ABSTRACT
The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and related sub-lineages. Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants at two levels: (i) we tracked over 400,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using antibody pools. (ii) we mapped the antibody response at the individual level using blood from strigently curated vaccine and convalescent cohorts. In pooled antibody samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases we observed increased antibody breadth to variants that were yet to be in circulation. Resolution of viral neutralisation at the cohort level supported equivalent coverage across prior and emerging variants with emerging isolates BQ.1.1, XBB.1 and BR.2.1 the most evasive. Further, these emerging variants were resistant to Evusheld, whilst neutralization resistance to Sotrovimab was restricted to BQ.1.1 and further supported by lack of Spike glycoprotein binding to this variant. An outgrowth advantage through better utilization of TMPRSS2 was observed across BQ lineages and not those derived from BA.2.75. We conclude at this current point in time that variants derived from BQ lineages can evade antibodies at levels equivalent to their most evasive BA.2.75 counterparts but sustain an entry phenotype that would promote an additional outgrowth advantage.
ABSTRACT
Respiratory viruses such as coronaviruses represent major ongoing global threats, causing epidemics and pandemics with huge economic burden. Rapid spread of virus through populations poses an enormous challenge for outbreak control. Like all respiratory viruses, the most recent novel human coronavirus SARS-CoV-2, initiates infection in the upper respiratory tract (URT). Infected individuals are often asymptomatic, yet highly infectious and readily transmit virus. A therapy that restricts initial replication in the URT has the potential to prevent progression of severe lower respiratory tract disease as well as limiting person-to-person transmission. We show that prophylactic intra-nasal administration of the TLR2/6 agonist INNA-051 in a SARS-CoV-2 ferret infection model effectively reduces levels of viral RNA in the nose and throat. The results of our study support clinical development of a therapy based on prophylactic TLR2/6 innate immune activation in the URT to reduce SARS-CoV-2 transmission and provide protection against COVID-19.
ABSTRACT
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is a new rapidly spreading infectious disease. Early reports of hospitalised COVID-19 cases have shown relatively low frequency of chronic lung diseases such as chronic obstructive pulmonary disease (COPD) but increased risk of adverse outcome. The mechanisms of altered susceptibility to viral acquisition and/or severe disease in at-risk groups are poorly understood. Inhaled corticosteroids (ICS) are widely used in the treatment of COPD but the extent to which these therapies protect or expose patients with a COPD to risk of increased COVID-19 severity is unknown. Here, using a combination of human and animal in vitro and in vivo disease models, we show that ICS administration attenuates pulmonary expression of the SARS-CoV-2 viral entry receptor angiotensin-converting enzyme (ACE)-2. This effect was mechanistically driven by suppression of type I interferon as exogenous interferon-{beta} reversed ACE2 downregulation by ICS. Mice deficient in the type I interferon-/{beta} receptor (Ifnar1-/-) also had reduced expression of ACE2. Collectively, these data suggest that use of ICS therapies in COPD reduces expression of the SARS-CoV-2 entry receptor ACE2 and this effect may thus contribute to altered susceptibility to COVID-19 in patients with COPD.