Shared genetic architecture and causal relationship between the age at first sex and COVID-19: A large-scale cross-trait analysis (preprint)

COVID-19 is genetically associated with numerous immune disorders, and young age at first intercourse (AFS) may lead to early activation of innate immunity. However, the genetic overlap between COVID-19 and AFS remains undetermined. Here we perform a large-scale cross-trait analysis to investigate their shared genetic etiology and causal relationship. An overall negative genetic correlation between the AFS and three COVID-19 traits was observed. We further identified 186, 221, and 213 shared genetic loci for AFS-COVID-19 infection, hospitalization, and severity, respectively. Among these shared loci, those closest to the genes CADM2, and ARPC1B showed the strongest signals. Our post-GWAS functional analysis revealed that the shared mapped genes were mainly involved in neural genesis and development within several brain structures. Finally, bidirectional Mendelian randomization (MR) results showed that earlier sexual debut may increase the risk of SARS-CoV-2 infection, hospitalization, and severity.

Tlda: A Transfer Learning Based Dual-Augmentation Strategy for Traditional Chinese Medicine Rare Disease Syndrome Differentiation (preprint)

The Traditional Chinese Medicine (TCM) has demonstrated its significant medical value over the decades, particularly during the COVID-19 pandemic. TCM-AI interdisciplinary models have been proposed to model TCM knowledge, diagnosis, and treatment experiments in clinical practice. Among them, numerous models have been developed to simulate the syndrome differentiation process of human TCM doctors for automatic syndrome diagnosis. However, these models are designed for normal scenarios and trained using a supervised learning paradigm which needs tens of thousands of training samples. They fail to effectively differentiate syndromes in rare disease scenarios where the available TCM electronic medical records (EMRs) are very limited for each unique syndrome. To address the challenge of rare diseases, this study proposes a simple yet effective method called Transfer Learning based Dual-Augmentation (TLDA). TLDA aims to augment the limited EMRs at both the sample-level and feature-level, enriching the pathological and medical information during training. Extended experiments involving 11 comparison models, including the state-of-the-art model, demonstrate the effectiveness of TLDA. TLDA outperforms all comparison models by a significant margin. Furthermore, TLDA can also be extended to other medical tasks when the EMRs for diagnosis are limited in samples.

A comparison of the protective effect of vaccination and clinical features between the SARS-CoV-2 wild-type strain and Delta (B.1.617.2) variant

Introduction This study aimed to investigate the clinical features and vaccine effectiveness of patients with the SARS-CoV-2 wild-type strain and the Delta variant. Methods We retrospectively evaluated patients with the SARS-CoV-2 wild-type strain and the Delta variant. Results The Delta-variant group showed a higher infection rate in minors, who had higher incidence of anosmia or dysgeusia and shorter incubation period. Unvaccinated patients had a 15.59-fold higher risk of severe classification than vaccinated patients. The viral clearance time was significantly shorter in the Delta-variant group. Conclusions The Delta-variant group show higher transmissibility, and vaccination reduces the incidence of severe classification and promotes viral clearance.

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]

Preliminary safety, tolerability and efficacy results of KN026 in combination with KN046 in patients with HER2 aberrated solid tumors

BackgroundHER2 potently inhibits innate immunity through cGAS–STING signaling,1 Meanwhile HER2 antibody induced ADCP will also lead to macrophage mediated immune suppression. Both preclinical and clinical studies have suggested a coordination of engagement of innate and adaptive immunity with the combination of an anti-HER2 antibody and an immune checkpoint blockade. KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1/CD80 and CTLA-4 interaction with CD80/CD86. Here we reported the interim results from an ongoing phase Ib dose escalation and expansion study assessing the safety, tolerability and preliminary efficacy for KN026 in combination with KN046 in Patients with HER2 aberrated solid tumors.MethodsThis study enrolled pts with solid tumors who failed available standard of care, HER2 aberration status confirmed locally (HER2 mutation, HER2 amplification and/or HER2 overexpression). Eligible pts received combination of KN026 and KN046 at three dose levels until disease progression, unacceptable toxicity or withdrawal of informed consent (DL1: KN026 20 mg/kg Q2W + KN046 3 mg/kg Q2W;DL2: KN026 20 mg/kg Q2W with loading on Days 1, 8 of Cycle 1 + KN046 5 mg/kg Q3W;DL3: KN026 30 mg/kg Q3W with loading on Days 1, 8 of Cycle 1 + KN046 5 mg/kg Q3W). Tumor response was evaluated Q8W per RECIST 1.1. Primary endpoint was DLT and key secondary endpoints were efficacy parameters (ORR, DOR, PFS).ResultsAs of the Sep. 08, 2020, 25 pts were enrolled into DL1 (n = 20, 3 for dose escalation), DL2 (n = 3) and DL3 (n = 2) (mGC/GEJ 15 pts;mCRC 8 pts;other solid tumors 2 pts). 15 pts remained on the study treatment and 10 pts discontinued treatment due to disease progression (n=5), death (n=2) and other reasons (n=3). 18 pts had HER2-positive status (12 of 18 failed previous trastuzumab therapy), 2 pts had HER2 mutation and 5 pts had HER2 low expression (without FISH amplification). No DLTs were observed. No pts experienced LVEF decreased or other clinically meaningful cardiac AEs. Treatment-related TEAEs occurred in 23 (92%) pts, of which 6 (24%) pts experienced grade 3 or above treatment-related TEAEs. 11 (44%) pts experienced irAEs, majority were of grade 1 or 2 except that 1 patient experienced grade 3 immune-mediated endocrinopathy. The most common (frequency ≥ 15%) KN026 or KN046 related TEAEs were infusion related reaction (n=11, 44.0%), anaemia (n=9, 36.0%), white blood cell count decreased (n=6, 24.0%), diarrhea (n=5, 20.0%), AST increased (n=5, 20.0%), platelet count decreased (n=5, 20.0%), rash (n=5, 20.0%) and ALT increased (n=4, 16.0%). The objective response rate in pts with HER2-positive tumors (n = 14 efficacy evaluable pts) was 9/14 (64.3%, 95% CI 35.1~87.2%) and disease control rate 13/14 (92.9%, 95% CI 66.1~99.8%). 4 out of 5 pts with HER2 mutation or low expression achieved SD including one patient with SD for more than 24 weeks. 2 death cases due to disease progression were reported, both only received one cycle of KN026 plus KN046 due to COVID-19 restriction.ConclusionsKN026 combined with KN046 is well tolerated and has demonstrated preliminary albeit profound anti-tumor activity in HER2-positive solid tumors.Trial RegistrationClinical trial information: NCT04040699ReferenceShiying Wu, Qian Zhang, Fei Zhang, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nature Cell Biology 2019;21:1027–1040.

Preliminary safety, tolerability and efficacy results of KN026 (a HER2-targeted Bispecific Antibody) in combination with KN046 (an anti-PD-L1/CTLA-4 Bispecific Antibody) in patients (pts) with HER2 aberrated solid tumors

BackgroundHER2 potently inhibits innate immunity through cGAS–STING signalling,1 meanwhile HER2 antibody induced ADCP will also lead to macrophage mediated immune suppression. Preclinical and clinical studies suggested a coordination of engagement of innate and adaptive immunity with the combination of an anti-HER2 antibody and an immune checkpoint blockade. KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1 and CTLA-4 interaction with CD80/CD86. Here we reported the interim results from an ongoing phase Ib dose escalation and expansion study assessing the safety, tolerability and preliminary efficacy for KN026 in combination with KN046.MethodsThis study enrolled pts with solid tumors who failed available standard of care, HER2 aberration status confirmed locally (HER2 mutation, HER2 amplification and/or HER2 overexpression). Eligible pts received combination of KN026 and KN046 at two dose levels until disease progression, unacceptable toxicity or withdrawal of informed consent (DL1: KN026 20 mg/kg Q2W + KN046 3 mg/kg Q2W;DL2: KN026 20 mg/kg Q2W with loading on Days 1, 8 of Cycle 1 + KN046 5 mg/kg Q3W). Tumor response was evaluated Q8W per RECIST 1.1. Primary endpoint was DLT and key secondary endpoints were efficacy parameters (ORR, DOR, PFS).ResultsAs of the Jul. 13, 2020, 21 pts were enrolled into DL1 (n = 18, 3 for dose escalation) and DL2 (n = 3) (mGC/GEJ 12 pts;mCRC 7 pts;other solid tumors 2 pts). 11 pts remained on the study treatment and 10 pts discontinued treatment due to disease progression (n=5), death (n=2) and other reasons (n=3). 15 pts had HER2-positive status (11 of 15 failed previous trastuzumab therapy), 1 pts had HER2 mutation and 5 pts had HER2 low expression (without FISH amplification). No DLTs were observed. No pts experienced LVEF decreased or other clinically meaningful cardiac AEs. Treatment-related TEAEs occurred in 13 pts, of which 1 pts experienced grade 3 or above treatment-related TEAEs. 7 pts experienced irAEs, all of which were grade 1 or 2. The most common (≥ 10%) KN026 or KN046 related TEAEs were anaemia (n=5, 23.8%), AST increased (n=4, 19.0%), rash (n=4, 19.0%), diarrhea (n=4, 19.0%), blood bilirubin increased (n=3, 14.3%) and infusion related reaction (n=3, 14.3%). The objective response rate in pts with HER2-positive tumors (n = 7 efficacy evaluable pts) was 4/7 (57.1%, 95% CI 18.4~90.1%) and disease control rate 6/7 (85.7%, 95% CI 42.1~99.6%). 3 pts with HER2 mutation or low expression achieved SD including one patient with SD for more than 24 weeks. 2 death cases only received one cycle of KN026 plus KN046 due to COVID-19 restriction before died from clinical deterioration from underlying tumors.ConclusionsKN026 combined with KN046 is well tolerated and has demonstrated profound anti-tumor activity in HER2-positive solid tumors.Trial RegistrationNCT04040699Ethics ApprovalThe study was approved by Beijing Cancer Hospital Institution’s Ethics Board, approval number 2019YJZ37.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferenceShiying Wu, Qian Zhang, Fei Zhang, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nature Cell Biology 2019;21: 1027–1040.

Test-optional Policies: Overcoming Strategic Behavior and Informational Gaps (preprint)

Due to the Covid-19 pandemic, more than 500 US-based colleges and universities went "test-optional" for admissions and promised that they would not penalize applicants for not submitting test scores, part of a longer trend to rethink the role of testing in college admissions. However, it remains unclear how (and whether) a college can simultaneously use test scores for those who submit them, while not penalizing those who do not--and what that promise even means. We formalize these questions, and study how a college can overcome two challenges with optional testing: $\textit{strategic applicants}$ (when those with low test scores can pretend to not have taken the test), and $\textit{informational gaps}$ (it has more information on those who submit a test score than those who do not). We find that colleges can indeed do so, if and only if they are able to use information on who has test access and are willing to randomize admissions.

Pandemic-induced fear and stock market returns: Evidence from China

We construct a pandemic-induced fear (PIF) index to measure fear of the COVID-19 pandemic using Internet search volumes of the Chinese local search engine and empirically investigate the impact of fear of the pandemic on Chinese stock market returns. A reduced-bias estimation approach for multivariate regression is employed to address the issue of small-sample bias. We find that the PIF index has a negative and significant impact on cumulative stock market returns. The impact of PIF is persistent, which can be explained by mispricing from investors' excessive pessimism. We further reveal that the PIF index directly predicts stock market returns through noise trading. Investors' Internet search behaviors enhance the fear of the pandemic, and pandemic-induced fear determines future stock market returns, rather than the number of cases and deaths caused by the COVID-19 pandemic.

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.

Implications of the virus-encoded miRNA and host miRNA in the pathogenicity of SARS-CoV-2 (preprint)

The outbreak of COVID-19 caused by SARS-CoV-2 has rapidly spread worldwide and has caused over 1,400,000 infections and 80,000 deaths. There are currently no drugs or vaccines with proven efficacy for its prevention and little knowledge was known about the pathogenicity mechanism of SARS-CoV-2 infection. Previous studies showed both virus and host-derived MicroRNAs (miRNAs) played crucial roles in the pathology of virus infection. In this study, we use computational approaches to scan the SARS-CoV-2 genome for putative miRNAs and predict the virus miRNA targets on virus and human genome as well as the host miRNAs targets on virus genome. Furthermore, we explore miRNAs involved dysregulation caused by the virus infection. Our results implicated that the immune response and cytoskeleton organization are two of the most notable biological processes regulated by the infection-modulated miRNAs. Impressively, we found hsa-miR-4661-3p was predicted to target the S gene of SARS-CoV-2, and a virus-encoded miRNA MR147-3p could enhance the expression of TMPRSS2 with the function of strengthening SARS-CoV-2 infection in the gut. The study may provide important clues for the mechisms of pathogenesis of SARS-CoV-2.

Clinical characteristics of 10 children with COVID-19 outside of Wuhan in Hubei Province (preprint)

Background：An outbreak of coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) began in Wuhan, Hubei Province, China in December 2019. This study aims to report the clinical characteristics of children COVID-19 in Xiangyang, a city outside of Wuhan within Hubei Province.Methods：We retrospectively investigated the clinical manifestations, Chest CT imaging, and laboratory characteristics of confirmed cases of children with COVID-19 with WHO interim guidance in Xiangyang Central Hospital from Feb 1 to Mar 10, 2020. 10 children cases were confirmed by real-time RT-PCR and were analyzed for epidemiological, demographic, clinical, radiological features and laboratory data. Outcomes were followed up until Mar 10, 2020.Results：6 cases (60%) had never been to Wuhan but closely contacted with family members with confirmed COVID-19, and 4 cases (40%) had made short term trips to Wuhan alone without familial clustering. The most common symptoms were cough (50%) followed by fever (40%), 4 cases (40%) showed asymptomatic characteristics including 2 cases (20%) with abnormal chest computed tomograms (CT) image. 9 cases (90%) were mild type, only 1 case (10%) was moderate type, none of them progressed in severe or critical disease. 4 (40%) cases showed leucopenia but none lymphopenia. Abnormalities on chest CT were detected among 8 cases (80%), 2 of 4 cases without obvious symptoms had abnormal chest CT.Conclusions: Children's infection is mainly caused by family clusters. No transmission to other individuals from children was found in our observation. The clinical manifestations in children with COVID-19 are non-specific with milder symptoms and good outcomes.