Two antibodies against flaviviruses: Flaviviruses are a group of RNA viruses that include the human pathogens dengue virus, Zika virus, and West Nile virus. The envelope protein (E) on the virus surface has been the target of vaccine development, but problems have arisen with antibodies against E, leading to enhanced infection. Now, Modhiran et al. and Biering et al. describe two different antibodies that bind to the flavivirus NS1 protein and prevent it from disrupting epithelial cells, which is associated with severe disease. Both antibodies cross-react with multiple flavivirus NS1 proteins. The antibodies reduce viremia and increase survival in mouse models of flavivirus disease. Both papers include structures of NS1 bound to an antibody, which give insight into the protective mechanism. Science , this issue p. 190 , p. 194

The epidemic emergence of relatively rare and geographically isolated flaviviruses adds to the ongoing disease burden of viruses such as dengue. Structural analysis is key to understand and combat these pathogens. Here, we present a chimeric platform based on an insect-specific flavivirus for the safe and rapid structural analysis of pathogenic viruses. We use this approach to resolve the architecture of two neurotropic viruses and a structure of dengue virus at 2.5 Å, the highest resolution for an enveloped virion. These reconstructions allow improved modelling of the stem region of the envelope protein, revealing two lipid-like ligands within highly conserved pockets. We show that these sites are essential for viral growth and important for viral maturation. These findings define a hallmark of flavivirus virions and a potential target for broad-spectrum antivirals and vaccine design. We anticipate the chimeric platform to be widely applicable for investigating flavivirus biology.

Yellow fever virus (YFV) is a re-emerging flavivirus that causes severe hepatic disease and mortality in humans. Despite being researched for over a century, the structure of YFV has remained elusive. Here we use a chimeric virus platform to resolve the first high resolution cryo-EM structures of YFV. Stark differences in particle morphology and homogeneity are observed between vaccine and virulent strains of YFV, and these are found to have significant implications on antibody recognition and neutralisation. We identify a single residue (R380) in the YFV _17D envelope protein that stabilises the virion surface, and leads to reduced exposure of the cross-reactive fusion loop epitope. The differences in virion morphology between YFV strains also contribute to the reduced sensitivity of the virulent YFV virions to vaccine-induced antibodies. These findings have significant implications for YFV biology, vaccinology and structure-based flavivirus antigen design.

Efforts to develop and deploy effective vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continue at pace with more than 30 candidate vaccines now in clinical evaluation. Here we describe the preclinical development of an adjuvanted, prefusion-stabilised Spike (S) protein “Sclamp” subunit vaccine, from rational antigen design through to assessing manufacturability and vaccine efficacy. In mice, the vaccine candidate elicits high levels of neutralising antibodies to epitopes both within and outside the receptor binding domain (RBD) of S, as well as broadly reactive and polyfunctional S-specific CD4+ and cytotoxic CD8+ T cells. We also show protection in Syrian hamsters, which has emerged as a robust animal model for pulmonary SARS-CoV-2 infection. No evidence of vaccine enhanced disease was observed in animal challenge studies and pre-clinical safety was further demonstrated in a GLP toxicology study in rats. The Sclamp vaccine candidate is currently progressing rapidly through clinical evaluation in parallel with large-scale manufacture for pivotal efficacy trials and potential widespread distribution.

The use of dengue virus (DENV) vaccines has been hindered by the complexities of antibody dependent enhancement (ADE). Current late-stage vaccine candidates utilize attenuated and chimeric DENVs that produce particles of varying maturities. Antibodies that are elicited by preferentially exposed epitopes on immature virions have been linked to increased ADE. We aimed to further understand the humoral immunity promoted by DENV particles of varying maturities in an AG129 mouse model using a chimeric insect specific vaccine candidate, bDENV-2. We immunized mice with mature, partially mature, and immature bDENV-2 and found that immunization with partially mature bDENV-2 produced more robust and cross-neutralizing immune responses than immunization with immature or mature bDENV-2. Upon challenge with mouse adapted DENV-2 (D220), we observed 80% protection for mature bDENV-2 vaccinated mice and 100% for immature and partially mature vaccinated mice, suggesting that protection to homotypic challenge is not dependent on maturation. Finally, we found reduced in vitro ADE at subneutralising serum concentrations for mice immunized with mature bDENV-2. These results suggest that both immature and mature DENV particles play a role in homotypic protection; however, the increased risk of in vitro ADE from immature particles indicates potential safety benefits from mature DENV-based vaccines.