Link Between the G Protein-Coupled Receptor (GPCR), SARS-CoV-2 Spike Protein, ACE2, Vaccines, and Long COVID (preprint)

The knowledge of COVID-19 impact on the human body has increased rapidly. Although many people recover from COVID-19, some continue to experience persistent symptoms that have been identified as Long COVID. This condition can have a severe impact on quality of life, and it remains a significant concern for medical professionals and researchers. One of the key components of the SARS-CoV-2 virus that enables it to enter human cells is the spike (S) protein. Recent studies have revealed a complex network of interactions between G proteins, spike (S) protein, and the Renin-Angiotensin System (RAS) may be responsible, at least in part, for long COVID. SARS-CoV-2 can also affect the brain, leading to neurological symptoms such as confusion, memory loss, and fatigue. Increasing evidence suggests that COVID-19 is not just a respiratory illness since it is likely that the virus could influence signal transduction pathways such as G-protein-coupled receptor (GPCR), among others, in the brain, either directly or indirectly, affecting neural functions. These interactions with the spike (S) protein and RAS, alongside the brain, are complex and require deep research to understand their implications for Long COVID-19 manifestation fully. While recent research has shed light on the complex interactions between G proteins, spike (S) protein, the brain, and the angiotensin system, this article explores these interconnected pathways and their implications for long COVID-19 manifestations. The present review summarises current research on different molecular mechanisms in Long COVID pathophysiology and may help identify possible targets or new strategies for the diagnosis and treatment.

Plasma proteomic evidence for increased Alzheimer's disease-related brain pathology after SARS-CoV-2 infection (preprint)

Viral infections have been linked to an increased risk for dementia. We investigated whether SARS-CoV-2 infection increases preclinical brain pathology associated with Alzheimer's disease (AD) by comparing changes in plasma biomarkers in UK Biobank participants with and without prior SARS-CoV-2 infection. We discovered an association between SARS-CoV-2 infection and reduced plasma A{beta}42:A{beta}40 concentration ratio. In older participants, SARS-CoV-2 infection was associated with both lower plasma A{beta}42 and higher plasma pTau-181. These biomarker changes, which have been associated with beta-amyloid accumulation and prodromal AD, were associated with increased brain imaging signatures of AD, poorer cognitive scores, and worse assessments of overall health and appeared to be greater in participants who had been hospitalised with COVID-19. Protein biomarker risk scores for other diseases were also raised among individuals who had past SARS-CoV-2 infections. Our data provide support for the hypothesis that viral infections can accelerate prodromal AD pathology and highlight biomarker profiles indicative of an increased risk of dementia and systemic diseases after SARS-CoV-2 infection, particularly in older people.

Sex and gender differences in adverse events following receipt of influenza and COVID-19 vaccination among healthcare workers (preprint)

IntroductionActive and passive surveillance studies have found that a greater proportion of females report adverse events (AE) following receipt of either the COVID-19 or seasonal influenza vaccine compared to males. We sought to determine the intersection of biological sex and sociocultural gender differences in prospective active reporting of vaccine outcomes, which remains poorly characterized. MethodsThis cohort study enrolled Johns Hopkins Health System healthcare workers (HCWs) who were recruited from the annual fall 2019-2022 influenza vaccine and the fall 2022 COVID-19 bivalent vaccine campaigns. Vaccine recipients were enrolled the day of vaccination and AE surveys were administered two days post-vaccination (DPV) for bivalent COVID-19 and Influenza vaccine recipients. Data were collected regarding the presence of a series of solicited local and systemic AEs. Open-ended answers about participants experiences with AEs also were collected for the COVID-19 vaccine recipients. ResultsFemales were more likely to report local AEs after influenza (OR=2.28, p=0.001) or COVID-19 (OR=2.57, p=0.008) vaccination compared to males, regardless of age or race. Males and females had comparable probabilities of reporting systemic AEs after influenza (OR=1.18, p=0.552) or COVID-19 (OR=0.96, p=0.907) vaccination. Exogenous hormones from birth control use did not impact the rates of reported AEs following COVID-19 vaccination among reproductive-aged female HCWs. Women reported more interruptions in their daily routine following COVID-19 vaccination than men and were more likely to seek out self-treatment. More women than men scheduled their COVID-19 vaccination before their days off in anticipation of AEs. ConclusionsOur findings highlight the need for sex- and gender-inclusive policies to inform more effective occupational health vaccination strategies. Further research is needed to evaluate the potential disruption of AEs on occupational responsibilities following mandated vaccination for healthcare workers and to more fully characterize the post-vaccination behavioral differences between men and women. KEY MESSAGEO_ST_ABSWhat is already known on this topicC_ST_ABS{Rightarrow} Among diversely aged adults 18-64 years, females report more AEs to vaccines, including the influenza and COVID-19 vaccines, than males. {Rightarrow}Vaccine AEs play a role in shaping vaccine hesitancy and uptake. {Rightarrow}Vaccine uptake related to influenza and COVID-19 are higher among men than women. {Rightarrow}Research that addresses both the sex and gender disparities of vaccine outcomes and behaviors is lacking. What this study adds{Rightarrow} This prospective active reporting study uses both quantitative and qualitative survey data to examine sex and gender differences in AEs following influenza or COVID-19 vaccination among a cohort of reproductive-aged healthcare workers. How this study might affect research, practice, or policy{Rightarrow} Sex and gender differences in AEs and perceptions relating to vaccination should drive the development of more equitable and effective vaccine strategies and policies in occupational health settings.

A human primary airway microphysiological system infected with SARS-CoV-2 distinguishes the treatment efficacy between nirmatrelvir and repurposed compounds fluvoxamine and amodiaquine (preprint)

The COVID-19 pandemic necessitated a rapid mobilization of resources toward the development of safe and efficacious vaccines and therapeutics. Finding effective treatments to stem the wave of infected individuals needing hospitalization and reduce the risk of adverse events was paramount. For scientists and healthcare professionals addressing this challenge, the need to rapidly identify medical countermeasures became urgent, and many compounds in clinical use for other indications were repurposed for COVID-19 clinical trials after preliminary preclinical data demonstrated antiviral activity against SARS-CoV-2. Two repurposed compounds, fluvoxamine and amodiaquine, showed efficacy in reducing SARS-CoV-2 viral loads in preclinical experiments, but ultimately failed in clinical trials, highlighting the need for improved predictive preclinical tools that can be rapidly deployed for events such as pandemic emerging infectious diseases. The PREDICT96-ALI platform is a high-throughput, high-fidelity microphysiological system (MPS) that recapitulates primary human tracheobronchial tissue and supports highly robust and reproducible viral titers of SARS-CoV-2 variants Delta and Omicron. When amodiaquine and fluvoxamine were tested in PREDICT96-ALI, neither compound demonstrated an antiviral response, consistent with clinical outcomes and in contrast with prior reports assessing the efficacy of these compounds in other human cell-based in vitro platforms. These results highlight the unique prognostic capability of the PREDICT96-ALI proximal airway MPS to assess the potential antiviral response of lead compounds.

COVID-19 infection and women's health; which women are more vulnerable in terms of gynecological health? (preprint)

Background Given gender-specific differences and ACE2 commonly expressed in the ovaries and uterus, it may be important to know which women are at greater risk of COVID-19 infection. Therefore, this study sought to determine which women are more affected by COVID- 19 infection, especially in terms of gynecological pathologies.Methods This retrospective and descriptive study examined the effect and course of COVID-19 in terms of gynecological pathologies in a total of 380 women of reproductive age without systemic disease. General demographics, obstetric and gynecological conditions, and parameters related to COVID-19 were evaluated. All parameters were compared for three groups defined on the basis of COVID-19 severity (mild, moderate, and severe).Results A total of 380 women with a mean age of 35.39 ± 8.94 were included in the study. The mean body mass index (BMI) of the women was 24.35 ± 4.53. The proportion of women with at least one pregnancy history was 69.2%. The mean gravidity of the women was 1.47 ± 1.34 and the parity was 1.16 ± 1.02. Of the women, 112 (29.5%) mild, 207 (54.5%) moderate and 61 (16.0%) severe cases of COVID-19 were seen. The mean age and median BMI of the women were similar in all three groups (p = 0.163, p = 0.127, respectively). Severe disease rates (29.5%) were significantly higher in women with 2 or more cases of COVID-19 than mild disease (14%) (p = 0.018). Severe disease rates (57.4%) in women with at least one pregnancy history were statistically significantly lower than mild disease rates (78.6%) (p = 0.010). The median parity number was significantly higher in the mild disease group than in the moderate disease group (p = 0.021). The most common benign gynecological pathology in women was chronic urinary tract infection (13.2%). Other common pathologies were chronic vaginal infection (12.6%), and polycystic ovary syndrome (PCOS) (11.6%). A history of chronic urinary tract infection was statistically significantly higher in the severe disease group (24.6%), mild (8.9%, p = 0.015) and moderate (12.1%, p = 0.024) disease groups. PCOS, endometriosis (6.3%), abnormal uterine bleeding (AUB) (8.4%), and hormone therapy history (8.2%) were found to be higher in severe disease groups, although not statistically significant (p = 0.596, p = 0.074, p = 0.305, p = 0.059, respectively). The history of leiomyoma (7.1%) was higher in the mild and moderate disease groups than in the severe disease group, but it was not statistically significant (p = 0.794). Benign gynecological operation history (31.3%) was significantly higher in mild (36.6%, p = 0.007), and moderate (33.3%, p = 0.007) disease groups than in the severe group (9, 14.8%).Conclusion Certain obstetric and gynecological conditions are thought to affect COVID 19 susceptibility and severity in women without systemic disease.

Covid-19 May Impact the Acute Attack of Primary Angle-closure Glaucoma (preprint)

Objects: To compare the medical records of inpatients with acute angle-closure glaucoma(AACG) in the period of pandemic 2022(2022.12.9-2023.1.19) , and the same time period of last three years.To analyses covid-19 infection-related conditions in patients with AACG of the pandemic 2022. Methods: Patients with AACG who first hospitalized for surgical treatment in the ophthalmology department of the First Affiliated Hospital of Nanjing Medical University from 2022.12.9 to 2023.1.19(after the adjustment of China's pandemic prevention policies) were included, and the patients of same time of last three years,(2019group:2019.12.9-2020.1.19, pandemic 2020:2020.12.9-2021.1.19 and pandemic 2021:2021.12.9-2022.1.19).These inpatients’ medical records were compared.During the period from 2022.12.9 to 2023.1.19,patients with acute ACG who were first diagnosed or first hospitalized for surgical treatment, an online questionnaire was administered, and whether they had glaucoma attacks during COVID-19 infection was used as a subgroup question to compare the two groups of people with AACG in general differences in conditions. Results: A total of 114 patients (135 operated eyes) with medical records were included：24 (28 eyes) of 2019 group，27 (27 eyes) of pandemic 2020,29(37eyes)of pandemic 2021 and 34 (43 eyes) of pandemic 2022 respectively. 72 patients participated in the questionnaire. The number of patients hospitalized for surgery for AACG in the period following the COVID-19 pandemic was significantly higher by approximately 41.6% compared to the 2019 group, accounting for a significantly higher percentage (p=0.004),a significant difference in the status of comorbid systemic disease and comorbid hypertension among surgically treated patients (p=0.042, p=0.010) Significant difference in the rate of trabeculectomy(Trab) for glaucoma decreasing from year to year (p=0.019) and a significant increasing trend in the rate of goniosynechialysis(GSL) (p=0.007) Whether the pandemic environment or viral infection precipitates glaucoma attacks may be related to whether patients drink alcohol (p=0.028) and whether they have combined hypertension (p=0.014). Conclusion: The COVID-19 pandemic may promote an increase in the number of patients with AACG, and COVID-19 infection has the potential to contribute to the attack of primary angle-closure glaucoma.

Bank’s strategic interaction, adverse price dynamics, and systemic liquidity risk (preprint)

In this paper, we introduce two measures, the Systemic Liquidity Buffer (SLB) and the Systemic Liquidity Shortfall (SLS), to assess liquidity in the banking system. The SLB takes an aggregated perspective on liquidity risks in the banking system. In contrast, the SLS focuses on the problematic banks which suffer a liquidity shortfall. These measures provide an add-on to regulatory liquidity measures such as the LCR because they better incorporate a systemic perspective: (1) They model the impact of a funding shock by valuing assets at depressed market prices, (2) Doing so, they explicitly incorporate banks’ strategic responses to a market undergoing sharp price declines. We test our approach using several applications capturing both a short (5 days) and a medium-term (30 days) stress scenario, a sudden rise in interest rates, the impact of banks’ US dollar business, and the recent COVID-19 crisis. JEL classification: C63, G01, G17, G21, G28.

A PUBLIC HEALTH HACKATHON FOR MEDICAL STUDENTS IN AFRICA: PROCESS, OUTCOME AND RECOMMENDATIONS (preprint)

Africa has a dual burden of disease, which causes preventable morbidities and fatalities. This is a result of our healthcare system's deficiencies, which has suffered a serious decline since the COVID-19 pandemic. However, this opened up the possibilities for digital health interventions, which innovators could utilize to provide solutions to these public health issues. Health hackathons, which offer an environment for innovators to brainstorm and collaborate, are rare in Africa. This paper outlines the planning and execution of a virtual hackathon and explores its implications for the promotion of public health in Africa. Over the course of a month, we collaborated with innovation hubs in Africa to hold an open call, a training session, a design sprint, as well as a 48-hour virtual hackathon. We received 68 submissions from 13 African nations. Following the selection of 10 teams, design thinking was employed to develop solutions to a public health problem in Africa. The theme for the hackathon was 'Promoting Health Equity with Digital Technology in Africa' and areas of focus were non-communicable diseases; infectious disease epidemiology and surveillance; and health information and data management. All ten teams developed prototypes, the top three teams were offered the opportunity to continue on to the startup accelerator program, while the winning team also received a cash prize. In conclusion, the public health hackathon challenged African medical students to develop innovations to healthcare problems. There is need for further study to evaluate the solutions developed.

Epidemiological transition in Australia: An analysis of immigration patterns in relation to circulatory system diseases and all-cause mortality in the mid-twentieth century (preprint)

Background and Objectives: Circulatory System Diseases (CSD) patterns vary over time and between countries, related to lifestyle risk factors, associated in turn with socio-economic circumstances. Current global CSD epidemics in developing economies are similar in scale to those observed previously in the USA and Australasia. Australia exhibits an important macroeconomic phenomenon as a rapidly transitioning economy with high immigration throughout the 19th and 20th centuries. We wished to examine how that historical immigration related to CSD patterns subsequently. Methods and Setting: We provide a novel empirical analysis employing census-derived place of birth by age bracket and sex from 1891 to 1986, in order to map patterns of immigration against CSD mortality rates from 1907 onwards. Age-specific generalised additive models for both CSD mortality in the general population, and all-cause mortality for the foreign-born (FB) only, from 1910 to 1980 were also devised for both males and females. Results: The % FB fell from 32% in 1891 to 9.8% in 1947. Rates of CSD rose consistently, particularly from the 1940s onwards, peaked in the 1960s, then declined sharply in the 1980s and showed a strong period effect across age groups and genders. The main effects of age and census year and their interaction were highly statistically significant for CSD mortality for males (p < 0.001, each term) and for females (p < 0.001, each term). The main effect of age was statistically significant for all-cause mortality minus net migration rates for the FB males (p =0.005) and for FB females, both age (p < 0.001) and the interaction term (p=0.002) were significant. Conclusions: We argue our empirical calculations, supported by historical and socio-epidemiological evidence, employing immigration patterns as a proxy for epidemiological transition, affirm the lifecourse hypothesis that both early life circumstances and later life lifestyle drive CSD patterns.

Mathematical Modeling of Impacts of Patient Differences on COVID-19 Lung Fibrosis Outcomes (preprint)

Patient-specific premorbidity, age, and sex are significant heterogeneous factors that influence the severe manifestation of lung diseases, including COVID-19 fibrosis. The renin-angiotensin system (RAS) plays a prominent role in regulating effects of these factors. Recent evidence suggests that patient-specific alteration of RAS homeostasis with premorbidity and the expression level of angiotensin converting enzyme 2 (ACE2), depending on age and sex, is correlated with lung fibrosis. However, conflicting evidence suggests decreases, increases, or no changes in RAS after SARS-CoV-2 infection. In addition, detailed mechanisms connecting the patient-specific conditions before infection to infection-induced fibrosis are still unknown. Here, a mathematical model is developed to quantify the systemic contribution of heterogeneous factors of RAS in the progression of lung fibrosis. Three submodels are connected - a RAS model, an agent-based COVID-19 in-host immune response model, and a fibrosis model - to investigate the effects of patient-group-specific factors in the systemic alteration of RAS and collagen deposition in the lung. The model results indicate cell death due to inflammatory response as a major contributor to the reduction of ACE and ACE2, whereas there are no significant changes in ACE2 dynamics due to viral-bound internalization of ACE2. Reduction of ACE reduces the homeostasis of RAS including angiotensin II (ANGII), while the decrease in ACE2 increases ANGII and results in severe lung injury and fibrosis. The model explains possible mechanisms for conflicting evidence of RAS alterations in previously published studies. Also, the results show that ACE2 variations with age and sex significantly alter RAS peptides and lead to fibrosis with around 20% additional collagen deposition from systemic RAS with slight variations depending on age and sex. This model may find further applications in patient-specific calibrations of tissue models for acute and chronic lung diseases to develop personalized treatments.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground? (preprint)

A Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology under growing interest now in view of the increasingly recognized post-COVID syndrome as a new entity with similar clinical presentation. We performed the first cross-sectional study of ME/CFS in community population in Russia and then described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders. Of the cohort of 76 individuals who suggested themselves suffering from ME/CFS 56 subsequently were confirmed as having CFS/ME according to ≥1 of the 4 most commonly used case definition. Of the cohort of 14 individuals with post-COVID-19 syndrome 14 met diagnostic criteria for ME/CFS. The prevalence of clinically expressed and subclinical anxiety and depression in ME / CFS and post-COVID ME/CFS did not differ significantly from that in healthy individuals. Severity of anxiety / depressive symptoms did not correlate with the severity of fatigue neigther in ME / CFS nor in post-COVID ME/CFS, but the positive correlation was found between the severity of fatigue and 20 other symptoms of ME / CFS related to the domains of “post-exertional exhaustion”, “immune dysfunction”, “sleep disturbances”, "dysfunction of the autonomic nervous system", "neurological sensory / motor disorders" and "pain syndromes". Immunological abnormalities were identified in 12/12 patients with ME / CFS according to the results of laboratory testing. The prevalence of postural orthostatic tachycardia assessed by the active standing test was 37.5% in ME / CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02) There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group. Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls. The identified pattern corresponded to the hyperemic form of microcirculation disorders, usually observed in acute inflammatory processes or in deficiency of systemic vasoconstriction influences.

Data Source Concordance for Infectious Disease Epidemiology (preprint)

Background: As highlighted by the COVID-19 pandemic, researchers are eager to make use of a wide variety of data sources, both government-sponsored and alternative, to characterize the epidemiology of infectious diseases. To date, few studies have investigated the strengths and limitations of sources currently being used for such research. These are critical for policy makers to understand when interpreting study findings. Methods: To fill this gap in the literature, we compared infectious disease reporting for three diseases (measles, mumps, and varicella) across four different data sources: Optum (health insurance billing claims data), HealthMap (online news surveillance data), Morbidity and Mortality Weekly Reports (official government reports), and National Notifiable Disease Surveillance System (government case surveillance data). We reported the yearly number of national- and state-level disease-specific case counts and disease clusters according to each of our sources during a five-year study period (2013-2017). Findings: Our study demonstrated drastic differences in reported infectious disease incidence across data sources. When compared against the other three sources of interest, Optum data showed substantially higher, implausible standardized case counts for all three diseases. Although there was some concordance in identified state-level case counts and disease clusters, all four sources identified variations in state-level reporting. Interpretation: Researchers should consider data source limitations when attempting to characterize the epidemiology of infectious diseases. Some data sources, such as billing claims data, may be unsuitable for epidemiological research within the infectious disease context.

Patient satisfaction with telemedicine in the Philippines during the COVID-19 pandemic (preprint)

Introduction: The capacity to deliver essential health services has been negatively impacted by the COVID-19 pandemic particularly due to lockdown restrictions. Telemedicine provides a safe, efficient, and effective solution that addresses the needs of patients and the health system. However, there remain implementation challenges and barriers to patient adoption in resource-limited settings as in the Philippines. This study thus aimed to describe patient perspectives and experiences with telemedicine services, and explore the factors that influence telemedicine use and satisfaction. Methods: This study used a mixed-methods design through online surveys and in-depth interviews. An online survey using Consumer Assessment of Healthcare Providers and Systems (CAHPS) Clinician & Group Adult Visit Survey 4.0 (beta) and Telehealth Usability Questionnaire (TUQ) was accomplished by 200 participants aged 18 to 65 years. A subsample of 16 participants was interviewed to provide insights to the quantitative data. We used descriptive statistics to analyze survey data and grounded theory to analyze data from interviews. Results: Participants were generally satisfied with telemedicine services, with most reporting that this was an efficient and convenient alternative to face-to-face consultations. However, only 2 in 5 perceived telemedicine as affordable. Our quantitative findings suggest that participants preferred telemedicine services rather than in-person consultations, especially in cases where they feel that their condition is not urgent and does not need extensive physical examination. Safety against COVID-19, and the availability of multiple communication platforms contributed to patient satisfaction with telemedicine. Negative perceptions of patients on their telemedicine provider, perceived higher costs, poor connectivity and other technological issues were found to be barriers to patient satisfaction. Discussion: Telemedicine is viewed as a safe and efficient alternative to receiving care. Continued adoption of telemedicine will require improvements in technology and better patient communication related to their telemedicine provider and the associated costs.

New austalide derivative from the marine-derived Aspergillus sp. and evaluation of its biological activity (preprint)

Chemical investigation of the ethyl acetate extract of Aspergillus sp. isolated from the soft coral Sinularia species resulted in the isolation of one new meroterpenoid austalide X ( 1 ), one known austalide W ( 2 ), six known prenylated indole diketopiperazine alkaloids ( 3-8 ) and phthalic acid and its ethyl derivative ( 9-10 ) . The structures were established using 1D and 2D NMR experiments supported by UV analysis and ESI-MS (Electrospray ionization mass spectrometry). The effect of changing the fermentation media was also investigated using LC-PDA-MS (Liquid chromatography-photodiode-array-mass spectrometry) employing rice and beans media. It showed significant quantitative and qualitative variations particularly in the diketopiperazine content. In vitro cytotoxic evaluation was performed using MTT assay. Results showed that the examined compounds revealed weak to moderate activities where the new meroterpenoid, austalide X ( 1 ) displayed IC 50 value of 51.6 µg/mL. In silico molecular docking was done to evaluate COVID-19 inhibitory potential of isolated compounds on 2019-nCoV main protease, spike glycoprotein and Angiotensin-Converting Enzyme 2 (ACE2). Compound (10) followed by compound (9) exerted a potent inhibition on all the examined proteins with high fitting scores. ADME/TOPKAT (absorption, distribution, metabolism, excretion, and toxicity) predication performed in silico showed that most of the isolated compounds revealed reasonable pharmacokinetic, pharmacodynamic and toxicity properties.

UB-612, a Multitope Universal Vaccine Eliciting a Balanced B and T Cell Immunity against SARS-CoV-2 Variants of Concern (preprint)

Importance. The SARS-CoV-2 non-spike structural proteins of nucleocapsid (N), membrane (M) and envelope (E) are critical in the host cell interferon response and memory T-cell immunity and have been grossly overlooked in the development of COVID vaccines. Objective. To determine the safety and immunogenicity of UB-612, a multitope vaccine containing S1-RBD-sFc protein and rationally-designed promiscuous peptides representing sequence-conserved Th and CTL epitopes on the Sarbecovirus nucleocapsid (N), membrane (M) and spike (S2) proteins. Design, setting and participants. UB-612 booster vaccination was conducted in Taiwan. A UB-612 booster dose was administered 6-8 months post-2nd dose in 1,478 vaccinees from 3,844 healthy participants (aged 18-85 years) who completed a prior placebo (saline)-controlled, randomized, observer-blind, multi-center Phase-2 primary 2-dose series (100-ug per dose; 28-day apart) of UB-612. The interim safety and immunogenicity were evaluated until 14 days post-booster. Exposure. Vaccination with a booster 3rd-dose (100-ug) of UB-612 vaccine. Main outcomes and measures. Solicited local and systemic AEs were recorded for seven days in the e-diaries of study participants, while skin allergic reactions were recorded for fourteen days. The primary immunogenicity endpoints included viral-neutralizing antibodies against live SARS-CoV-2 wild-type (WT, Wuhan strain) and live Delta variant (VNT50), and against pseudovirus WT and Omicron variant (pVNT50). The secondary immunogenicity endpoints included anti-S1-RBD IgG antibody, S1-RBD:ACE2 binding inhibition, and T-cell responses by ELISpot and Intracellular Staining. Results. No post-booster vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. The UB-612 booster prompted a striking upsurge of neutralizing antibodies against live WT Wuhan strain (VNT50, 1,711) associated with unusually high cross-neutralization against Delta variant (VNT50, 1,282); and similarly with a strong effect against pseudovirus WT (pVNT50, 6,245) and Omicron variant (pVNT50, 1,196). Upon boosting, the lower VNT50 and pVNT50 titers of the elderly in the primary series were uplifted to the same levels as those of the young adults. The UB-612 also induced robust, durable VoC antigen-specific Th1-oriented (IFN-{gamma}+-) responses along with CD8+ T-cell (CD107a+-Granzyme B+) cytotoxicity. Conclusions and relevance. With a pronounced cross-reactive booster effect on B- and T-cell immunity, UB-612 may serve as a universal vaccine booster for comprehensive immunity enhancement against emergent VoCs. Trial registration. [ClinicalTrials.gov: NCT04773067]

Development and evaluation of low-volume tests to detect and characterise antibodies to SARS-CoV-2 (preprint)

Low-volume antibody assays can be used to track SARS-CoV-2 infection rates in settings where active testing for virus is limited and remote sampling is optimal. We developed 12 ELISAs detecting total or antibody isotypes to SARS-CoV-2 nucleocapsid, spike protein or its receptor binding domain (RBD), 3 anti-RBD isotype specific luciferase immunoprecipitation system (LIPS) assays and a novel Spike-RBD bridging LIPS total-antibody assay. We utilised pre-pandemic (n=984) and confirmed/suspected recent COVID-19 sera taken pre-vaccination rollout in 2020 (n=269). Assays measuring total antibody discriminated best between pre-pandemic and COVID-19 sera and were selected for diagnostic evaluation. In the blind evaluation, two of these assays (Spike Pan ELISA and Spike-RBD Bridging LIPS assay) demonstrated >97% specificity and >92% sensitivity for samples from COVID-19 patients taken >21 days post symptom onset or PCR test. These assays offered better sensitivity for the detection of COVID-19 cases than a commercial assay which requires 100-fold larger serum volumes. This study demonstrates that low-volume in-house antibody assays can provide good diagnostic performance, and highlights the importance of using well-characterised samples and controls for all stages of assay development and evaluation. These cost-effective assays may be particularly useful for seroprevalence studies in low and middle-income countries.

CHANGES IN LIFE EXPECTANCY BETWEEN 2019 AND 2021 IN THE UNITED STATES AND 21 PEER COUNTRIES (preprint)

ABSTRACT BACKGROUND Prior studies reported large decreases in US life expectancy during 2020 as a result of the COVID-19 pandemic, disproportionately affecting Hispanic and Black populations and vastly exceeding the average change in life expectancy in other high-income countries. Life expectancy estimates for 2021 have not been reported. This study estimated changes in life expectancy during 2019-2021 in the US population, in US racial/ethnic groups, and in 21 peer countries. The study compared outcomes across five US racial/ethnic groups and is the first to estimate changes in life expectancy during the pandemic in non-Hispanic American Indian/Alaska Native and Asian populations. METHODS US and peer country death data for 2019-2021 were obtained from the National Center for Health Statistics, the Human Mortality Database, and overseas statistical agencies. The 21 peer countries included Australia, Austria, Belgium, Canada, Denmark, England and Wales, Finland, France, Germany, Israel, Italy, Netherlands, New Zealand, Northern Ireland, Norway, Portugal, Scotland, South Korea, Spain, Sweden, and Switzerland. Life expectancy was calculated for 2019 and 2020 and estimated for 2021 using a previously validated modeling method. RESULTS US life expectancy decreased from 78.85 years in 2019 to 76.98 years in 2020 and 76.44 years in 2021, a net loss of 2.41 years. In contrast, peer countries averaged a smaller decrease in life expectancy between 2019 and 2020 (0.55 years) and a 0.26-year increase between 2020 and 2021, widening the gap in life expectancy between the United States and peer countries to more than five years. The decrease in US life expectancy was highly racialized: whereas the largest decreases in 2020 occurred among non-Hispanic (NH) American Indian/Alaska Native, Hispanic, NH Black, and NH Asian populations, in 2021 the largest decreases occurred in the NH White population. DISCUSSION The US mortality experience during 2020 and 2021 was more severe than in peer countries, deepening a US disadvantage in health and survival that has been building for decades. Over the two-year period between 2019 and 2021, US NH American Indian/Alaska Native, Hispanic, and NH Black populations experienced the largest losses in life expectancy, reflecting the ongoing legacy of systemic racism as well as inadequacies in the US handling of the pandemic. The crossover in racialized outcomes between 2020 and 2021, in which the NH White population experienced the largest decreases, likely has multiple explanations.

Increased blood monocytic myeloid derived suppressor cells (MDSCs) and decreased activated T lymphocytes in COVID-19 patients (preprint)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may produce a systemic disease, the coronavirus disease-19 (COVID-19), with high morbidity and mortality. Even though we do not fully understand the interaction of innate and adaptive immunity in the control and complications of the viral infection, it is well recognized that SARS-CoV-2 induces an immunodepression that impairs the elimination of the virus and favors its rapid dissemination in the organism. Even less is known the possible participation of inhibitory cells of the innate immune system, such as the myeloid-derived suppressor cells (MDSCs), or the adaptive immune system, such as the T regulatory cells (Tregs). That is why we aimed to study blood levels of MDSCs as well as lymphocyte subpopulations including Tregs, and activated (OX-40+) and inhibited (PD-1) T lymphocytes in patients with COVID-19 in comparison with data obtained from control donors. We have found that 12 hospitalized patients with COVID-19 and no health history of immnosuppression had a significant increase in the number of peripheral monocytic MDSCs, but not Tregs, as well as an increase in the number of inhibited or exhausted T cells, whereas the number of activated T cells was significantly decreased compared with that from 20 healthy controls. Moreover, there was a significant negative correlation (- 0.791) between the number of M-MDSC and the number of activated T cells. Therefore, SARS-Cov-2 seems to recruit MDSCs, and these inhibitory cells may contribute to the immunosuppression observed in patients with COVID-19.

COVID-19 in a case of Toxic Epidermal Necrolysis (preprint)

The COVID-19 pandemic is a major health issue and patients with underlying conditions are more susceptible to catastrophic outcomes. Toxic epidermal necrolysis (TEN) is a severe systemic disease caused by immune system hypersensitive reaction. We present a case of TEN that later complicated with COVID-19,Deep Vein Thrombosis(DVT),Pulmonary Emboli(PE),and death.

Production of anti-spike antibodies in response to COVID vaccine in lymphoma patients (preprint)

Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. There is limited data on the efficacy of the COVID vaccines in lymphoma patients, and to suggest the optimal timing of vaccination to elicit immunity in patients receiving immunochemotherapy. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody titer following the primary COVID vaccination series. The primary series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fisher’s exact test, and unadjusted and adjusted logistic regression models were used for univariate (UVA) and multivariate (MVA) analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitt’s, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); and 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p=0.04). Lymphoma patients are capable of mounting a humoral response to the COVID mRNA vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population.