The emergence of numerous variants of SARS-CoV-2, the causative agent of COVID-19, has presented new challenges to the global efforts to control the COVID-19 pandemic. Here, we obtain two cross-neutralizing antibodies (7D6 and 6D6) that target Sarbecoviruses’ receptor-binding domain (RBD) with sub-picomolar affinities and potently neutralize authentic SARS-CoV-2. Crystal structures show that both antibodies bind a cryptic site different from that recognized by existing antibodies and highly conserved across Sarbecovirus isolates. Binding of these two antibodies to the RBD clashes with the adjacent N-terminal domain and disrupts the viral spike. Both antibodies confer good resistance to mutations in the currently circulating SARS-CoV-2 variants. Thus, our results have direct relevance to public health as options for passive antibody therapeutics and even active prophylactics. They can also inform the design of pan-sarbecovirus vaccines.

Influenza A viruses pose a significant threat globally each year, underscoring the need for a vaccine- or antiviral-based broad-protection strategy. Here, we describe a chimeric monoclonal antibody, C12H5, that offers neutralization against seasonal and pandemic H1N1 viruses, and cross-protection against some H5N1 viruses. Notably, C12H5 mAb offers broad neutralizing activity against H1N1 and H5N1 viruses by controlling virus entry and egress, and offers protection against H1N1 and H5N1 viral challenge in vivo. Through structural analyses, we show that C12H5 engages hemagglutinin (HA), the major surface glycoprotein on influenza, at a distinct epitope overlapping the receptor binding site and covering the 140-loop. We identified eight highly conserved (~90%) residues that are essential for broad H1N1 recognition, with evidence of tolerance for Asp or Glu at position 190; this site is a molecular determinant for human or avian host-specific recognition and this tolerance endows C12H5 with cross-neutralization potential. Our results could benefit the development of antiviral drugs and the design of broad-protection influenza vaccines.

Pseudorabies virus (PRV) is a major etiological agent of swine infectious diseases and is responsible for significant economic losses in the swine industry. Recent data points to human viral encephalitis caused by PRV infection, suggesting that PRV may be able to overcome the species barrier to infect humans. To date, there is no available therapeutic for PRV infection. Here, we report the near-atomic structures of the PRV A-capsid and C-capsid, and illustrate the interaction that occurs between these subunits. We show that the C-capsid portal complex is decorated with capsid-associated tegument complexes. The PRV capsid structure is highly reminiscent of other α-herpesviruses, with some additional structural features of β- and γ-herpesviruses. These results illustrate the structure of the PRV capsid and elucidate the underlying assembly mechanism at the molecular level. This knowledge may be useful for the development of oncolytic agents or specific therapeutics against this arm of the herpesvirus family.

Tailed bacteriophages (order, Caudovirales) account for the majority of all phages. However, the long flexible tail of siphophages hinders comprehensive investigation of the mechanism of viral gene delivery. Here, we report the atomic capsid and in-situ structures of the tail machine of the marine siphophage, vB_DshS-R4C (R4C), which infects Roseobacter. The R4C virion, comprising 12 distinct structural protein components, has a unique five-fold vertex of the icosahedral capsid that allows genome delivery. The specific position and interaction pattern of the tail tube proteins determine the atypical long rigid tail of R4C, and further provide negative charge distribution within the tail tube. A ratchet mechanism assists in DNA transmission, which is initiated by an absorption device that structurally resembles the phage-like particle, RcGTA. Overall, these results provide in-depth knowledge into the intact structure and underlining DNA delivery mechanism for the ecologically important siphophages.

Currently, SARS-CoV-2 has evolved into various variants, including the numerous highly mutated Omicron sub-lineages, significantly increasing immune evasion ability. The development raises concerns about the possibly diminished effectiveness of available vaccines and antibody-based therapeutics. Here, we describe those representative categories of broadly neutralizing antibodies (bnAbs) that retain prominent effectiveness against emerging variants including Omicron sub-lineages. The molecular characteristics, epitope conservation, and resistance mechanisms of these antibodies are further detailed, aiming to offer suggestion or direction for the development of therapeutic antibodies, and facilitate the design of vaccines with broad-spectrum potential.