ABSTRACT
The emerging SARS-CoV-2 variants of concern (VOC) harbor mutations associated with increasing transmission and immune escape, hence undermine the effectiveness of current COVID-19 vaccines. In late November of 2021, the Omicron (B.1.1.529) variant was identified in South Africa and rapidly spread across the globe. It was shown to exhibit significant resistance to neutralization by serum not only from convalescent patients, but also from individuals recieving currently used COVID-19 vaccines with multiple booster shots. Therefore, there is an urgent need to develop next generation vaccines against VOCs like Omicron. In this study, we develop a panel of mRNA-LNP-based vaccines using the receptor binding domain (RBD) of Omicron and Delta variants, which are dominant in the current wave of COVID-19. In addition to the Omicron- and Delta-specific vaccines, the panel also includes a Hybrid vaccine that uses the RBD containing all 16 point-mutations shown in Omicron and Delta RBD, as well as a bivalent vaccine composed of both Omicron and Delta RBD-LNP in half dose. Interestingly, both Omicron-specific and Hybrid RBD-LNP elicited extremely high titer of neutralizing antibody against Omicron itself, but few to none neutralizing antibody against other SARS-CoV-2 variants. The bivalent RBD-LNP, on the other hand, generated antibody with broadly neutralizing activity against the wild-type virus and all variants. Surprisingly, similar cross-protection was also shown by the Delta-specifc RBD-LNP. Taken together, our data demonstrated that Omicron-specific mRNA vaccine can induce potent neutralizing antibody response against Omicron, but the inclusion of epitopes from other variants may be required for eliciting cross-protection. This study would lay a foundation for rational development of the next generation vaccines against SARS-CoV-2 VOCs.
Subject(s)
COVID-19 , Severe Acute Respiratory SyndromeABSTRACT
Nucleotide analogs targeting viral RNA polymerase have been proved to be an effective strategy for antiviral treatment and are promising antiviral drugs to combat the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. In this study, we developed a robust in vitro nonradioactive primer extension assay to quantitatively evaluate the efficiency of incorporation of nucleotide analogs by SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Our results show that many nucleotide analogs can be incorporated into RNA by SARS-CoV-2 RdRp and that the incorporation of some of them leads to chain termination. The discrimination values of nucleotide analogs over those of natural nucleotides were measured to evaluate the incorporation efficiency of nucleotide analog by SARS-CoV-2 RdRp. In agreement with the data published in the literature, we found that the incorporation efficiency of remdesivir-TP is higher than that of ATP and incorporation of remdesivir-TP caused delayed chain termination, which can be overcome by higher concentrations of the next nucleotide to be incorporated. Our data also showed that the delayed chain termination pattern caused by remdesivir-TP incorporation is different for different template sequences. Multiple incorporations of remdesivir-TP caused chain termination under our assay conditions. Incorporation of sofosbuvir-TP is very low, suggesting that sofosbuvir may not be very effective in treating SARS-CoV-2 infection. As a comparison, 2'-C-methyl-GTP can be incorporated into RNA efficiently, and the derivative of 2'-C-methyl-GTP may have therapeutic application in treating SARS-CoV-2 infection. This report provides a simple screening method that should be useful for evaluating nucleotide-based drugs targeting SARS-CoV-2 RdRp and for studying the mechanism of action of selected nucleotide analogs.
Subject(s)
Antiviral Agents/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/genetics , Drug Evaluation, Preclinical/methods , Nucleotides/pharmacology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/genetics , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/genetics , Alanine/pharmacology , Antiviral Agents/chemistry , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Nucleotides/chemistry , RNA , RNA, Viral/biosynthesis , Viral Nonstructural ProteinsSubject(s)
Antiviral Agents , Guanine/analogs & derivatives , Hepatitis B virus , Hepatitis B/drug therapy , Meta-Analysis as Topic , Systematic Reviews as Topic , Tenofovir , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Guanine/administration & dosage , Guanine/adverse effects , Humans , Patient Selection , Randomized Controlled Trials as Topic , Tenofovir/administration & dosage , Tenofovir/adverse effectsABSTRACT
BACKGROUND: During the COVID-19 period, there was a huge gap in the understanding of masks between east and west. At the same time, the mechanism of the mask and the effect after use, also appeared differences. The Objective of this Meta-analysis is to systematically evaluate the efficacy of masks for influenza in the community. METHODS: The Web of Science, PubMed, The Cochrane Library, EMBASE and Clinical Trials will be electronically searched to collect randomized controlled trials regarding the efficacy of masks for influenza in the community through Apr 2020. Two researchers independently screened and evaluated the obtained studies and extracted the outcome indexes. Revman 5.3 software will be used for the meta-analysis. RESULTS: The outbreak is continuing, and we need to be prepared for a long fight. If masks are effective, we need to promote their use as soon as possible. If masks are ineffective, strong evidence should be given. This is an urgent task and our team will finish it as soon as possible. CONCLUSION: Provide stronger evidence to solve the problem, should we wear masks or not right now.