Higher Delta variant-specific neutralizing antibodies prevented infection in close contacts vaccinated with ancestral mRNA vaccines during the SARS-CoV-2 Delta wave.

Identification of the risk factors and the high-risk groups which are most vulnerable is critical in COVID-19 disease management at a population level. Evaluating the efficacy of vaccination against infections is necessary to determine booster vaccination strategies for better protection in high-risk groups. In this study, we recruited 158 mRNA-vaccinated individuals during the Delta wave of SARS-CoV-2 infections in Singapore and examined the antibody profiles of infected individuals. We found that, despite high exposure due to communal living conditions in proximity, 4% of individuals (6/158) had PCR-confirmed infections and 96% (152/158) remained uninfected. Time-course analysis of the antibody profile at the start and the end of quarantine period showed Delta-specific boosting of anti-spike antibody response in 57% of the uninfected individuals (86/152). In the remaining 43% of the uninfected individuals (66/152) with no Delta-specific antibody boost, we found a higher Delta-specific antibody response at the start of quarantine period, which correlated with higher Delta pseudovirus neutralizing capacity. Our findings indicate that a higher basal variant-specific antibody response in the mRNA-vaccinated individuals contributes to better protection against infections by the new emerging SARS-CoV-2 variants.

Tumor-mediated microbiota alteration impairs synaptic tagging/capture in the hippocampal CA1 area via IL-1ß production.

Cancer patients often experience impairments in cognitive function. However, the evidence for tumor-mediated neurological impairment and detailed mechanisms are still lacking. Gut microbiota has been demonstrated to be involved in the immune system homeostasis and brain functions. Here we find that hepatocellular carcinoma (HCC) growth alters the gut microbiota and impedes the cognitive functions. The synaptic tagging and capture (STC), an associative cellular mechanism for the formation of associative memory, is impaired in the tumor-bearing mice. STC expression is rescued after microbiota sterilization. Transplantation of microbiota from HCC tumor-bearing mice induces similar STC impairment in wide type mice. Mechanistic study reveals that HCC growth significantly elevates the serum and hippocampus IL-1ß levels. IL-1ß depletion in the HCC tumor-bearing mice restores the STC. Taken together, these results demonstrate that gut microbiota plays a crucial role in mediating the tumor-induced impairment of the cognitive function via upregulating IL-1ß production.

Comprehensive engineering of a therapeutic neutralizing antibody targeting SARS-CoV-2 spike protein to neutralize escape variants.

The emergence of escape variants of SARS-CoV-2 carrying mutations in the spike protein poses a challenge for therapeutic antibodies. Here, we show that through the comprehensive engineering of the variable region of the neutralizing monoclonal antibody 5A6, the engineered antibody, 5A6CCS1, is able to neutralize SARS-CoV-2 variants that escaped neutralization by the original 5A6 antibody. In addition to the improved affinity against variants, 5A6CCS1 was also optimized to achieve high solubility and low viscosity, enabling a high concentration formulation for subcutaneous injection. In cynomolgus monkeys, 5A6CCS1 showed a long plasma half-life and good subcutaneous bioavailability through engineering of the variable and constant region. These data demonstrate that 5A6CCS1 is a promising antibody for development against SARS-CoV-2 and highlight the importance of antibody engineering as a potential method to counteract escape variants.