Structural basis for a conserved neutralization epitope on the receptor-binding domain of SARS-CoV-2.

Antibody-mediated immunity plays a crucial role in protection against SARS-CoV-2 infection. We isolated a panel of neutralizing anti-receptor-binding domain (RBD) antibodies elicited upon natural infection and vaccination and showed that they recognize an immunogenic patch on the internal surface of the core RBD, which faces inwards and is hidden in the "down" state. These antibodies broadly neutralize wild type (Wuhan-Hu-1) SARS-CoV-2, Beta and Delta variants and some are effective against other sarbecoviruses. We observed a continuum of partially overlapping antibody epitopes from lower to upper part of the inner face of the RBD and some antibodies extend towards the receptor-binding motif. The majority of antibodies are substantially compromised by three mutational hotspots (S371L/F, S373P and S375F) in the lower part of the Omicron BA.1, BA.2 and BA.4/5 RBD. By contrast, antibody IY-2A induces a partial unfolding of this variable region and interacts with a conserved conformational epitope to tolerate all antigenic variations and neutralize diverse sarbecoviruses as well. This finding establishes that antibody recognition is not limited to the normal surface structures on the RBD. In conclusion, the delineation of functionally and structurally conserved RBD epitopes highlights potential vaccine and therapeutic candidates for COVID-19.

Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants of concern in real-world: a literature review and meta-analysis.

Knowing vaccine effectiveness (VE) against variants of concern (VOCs) in the real-world setting is essential for public health decision-making. A systematic landscape of the VE against a series of clinical outcomes caused by the VOCs in the real-world setting is needed. We systematically searched for studies that evaluated VE against VOCs in the real-world setting and collected individual data. We identified 113 studies meeting the eligibility criteria. We found full vaccination provided strong protection against each clinical outcome with summary VE ranging from 86.8% to 96.0% Alpha, moderate protection against infection caused by Beta, Gamma and Delta with summary VE ranging from 70.9% to 72.8%, strong protection against severe disease caused by Delta with summary VE ranging from 84.9% to 90.3%, limited protection with summary VE of 23.5% (95% CI, 17.0-29.5) against infection and moderate protection with summary VE ranging from 56.5% to 82.4% against severe diseases caused by Omicron. Booster vaccination can provide a substantial improvement in protection against Delta and Omicron, but not as much as the Delta. The meta-regression analysis showed that the VE against the Omicron wanned over time, and the VE against hospitalization declined relatively slowly, compared to against infection. Those findings supported the need for public health measures, increasing booster vaccination coverage in response to current and new infectious waves driven by variants and developing broadly protective vaccines to confront virus evolution.

Vaccination with SARS-CoV-2 spike protein lacking glycan shields elicits enhanced protective responses in animal models.

A major challenge to end the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is to develop a broadly protective vaccine that elicits long-term immunity. As the key immunogen, the viral surface spike (S) protein is frequently mutated, and conserved epitopes are shielded by glycans. Here, we revealed that S protein glycosylation has site-differential effects on viral infectivity. We found that S protein generated by lung epithelial cells has glycoforms associated with increased infectivity. Compared to the fully glycosylated S protein, immunization of S protein with N-glycans trimmed to the mono-GlcNAc-decorated state (SMG) elicited stronger immune responses and better protection for human angiotensin-converting enzyme 2 (hACE2) transgenic mice against variants of concern (VOCs). In addition, a broadly neutralizing monoclonal antibody was identified from SMG-immunized mice that could neutralize wild-type SARS-CoV-2 and VOCs with subpicomolar potency. Together, these results demonstrate that removal of glycan shields to better expose the conserved sequences has the potential to be an effective and simple approach for developing a broadly protective SARS-CoV-2 vaccine.

Real-world effectiveness of COVID-19 vaccines: a literature review and meta-analysis.

OBJECTIVE: To estimate the coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE) against concerned outcomes in real-world settings. METHODS: Studies reporting COVID-19 VE from August 6, 2020 to October 6, 2021 were included. The summary VE (with 95% confidence intervals (95% CI)) against disease related to COVID-19 was estimated. The results were presented in forest plots. Predefined subgroup analyses and sensitivity analyses were also performed. RESULTS: A total of 51 records were included in this meta-analysis. In fully vaccinated populations, the VE against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19-related hospitalization, admission to the intensive care unit, and death was 89.1% (95% CI 85.6-92.6%), 97.2% (95% CI 96.1-98.3%), 97.4% (95% CI 96.0-98.8%), and 99.0% (95% CI 98.5-99.6%), respectively. The VE against infection in the general population aged ≥16 years, the elderly, and healthcare workers was 86.1% (95% CI 77.8-94.4%), 83.8% (95% CI 77.1-90.6%), and 95.3% (95% CI 92.0-98.6%), respectively. For those fully vaccinated against infection, the observed effectiveness of the Pfizer-BioNTech vaccine was 91.2% and of the Moderna vaccine was 98.1%, while the effectiveness of the CoronaVac vaccine was found to be 65.7%. CONCLUSIONS: The COVID-19 vaccines are highly protective against SARS-CoV-2-related diseases in real-world settings.

Structures and therapeutic potential of anti-RBD human monoclonal antibodies against SARS-CoV-2.

Background: Administration of potent anti-receptor-binding domain (RBD) monoclonal antibodies has been shown to curtail viral shedding and reduce hospitalization in patients with SARS-CoV-2 infection. However, the structure-function analysis of potent human anti-RBD monoclonal antibodies and its links to the formulation of antibody cocktails remains largely elusive. Methods: Previously, we isolated a panel of neutralizing anti-RBD monoclonal antibodies from convalescent patients and showed their neutralization efficacy in vitro. Here, we elucidate the mechanism of action of antibodies and dissect antibodies at the epitope level, which leads to a formation of a potent antibody cocktail. Results: We found that representative antibodies which target non-overlapping epitopes are effective against wild type virus and recently emerging variants of concern, whilst being encoded by antibody genes with few somatic mutations. Neutralization is associated with the inhibition of binding of viral RBD to ACE2 and possibly of the subsequent fusion process. Structural analysis of representative antibodies, by cryo-electron microscopy and crystallography, reveals that they have some unique aspects that are of potential value while sharing some features in common with previously reported neutralizing monoclonal antibodies. For instance, one has a common VH 3-53 public variable region yet is unusually resilient to mutation at residue 501 of the RBD. We evaluate the in vivo efficacy of an antibody cocktail consisting of two potent non-competing anti-RBD antibodies in a Syrian hamster model. We demonstrate that the cocktail prevents weight loss, reduces lung viral load and attenuates pulmonary inflammation in hamsters in both prophylactic and therapeutic settings. Although neutralization of one of these antibodies is abrogated by the mutations of variant B.1.351, it is also possible to produce a bi-valent cocktail of antibodies both of which are resilient to variants B.1.1.7, B.1.351 and B.1.617.2. Conclusions: These findings support the up-to-date and rational design of an anti-RBD antibody cocktail as a therapeutic candidate against COVID-19.

Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection.

The outbreak of COVID-19 caused by SARS-CoV-2 has resulted in more than 50 million confirmed cases and over 1 million deaths worldwide as of November 2020. Currently, there are no effective antivirals approved by the Food and Drug Administration to contain this pandemic except the antiviral agent remdesivir. In addition, the trimeric spike protein on the viral surface is highly glycosylated and almost 200,000 variants with mutations at more than 1,000 positions in its 1,273 amino acid sequence were reported, posing a major challenge in the development of antibodies and vaccines. It is therefore urgently needed to have alternative and timely treatments for the disease. In this study, we used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 µM. Two enzymatic assays, along with molecular modeling, were then developed to confirm those targeting the virus 3CL protease and the RNA-dependent RNA polymerase. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti-SARS-CoV-2 agents. Some of the active compounds identified in the screen were further tested in vivo, and it was found that mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens, and Mentha haplocalyx were effective in a challenge study using hamsters as disease model.

A Carbohydrate-Binding Protein from the Edible Lablab Beans Effectively Blocks the Infections of Influenza Viruses and SARS-CoV-2.

The influenza virus hemagglutinin (HA) and coronavirus spike (S) protein mediate virus entry. HA and S proteins are heavily glycosylated, making them potential targets for carbohydrate binding agents such as lectins. Here, we show that the lectin FRIL, isolated from hyacinth beans (Lablab purpureus), has anti-influenza and anti-SARS-CoV-2 activity. FRIL can neutralize 11 representative human and avian influenza strains at low nanomolar concentrations, and intranasal administration of FRIL is protective against lethal H1N1 infection in mice. FRIL binds preferentially to complex-type N-glycans and neutralizes viruses that possess complex-type N-glycans on their envelopes. As a homotetramer, FRIL is capable of aggregating influenza particles through multivalent binding and trapping influenza virions in cytoplasmic late endosomes, preventing their nuclear entry. Remarkably, FRIL also effectively neutralizes SARS-CoV-2, preventing viral protein production and cytopathic effect in host cells. These findings suggest a potential application of FRIL for the prevention and/or treatment of influenza and COVID-19.