Heterologous vaccination interventions to reduce pandemic morbidity and mortality: Modeling the US winter 2020 COVID-19 wave

COVID-19 remains a stark health threat worldwide, in part because of minimal levels of targeted vaccination outside high-income countries and highly transmissible variants causing infection in vaccinated individuals. Decades of theoretical and experimental data suggest that nonspecific effects of non–COVID-19 vaccines may help bolster population immunological resilience to new pathogens. These routine vaccinations can stimulate heterologous cross-protective effects, which modulate nontargeted infections. For example, immunization with Bacillus Calmette–Guérin, inactivated influenza vaccine, oral polio vaccine, and other vaccines have been associated with some protection from SARS-CoV-2 infection and amelioration of COVID-19 disease. If heterologous vaccine interventions (HVIs) are to be seriously considered by policy makers as bridging or boosting interventions in pandemic settings to augment nonpharmaceutical interventions and specific vaccination efforts, evidence is needed to determine their optimal implementation. Using the COVID-19 International Modeling Consortium mathematical model, we show that logistically realistic HVIs with low (5 to 15%) effectiveness could have reduced COVID-19 cases, hospitalization, and mortality in the United States fall/winter 2020 wave. Similar to other mass drug administration campaigns (e.g., for malaria), HVI impact is highly dependent on both age targeting and intervention timing in relation to incidence, with maximal benefit accruing from implementation across the widest age cohort when the pandemic reproduction number is >1.0. Optimal HVI logistics therefore differ from optimal rollout parameters for specific COVID-19 immunizations. These results may be generalizable beyond COVID-19 and the US to indicate how even minimally effective heterologous immunization campaigns could reduce the burden of future viral pandemics.

Placebo Selection in Survey Experiments: An Agnostic Approach

Although placebo conditions are ubiquitous in survey experiments, little evidence guides common practices for their use and selection. How should scholars choose and construct placebos? First, we review the role of placebos in published survey experiments, finding that placebos are used inconsistently. Then, drawing on the medical literature, we clarify the role that placebos play in accounting for nonspecific effects (NSEs), or the effects of ancillary features of experiments. We argue that, in the absence of precise knowledge of NSEs that placebos are adjusting for, researchers should average over a corpus of many placebos. We demonstrate this agnostic approach to placebo construction through the use of GPT-2, a generative language model trained on a database of over 1 million internet news pages. Using GPT-2, we devise 5,000 distinct placebos and administer two experiments (N = 2,975). Our results illustrate how researchers can minimize their role in placebo selection through automated processes. We conclude by offering tools for incorporating computer-generated placebo text vignettes into survey experiments and developing recommendations for best practice.

Effect of Glucocorticoid Receptor Antagonism on Alcohol Self-Administration in Genetically-Selected Marchigian Sardinian Alcohol-Preferring and Non-Preferring Wistar Rats

Alcoholism is a chronically relapsing disorder characterized by high alcohol intake and a negative emotional state during abstinence, which contributes to excessive drinking and susceptibility to relapse. Stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and alterations in glucocorticoid receptor (GR) function have been linked to transition from recreational consumption to alcohol use disorder (AUD). Here, we investigated the effect of pharmacological antagonisms of GR on alcohol self-administration (SA) using male and female Wistar and Marchigian Sardinian alcohol-preferring (msP) rats, a rodent line genetically selected for excessive alcohol drinking and highly sensitive to stress. Animals were trained to self-administer 10% (v/v) alcohol. Once a stable alcohol SA baseline was reached, we tested the effect of the GR antagonists mifepristone (0.0, 10, 30 and 60 mg/kg; i.p.) and CORT113176 (0.0, 10, 30 and 60 mg/kg) on alcohol SA. To evaluate whether the effects of the two compounds were specific for alcohol, the two drugs were tested on a similar saccharin SA regimen. Finally, basal blood corticosterone (CORT) levels before and after alcohol SA were determined. Systemic injection with mifepristone dose-dependently reduced alcohol SA in male and female Wistars but not in msPs. Administration of CORT113176 decreased alcohol SA in male and female Wistars as well as in female msPs but not in male msP rats. At the highest dose, mifepristone also reduced saccharin SA in male Wistars and female msPs, suggesting the occurrence of some nonspecific effects at 60 mg/kg of the drug. Similarly, the highest dose of CORT113176 (60 mg/kg) decreased saccharin intake in male Wistars. Analysis of CORT levels revealed that females of both rat lines had higher blood levels of CORT compared to males. Alcohol consumption reduced CORT in females but not in males. Overall, these findings indicate that selective blockade of GR selectively reduces alcohol SA, and genetically selected msP rats are less sensitive to this pharmacological manipulation compared to heterogeneous Wistars. Moreover, results suggest sex differences in response to GR antagonism and the ability of alcohol to regulate GR transmission.

Lower Risk for Dementia Following Adult Tetanus, Diphtheria and Pertussis (Tdap) Vaccination

Background Adult vaccinations may reduce risk for dementia. However it has not been established whether tetanus, diphtheria, pertussis (Tdap) vaccination is associated with incident dementia. Methods Hypotheses were tested in a Veterans Health Affairs (VHA) cohort and replicated in a MarketScan medical claims cohort. Patients were ≥65 years of age and free of dementia for 2 years prior to index date. Patients either had or did not have a Tdap vaccination by the start of either of two index periods (2011 or 2012). Follow-up continued through 2018. Controls had no Tdap vaccination for the duration of follow-up. Confounding was controlled using entropy balancing. Competing risk (VHA) and Cox proportional hazard (MarketScan) models estimated the association between Tdap vaccination and incident dementia in all patients and in age sub-groups (65-69, 70-74, ≥75 years of age). Results VHA patients were, on average, 75.6 (SD±7.5) years of age, 4% female, and 91.2% were white race. MarketScan patients were 69.8 (SD±5.6) years of age, on average and 65.4% were female. After controlling for confounding, patients with, compared to without Tdap vaccination, had a significantly lower risk for dementia in both cohorts (VHA: HR=0.58; 95%CI:0.54 - 0.63 and MarketScan: HR=0.58; 95%CI:0.48 - 0.70). Conclusions Tdap vaccination was associated with a 42% lower dementia risk in two cohorts with different clinical and sociodemographic characteristics. Several vaccine types are linked to decreased dementia risk, suggesting that these associations are due to nonspecific effects on inflammation rather than vaccine-induced pathogen-specific protective effects.

Direct single-molecule imaging for diagnostic and blood screening assays

Every year, over 100 million units of donated blood undergo mandatory screening for HIV, hepatitis B, hepatitis C, and syphilis worldwide. Often, donated blood is also screened for human T cell leukemia–lymphoma virus, Chagas, dengue, Babesia, cytomegalovirus, malaria, and other infections. Several billion diagnostic tests are performed annually around the world to measure more than 400 biomarkers for cardiac, cancer, infectious, and other diseases. Considering such volumes, every improvement in assay performance and/or throughput has a major impact. Here, we show that medically relevant assay sensitivities and specificities can be fundamentally improved by direct single-molecule imaging using regular epifluorescence microscopes. In current microparticle-based assays, an ensemble of bound signal-generating molecules is measured as a whole. By contrast, we acquire intensity profiles to identify and then count individual fluorescent complexes bound to targets on antibody-coated microparticles. This increases the signal-to-noise ratio and provides better discrimination over nonspecific effects. It brings the detection sensitivity down to the attomolar (10−18 M) for model assay systems and to the low femtomolar (10−16 M) for measuring analyte in human plasma. Transitioning from counting single-molecule peaks to averaging pixel intensities at higher analyte concentrations enables a continuous linear response from 10−18 to 10−5 M. Additionally, our assays are insensitive to microparticle number and volume variations during the binding reaction, eliminating the main source of uncertainties in standard assays. Altogether, these features allow for increased assay sensitivity, wide linear detection ranges, shorter incubation times, simpler assay protocols, and minimal reagent consumption.

Systematic analysis of specific and nonspecific auxin effects on endocytosis and trafficking

The phytohormone auxin and its directional transport through tissues are intensively studied. However, a mechanistic understanding of auxin-mediated feedback on endocytosis and polar distribution of PIN auxin transporters remains limited due to contradictory observations and interpretations. Here, we used state-of-the-art methods to reexamine the auxin effects on PIN endocytic trafficking. We used high auxin concentrations or longer treatments versus lower concentrations and shorter treatments of natural indole-3-acetic acid (IAA) and synthetic naphthalene acetic acid (NAA) auxins to distinguish between specific and nonspecific effects. Longer treatments of both auxins interfere with Brefeldin A-mediated intracellular PIN2 accumulation and also with general aggregation of endomembrane compartments. NAA treatment decreased the internalization of the endocytic tracer dye, FM4-64; however, NAA treatment also affected the number, distribution, and compartment identity of the early endosome/trans-Golgi network, rendering the FM4-64 endocytic assays at high NAA concentrations unreliable. To circumvent these nonspecific effects of NAA and IAA affecting the endomembrane system, we opted for alternative approaches visualizing the endocytic events directly at the plasma membrane (PM). Using total internal reflection fluorescence microscopy, we saw no significant effects of IAA or NAA treatments on the incidence and dynamics of clathrin foci, implying that these treatments do not affect the overall endocytosis rate. However, both NAA and IAA at low concentrations rapidly and specifically promoted endocytosis of photo-converted PIN2 from the PM. These analyses identify a specific effect of NAA and IAA on PIN2 endocytosis, thus, contributing to its polarity maintenance and furthermore illustrate that high auxin levels have nonspecific effects on trafficking and endomembrane compartments.

The Specific and Nonspecific Effects of Tai Chi and Its Possible Central Responses: A Protocol of Neuroimaging Study

Tai Chi has been proven to be a safe and effective assistant therapy for healthcare and disease treatment. However, whether the adjuvant therapeutic effect of Tai Chi is general or disease-oriented remains uncertain. This trial focuses on exploring the specific and nonspecific effects of Tai Chi and its potential central responses. The results will deepen our understanding of the characteristics of Tai Chi exercise for adjuvant therapeutic effects and promote its application in the clinic. In this neuroimaging trial, 40 functional constipation (FC) patients and 40 healthy subjects (HS) will be recruited and will receive 10 weeks of Tai Chi exercise. The motor function, respiratory function, stool-related symptoms, quality of life, and emotional state of the participants will be evaluated at the baseline, the 5-week Tai Chi practice, and the end of practice. The potential changes in the heart rate variability and the cerebral function will be recorded by the 24 h dynamic electrocardiogram at the baseline and the functional magnetic resonance imaging at the end of practice. The possible correlations among the clinical variables, the heart rate variability, and the cerebral activity alterations in FC patients and HS will be analyzed. The healthcare and therapeutic effects of Tai Chi exercise might consist of the specific and nonspecific effects. This study provides not only a new perspective for understanding Tai Chi but also a new approach for investigating the mind-body exercise. This trial was registered in the Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=33243) on 28 November 2018 (registration number: ChiCTR1800019781; protocol version number: V1.0). This trial is currently in the stage of recruiting patients. The first patient was included on 1 December 2018. To date, 18 FC patients and 20 HS have been included. Recruitment will be completed in December 2020.

BCG, muramylpeptides, trained immunity (part II): a low molecular weight alternative to multicomponent bacterial immunostimulants for prevention of respiratory infections during a pandemic

During a pandemic, nonspecific immunoprophylaxis of SARS-CoV-2 infection and other acute respiratory infections (ARI), which can worsen the course of COVID-19, is increasingly in demand in addition to specific immunization. BCG vaccine appears to be one of the candidate immunostimulants in this regard. At the same time, other microbe-derived preparations capable of inducing a state of trained immunity deserve attention. BCG and other bacterial immunostimulatory agents containing a large number of biologically active subunits have long been considered as objects of search for promising pharmacological substances. The review analyzes the linkages between BCG, mycobacterial adjuvants, bacterial lysates, trained immunity, muramylpeptides (MPs) and NOD2 receptors in light of the choice of a low molecular weight alternative to multicomponent bacterial immunostimulants for ARI prevention during the COVID-19 pandemic. The search for key molecules by which bacteria stimulate innate and adaptive immune responses proceeds in a spiral. On different loops of this spiral, MPs have repeatedly reproduced the nonspecific effects of multicomponent bacterial adjuvants, vaccines and immunostimulants. MPs and peptidoglycans containing MPs determine the adjuvant properties of the cell walls of mycobacteria and their peptide-glycolipid fraction (wax D). MPs were able to replace Mycobacterium tuberculosis in complete Freunds adjuvant. MPs determine the NOD2-dependent ability of BCG to induce trained immunity. Probably, MPs provide NOD2-mediated long-term prophylactic action of bacterial lysates. All of the above has prompted revisiting the previously obtained evidence of the efficacy of glucosaminylmuramyl dipeptide (GMDP) as a NOD2 agonist in treatment/prevention of respiratory infections. We speculate here that MPs, in particular GMDP, at rational dosing regimens will be able to reproduce many aspects of the nonspecific effects of BCG and multicomponent bacterial immunostimulants in preventing ARI during the COVID-19 pandemic and in the post-pandemic period.

PECULIARITIES OF NON-AUDITORY EFFECTS OF NOISE DEPENDING ON THE DOSE AND PROCESSED AMOUNT OF ACOUSTIC INFORMATION

Most of non-auditory effects cannot be explained as a simple consequence of noise energy influence. The level of arousal also depends on predictability of acoustic signals (level of entropy). The present article aims to analyse the contribution of noise dose and the level of entropy in non-auditory effects. 117 metallurgists and 15 healthy non-adapted to noise men were exposed to 4 different combinations of noise dose and entropy (during 8 hour working shift and 1 hour in a soundproof room correspondingly). Experiment was 2x2 factorial design. Functional state of cardiovascular and central nervous system was evaluated before and after exposure. The chosen noise characteristics account for up to 80% of the dispersion of nonspecific effects. The largest number of significant differences were between the groups, where the controlled factors were either at the lower or the upper level of variation. Noise dose and entropy contribute to such non-specific reactions as systolic/diastolic blood pressure, Stress Index, Kerdo index, duration of RR intervals, visual/hearing motion time delay. The cardiovascular system is the most sensitive to the variation of the entropy of the acoustic field.