July 20, 2023

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Clinical Reports

Omicron subvariant BA.5 efficiently infects lung cells
The SARS-CoV-2 Omicron subvariants BA.1 and BA.2 exhibit reduced lung cell infection relative to previously circulating SARS-CoV-2 variants, which may account for their reduced pathogenicity. However, it is unclear whether lung cell infection by BA.5, which displaced these variants, remains attenuated. Here, researchers show that the spike (S) protein of BA.5 exhibits increased cleavage at the S1/S2 site and drives cell-cell fusion and lung cell entry with higher efficiency than its counterparts from BA.1 and BA.2. Increased lung cell entry depends on mutation H69Δ/V70Δ and is associated with efficient replication of BA.5 in cultured lung cells. Further, BA.5 replicates in the lungs of female Balb/c mice and the nasal cavity of female ferrets with much higher efficiency than BA.1. These results suggest that BA.5 has acquired the ability to efficiently infect lung cells, a prerequisite for causing severe disease, suggesting that evolution of Omicron subvariants can result in partial loss of attenuation.
A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection
Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, researchers enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. This discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. Researchers tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, researchers show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01–peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.
The immunology of long COVID
Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing–remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein–Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.

Antiviral Therapeutics and Vaccines

FDA Approved a New Drug to Prevent RSV in Babies and Toddlers
The U.S. Food and Drug Administration approved Beyfortus (nirsevimab-alip) for the prevention of Respiratory Syncytial Virus (RSV) lower respiratory tract disease in neonates and infants born during or entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.

Diagnostics

COVID-19 scent dog research highlights and synthesis during the pandemic of December 2019−April 2023
This review was undertaken to provide information concerning the advancement of research in the area of COVID-19 screening and testing during the worldwide pandemic from December 2019 through April 2023. In this review, researchers have examined the safety, effectiveness, and practicality of utilizing trained scent dogs in clinical and public situations for COVID-19 screening. Specifically, results of 29 trained scent dog screening peer-reviewed studies were compared with results of real-time reverse-transcription polymerase chain reaction (RT-PCR) and rapid antigen (RAG) COVID-19 testing methods. A total of 8,043 references were identified through this literature search. After removal of duplicates, there were 7,843 references that were screened. Of these, 100 were considered for full-text eligibility, 43 were included for qualitative synthesis, and 29 were utilized for quantitative analysis. The most relevant peer-reviewed COVID-19 scent dog references were identified and categorized. Utilizing all of the scent dog results provided for this review, researchers found that 92.3 % of the studies reached sensitivities exceeding 80 and 32.0 % of the studies exceeding specificities of 97 %. However, 84.0 % of the studies reported specificities above 90 %. Highlights demonstrating the effectiveness of the scent dogs include: (1) samples of breath, saliva, trachea-bronchial secretions and urine as well as face masks and articles of clothing can be utilized; (2) trained COVID-19 scent dogs can detect presymptomatic and asymptomatic patients; (3) scent dogs can detect new SARS-CoV-2 variants and Long COVID-19; and (4) scent dogs can differentiate SARS-CoV-2 infections from infections with other novel respiratory viruses. The effectiveness of the trained scent dog method is comparable to or in some cases superior to the real-time RT-PCR test and the RAG test. Trained scent dogs can be effectively utilized to provide quick (seconds to minutes), nonintrusive, and accurate results in public settings and thus reduce the spread of the COVID-19 virus or other viruses. Finally, scent dog research as described in this paper can serve to increase the medical community’s and public’s knowledge and acceptance of medical scent dogs as major contributors to global efforts to fight diseases.

Epidemiology

Transmission of SARS-CoV-2 in free-ranging white-tailed deer in the United States
SARS-CoV-2 is a zoonotic virus with documented bi-directional transmission between people and animals. Transmission of SARS-CoV-2 from humans to free-ranging white-tailed deer (Odocoileus virginianus) poses a unique public health risk due to the potential for reservoir establishment where variants may persist and evolve. Researchers collected 8,830 respiratory samples from free-ranging white-tailed deer across Washington, D.C. and 26 states in the United States between November 2021 and April 2022. Researchers obtained 391 sequences and identified 34 Pango lineages including the Alpha, Gamma, Delta, and Omicron variants. Evolutionary analyses showed these white-tailed deer viruses originated from at least 109 independent spillovers from humans, which resulted in 39 cases of subsequent local deer-to-deer transmission and three cases of potential spillover from white-tailed deer back to humans. Viruses repeatedly adapted to white-tailed deer with recurring amino acid substitutions across spike and other proteins. Overall, these findings suggest that multiple SARS-CoV-2 lineages were introduced, became enzootic, and co-circulated in white-tailed deer.
T-Cell Immunity Against Severe Acute Respiratory Syndrome Coronavirus 2 Measured by an Interferon-γ Release Assay Is Strongly Associated With Patient Outcomes in Vaccinated Persons Hospitalized With Delta or Omicron Variants
Researchers measured T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vaccinated patients hospitalized for coronavirus disease 2019 (COVID-19) and explored their potential value to predict outcomes. This was a prospective, longitudinal study including vaccinated patients hospitalized with Delta and Omicron SARS-CoV-2 variants. TrimericS-IgG antibodies and SARS-CoV-2 T-cell response were measured using a specific quantitative interferon-γ release assay (IGRA). Primary outcome was all-cause 28-day mortality or need for intensive care unit (ICU) admission. Cox models were used to assess associations with outcomes. Of 181 individuals, 158 (87.3%) had detectable SARS-CoV-2 antibodies, 92 (50.8%) showed SARS-CoV-2–specific T-cell responses, and 87 (48.1%) had both responses. Patients who died within 28 days or were admitted to ICU were less likely to have both unspecific and specific T-cell responses in IGRA. In adjusted analyses (adjusted hazard ratio [95% confidence interval]), for the entire cohort, having both T-cell and antibody responses at admission (0.16 [.05–.58]) and Omicron variant (0.38 [.17–.87]) reduced the hazard of 28-day mortality or ICU admission, whereas higher Charlson comorbidity index score (1.27 [1.07–1.51]) and lower oxygen saturation to fraction of inspired oxygen ratio (2.36 [1.51–3.67]) increased the risk. Preexisting immunity against SARS-CoV-2 is strongly associated with patient outcomes in vaccinated individuals requiring hospital admission for COVID-19. Persons showing both T-cell and antibody responses have the lowest risk of severe outcomes.