A novel RBD-protein/peptide vaccine elicits broadly neutralizing antibodies and protects mice and macaques against SARS-CoV-2.

The development of safe and effective vaccines to respond to COVID-19 pandemic/endemic remains a priority. We developed a novel subunit protein-peptide COVID-19 vaccine candidate (UB-612) composed of: (i) receptor binding domain of SARS-CoV-2 spike protein fused to a modified single-chain human IgG1 Fc; (ii) five synthetic peptides incorporating conserved helper and cytotoxic T lymphocyte (Th/CTL) epitopes derived from SARS-CoV-2 structural proteins (three from S2 subunit, one from membrane and one from nucleocapsid), and one universal Th peptide; (iii) aluminum phosphate as adjuvant. The immunogenicity and protective immunity induced by UB-612 vaccine were evaluated in four animal models: Sprague-Dawley rats, AAV-hACE2 transduced BALB/c mice, rhesus and cynomolgus macaques. UB-612 vaccine induced high levels of neutralizing antibody and T-cell responses, in all animals. The immune sera from vaccinated animals neutralized the SARS-CoV-2 original wild-type strains and multiple variants of concern, including Delta and Omicron. The vaccination significantly reduced viral loads, lung pathology scores, and disease progression after intranasal and intratracheal challenge with SARS-CoV-2 in mice, rhesus and cynomolgus macaques. UB-612 has been tested in primary regimens in Phase 1 and Phase 2 clinical studies and is currently being evaluated in a global pivotal Phase 3 clinical study as a single dose heterologous booster.

High Neutralizing Antibody Levels Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron BA.1 and BA.2 After UB-612 Vaccine Booster.

The highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has caused high rates of breakthrough infections in those previously vaccinated with ancestral strain coronavirus disease 2019 (COVID-19) vaccines. Here, we demonstrate that a booster dose of UB-612 vaccine candidate delivered 7-9 months after primary vaccination increased neutralizing antibody levels by 131-, 61-, and 49-fold against ancestral SARS-CoV-2 and the Omicron BA.1 and BA.2 variants, respectively. Based on the receptor-binding domain protein binding antibody responses, the UB-612 third-dose booster may lead to an estimated approximately 95% efficacy against symptomatic COVID-19 caused by the ancestral strain. Our results support UB-612 as a potential potent booster against current and emerging SARS-CoV-2 variants.

Outpatient Randomized Crossover Comparison of Zone Model Predictive Control Automated Insulin Delivery with Weekly Data Driven Adaptation Versus Sensor-Augmented Pump: Results from the International Diabetes Closed-Loop Trial 4.

Background: Automated insulin delivery (AID) systems have proven effective in increasing time-in-range during both clinical trials and real-world use. Further improvements in outcomes for single-hormone (insulin only) AID may be limited by suboptimal insulin delivery settings. Methods: Adults (≥18 years of age) with type 1 diabetes were randomized to either sensor-augmented pump (SAP) (inclusive of predictive low-glucose suspend) or adaptive zone model predictive control AID for 13 weeks, then crossed over to the other arm. Each week, the AID insulin delivery settings were sequentially and automatically updated by an adaptation system running on the study phone. Primary outcome was sensor glucose time-in-range 70-180 mg/dL, with noninferiority in percent time below 54 mg/dL as a hierarchical outcome. Results: Thirty-five participants completed the trial (mean age 39 ± 16 years, HbA1c at enrollment 6.9% ± 1.0%). Mean time-in-range 70-180 mg/dL was 66% with SAP versus 69% with AID (mean adjusted difference +2% [95% confidence interval: -1% to +6%], P = 0.22). Median time <70 mg/dL improved from 3.0% with SAP to 1.6% with AID (-1.5% [-2.4% to -0.5%], P = 0.002). The adaptation system decreased initial basal rates by a median of 4% (-8%, 16%) and increased initial carbohydrate ratios by a median of 45% (32%, 59%) after 13 weeks. Conclusions: Automated adaptation of insulin delivery settings with AID use did not significantly improve time-in-range in this very well-controlled population. Additional study and further refinement of the adaptation system are needed, especially in populations with differing degrees of baseline glycemic control, who may show larger benefits from adaptation.

High neutralizing antibody levels against SARS-CoV-2 Omicron after UB-612 booster vaccination (preprint)

Omicron, a highly transmissible SARS-CoV-2, emerged in November 2021. The high mutation rates within spike protein of Omicron raised concerns about increased breakthrough infections among the vaccinated. We tested cross-reactivity of antibodies induced by UB-612 against Omicron and other variants. After 2 doses, UB-612 elicited low levels of neutralization antibodies against ancestral virus and Omicron. A booster dose delivered 7-9 months after primary vaccination dramatically increased antibody levels, with only a 1.4-fold loss in neutralization titer against Omicron compared to the ancestral strain. Using a model bridging vaccine efficacy with ancestral virus RBD binding antibody responses, predicted efficacy against symptomatic COVID-19 after UB-612 booster is estimated at 95%. UB-612 is anticipated to be a potent booster against current and emerging SARS-CoV-2 variants.

Acceptance of virtual consultations among older adults and caregivers in Malaysia: a pilot study during the COVID-19 pandemic.

AIM: The COVID-19 pandemic has disrupted the delivery of healthcare to vulnerable older adults, prompting the expansion of telemedicine usage. This study surveyed the acceptance of virtual medical consultations among older adults and caregivers within geriatric outpatient services in a tertiary hospital during the pandemic. METHODS: A cross-sectional survey was conducted among caregivers and patients attending geriatric outpatient services in Kuala Lumpur, Malaysia. The survey measured the availability of equipment for virtual consultations, prior knowledge and experience of telemedicine, and willingness to consult geriatricians through virtual technology, using the Unified Theory of Acceptance and Use of Technology (UTAUT) scale. RESULTS: A total of 197 caregivers and 42 older patients with a mean age of 54.28 (±13.22) and 75.62 (±7.32) years, respectively, completed the survey. One hundred and fifty-six (79.2%) of the caregivers were adult children accompanying patients. The mean UTAUT score was 65.97 (±13.71) out of 90, with 66.64 (±13.25) for caregivers and 62.79 (±15.44) for older adults, suggesting a high acceptance of adopting virtual consultations in lieu of face-to-face care. The independent predictors of acceptance of virtual consultation were : possession of an electronic device capable of video-communication, living with someone, living in a care home, weekly online banking usage, and perceived familiarity with virtual platforms. CONCLUSION: Caregivers and patients indicated a high level of acceptance of virtual medical consultations, which is likely facilitated by caregivers such as adult children or spouses at home or staff in care homes. To minimize the transmission of COVID-19 in a highly vulnerable group, virtual consultations are an acceptable alternative to face-to-face consultations for older people and their caregivers in our setting.

Potent Anti-Delta Effect By a Booster Third-Dose of UB-612, a Precision-Designed SARS-CoV-2 Multitope Protein-Peptide Vaccine (preprint)

SARS-CoV-2 breakthrough infection occurs due to waning immunity time-to-vaccine, to which the globally-dominant, highly-contagious Delta variant is behind the scene. In the primary 2-dose and booster series of clinical Phase-1 trial, UB-612 vaccine, which contains S1-RBD and synthetic Th/CTL peptide pool for activation of humoral and T-cell immunity, induces substantial, prolonged viral-neutralizing antibodies that goes parallel with a long-lasting T-cell immunity; and a booster (3rd ) dose can prompt recall of memory immunity to induce profound, striking antibodies with the highest level of 50% viral-neutralizing GMT titers against live Delta variant reported for any vaccine. The unique design of S1-RBD only plus multitope T-cell peptides may have underpinned UB-612’s potent anti-Delta effect, while the other full S protein-based vaccines are affected additionally by mutations in the N-terminal domain sequence which contains additional neutralizing epitopes. UB-612, safe and well-tolerated, could be effective for boosting other vaccine platforms that have shown modest homologous boosting. [Funded by United Biomedical Inc., Asia; ClinicalTrials.gov ID: NCT04967742 and NCT04545749]

Overcoming COVID-19 in China despite shortcomings of the public health system: what can we learn?

BACKGROUND AND OBJECTIVE: The COVID-19 pandemic started in Wuhan, China, in December 2019. Although there are some doubts about the reporting of cases and deaths in China, it seems that this country was able to control the epidemic more effectively than many other countries. In this paper, we would like to analyze the measures taken in China and compare them with other countries in order to find out what they can learn from China. METHODS: We develop a system dynamics model of the COVID-19 pandemic in Wuhan. Based on a number of simulations we analyze the impact of changing parameters, such as contact rates, on the development of a second wave. RESULTS: Although China's health care system seems to be poorly financed and inefficient, the epidemic was brought under control in a comparably short period of time and no second wave was experienced in Wuhan until today. The measures to contain the epidemic do not differ from what was implemented in other countries, but China applied them very early and rigorously. For instance, the consequent implementation of health codes and contact-tracking technology contributed to contain the disease and effectively prevented the second and third waves. CONCLUSIONS: China's success in fighting COVID-19 is based on a very strict implementation of a set of measures, including digital management. While other countries discuss relaxing the lock-down at a rate of 50 per 100,000 inhabitants, China started local lock-downs at a rate of 3 per 100,000. We call for a public debate whether this policy would be feasible for more liberal countries as well.

A multi-omics investigation of the composition and function of extracellular vesicles along the temporal trajectory of COVID-19.

Exosomes represent a subtype of extracellular vesicle that is released through retrograde transport and fusion of multivesicular bodies with the plasma membrane1. Although no perfect methodologies currently exist for the high-throughput, unbiased isolation of pure plasma exosomes2,3, investigation of exosome-enriched plasma fractions of extracellular vesicles can confer a glimpse into the endocytic pathway on a systems level. Here we conduct high-coverage lipidomics with an emphasis on sterols and oxysterols, and proteomic analyses of exosome-enriched extracellular vesicles (EVs hereafter) from patients at different temporal stages of COVID-19, including the presymptomatic, hyperinflammatory, resolution and convalescent phases. Our study highlights dysregulated raft lipid metabolism that underlies changes in EV lipid membrane anisotropy that alter the exosomal localization of presenilin-1 (PS-1) in the hyperinflammatory phase. We also show in vitro that EVs from different temporal phases trigger distinct metabolic and transcriptional responses in recipient cells, including in alveolar epithelial cells, which denote the primary site of infection, and liver hepatocytes, which represent a distal secondary site. In comparison to the hyperinflammatory phase, EVs from the resolution phase induce opposing effects on eukaryotic translation and Notch signalling. Our results provide insights into cellular lipid metabolism and inter-tissue crosstalk at different stages of COVID-19 and are a resource to increase our understanding of metabolic dysregulation in COVID-19.

A Novel SARS-CoV-2 Multitope Protein/Peptide Vaccine Candidate is Highly Immunogenic and Prevents Lung Infection in an Adeno Associated Virus Human Angiotensin-Converting Enzyme 2 (AAV hACE2) Mouse Model (preprint)

In this report, we describe the initial development and proof-of-concept studies for UB-612, the first multitope protein-peptide vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen responsible for the Coronavirus Disease of 2019 (COVID-19). UB-612 consists of eight components rationally designed for induction of high neutralizing antibodies and broad T cell responses against SARS-CoV-2: the S1-RBD-sFc fusion protein, six synthetic peptides (one universal peptide and five SARS-CoV-2-derived peptides), a proprietary CpG TLR-9 agonist, and aluminum phosphate adjuvant. Through immunogenicity studies in guinea pigs and rats, we optimized the design of protein/peptide immunogens and selected an adjuvant system, yielding a vaccine that provided excellent S1-RBD binding and high neutralizing antibody responses, robust cellular responses, and a Th1-oriented response at low doses of the vaccine. Our candidate vaccine was then advanced into challenge studies, in which it reduced viral load and prevented development of disease in a mouse challenge model and in nonhuman primates (NHP, immunogenicity part is completed, challenge is ongoing). A GLP-compliant toxicity study has shown a favorable safety profile for the vaccine. With the Phase 1 trial ongoing in Taiwan and additional trials planned worldwide, UB-612 is a highly promising and differentiated vaccine candidate for prevention of SARS-CoV-2 transmission and COVID-19 disease.

Emetine as an antiviral agent suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E: An in vitro study (preprint)

Emetine is a FDA-approved drug for the treatment of amebiasis. In the recent times we had also demonstrated the antiviral efficacy of emetine against some RNA and DNA viruses. Following emergence of the COVID-19, we further evaluated the in vitro antiviral activity of emetine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The therapeutic index of emetine was determined to be 10910.4, at a cytotoxic concentration 50 (CC50) of 1603.8 nM and effective concentration 50 (EC50) of 0.147 nM. Besides, we also demonstrated the protective efficacy of emetine against lethal challenge with infectious bronchitis virus (IBV; a chicken coronavirus) in the embryonated chicken egg infection model. Emetine treatment was shown to decrease viral RNA and protein synthesis without affecting other steps of viral life cycle such as attachment, entry and budding. In a chromatin immunoprecipitation (CHIP) assay, emetine was shown to disrupt the binding of SARS-CoV-2 RNA with eIF4E (eukaryotic translation initiation factor 4E, a cellular cap-binding protein required for initiation of protein translation). Further, SARS-CoV-2 was shown to exploit ERK/MNK1/eIF4E signalling pathway for its effective replication in the target cells. To conclude, emetine targets SARS-CoV-2 protein synthesis which is mediated via inhibiting the interaction of SARS-CoV-2 RNA with eIF4E. This is a novel mechanistic insight on the antiviral efficacy of emetine. In vitro antiviral efficacy against SARS-CoV-2 and its ability to protect chicken embryos against IBV suggests that emetine could be repurposed to treat COVID-19.

Clinical course and risk factors for mortality of COVID-19 patients with pre-existing cirrhosis: A multicenter cohort study (preprint)

Background: Patients with pre-existing cirrhosis are considered at increased risk of severe coronavirus disease 2019 (COVID-19) but the clinical course in these patients has not yet been reported. This study aimed to provide a detailed report of the clinical characteristics and outcomes among COVID-19 patients with pre-existing cirrhosis. Methods: In this retrospective, multicenter cohort study, we consecutively included all adult inpatients with laboratory-confirmed COVID-19 and pre-existing cirrhosis that had been discharged or had died by 24 March 2020 from 16 designated hospitals in China. Demographic, clinical, laboratory and radiographic findings on admission, treatment, complications during hospitalization and clinical outcomes were collected and compared between survivors and non-survivors. Findings: Twenty-one patients were included in this study, of whom 16 were cured and 5 died in hospital. Seventeen patients had compensated cirrhosis and hepatitis B virus infection was the most common etiology. Lymphocyte and platelet counts were lower, and direct bilirubin levels were higher in patients who died than those who survived (p= 0.040, 0.032, and 0.006, respectively). Acute respiratory distress syndrome and secondary infection were both the most frequently observed complications. Only one patient developed acute on chronic liver failure. Of the 5 non-survivors, all patients developed acute respiratory distress syndrome and 2 patients progressed to multiple organ dysfunction syndrome. Interpretation: Lower lymphocyte and platelet counts, and higher direct bilirubin level might represent poor prognostic indicators in SARS-CoV-2-infected patients with pre-existing cirrhosis.