Deep learning guided optimization of human antibody against SARS-CoV-2 variants with broad neutralization.

SignificanceSARS-CoV-2 continues to evolve through emerging variants, more frequently observed with higher transmissibility. Despite the wide application of vaccines and antibodies, the selection pressure on the Spike protein may lead to further evolution of variants that include mutations that can evade immune response. To catch up with the virus's evolution, we introduced a deep learning approach to redesign the complementarity-determining regions (CDRs) to target multiple virus variants and obtained an antibody that broadly neutralizes SARS-CoV-2 variants.

Unmethylated CpG motif-containing genomic DNA fragments of bacillus calmette-guerin improves immune response towards a DNA vaccine for COVID-19.

The development of an effective vaccine to control the global coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2) is of utmost importance. In this study, a synthetic DNA-based vaccine candidate, known as pSV10-SARS-CoV-2, expressing the SARS-CoV-2 spike protein was designed and tested in 39 BALB/c mice with BC01, an adjuvant derived from unmethylated CpG motif-containing DNA fragments from the Bacillus Calmette-Guerin genome. Mice vaccinated with pSV10-SARS-CoV-2 with BC01 produced early neutralizing antibodies and developed stronger humoral and cellular immune responses compared to mice that received the DNA vaccine only. Moreover, sera from mice vaccinated with pSV10-SARS-CoV-2 with BC01 can neutralize certain variants, including 614G, 614G + 472 V, 452R, 483A, 501Y.V2, and B.1.1.7. The results of this study demonstrate that the addition of BC01 to a DNA-vaccine for COVID-19 could elicit more effective neutralizing antibody titers for disease prevention.

Single-Dose Immunization With a Chimpanzee Adenovirus-Based Vaccine Induces Sustained and Protective Immunity Against SARS-CoV-2 Infection.

The development of a safe and effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we aim to develop novel SARS-CoV-2 vaccines based on a derivative of less commonly used rare adenovirus serotype AdC68 vector. Three vaccine candidates were constructed expressing either the full-length spike (AdC68-19S) or receptor-binding domain (RBD) with two different signal sequences (AdC68-19RBD and AdC68-19RBDs). Single-dose intramuscular immunization induced robust and sustained binding and neutralizing antibody responses in BALB/c mice up to 40 weeks after immunization, with AdC68-19S being superior to AdC68-19RBD and AdC68-19RBDs. Importantly, immunization with AdC68-19S induced protective immunity against high-dose challenge with live SARS-CoV-2 in a golden Syrian hamster model of SARS-CoV-2 infection. Vaccinated animals demonstrated dramatic decreases in viral RNA copies and infectious virus in the lungs, as well as reduced lung pathology compared to the control animals. Similar protective effects were also found in rhesus macaques. Taken together, these results confirm that AdC68-19S can induce protective immune responses in experimental animals, meriting further development toward a human vaccine against SARS-CoV-2.

Potent and protective IGHV3-53/3-66 public antibodies and their shared escape mutant on the spike of SARS-CoV-2.

Neutralizing antibodies (nAbs) to SARS-CoV-2 hold powerful potentials for clinical interventions against COVID-19 disease. However, their common genetic and biologic features remain elusive. Here we interrogate a total of 165 antibodies from eight COVID-19 patients, and find that potent nAbs from different patients have disproportionally high representation of IGHV3-53/3-66 usage, and therefore termed as public antibodies. Crystal structural comparison of these antibodies reveals they share similar angle of approach to RBD, overlap in buried surface and binding residues on RBD, and have substantial spatial clash with receptor angiotensin-converting enzyme-2 (ACE2) in binding to RBD. Site-directed mutagenesis confirms these common binding features although some minor differences are found. One representative antibody, P5A-3C8, demonstrates extraordinarily protective efficacy in a golden Syrian hamster model against SARS-CoV-2 infection. However, virus escape analysis identifies a single natural mutation in RBD, namely K417N found in B.1.351 variant from South Africa, abolished the neutralizing activity of these public antibodies. The discovery of public antibodies and shared escape mutation highlight the intricate relationship between antibody response and SARS-CoV-2, and provide critical reference for the development of antibody and vaccine strategies to overcome the antigenic variation of SARS-CoV-2.

Single-Cell RNA Sequencing Analysis of the Immunometabolic Rewiring and Immunopathogenesis of Coronavirus Disease 2019.

Although immune dysfunction is a key feature of coronavirus disease 2019 (COVID-19), the metabolism-related mechanisms remain elusive. Here, by reanalyzing single-cell RNA sequencing data, we delineated metabolic remodeling in peripheral blood mononuclear cells (PBMCs) to elucidate the metabolic mechanisms that may lead to the progression of severe COVID-19. After scoring the metabolism-related biological processes and signaling pathways, we found that mono-CD14+ cells expressed higher levels of glycolysis-related genes (PKM, LDHA and PKM) and PPP-related genes (PGD and TKT) in severe patients than in mild patients. These genes may contribute to the hyperinflammation in mono-CD14+ cells of patients with severe COVID-19. The mono-CD16+ cell population in COVID-19 patients showed reduced transcription levels of genes related to lysine degradation (NSD1, KMT2E, and SETD2) and elevated transcription levels of genes involved in OXPHOS (ATP6V1B2, ATP5A1, ATP5E, and ATP5B), which may inhibit M2-like polarization. Plasma cells also expressed higher levels of the OXPHOS gene ATP13A3 in COVID-19 patients, which was positively associated with antibody secretion and survival of PCs. Moreover, enhanced glycolysis or OXPHOS was positively associated with the differentiation of memory B cells into plasmablasts or plasma cells. This study comprehensively investigated the metabolic features of peripheral immune cells and revealed that metabolic changes exacerbated inflammation in monocytes and promoted antibody secretion and cell survival in PCs in COVID-19 patients, especially those with severe disease.

[A single arm clinical study of 86 patients with common type of coronavirus disease 2019 treated by integrated traditional Chinese and Western medicine: multicenter case observation from 7 designated hospitals in Henan Province].

OBJECTIVE: To evaluate the clinical effect of integrated traditional Chinese and Western medicine on common type of coronavirus disease 2019 (COVID-19) in Henan Province. METHODS: A prospective single arm clinical study was performed. Patients with common type of COVID-19 admitted to seven designated hospitals for COVID-19 in Henan Province from January 25th to February 26th, 2020 were enrolled, and treated with integrated traditional Chinese and Western medicine. The negative transformation of 2019 novel coronavirus (2019-nCoV) nucleic acid, disease outcome, hospital stay, clinical symptoms and signs scores, and chest imaging performance were observed. RESULTS: Totally 86 cases were included in the analysis, including 48 males (55.8%), aged 43.5 (35.0, 53.3) years old, 24 patients (27.9%) with previous medical history. Fifty-eight patients were primarily diagnosed COVID-19 and 28 patients were transferred. The 2019-nCoV nucleic acid of 86 cases (100%) turned negative, and the median time of turning negative was 10 (7, 14) days. Eighty-six cases (100%) were discharged from hospital, and none turned into the severe type; the average length of hospital stay was (13.8±5.6) days. The scores of fever, cough, chest tightness, shortness of breath, and fatigue decreased with the treatment time, and the scores of 7 days and 14 days after treatment were significantly lower than those before treatment [fever (points): 0 (0, 0), 0 (0, 0) vs. 1 (0, 1); cough (points): 1 (0, 1), 0 (0, 1) vs. 1 (0, 2); chest tightness (points): 0 (0, 0), 0 (0, 0) vs. 0 (0, 1); shortness of breath (points): 0 (0, 0), 0 (0, 0) vs. 0 (0, 1); fatigue (points): 0 (0, 1), 0 (0, 1) vs. 1 (0, 1); all P < 0.05]. The improvement rate of X ray and CT image was 42.9% (12/28) and 81.0% (64/79), respectively. CONCLUSIONS: The treatment with integrated traditional Chinese and Western medicine has good curative effect on common type of COVID-19 in 7 designated hospitals of Henan Province. It can improve the clinical symptoms, promote the absorption of pulmonary inflammation, and to some extent control the progress of disease and shorten the time of turning negative of virus nucleic acid and hospital stay.