Simultaneous and sequential multi-species coronavirus vaccination

Although successful COVID-19 vaccines have been developed, multiple pathogenic coronavirus species exist, urging for development of multi-species coronavirus vaccines. Here we developed prototype LNP-mRNA vaccine candidates against SARS-CoV-2 (Delta variant), SARS-CoV and MERS-CoV, and test how multiplexing of these LNP-mRNAs can induce effective immune responses in animal models. A triplex scheme of LNP-mRNA vaccination induced antigen-specific antibody responses against SARS-CoV-2, SARS-CoV and MERS-CoV, with a relatively weaker MERS-CoV response in this setting. Single cell RNA-seq profiled the global systemic immune repertoires and the respective transcriptome signatures of multiplexed vaccinated animals, which revealed a systemic increase in activated B cells, as well as differential gene expression signatures across major adaptive immune cells. Sequential vaccination showed potent antibody responses against all three species, significantly stronger than simultaneous vaccination in mixture. These data demonstrated the feasibility, antibody responses and single cell immune profiles of multi-species coronavirus vaccination. The direct comparison between simultaneous and sequential vaccination offers insights on optimization of vaccination schedules to provide broad and potent antibody immunity against three major pathogenic coronavirus species. One sentence summaryMultiplexed mRNA vaccination in simultaneous and sequential modes provide broad and potent immunity against pathogenic coronavirus species.

Nonstructural protein 1 of SARS-CoV-2 is a potent pathogenicity factor redirecting host protein synthesis machinery toward viral RNA.

The COVID-19 pandemic affects millions of people worldwide with a rising death toll. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses its nonstructural protein 1 (Nsp1) to redirect host translation machinery to the viral RNA by binding to the ribosome and suppressing cellular, but not viral, protein synthesis through yet unknown mechanisms. We show here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the transcriptome in human cells. The changes include repression of major gene clusters in ribosomal RNA processing, translation, mitochondria function, cell cycle and antigen presentation; and induction of factors in transcriptional regulation. We further gained a mechanistic understanding of the Nsp1 function by determining the cryo-EM structure of the Nsp1-40S ribosomal subunit complex, which shows that Nsp1 inhibits translation by plugging the mRNA entry channel of the 40S. We also determined the cryo-EM structure of the 48S preinitiation complex (PIC) formed by Nsp1, 40S, and the cricket paralysis virus (CrPV) internal ribosome entry site (IRES) RNA, which shows that this 48S PIC is nonfunctional due to the incorrect position of the 3 region of the mRNA. Results presented here elucidate the mechanism of host translation inhibition by SARS-CoV-2, provide insight into viral protein synthesis, and furnish a comprehensive understanding of the impacts from one of the most potent pathogenicity factors of SARS-CoV-2. HighlightsORF screen identified Nsp1 as a major cellular pathogenicity factor of SARS-CoV-2 Nsp1 broadly alters the gene expression programs in human cells Nsp1 inhibits translation by blocking mRNA entry channel Nsp1 prevents physiological conformation of the 48S PIC

Analysis on the current situation of insufficient sleep and its association with physical exercise among Chinese Han students aged 9-18 years, in 2014 / 中华流行病学杂志

Objective: To describe the situation of insufficient sleep and the association between insufficient sleep and physical exercise, among Chinese Han students aged 9-18 years. Methods: We selected 172 197 Chinese Han students aged 9-18 years from the project 2014 Chinese National Survey on Students Constitution and Health. The average sleep duration per day of less than 9 h for children aged 9-12 years and of less than 8 h for adolescents aged 13-18 years, were defined as insufficient sleep. We described the distribution of sleep duration and the prevalence rates of insufficient sleep for each subgroup. Logistic regression models were established to assess the association between insufficient sleep and physical exercise. Results: In 2014, 6.6%, 30.8%, 26.3%, 20.8%, 13.8% and 1.8% of the Chinese Han students self-reported sleep duration were <6, 6-, 7-, 8- and ≥10 h, respectively. The overall prevalence rate of insufficient sleep was 77.2%, with 75.8% for boys and 78.6% for girls. No gender disparity was found at each 9-11 age groups. However, in the 12-18 age groups, the prevalence rates for girls were significantly higher than that for boys. The prevalence rates of insufficient sleep for primary school, middle school and high school students were66.6%, 74.1% and 93.8%, respectively. Rates were increasing with age for children aged 9-12 years and adolescents aged 13-18 years respectively. The three provinces with the lowest prevalence rates of insufficient sleep were Zhejiang (68.8%), Jiangsu (66.7%) and Shaanxi (65.2%). Data from the logistic regression models revealed that, when comparing to those students with only exercise of <0.5 h per day, the exercise hours of 0.5-1 h (OR=0.72, 95%CI: 0.69-0.74) or ≥1 h (OR=0.46, 95%CI: 0.44-0.47) per day seemed as protective factors for insufficient sleep. When compared with physical exercise frequency <2 times per week, the 2 times (OR=0.82, 95%CI: 0.78-0.86) or >2 times (OR=0.65, 95%CI: 0.62-0.68) frequencies also appeared as protective. Conclusions: The prevalence rate of insufficient sleep prevailing among students aged 9-18 years was high, in China. Our data called for setting up effective measures to deal with this situation.