Key questions in COVID-19 are the duration and determinants of infectious virus shedding. Here, we report that infectious virus shedding is detected by virus cultures in 23 of the 129 patients ...(17.8%) hospitalized with COVID-19. The median duration of shedding infectious virus is 8 days post onset of symptoms (IQR 5-11) and drops below 5% after 15.2 days post onset of symptoms (95% confidence interval (CI) 13.4-17.2). Multivariate analyses identify viral loads above 7 log
RNA copies/mL (odds ratio OR of 14.7 (CI 3.57-58.1; p < 0.001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract. A serum neutralizing antibody titre of at least 1:20 (OR of 0.01 (CI 0.003-0.08; p < 0.001) is independently associated with non-infectious SARS-CoV-2. We conclude that quantitative viral RNA load assays and serological assays could be used in test-based strategies to discontinue or de-escalate infection prevention and control precautions.
The lymph nodes (LNs) and spleen have an optimal structure that allows the interaction between T cells, B cells and antigen-presenting dendritic cells (DCs) on a matrix made up by stromal cells. Such ...a highly organized structure can also be formed in tertiary lymphoid organs (TLOs) at sites of infection or chronic immune stimulation. This review focuses on the molecular mechanisms of TLO formation and maintenance, the controversies surrounding the nature of the inducing events, and the functions of these structures in infection, transplantation and autoimmunity.
Patients with cancer have a higher risk of severe coronavirus disease (COVID-19) and associated mortality than the general population. Owing to this increased risk, patients with cancer have been ...prioritized for COVID-19 vaccination globally, for both primary and booster vaccinations. However, given that these patients were not included in the pivotal clinical trials, considerable uncertainty remains regarding vaccine efficacy, and the extent of humoral and cellular immune responses in these patients, as well as the risks of vaccine-related adverse events. In this Review, we summarize the current knowledge generated in studies conducted since COVID-19 vaccines first became available. We also highlight critical points that might affect vaccine efficacy in patients with cancer in the future.
Based on seroconversion rates on day 43 in adults aged 30 years and older, VLA2001 was non-inferior to ChAdOx1-S (both led to >95% seroconversion), but VLA2001 induced superior neutralising antibody ...titres (geometric mean titre GMT 803·5 95% CI 748·5–862·6 in the VLA2001 group vs 576·6 543·6–611·7 in the ChAdOx1-S group; GMT ratio 1·39 95% CI 1·25–1·56; p<0·0001). Because of the geographical differences in the use of mRNA-based or vector-based vaccines compared with inactivated vaccines, clinical trials making direct comparisons between multiple vaccine platforms are extremely rare, making this study by Lazarus and colleagues unique. Notably, polyclonal T-cell responses do not seem to be affected by the mutations detected to date in the S protein, whereas these mutations do lead to at least partial escape from neutralising antibodies, making standardised T-cell assessments even more important.4,5 Unfortunately, to date, clinical trials addressing the crucial endpoints we propose have not been performed for whole-virus inactivated vaccines. ...the report of a phase 2 trial in which a third dose of CoronaVac was administered to CoronaVac-primed individuals clearly showed immunological recall responses but did not include an analysis of variant-specific antibodies or virus-specific T cells.6 In a direct comparison between BNT162b2 and CoronaVac booster vaccination in CoronaVac-primed individuals, restoration of omicron (B.1.1.529) BA.1 neutralisation was observed after BNT162b2 booster immunisation but not after a third dose of CoronaVac; again, virus-specific T-cell responses were not measured.7 Taken together, VLA2001 can be regarded a promising addition to the arsenal of COVID-19 vaccines.
Animal experiments have shown that nonhuman primates, cats, ferrets, hamsters, rabbits, and bats can be infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, ...SARS-CoV-2 RNA has been detected in felids, mink, and dogs in the field. Here, we describe an in-depth investigation using whole-genome sequencing of outbreaks on 16 mink farms and the humans living or working on these farms. We conclude that the virus was initially introduced by humans and has since evolved, most likely reflecting widespread circulation among mink in the beginning of the infection period, several weeks before detection. Despite enhanced biosecurity, early warning surveillance, and immediate culling of animals in affected farms, transmission occurred between mink farms in three large transmission clusters with unknown modes of transmission. Of the tested mink farm residents, employees, and/or individuals with whom they had been in contact, 68% had evidence of SARS-CoV-2 infection. Individuals for which whole genomes were available were shown to have been infected with strains with an animal sequence signature, providing evidence of animal-to-human transmission of SARS-CoV-2 within mink farms.
Middle East respiratory syndrome coronavirus (MERS-CoV) infections in humans can cause asymptomatic to fatal lower respiratory lung disease. Despite posing a probable risk for virus transmission, ...asymptomatic to mild infections can go unnoticed; a lack of seroconversion among some PCR-confirmed cases has been reported. We found that a MERS-CoV spike S1 protein-based ELISA, routinely used in surveillance studies, showed low sensitivity in detecting infections among PCR-confirmed patients with mild clinical symptoms and cross-reactivity of human coronavirus OC43-positive serum samples. Using in-house S1 ELISA and protein microarray, we demonstrate that most PCR-confirmed MERS-CoV case-patients with mild infections seroconverted; nonetheless, some of these samples did not have detectable levels of virus-neutralizing antibodies. The use of a sensitive and specific serologic S1-based assay can be instrumental in the accurate estimation of MERS-CoV prevalence.
SARS-CoV-2, the causative agent of COVID-19
, features a receptor-binding domain (RBD) for binding to the host cell ACE2 protein
. Neutralizing antibodies that block RBD-ACE2 interaction are ...candidates for the development of targeted therapeutics
. Llama-derived single-domain antibodies (nanobodies, ~15 kDa) offer advantages in bioavailability, amenability, and production and storage owing to their small sizes and high stability. Here, we report the rapid selection of 99 synthetic nanobodies (sybodies) against RBD by in vitro selection using three libraries. The best sybody, MR3 binds to RBD with high affinity (K
= 1.0 nM) and displays high neutralization activity against SARS-CoV-2 pseudoviruses (IC
= 0.42 μg mL
). Structural, biochemical, and biological characterization suggests a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency have been generated by structure-based design, biparatopic construction, and divalent engineering. Two divalent forms of MR3 protect hamsters from clinical signs after live virus challenge and a single dose of the Fc-fusion construct of MR3 reduces viral RNA load by 6 Log
. Our results pave the way for the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid development of targeted medical interventions during an outbreak.
In kidney patients COVID-19 is associated with severely increased morbidity and mortality. A comprehensive comparison of the immunogenicity, tolerability, and safety of COVID-19 vaccination in ...different cohorts of kidney patients and a control cohort is lacking.
This investigator driven, prospective, controlled multicenter study included 162 participants with chronic kidney disease (CKD) stages G4/5 (eGFR < 30 mL/min/1.73m2), 159 participants on dialysis, 288 kidney transplant recipients, and 191 controls. Participants received 2 doses of the mRNA-1273 COVID-19 vaccine (Moderna). The primary endpoint was seroconversion.
Transplant recipients had a significantly lower seroconversion rate when compared with controls (56.9% versus 100%, P < 0.001), with especially mycophenolic acid, but also, higher age, lower lymphocyte concentration, lower eGFR, and shorter time after transplantation being associated with nonresponder state. Transplant recipients also showed significantly lower titers of neutralizing antibodies and T-cell responses when compared with controls. Although a high seroconversion rate was observed for participants with CKD G4/5 (100%) and on dialysis (99.4%), mean antibody concentrations in the CKD G4/5 cohort and dialysis cohort were lower than in controls (2405 interquartile interval 1287-4524 and 1650 698-3024 versus 3186 1896-4911 BAU/mL, P = 0.06 and P < 0.001, respectively). Dialysis patients and especially kidney transplant recipients experienced less systemic vaccination related adverse events. No specific safety issues were noted.
The immune response following vaccination in patients with CKD G4/5 and on dialysis is almost comparable to controls. In contrast, kidney transplant recipients have a poor response. In this latter, patient group development of alternative vaccination strategies are warranted.
During a meeting in Munich, Germany, a presymptomatic attendee with severe acute respiratory syndrome coronavirus 2 infected at least 11 of 13 other participants. Although 5 participants had no or ...mild symptoms, 6 had typical coronavirus disease, without dyspnea. Our findings suggest hand shaking and face-to-face contact as possible modes of transmission.
More than 88 000 laboratory-confirmed human monkeypoxvirus (hMPXV) infections were reported in the 2022–23 global mpox (formerly known as monkeypox) outbreak, which presented substantial challenges ...to public health systems worldwide.1,2 In response, various interventions were implemented; these included initiatives aimed at reducing transmission among groups at high risk, as well as therapeutic and prophylactic medical interventions. ...generation smallpox vaccines such as the Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN; also known as IMVANEX, IMVAMUNE, or JYNNEOS) were rapidly administered to sexually active men who have sex with men (MSM), who were primarily affected by the outbreak,2 to protect against mpox disease. Nonetheless, although this case series is the most extensive reported to date, only a small number of cases was described. Because our understanding of mpox disease reporting is limited, it has to be kept in mind that this reported difference could have been affected by inaccurate reporting, both during the 2022–23 outbreak, in which many mild or asymptomatic cases were likely missed, and during this period of vigilance, in which cases in individuals with previous immunity are probably reported.
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