Reduced sera neutralization to Omicron SARS-CoV-2 by bothinactivated and protein subunit vaccines and the convalescents (preprint)

Omicron variant continues to spread all over the world. There are lots of scientific questions remaining to be answered for such a devastating variant. There are a dozen of vaccines already in clinical use. The very urgent scientific question would be whether or not these vaccines can protect Omicron variant. Here, we tested the sera from both convalescents and vaccine recipients receiving either inactivated or protein subunits vaccines (CoronaVac from Sinovac, or BBIBP-CoV from Sinopharm, or ZF2001 from Zhifei longcom) for the binding antibody titers (ELISA) and neutralization antibodies titers (pseudovirus neutralization assay). We showed that Omicron do have severe immune escape in convalescents, with 15 of 16 were negative in neutralization. By contrast, in vaccinees who received three jabs of inactivated or protein subunit vaccine, the neutralizing activity was much better preserved. Especially in the ZF2001 group with an extended period of the second and third jab (4-6 months) remains 100% positive in Omicron neutralization, with only 3.1-folds reduction in neutralizing antibody (NAb) titer. In this case, we proposed that, the multi-boost strategy with an extended interval between the second and third jab for immune maturation would be beneficial for NAb against devastating variants such as Omicron.

Comparative evaluation of the transmissibility of SARS-CoV-2 variants of concern (preprint)

Since the start of the SARS-CoV-2 pandemic in late 2019, several variants of concern (VOC) have been reported, such as B.1.1.7, B.1.351, P.1, and B.1.617.2. The exact reproduction number Rt for these VOCs is important to determine appropriate control measures. Here, we estimated the transmissibility for VOCs and lineages of SAR-CoV-2 based on genomic data and Bayesian inference under an epidemiological model to infer the reproduction number (Rt). We analyzed data for multiple VOCs from the same time period and countries, in order to compare their transmissibility while controlling for geographical and temporal factors. The lineage B had a significantly higher transmissibility than lineage A, and contributed to the global pandemic to a large extent. In addition, all VOCs had increased transmissibility when compared with other lineages in each country, indicating they are harder to control and present a high risk to public health. All countries should formulate specific prevention and control policies for these VOCs when they are detected to curve their potential for large-scale spread.

A single-dose mRNA vaccine provides a long-term protection for hACE2 transgenic mice from SARS-CoV-2 (preprint)

The rapid expansion of COVID-19 pandemic has made the development of a SARS-CoV-2 vaccine a global health and economic priority. Taking advantages of versatility and rapid development, three SARS-CoV-2 mRNA vaccine candidates has entered clinical trials with a two-dose immunization regimen. However, the waning antibodies response in convalescent patients after SARS-CoV-2 infection and the emergence of human re-infection have raised widespread concern about a short duration of SARS-CoV-2 vaccine protection. Here, we developed a nucleoside-modified mRNA vaccine in lipid-encapsulated form which encoded SARS-CoV-2 RBD, termed as mRNA-RBD. A single immunization of mRNA-RBD elicited both robust neutralizing antibody and cellular response, and conferred a near-complete protection against wild SARS-CoV-2 infection in lungs of hACE2 transgenic mice. Noticeably, high levels of neutralizing antibodies response induced by mRNA-RBD vaccination could maintain for at least 6.5 months and conferred a long-term remarkable protection for hACE2 transgenic mice against SARS-CoV-2 infection in sera transfer study. These data demonstrated that a single dose of mRNA-RBD provided long-term protection against SARS-CoV-2 challenge.

Do Lockdowns Bring about Additional Mortality Benefits or Costs? Evidence based on Death Records from 300 Million Chinese People (preprint)

After the COVID-19 outbreak, China immediately adopted stringent lockdown policies to contain the virus. Using comprehensive death records covering around 300 million Chinese people, we estimate the impacts of city and community lockdowns on non-COVID-19 mortality outside of Wuhan. Employing a difference-in-differences method, we find that lockdowns reduced the number of non-COVID-19 deaths by 4.9% (cardiovascular deaths by 6.2%, injuries by 9.2%, and non-COVID-19 pneumonia deaths by 14.3%). The health benefits are likely driven by significant reductions in air pollution, traffic, and human interactions. A back-of-the-envelope calculation shows that more than 32,000 lives could have been saved from non-COVID-19 diseases/causes during the 40 days of the lockdown on which we focus. The results suggest that the rapid and strict virus countermeasures not only effectively controlled the spread of COVID-19 but also brought about massive unintended public health benefits. These findings can help better inform policymakers around the world about the benefits and costs of city and community lockdowns policies in dealing with the COVID-19 pandemic.

Recombinant SARS-CoV-2 RBD molecule with a T helper epitope as a built in adjuvant induces strong neutralization antibody response (preprint)

Without approved vaccines and specific treatment, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading around the world with above 20 million COVID-19 cases and approximately 700 thousand deaths until now. An efficacious and affordable vaccine is urgently needed. The Val308 - Gly548 of Spike protein of SARS-CoV-2 linked with Gln830 - Glu843 of Tetanus toxoid (TT peptide) (designated as S1-4) and without TT peptide (designated as S1-5), and prokaryotic expression, chromatography purification and the rational renaturation of the protein were performed. The antigenicity and immunogenicity of S1-4 protein was evaluated by Western Blotting (WB) in vitro and immune responses in mice, respectively. The protective efficiency of it was measured by virus neutralization test in Vero E6 cells with SARS-CoV-2. S1-4 protein was prepared to high homogeneity and purity by prokaryotic expression and chromatography purification. Adjuvanted with Alum, S1-4 protein stimulated a strong antibody response in immunized mice and caused a major Th2-type cellular immunity compared with S1-5 protein. Furthermore, the immunized sera could protect the Vero E6 cells from SARS-CoV-2 infection with neutralization antibody GMT 256. The candidate subunit vaccine molecule could stimulate strong humoral and Th1 and Th2-type cellular immune response in mice, giving us solid evidence that S1-4 protein could be a promising subunit vaccine candidate.

Functional and druggability analysis of the SARS-CoV-2 proteome (preprint)

The infectious coronavirus disease (COVID-19) pandemic, caused by the coronavirus SARS-CoV-2, appeared in December 2019 in Wuhan, China, and has spread worldwide. As of today, more than 22 million people have been infected, with almost 800,000 fatalities. With the purpose of contributing to the development of effective therapeutics, this work provides an overview of the viral machinery and functional role of each SARS-CoV-2 protein, and a thorough analysis of the structure and druggability assessment of the viral proteome. All structural, non-structural, and accessory proteins of SARS-CoV-2 have been studied, and whenever experimental structural data of SARS-CoV-2 proteins were not available, homology models were built based on solved SARS-CoV structures. Several potential allosteric or protein-protein interaction druggable sites on different viral targets were identified, knowledge that could be used to expand current drug discovery endeavors beyond the cysteine proteases and the polymerase complex. It is our hope that this study will support the efforts of the scientific community both in understanding the molecular determinants of this disease and in widening the repertoire of viral targets in the quest for repurposed or novel drugs against COVID-19.

A non-competing pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2 (preprint)

Neutralizing antibodies could be antivirals against COVID-19 pandemics. Here, we report the isolation of four human-origin monoclonal antibodies from a convalescent patient in China. All of these isolated antibodies display neutralization abilities in vitro. Two of them (B38 and H4) block the binding between RBD and vial cellular receptor ACE2. Further competition assay indicates that B38 and H4 recognize different epitopes on the RBD, which is ideal for a virus-targeting mAb-pair to avoid immune escape in the future clinical applications. Moreover, therapeutic study on the mouse model validated that these two antibodies can reduce virus titers in the infected mouse lungs. Structure of RBD-B38 complex revealed that most residues on the epitope are overlapped with the RBD-ACE2 binding interface, which explained the blocking efficacy and neutralizing capacity. Our results highlight the promise of antibody-based therapeutics and provide the structural basis of rational vaccine design. One Sentence SummaryA pair of human neutralizing monoclonal antibodies against COVID-19 compete cellular receptor binding but with different epitopes, and with post-exposure viral load reduction activity.

Recombinant SARS-CoV-2 spike S1-Fc fusion protein induced high levels of neutralizing responses in nonhuman primates (preprint)

The COVID-19 outbreak has become a global pandemic responsible for over 2,000,000 confirmed cases and over 126,000 deaths worldwide. In this study, we examined the immunogenicity of CHO-expressed recombinant SARS-CoV-2 S1-Fc fusion protein in mice, rabbits, and monkeys as a potential candidate for a COVID-19 vaccine. We demonstrate that the S1-Fc fusion protein is extremely immunogenic, as evidenced by strong antibody titers observed by day 7. Strong virus neutralizing activity was observed on day 14 in rabbits immunized with the S1-Fc fusion protein using a pseudovirus neutralization assay. Most importantly, in less than 20 days and three injections of the S1-Fc fusion protein, two monkeys developed higher virus neutralizing titers than a recovered COVID-19 patient in a live SARS-CoV-2 infection assay. Our data strongly suggests that the CHO-expressed SARS-CoV-2 S1-Fc recombinant protein could be a strong candidate for vaccine development against COVID-19. HighlightsO_LICHO-expressed S1-Fc protein is very immunogenic in various animals and can rapidly induce strong antibody production C_LIO_LIS1-Fc protein solicits strong neutralizing activities against live virus C_LIO_LIStable CHO cell line expressing 50 mg/L of S1-Fc and a 3,000 L Bioreactor can produce 3 million doses of human COVID-19 vaccine every 10 days, making it an accessible and affordable option for worldwide vaccination C_LI