Neutralization sensitivity, fusogenicity, and infectivity of Omicron subvariants.

BACKGROUND: The emergence of SARS-CoV-2 Omicron subvariants has raised questions regarding resistance to immunity by natural infection or immunization. We examined the sensitivity of Delta and Omicron subvariants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4/5, and BA.3) to neutralizing antibodies from BBIBP-CorV-vaccinated and BBIBP-CorV- or ZF2001-boosted individuals, as well as individuals with Delta and BA.1 breakthrough infections, and determined their fusogenicity and infectivity. METHODS: In this cross-sectional study, serum samples from two doses of BBIBP-CorV-vaccinated individuals 1 (n = 36), 3 (n = 36), and 7 (n = 37) months after the second dose; BBIBP-CorV- (n = 25) or ZF2001-boosted (n = 30) individuals; and fully vaccinated individuals with Delta (n = 30) or BA.1 (n = 26) infection were collected. The serum-neutralizing reactivity and potency of bebtelovimab were assessed against D614G, Delta, and Omicron subvariants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4/5, and BA.3) through a pseudovirus neutralization assay. The fusogenicity and infectivity of D614G, Delta, and Omicron subvariants were determined by cell-cell fusion assay and pseudovirus infection assay, respectively. RESULTS: Omicron subvariants markedly escaped vaccine-elicited neutralizing antibodies after two doses of BBIBP-CorV with comparable efficiency. A third dose vaccination of BBIBP-CorV or ZF2001 increased neutralizing antibody titers and breadth against Delta and three Omicron subvariants. Delta and BA.1 breakthrough infections induced comparable neutralizing antibody titers against D614G and Delta variants, whereas BA.1 breakthrough infections elicited a stronger and broader antibody response against three Omicron subvariants than Delta breakthrough infections. BA.2.12.1 and BA.4/5 are more resistant to immunity induced by breakthrough infections. Bebtelovimab had no significant loss of potency against the Delta and Omicron subvariants. Cell culture experiments showed Omicron subvariants to be less fusogenic and have higher infectivity than D614G and Delta with comparable efficiency. CONCLUSIONS: These findings have important public health implications and highlight the importance of repeated exposure to SARS-CoV-2 antigens to broaden the neutralizing antibody response against Omicron subvariants.

Spatial-Temporal Synchronous Graph Transformer network (STSGT) for COVID-19 forecasting (preprint)

COVID-19 has become a matter of serious concern over the last few years. It has adversely affected numerous people around the globe and has led to the loss of billions of dollars of business capital. In this paper, we propose a novel Spatial-Temporal Synchronous Graph Transformer network (STSGT) to capture the complex spatial and temporal dependency of the COVID-19 time series data and forecast the future status of an evolving pandemic. The layers of STSGT combine the graph convolution network (GCN) with the self-attention mechanism of transformers on a synchronous spatial-temporal graph to capture the dynamically changing pattern of the COVID time series. The spatial-temporal synchronous graph simultaneously captures the spatial and temporal dependencies between the vertices of the graph at a given and subsequent time-steps, which helps capture the heterogeneity in the time series and improve the forecasting accuracy. Our extensive experiments on two publicly available real-world COVID-19 time series datasets demonstrate that STSGT significantly outperforms state-of-the-art algorithms that were designed for spatial-temporal forecasting tasks. Specifically, on average over a 12-day horizon, we observe a potential improvement of 12.19% and 3.42% in Mean Absolute Error(MAE) over the next best algorithm while forecasting the daily infected and death cases respectively for the 50 states of US and Washington, D.C. Additionally, STSGT also outperformed others when forecasting the daily infected cases at the state level, e.g., for all the counties in the State of Michigan. The code and models are publicly available at https://github.com/soumbane/STSGT.

Persistence of Antibody and Cellular Immune Responses in Coronavirus Disease 2019 Patients Over Nine Months After Infection.

BACKGROUND: The duration of humoral and T and B cell response after the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unclear. METHODS: We performed a cross-sectional study to assess the virus-specific antibody and memory T and B cell responses in coronavirus disease 2019 (COVID-19) patients up to 343 days after infection. Neutralizing antibodies and antibodies against the receptor-binding domain, spike, and nucleoprotein of SARS-CoV-2 were measured. Virus-specific memory T and B cell responses were analyzed. RESULTS: We enrolled 59 patients with COVID-19, including 38 moderate, 16 mild, and 5 asymptomatic patients; 31 (52.5%) were men and 28 (47.5%) were women. The median age was 41 years (interquartile range, 30-55). The median day from symptom onset to enrollment was 317 days (range 257 to 343 days). We found that approximately 90% of patients still have detectable immunoglobulin (Ig)G antibodies against spike and nucleocapsid proteins and neutralizing antibodies against pseudovirus, whereas ~60% of patients had detectable IgG antibodies against receptor-binding domain and surrogate virus-neutralizing antibodies. The SARS-CoV-2-specific IgG+ memory B cell and interferon-γ-secreting T cell responses were detectable in more than 70% of patients. CONCLUSIONS: Severe acute respiratory syndrome coronavirus 2-specific immune memory response persists in most patients approximately 1 year after infection, which provides a promising sign for prevention from reinfection and vaccination strategy.

Major Characteristics of Severity and Mortality in Diabetic Patients With COVID-19 and Establishment of Severity Risk Score.

Objectives: Diabetes is a risk factor for poor COVID-19 prognosis. The analysis of related prognostic factors in diabetic patients with COVID-19 would be helpful for further treatment of such patients. Methods: This retrospective study involved 3623 patients with COVID-19 (325 with diabetes). Clinical characteristics and laboratory tests were collected and compared between the diabetic group and the non-diabetic group. Binary logistic regression analysis was applied to explore risk factors associated in diabetic patients with COVID-19. A prediction model was built based on these risk factors. Results: The risk factors for higher mortality in diabetic patients with COVID-19 were dyspnea, lung disease, cardiovascular diseases, neutrophil, PLT count, and CKMB. Similarly, dyspnea, cardiovascular diseases, neutrophil, PLT count, and CKMB were risk factors related to the severity of diabetes with COVID-19. Based on these factors, a risk score was built to predict the severity of disease in diabetic patients with COVID-19. Patients with a score of 7 or higher had an odds ratio of 7.616. Conclusions: Dyspnea is a critical clinical manifestation that is closely related to the severity of disease in diabetic patients with COVID-19. Attention should also be paid to the neutrophil, PLT count and CKMB levels after admission.

A SARS-CoV-2 spike ferritin nanoparticle vaccine protects against heterologous challenge with B.1.1.7 and B.1.351 virus variants in Syrian golden hamsters (preprint)

The emergence of SARS-CoV-2 variants of concern (VOC) requires adequate coverage of vaccine protection. We evaluated whether a spike ferritin nanoparticle vaccine (SpFN), adjuvanted with the Army Liposomal Formulation QS21 (ALFQ), conferred protection against the B.1.1.7 and B.1.351 VOCs in Syrian golden hamsters. SpFN-ALFQ was administered as either single or double-vaccination (0 and 4 week) regimens, using a high (10 g) or low (0.2 g) immunogen dose. Animals were intranasally challenged at week 11. Binding antibody responses were comparable between high- and low-dose groups. Neutralizing antibody titers were equivalent against WA1, B.1.1.7, and B.1.351 variants following two high dose two vaccinations. SpFN-ALFQ vaccination protected against SARS-CoV-2-induced disease and viral replication following intranasal B.1.1.7 or B.1.351 challenge, as evidenced by reduced weight loss, lung pathology, and lung and nasal turbinate viral burden. These data support the development of SpFN-ALFQ as a broadly protective, next-generation SARS-CoV-2 vaccine.

Efficacy and breadth of adjuvanted SARS-CoV-2 receptor-binding domain nanoparticle vaccine in macaques (preprint)

Emergence of novel variants of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean neutralizing antibody titers of 14,000-21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within four days in 7 of 8 animals receiving 50 {micro}g RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only [~]2-fold relative to USA-WA1. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-like betacoronavirus vaccine development. Significance StatementThe emergence of SARS-CoV-2 variants of concern (VOC) that reduce the efficacy of current COVID-19 vaccines is a major threat to pandemic control. We evaluate a SARS-CoV-2 Spike receptor-binding domain ferritin nanoparticle protein vaccine (RFN) in a nonhuman primate challenge model that addresses the need for a next-generation, efficacious vaccine with increased pan-SARS breadth of coverage. RFN, adjuvanted with a liposomal-QS21 formulation (ALFQ), elicits humoral and cellular immune responses exceeding those of current vaccines in terms of breadth and potency and protects against high-dose respiratory tract challenge. Neutralization activity against the B.1.351 VOC within two-fold of wild-type virus and against SARS-CoV-1 indicate exceptional breadth. Our results support consideration of RFN for SARS-like betacoronavirus vaccine development.

Efficacy of a Broadly Neutralizing SARS-CoV-2 Ferritin Nanoparticle Vaccine in Nonhuman Primates (preprint)

The emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants stresses the continued need for next-generation vaccines that confer broad protection against coronavirus disease 2019 (COVID-19). We developed and evaluated an adjuvanted SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine in nonhuman primates. High-dose (50 mcg) SpFN vaccine, given twice within a 28 day interval, induced a Th1-biased CD4 T cell helper response and a peak neutralizing antibody geometric mean titer of 52,773 against wild-type virus, with activity against SARS-CoV-1 and minimal decrement against variants of concern. Vaccinated animals mounted an anamnestic response on high-dose SARS-CoV-2 respiratory challenge that translated into rapid elimination of replicating virus in their upper and lower airways and lung parenchyma. The potent and broad immunogenicity profile of this vaccine and its resulting efficacy in NHPs supports its utility as a candidate platform for SARS-like betacoronaviruses.

Inhalable nanovaccine with biomimetic coronavirus structure to trigger mucosal immunity of respiratory tract against COVID-19.

The COVID-19 pandemic caused by SARS-CoV-2 seriously threatens global public health. It has previously been confirmed that SARS-CoV-2 is mainly transmitted between people through "respiratory droplets". Therefore, the respiratory tract mucosa is the first barrier to prevent virus invasion. It is very important to stimulate mucosal immunity to protect the body from respiratory virus infection. Inspired by this, we designed a bionic-virus nanovaccine, which can induce mucosal immunity by nasal delivery to prevent virus infection from respiratory tract. The nanovaccine that mimic virosome is composed of poly(I:C) mimicking viral genetic material as immune adjuvant, biomimetic pulmonary surfactant (bio-PS) liposomes as capsid structure of virus and the receptor binding domains (RBDs) of SARS-CoV-2 as "spike" to completely simulate the structure of the coronavirus. The nanovaccine can be administered by inhaling to imitate the process of SARS-CoV-2 infection through the respiratory tract. Our results demonstrated that the inhalable nanovaccine with bionic virus-like structure has a stronger mucosal protective effect than routine muscle and subcutaneous inoculation. In particular, high titer of secretory immunoglobulin A (sIgA) was detected in respiratory secretions, which effectively neutralize the virus and prevent it from entering the body through the respiratory tract. Through imitating the structure and route of infection, this inhalable nanovaccine strategy might inspire a new approach to the precaution of respiratory viruses.

Does Social Interaction Spread Fear among Institutional Investors? Evidence from COVID-19 (preprint)

We study how social connectedness affected fund manager stock holdings during the COVID-19 outbreak in the first quarter of 2020. Fund managers located in or socially connected to COVID hotspots sold more stock holdings during the quarter compared to a control group of unconnected managers. The economic impact of social connectedness on stock holdings is comparable to that of COVID hotspots. However, such reductions are panic driven as the unloaded stocks rebounded sharply in the subsequent quarter. Our evidence suggests that social connections can intensify salience bias for institutional investors, and policy makers should be wary of the destabilizing role of social networks during market downturns.

Epidemiological and clinical characteristics of 47 corona virus disease 2019 non-survivors in Huoshenshan Hospital

Objective To provide a basis for further optimizing the diagnosis and treatment strategies of severe and critical corona virus disease 2019 (COVID-19) by investigating and analyzing the epidemiological and clinical characteristics of the death cases. Methods The epidemiological and clinical characteristics of 47 death cases obtained from Huoshenshan Hospital in Whuhan, Hubei Province were retrospectively analyzed. Results All the patients developed initial symptoms in Wuhan. The time from onset to admission was (12.60±5.60) days. Most of them were male (68.09%) with non-nosocomial infection (91.49%), advanced age (>60 years, 89.36%). Over half of the cases (51.06%) reported a history of contact with suspected or confirmed patients, and comorbidity of chronic diseases (70.21%). Multiple organ dysfunction syndrome (MODS) occurred in 29 cases (61.70%) with heart failure (51.06%) and renal failure (36.17%). The main clinical symptoms included fever, fatigue, dyspnea and cough. At admission,most cases were severe (55.32%) or critical (42.55%), and the in-hospital survival was longer for the severe than for the critical (P=0.02). 76.59% of the patients received invasive mechanical ventilation, and they had a longer in-hospital survival than those with non-invasive mechanical ventilation (P<0.05). Conclusions This group of cases occurred during the peak of the COVID-19 outbreak in China, characterized by male, elder and history of chronic diseases. Acute respiratory distress syndrome (ARDS) caused by COVID-19 was responsible for patients' death, and MODS manifestated by heart and kidney failure also implicated in the process. Disease severity and invasive mechanical ventilation were related to in-hospital survival.