Epitope-focused immunogen design based on the ebolavirus glycoprotein HR2-MPER region.

The three human pathogenic ebolaviruses: Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) virus, cause severe disease with high fatality rates. Epitopes of ebolavirus glycoprotein (GP) recognized by antibodies with binding breadth for all three ebolaviruses are of major interest for rational vaccine design. In particular, the heptad repeat 2 -membrane-proximal external region (HR2-MPER) epitope is relatively conserved between EBOV, BDBV, and SUDV GP and targeted by human broadly-neutralizing antibodies. To study whether this epitope can serve as an immunogen for the elicitation of broadly-reactive antibody responses, protein design in Rosetta was employed to transplant the HR2-MPER epitope identified from a co-crystal structure with the known broadly-reactive monoclonal antibody (mAb) BDBV223 onto smaller scaffold proteins. From computational analysis, selected immunogen designs were produced as recombinant proteins and functionally validated, leading to the identification of a sterile alpha motif (SAM) domain displaying the BDBV-HR2-MPER epitope near its C terminus as a promising candidate. The immunogen was fused to one component of a self-assembling, two-component nanoparticle and tested for immunogenicity in rabbits. Robust titers of cross-reactive serum antibodies to BDBV and EBOV GPs and moderate titers to SUDV GP were induced following immunization. To confirm the structural composition of the immunogens, solution NMR studies were conducted and revealed structural flexibility in the C-terminal residues of the epitope. Overall, our study represents the first report on an epitope-focused immunogen design based on the structurally challenging BDBV-HR2-MPER epitope.

Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail.

Understanding the molecular basis for immune recognition of SARS-CoV-2 spike glycoprotein antigenic sites will inform the development of improved therapeutics. We determined the structures of two human monoclonal antibodies-AZD8895 and AZD1061-which form the basis of the investigational antibody cocktail AZD7442, in complex with the receptor-binding domain (RBD) of SARS-CoV-2 to define the genetic and structural basis of neutralization. AZD8895 forms an 'aromatic cage' at the heavy/light chain interface using germ line-encoded residues in complementarity-determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain. These structural features explain why highly similar antibodies (public clonotypes) have been isolated from multiple individuals. AZD1061 has an unusually long LCDR1; the HCDR3 makes interactions with the opposite face of the RBD from that of AZD8895. Using deep mutational scanning and neutralization escape selection experiments, we comprehensively mapped the crucial binding residues of both antibodies and identified positions of concern with regards to virus escape from antibody-mediated neutralization. Both AZD8895 and AZD1061 have strong neutralizing activity against SARS-CoV-2 and variants of concern with antigenic substitutions in the RBD. We conclude that germ line-encoded antibody features enable recognition of the SARS-CoV-2 spike RBD and demonstrate the utility of the cocktail AZD7442 in neutralizing emerging variant viruses.

An analysis of the domestic resumption of social production and life under the COVID-19 epidemic.

Population migration and urban traffic are two important aspects of the socioeconomic system. We analyze the trends of social production and resumption of life after the coronavirus disease 2019 (COVID-19)-influenced Spring Festival in 2020 with statistics on reported cases of COVID-19 from China's National Health Commission and big data from Baidu Migration (a platform collecting population migration data). We find that (1) the distribution of COVID-19 cases throughout mainland China has a specific spatial pattern. Provinces in eastern China have more reported cases than those in western China, and provinces adjacent to Hubei have more confirmed COVID-19 cases than nonadjacent provinces. Densely populated regions with well-developed economies and transportation are more likely to have cluster infection incidents. (2) The COVID-19 epidemic severely impacts the return of the migrant population in the Spring Festival travel rush, as demonstrated by the significant reduction in the return scale, along with the extended timespan and uncertainty regarding the end of the travel rush. Among 33 provinces, special administrative regions, autonomous regions and municipalities, 23 of them (approximately 70%) have a return rate below 60%. Hubei, Hong Kong, Xinjiang, and Inner Mongolia have the lowest return rates (below 5%), whereas the return rates in Hainan and Shandong, 272.72% and 97.35%, respectively, indicate the best trend of resumption. Due to government regulations, the population return in densely populated and well-developed regions shows a positive trend. (3) The resumption of urban traffic is slow and varies greatly in different regions. The urban traffic conditions in 22 provinces and municipalities have a more than 60% level of resumption. Guizhou and Yunnan have the highest level of resumption of urban traffic, whereas Xinjiang, Hubei, and Heilongjiang have the lowest (29.37%, 35.76%, and 37.90%, respectively). However, provinces and municipalities with well-developed intercity traffic have a lower level of resumption, mainly because of regulatory methods such as lockdowns and traffic restrictions. The increased public awareness of epidemic prevention and the decreased frequency of outdoor activities are also two positive factors slowing the spread of the epidemic. (4) Time will be necessary to fully resume social production and life throughout China. Xining and Jinan have the highest levels of resumption, 82.14% and 71.51%, respectively. Urumqi and Wuhan are the cities with the lowest levels of resumption, only 0.11% and 0.61%, respectively. Currently, 12 of 33 provinces and municipalities have levels of resumption of more than 80%; among them, Guizhou, Yunnan, and Gansu have with the highest levels of resumption and have nearly resumed the 2019 levels of work and life, whereas Xinjiang and Hubei have the lowest resumption rates, only 0.09% and 7.57%, respectively. Thus, relevant government departments should focus more on densely populated and well-developed provinces and cities when applying epidemic prevention and work resumption methods. We reveal the general conditions of the epidemic and the population return scale across China, along with urban traffic conditions and the resumption of social production and life under COVID-19, providing a scientific basis for local governments to make further decisions on work resumption.