFC diets except for DMI. As corn silage inclusion increased in the diet, feed efficiency decreased linearly (P < 0.01). Cattle-fed SFC gained 7.9% more (P < 0.01) and were 6.7% more efficient (P < 0.01) than cattle-fed DRC. In diets containing either DRC or SFC, corn silage can be included at up to 30% of the diet without negative impacts on ADG or HCW.

AAPM Task Group Report 299: Quality control in multi-energy computed tomography.

Multi-energy computed tomography (MECT) offers the opportunity for advanced visualization, detection, and quantification of select elements (e.g., iodine) or materials (e.g., fat) beyond the capability of standard single-energy computed tomography (CT). However, the use of MECT requires careful consideration as substantially different hardware and software approaches have been used by manufacturers, including different sets of user-selected or hidden parameters that affect the performance and radiation dose of MECT. Another important consideration when designing MECT protocols is appreciation of the specific tasks being performed; for instance, differentiating between two different materials or quantifying a specific element. For a given task, it is imperative to consider both the radiation dose and task-specific image quality requirements. Development of a quality control (QC) program is essential to ensure the accuracy and reproducibility of these MECT applications. Although standard QC procedures have been well established for conventional single-energy CT, the substantial differences between single-energy CT and MECT in terms of system implementations, imaging protocols, and clinical tasks warrant QC tests specific to MECT. This task group was therefore charged with developing a systematic QC program designed to meet the needs of MECT applications. In this report, we review the various MECT approaches that are commercially available, including information about hardware implementation, MECT image types, image reconstruction, and postprocessing techniques that are unique to MECT. We address the requirements for MECT phantoms, review representative commercial MECT phantoms, and offer guidance regarding homemade MECT phantoms. We discuss the development of MECT protocols, which must be designed carefully with proper consideration of MECT technology, imaging task, and radiation dose. We then outline specific recommended QC tests in terms of general image quality, radiation dose, differentiation and quantification tasks, and diagnostic and therapeutic applications.

Marine heatwaves alter the nursery function of coastal habitats for juvenile Gulf of Alaska Pacific cod.

Marine Heatwaves (MHWs) can directly influence survival of marine fishes, particularly for early life stages, including age-0 juveniles during their residence in coastal nursery habitats. However, the ability of nurseries to support high fish densities, optimize foraging and growth, and protect against predators may be altered during MHWs. Gulf of Alaska Pacific cod (Gadus macrocephalus) larval, juvenile, and adult abundances declined dramatically following MHW events in 2014-2016 and 2019. To evaluate coastal nursery function during MHWs, we compared diet composition, recent growth, size, condition, and abundance of age-0 juveniles throughout their first summer before, during, and between MHWs. Diet shifted to larger prey during MHWs, particularly mysids, but diet did not appear to influence growth. We observed faster growth rates during MHWs, yet even when accounting for growth, we could not explain the higher body sizes observed in August during MHWs. Together with lower abundance and the near absence of small fish in the nursery by August during MHWs, these patterns highlight potential for size-selection and a reduced ability of nursery habitats to buffer against environmental variability during MHWs, with only a small number of large "super survivors" persisting through the summer.

Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity.

Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.

Social determinants of health correlations and resource usefulness at a Milwaukee free clinic for uninsured individuals: A cross-sectional study.

Introduction: Addressing social determinants of health (SDOH) is fundamental to improving health outcomes. At a student-run free clinic, we developed a screening process to understand the SDOH needs and resource utilization of Milwaukee's uninsured population. Methods: In this cross-sectional study, we screened adult patients without health insurance (N = 238) for nine traditional SDOH needs as well as their access to dental and mental health care between October 2021 and October 2022. Patients were surveyed at intervals greater than or equal to 30 days. We assessed correlations between SDOH needs and trends in patient-reported resource usefulness. Results: Access to dental care (64.7%) and health insurance (51.3%) were the most frequently endorsed needs. We found significant correlations (P ≤ 0.05) between various SDOH needs. Notably, mental health access needs significantly correlated with dental (r = 0.41; 95% CI = 0.19, 0.63), medications (r = 0.51; 95% CI = 0.30, 0.72), utilities (r = 0.39; 95% CI = 0.17, 0.61), and food insecurity (r = 0.42; 95% CI = 0.19, 0.64). Food-housing (r = 0.55; 95% CI = 0.32, 0.78), housing-medications (r = 0.58; 95% CI = 0.35, 0.81), and medications-food (r = 0.53; 95% CI = 0.32, 0.74) were significantly correlated with each other. Longitudinal assessment of patient-reported usefulness informed changes in the resources offered. Conclusions: Understanding prominent SDOH needs can inform resource offerings and interventions, addressing root causes that burden under-resourced patients. In this study, patient-reported data about resource usefulness prompted the curation of new resources and volunteer roles. This proof-of-concept study shows how longitudinally tracking SDOH needs at low-resource clinics can inform psychosocial resources.

Effects of a Flavonoid-Rich Blackcurrant Beverage on Markers of the Gut-Brain Axis in Healthy Females: Secondary Findings From a 4-Week Randomized Crossover Control Trial.

The microbiota-gut-brain axis is a promising target to alleviate the growing burden of neurologic and mental health disorders. Dietary polyphenols act on multiple components of the microbiota-gut-brain axis, but this complex relationship requires further attention. This randomized, placebo-controlled, double-blind, crossover trial (ACTRN12622000850774) compared 4 wk of a commercially available flavonoid-rich blackcurrant beverage (FBB; 151 mg anthocyanins, 308 mg total polyphenols) with placebo in 40 healthy females (18-45 y). The primary outcome of stress reactivity was assessed by change in present feelings of stress, mood, and fatigue before and after completing a 20-min cognitive stressor [Purple multitasking framework (MTF)]. Secondary end points included cognitive performance (MTF), mood [profile of mood states (POMS)], sleep (Pittsburgh Sleep Quality Index), fecal microbiome composition and functional potential (shotgun sequencing), and blood biomarker concentrations (brain-derived neurotrophic factor, tryptophan, kynurenine, and interleukin 6). Statistical analyses were conducted on an intention-to-treat basis using linear mixed-effect models. Thirty-eight participants completed both intervention arms. There was no significant treatment effect on the primary outcome of stress reactivity. Compared with placebo, working memory (letter retrieval scores from MTF), and anxiety/tension and anger/hostility domains of the POMS improved with FBB supplementation (time × intervention interaction; P < 0.05). There were no treatment effects on gut microbiome composition or functional potential. Baseline abundances of Bifidobacterium genera and species (Bifidobacterium longum and Bifidobacterium bifidum) tended to be higher in participants with the greatest improvements in letter retrieval scores with FBB supplementation (nominally significant, P < 0.05). In conclusion, 4-wk FBB supplementation improved secondary outcomes of working memory performance during multitasking and mood outcomes in healthy adult females. These results should be confirmed in a larger cohort with a longer duration of follow-up.

Persistence and Variation of the Indirect Effects of COVID-19 Restrictions on the Spectrum of Notifiable Infectious Diseases in China: Analysis of National Surveillance Among Children and Adolescents From 2018 to 2021.

BACKGROUND: Beyond the direct effect of COVID-19 infection on young people, the wider impact of the pandemic on other infectious diseases remains unknown. OBJECTIVE: This study aims to assess changes in the incidence and mortality of 42 notifiable infectious diseases during the pandemic among children and adolescents in China, compared with prepandemic levels. METHODS: The Notifiable Infectious Disease Surveillance System of China was used to detect new cases and fatalities among individuals aged 5-22 years across 42 notifiable infectious diseases spanning from 2018 to 2021. These infectious diseases were categorized into 5 groups: respiratory, gastrointestinal and enterovirus, sexually transmitted and blood-borne, zoonotic, and vector-borne diseases. Each year (2018-2021) was segmented into 4 phases: phase 1 (January 1-22), phase 2 (January 23-April 7), phase 3 (April 8-August 31), and phase 4 (September 1-December 31) according to the varying intensities of pandemic restrictive measures in 2020. Generalized linear models were applied to assess the change in the incidence and mortality within each disease category, using 2018 and 2019 as the reference. RESULTS: A total of 4,898,260 incident cases and 3701 deaths were included. The overall incidence of notifiable infectious diseases decreased sharply during the first year of the COVID-19 pandemic (2020) compared with prepandemic levels (2018 and 2019), and then rebounded in 2021, particularly in South China. Across the past 4 years, the number of deaths steadily decreased. The incidence of diseases rebounded differentially by the pandemic phase. For instance, although seasonal influenza dominated respiratory diseases in 2019, it showed a substantial decline during the pandemic (percent change in phase 2 2020: 0.21, 95% CI 0.09-0.50), which persisted until 2021 (percent change in phase 4 2021: 1.02, 95% CI 0.74-1.41). The incidence of gastrointestinal and enterovirus diseases decreased by 33.6% during 2020 but rebounded by 56.9% in 2021, mainly driven by hand, foot, and mouth disease (percent change in phase 3 2021: 1.28, 95% CI 1.17-1.41) and infectious diarrhea (percent change in phase 3 2020: 1.22, 95% CI 1.17-1.28). Sexually transmitted and blood-borne diseases were restrained during the first year of 2021 but rebounded quickly in 2021, mainly driven by syphilis (percent change in phase 3 2020: 1.31, 95% CI 1.23-1.40) and gonorrhea (percent change in phase 3 2020: 1.10, 95% CI 1.05-1.16). Zoonotic diseases were not dampened by the pandemic but continued to increase across the study period, mainly due to brucellosis (percent change in phase 2 2020: 0.94, 95% CI 0.75-1.16). Vector-borne diseases showed a continuous decline during 2020, dominated by hemorrhagic fever (percent change in phase 2 2020: 0.68, 95% CI 0.53-0.87), but rebounded in 2021. CONCLUSIONS: The COVID-19 pandemic was associated with a marked decline in notifiable infectious diseases in Chinese children and adolescents. These effects were not sustained, with evidence of a rebound to prepandemic levels by late 2021. To effectively address the postpandemic resurgence of infectious diseases in children and adolescents, it will be essential to maintain disease surveillance and strengthen the implementation of various initiatives. These include extending immunization programs, prioritizing the management of sexually transmitted infections, continuing feasible nonpharmaceutical intervention projects, and effectively managing imported infections.

Culturing Cardiac Tissue Slices Under Continuous Physiological Mechanical Stretches.

Testing drugs in vivo and in vitro have been essential elements for the discovery of new therapeutics. Due to the recent advances in in vitro cell culture models, such as human-induced pluripotent stem cell-derived cardiomyocytes and 3D multicell type organoid culture methods, the detection of adverse cardiac events prior to human clinical trials has improved. However, there are still numerous therapeutics whose adverse cardiac effects are not detected until human trials due to the inability of these cell cultures to fully model the complex multicellular organization of an intact human myocardium. Cardiac tissue slices are a possible alternative solution. Myocardial slices are a 300-micron thin snapshot of the myocardium, capturing a section of the adult heart in a 1 × 1 cm section. Using a culture method that incorporates essential nutrients and electrical stimulation, tissue slices can be maintained in culture for 6 days with full viability and functionality. With the addition of mechanical stimulation and humoral cues, tissue slices can be cultured for 12 days. Here we provide detailed methods for how to culture cardiac tissue slices under continuous mechanical stimulation in the cardiac tissue culture model (CTCM) device. The CTCM incorporates four essential factors for maintaining tissue slices in culture for 12 days: mechanical stimulation, electrical stimulation, nutrients, and humoral cues. The CTCM can also be used to model disease conditions, such as overstretch-induced cardiac hypertrophy. The versatility of the CTCM illustrates its potential to be a medium-throughput screening platform for personalized drug testing.

B cell somatic hypermutation following COVID-19 vaccination with Ad26.COV2.S.

The viral vector-based COVID-19 vaccine Ad26.COV2.S has been recommended by the WHO since 2021 and has been administered to over 200 million people. Prior studies have shown that Ad26.COV2.S induces durable neutralizing antibodies (NAbs) that increase in coverage of variants over time, even in the absence of boosting or infection. Here, we studied humoral responses following Ad26.COV2.S vaccination in individuals enrolled in the initial Phase 1/2a trial of Ad26.COV2.S in 2020. Through 8 months post vaccination, serum NAb responses increased to variants, including B.1.351 (Beta) and B.1.617.2 (Delta), without additional boosting or infection. The level of somatic hypermutation, measured by nucleotide changes in the VDJ region of the heavy and light antibody chains, increased in Spike-specific B cells. Highly mutated mAbs from these sequences neutralized more SARS-CoV-2 variants than less mutated comparators. These findings suggest that the increase in NAb breadth over time following Ad26.COV2.S vaccination is mediated by affinity maturation.

Self-management intervention for patients following hospitalization for acute exacerbation of chronic obstructive pulmonary disease (AECOPD): A pilot randomized controlled trial.

The purpose of this study was to evaluate the handoff guidance (HG) self-management intervention for multimorbid chronic obstructive pulmonary disease (COPD) patients following hospitalization for acute exacerbation of COPD (AECOPD) using HG self-management intervention compared to a control group on COPD self-management outcomes (self-care, self-efficacy, health engagement) and assess feasibility, acceptability, and healthcare utilization. A randomized pilot study used a 2-group with repeated measures design. Adults with COPD who had been hospitalized for AECOPD were recruited. After discharge, the HG self-management intervention employed health coaching delivered at: 1-3, 10-12, and 20-22 days after hospital discharge. Follow-up data collected was collected at 1-3, 10-12, 20-22, 30, 60, and 90 days after hospital discharge. A total of 29 subjects participated, with a mean age of 66 (+8.7) years old, the majority were females (n = 18). Intervention participants reported the acceptability of the HG self-management intervention. Participants in both groups continued to report COPD symptoms after discharge, which decreased over time, although not significantly different by group. The use of COPD maintenance, monitoring, and management behaviors was higher in the treatment group, although not significantly different.

The Dysregulated IL-23/TH17 Axis in Endometriosis Pathophysiology.

Endometriosis is a chronic inflammatory disease in which endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. IL-23 is a key contributor in the development and differentiation of TH17 cells, driving TH17 cells toward a pathogenic profile. In a variety of inflammatory and autoimmune disorders, TH17 cells secrete proinflammatory cytokines, including IL-17, contributing to disease pathophysiology. Our studies and others have implicated IL-17 and TH17 cell dysregulation in endometriosis, which is associated with disease severity. In this article, we address whether IL-23-driven TH17 cells contribute to cardinal features of lesion proliferation, vascularization, and inflammation in endometriosis using patient samples, representative cell lines, and our established mouse model of endometriosis. The results indicated dysregulated expression of key genes in the IL-23/TH17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared with controls. In vitro studies using primary human TH cells determined that rIL-23 mixture treatment increased pathogenic TH17 cell frequency. Similarly, rIL-23 treatment of cell lines (12Z cells, EECCs, HUVECs, and hESCs) representative of the endometriotic lesion microenvironment increased cytokines and growth factors, which play a role in lesion establishment and maintenance. In a syngeneic mouse model of endometriosis, rIL-23 treatment altered numbers of myeloid and T cell subsets in peritoneal fluid and increased giant cells within the lesion. Lesions from rIL-23-treated mice did not reveal significant alterations in proliferation/vascularization, although trends of increased proliferation and vascularization were observed. Collectively, these findings provide insights into the impact of the IL-23/TH17 axis on local immune dysfunction and broadly on endometriosis pathophysiology.

Neurocognitive effects a combined polyphenolic-rich herbal extract in healthy middle-aged adults - a randomised, double-blind, placebo-controlled study.

Objective: This study assessed whether polyphenolic rich supplement containing Bacopa monnieri (BM: 300 mg), Panax quinquefolius ginseng (PQ: 100 mg) and whole coffee fruit extract (WCFE: 100 mg) could enhance cognitive performance, affect and cerebral-cortical activation over 28-days of intervention.Method: A randomised, double-blind, placebo-controlled, between-group study of 52 healthy adults between 35 and 65 years (M = 50.20, SD = 9.37) was conducted. Measures of cognition, affect and brain activity were measured at three time points: baseline, 28 days post intervention and 14 days post washout. At each time point, haemodynamic response in the prefrontal cortex (PFC) was measured using functional near-infrared spectroscopy (fNIRS), and serum brain-derived neurotrophic factor (BDNF).Results: The polyphenolic-rich supplement reliably improved positive affect and delayed recall compared to placebo following 28 days of supplementation. For the brain, those in the active condition showed greater PFC activation on performance of the 2-back tasks post supplementation compared to placebo (p < .05, d = 0.6).Discussion: This is the first report of a 28-day supplement intervention and 2-week follow-up study to assess changes in affect, cognition, cerebral haemodynamic response and BDNF in healthy middle-aged adults. The potential synergistic effects of polyphenolic compounds on neurocognitive function in middle-aged adults through emotional-cognitive processing and cognitive reserve are important for promoting brain and cognitive health.

Waning immunity and IgG4 responses following bivalent mRNA boosting.

Messenger RNA (mRNA) vaccines were highly effective against the ancestral SARS-CoV-2 strain, but the efficacy of bivalent mRNA boosters against XBB variants was substantially lower. Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses were primarily IgG2 and IgG4 responses with poor Fc functional activity. In contrast, a third monovalent mRNA immunization boosted all isotypes including IgG1 and IgG3 with robust Fc functional activity. These data show substantial immune imprinting for the ancestral spike and isotype switching to IgG4 responses following bivalent mRNA boosting, with important implications for future booster designs and boosting strategies.

Intimate partner violence in the lives of Indigenous and Black women in the upper Midwest of the United States during the COVID-19 pandemic: A mixed-methods protocol examining help-seeking behaviours and experiences.

Violent behaviour perpetrated against women has long-lasting negative physical and mental health consequences for women, their children, their families, and their communities. Intimate partner violence (IPV) is associated with many adverse physical, psychological, and emotional consequences. Structural racism and historical trauma affect women's trust and further hinder the ability of Indigenous and Black women to seek help after experiencing IPV. The availability of IPV support services, which can include shelter, food, group therapy, legal assistance, and advocacy, can be inaccessible to women due to the inability to access often limited resources in urban environments and reasons compounded by potential geographic distance if living in rural areas or living in community. Understanding the unique reasons why Indigenous and Black women do not seek help, and the barriers they experience when seeking help after IPV, is critical. Pandemics have the potential to create further complexities on how IPV is experienced. Black and Indigenous women experiencing IPV were therefore at even greater risk for IPV-related harm because of state and local "stay at home" measures put in place to minimise the spread COVID-19. The purpose of this manuscript is to explicate the methods for a large R01 study in the Upper Midwest.

Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques.

A limitation of current SARS-CoV-2 vaccines is that they provide minimal protection against infection with current Omicron subvariants1,2, although they still provide protection against severe disease. Enhanced mucosal immunity may be required to block infection and onward transmission. Intranasal administration of current vaccines has proven inconsistent3-7, suggesting that alternative immunization strategies may be required. Here we show that intratracheal boosting with a bivalent Ad26-based SARS-CoV-2 vaccine results in substantial induction of mucosal humoral and cellular immunity and near-complete protection against SARS-CoV-2 BQ.1.1 challenge. A total of 40 previously immunized rhesus macaques were boosted with a bivalent Ad26 vaccine by the intramuscular, intranasal and intratracheal routes, or with a bivalent mRNA vaccine by the intranasal route. Ad26 boosting by the intratracheal route led to a substantial expansion of mucosal neutralizing antibodies, IgG and IgA binding antibodies, and CD8+ and CD4+ T cell responses, which exceeded those induced by Ad26 boosting by the intramuscular and intranasal routes. Intratracheal Ad26 boosting also led to robust upregulation of cytokine, natural killer, and T and B cell pathways in the lungs. After challenge with a high dose of SARS-CoV-2 BQ.1.1, intratracheal Ad26 boosting provided near-complete protection, whereas the other boosting strategies proved less effective. Protective efficacy correlated best with mucosal humoral and cellular immune responses. These data demonstrate that these immunization strategies induce robust mucosal immunity, suggesting the feasibility of developing vaccines that block respiratory viral infections.