Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD.

Continual evolution of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has allowed for its gradual evasion of neutralizing antibodies (nAbs) produced in response to natural infection or vaccination. The rapid nature of these changes has incited a need for the development of superior broad nAbs (bnAbs) and/or the rational design of an antibody cocktail that can protect against the mutated virus strain. Here, we report two angiotensin-converting enzyme 2 competing nAbs-8H12 and 3E2-with synergistic neutralization but evaded by some Omicron subvariants. Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing. Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5. Together, these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.

Structural basis for broad neutralization of human antibody against Omicron sublineages and evasion by XBB variant.

IMPORTANCE: The ongoing COVID-19 pandemic has been characterized by the emergence of new SARS-CoV-2 variants including the highly transmissible Omicron XBB sublineages, which have shown significant resistance to neutralizing antibodies (nAbs). This resistance has led to decreased vaccine effectiveness and therefore result in breakthrough infections and reinfections, which continuously threaten public health. To date, almost all available therapeutic nAbs, including those authorized under Emergency Use Authorization nAbs that were previously clinically useful against early strains, have recently been found to be ineffective against newly emerging variants. In this study, we provide a comprehensive structural basis about how the Class 3 nAbs, including 1G11 in this study and noted LY-CoV1404, are evaded by the newly emerged SARS-CoV-2 variants.

Effectiveness of first and second boost COVID-19 vaccination in healthy adults during BA.5.2/BF.7 surge in China.

With the development of the SARS-CoV-2 pandemic, there have been doubts about the necessity of vaccine boosters for healthy adults. However, due to the lack of relevant evidence, current research is unable to provide reliable medical advice for COVID-19 boost in healthy adults. We conducted a retrospective observational study to evaluate the effectiveness of different COVID-19 vaccination regimens by investigating the SARS-CoV-2 infection status of healthy donors in Southeast China. From December 2022 to February 2023, 737 healthy adult blood donors were analyzed. Results showed that any COVID-19 vaccine boosts reduced the risk of Omicron BA.5.2/BF.7 infection compared to only receiving prime vaccination (rVE = 16%, 95%CI = 4, 27%). The second boost further enhanced vaccine effectiveness compared to the received first booster (rVE = 39%, 95%CI = 16, 55%). Through retrospective observation of healthy adults during the BA.5.2/BF.7 surge in China, we found that boost vaccinations significantly reduce the risk of SARS-CoV-2 infection and disease. Findings show healthy adults benefit from boost vaccinations, even if not at high-risk for severe COVID-19.

Lineage-mosaic and mutation-patched spike proteins for broad-spectrum COVID-19 vaccine.

SARS-CoV-2 spread in humans results in continuous emergence of new variants, highlighting the need for vaccines with broad-spectrum antigenic coverage. Using inter-lineage chimera and mutation-patch strategies, we engineered a recombinant monomeric spike variant (STFK1628x) that contains key regions and residues across multiple SAR-CoV-2 variants. STFK1628x demonstrated high immunogenicity and mutually complementary antigenicity to its prototypic form (STFK). In hamsters, a bivalent vaccine composed of STFK and STFK1628x elicited high titers of broad-spectrum neutralizing antibodies to 19 circulating SARS-CoV-2 variants, including Omicron sublineages BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, and BA.4/5. Furthermore, this vaccine conferred robust protection against intranasal challenges by either SARS-CoV-2 ancestral strain or immune-evasive Beta and Omicron BA.1. Strikingly, vaccination with the bivalent vaccine in hamsters effectively blocked within-cage virus transmission of ancestral SARS-CoV-2, Beta variant, and Omicron BA.1 to unvaccinated sentinels. Thus, our study provided insight and antigen candidates for the development of next-generation COVID-19 vaccines.

Prenatal exposure to a mixture of PAHs causes the dysfunction of islet cells in adult male mice: Association with type 1 diabetes mellitus.

Polycyclic aromatic hydrocarbons (PAHs) have been detected throughout the human body. Whether exposure to PAHs is associated with the incidence of type 1 diabetes mellitus should be investigated. To this end, pregnant mice were exposed to mixed PAHs (5, 50, or 500 µg/kg) once every other day during gestation. The adult male offspring displayed impaired glucose tolerance and reduced serum levels of glucagon and insulin. Immunohistochemical staining revealed increased numbers of apoptotic ß-cells and a reduced ß-cell mass in these males. The downregulated expression of pancreatic estrogen receptor α, androgen receptor, and transcription factor PDX1 was responsible for impacting ß-cell development. The relatively reduced α-cell area was associated with downregulated ARX expression. The transcription of Isn2 and Gcg in pancreatic tissue was downregulated, which indicated that the function of ß-cells and α-cells was impaired. Methylation levels in the Isn2 promotor were significantly elevated in mice prenatally exposed to 500 µg/kg PAHs, which was consistent with the change in its mRNA levels. The number of macrophages infiltrating islets was significantly increased, indicating that prenatal PAH exposure might reduce islet cell numbers in an autoimmune manner. This study shows that prenatal exposure to PAHs may promote the pathogenesis of type 1 diabetes mellitus.

Cross-species tropism and antigenic landscapes of circulating SARS-CoV-2 variants.

Mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) may alter viral host tropism and affect the activities of neutralizing antibodies. Here, we investigated 153 RBD mutants and 11 globally circulating variants of concern (VOCs) and variants of interest (VOIs) (including Omicron) for their antigenic changes and cross-species tropism in cells expressing 18 ACE2 orthologs. Several RBD mutations strengthened viral infectivity in cells expressing ACE2 orthologs of non-human animals, particularly those less susceptible to the ancestral strain. The mutations surrounding amino acids (aas) 439-448 and aa 484 are more likely to cause neutralization resistance. Strikingly, enhanced cross-species infection potential in the mouse and ferret, instead of the neutralization-escape scores of the mutations, account for the positive correlation with the cumulative prevalence of mutations in humans. These findings present insights for potential drivers of circulating SARS-CoV-2 variants and provide informative parameters for tracking and forecasting spreading mutations.