ABSTRACT
The emergence of the Omicron variant of SARS-CoV-2 represented a challenge to the treatment of COVID-19 with monoclonal antibodies. Only Sotrovimab maintained partial activity, allowing it to be used in high-risk patients infected with the Omicron variant. However, the reports of resistance mutations to Sotrovimab call for efforts to better understand the intra-patient emergence of this resistance. A retrospective genomic analysis was conducted on respiratory samples from immunocompromised patients infected with SARS-CoV-2 who received Sotrovimab at our hospital between December 2021 and August 2022. The study involved 95 sequential specimens from 22 patients (1-12 samples/patient; 3-107 days post-infusion (Ct [≤] 32)). Resistance mutations (in P337, E340, K356, and R346) were detected in 68% of cases; the shortest time to detection of a resistance mutation was 5 days after Sotrovimab infusion. The dynamics of resistance acquisition were highly complex, with up to 11 distinct amino acid changes in specimens from the same patient. In two patients, the mutation distribution was compartmentalized in respiratory samples from different sources. This is the first study to examine the acquisition of resistance to Sotrovimab in the BA.5 lineage, enabling us to determine the lack of genomic or clinical differences between Sotrovimab resistance in BA.5 relative to BA.1/2. Across all Omicron lineages, the acquisition of resistance delayed SARS-CoV-2 clearance (40.67 vs 19.5 days). Close, real-time genomic surveillance of patients receiving Sotrovimab should be mandatory to facilitate early therapeutic interventions.
Subject(s)
COVID-19ABSTRACT
Background Outbreak strains are good candidates to look for intrinsic transmissibility as they are responsible for a large number of cases with sustained transmission. However, assessment of the success of long-lived outbreak strains has been flawed by the use of low-resolution typing methods and restricted geographical investigations. We now have the potential to address the nature of outbreak strains by combining large genomic datasets and phylodynamic approaches. Methods We retrospectively sequenced the whole genome of representative samples assigned to an outbreak circulating in the Canary Islands (GC) since 1993; accounting for ∼20% of local TB cases. We selected a panel of specific SNP markers to in-silico search for additional outbreak related sequences within publicly-available TB genomic data. Using this information we inferred the origin, spread and epidemiological parameters of the GC-outbreak. Findings Our approach allowed us to accurately trace both the historical and recent dispersion of the strain. We evidenced its high success within the Canarian archipelago but found a limited expansion abroad. Estimation of epidemiological parameters from genomic data contradicts a distinct biology of the GC-strain. Interpretation With the increasing availability of genomic data allowing for an accurate inference of strain spread and key epidemiological parameters, we can now revisit the link between Mycobacterium tuberculosis genotypes and transmission, as routinely done for SARS-CoV-2 variants of concern. We show that the success of the GC-strain is better explained by social determinants rather than intrinsically higher bacterial transmissibility. Our approach can be used to trace and characterize strains of interest worldwide. Funding European Research Council (101001038-TB-RECONNECT), the Ministerio de Economía, Industria y Competitividad (PID2019-104477RB-I00), Instituto de Salud Carlos III (FIS18/0336), European Commission –NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global) to IC. Gobierno de Aragón/Fondo Social Europeo “Construyendo Europa desde Aragón” to SS Research in context Evidence before this study Identification of intrinsically highly transmissible strains of Mycobacterium tuberculosis remains elusive. Among candidates are those strains that have been thriving in a community for decades representing a significant contribution to the long-term local TB burden. These long-lived outbreak strains have been identified in different parts of the world and the speculation is that their success is linked to higher transmissibility. Several studies have attempted to analyze the epidemiological characteristics of these strains as well as their genomic composition to look for potential transmission determinants. However those studies are usually circunscribe to their original geographic boundaries. By contrast, this transmissibility should be replicated in different parts of the world, a lesson learnt from SARS-CoV-2 variants of concern. Previous attempts failed to examine the success of these outbreak strains at a global scale. Thus, it is unknown whether the long-lived outbreak strains had a similar or different trajectory in other countries, casting doubts about their transmissibility potential. Added value of this study Here we analyzed a strain causing a long-lived outbreak in the Canary Islands since 1993 using whole genome sequencing. As in previous studies with other similar outbreak strains, we analyzed the diversity and phylodynamics of the outbreak in the area where it was originally described. However, thanks to the possibility of interrogating the entire European Nucleotide Archive, we had the unique chance to look at the spread of the strains beyond its original geographic boundaries. This approach allowed us to comprehensively trace the real spatio-temporal spread of the outbreak from the emergence of its ancestor about 700 years ago to its recent transmission outside the Canary Islands. As a result, there is limited evidence for similar success of the strains outside Canary Islands. Furthermore, we complemented the analysis with epidemiological data of the early cases and with phylodynamic analysis to estimate key epidemiological parameters linked to the strain spread. All evidence strongly suggests that factors related to the host, instead of the bacteria, are behind the persistence and expansion of the outbreak strain. Implications of all the available evidence Infectious disease outbreaks are a major problem for public health. Tracing outbreak expansion and knowing the main factors behind their emergence and persistence are key to an effective disease control. Our study allows researchers and public health authorities to use WGS-based methods to trace outbreaks, and include available epidemiological information to evaluate the factors underpinning outbreak persistence. Taking advantage of all the information freely available in public repositories, researchers can accurately establish the expansion of the outbreak behind its original boundaries; and they can determine the potential risk of the strain to inform health authorities which, in turn, can define target strategies to mitigate its expansion and persistence. Finally, we show the need to evaluate strain transmissibility in different geographic contexts to unequivocally associate its spread to local or pathogen factors, a major lesson taken from SARS-CoV-2 genomic surveillance.
Subject(s)
TuberculosisABSTRACT
We report a COVID-19 case with unprecedented viral complexity. In the first severe episode, two different SARS-CoV-2 strains (superinfection) were identified within a week. Three months after discharge, patient was readmitted and was infected in a nosocomial outbreak with a different strain, suffering a second milder COVID-19 episode.
Subject(s)
COVID-19ABSTRACT
SARS-CoV-2 nosocomial outbreaks in the first COVID-19 wave were likely associated to a shortage of personal protective equipment and scare indications on control measures. Having covered these limitations, updates on current SARS-CoV-2 nosocomial outbreaks are required. We carried out an in-depth analysis of a 27-day nosocomial outbreak in a gastroenterology ward in our hospital, potentially involving 15 patients and three healthcare workers. Patients had stayed in one of three neighbouring rooms in the ward. The severity of the infections in six of the cases and a high fatality rate suggested the possible involvement of a single virulent strain persisting in those rooms. Whole genome sequencing of the strains from 12 patients and one healthcare worker revealed an unexpected complexity. Five different SARS-CoV-2 strains were identified, two infecting a single patient each, ruling out their relationship with the outbreak; the remaining three strains were involved in three independent overlapping limited transmission clusters with three, three, and five cases. Whole genome sequencing was key to understand the complexity of this outbreak.
Subject(s)
COVID-19ABSTRACT
The COVID-19 pandemic has shaken the world since the beginning of 2020. Spain is among the European countries with the highest incidence of the disease during the first pandemic wave. We established a multidisciplinar consortium to monitor and study the evolution of the epidemic, with the aim of contributing to decision making and stopping rapid spreading across the country. We present the results for 2170 sequences from the first wave of the SARS-Cov-2 epidemic in Spain and representing 12% of diagnosed cases until 14th March. This effort allows us to document at least 500 initial introductions, between early February-March from multiple international sources. Importantly, we document the early raise of two dominant genetic variants in Spain (Spanish Epidemic Clades), named SEC7 and SEC8, likely amplified by superspreading events. In sharp contrast to other non-Asian countries those two variants were closely related to the initial variants of SARS-CoV-2 described in Asia and represented 40% of the genome sequences analyzed. The two dominant SECs were widely spread across the country compared to other genetic variants with SEC8 reaching a 60% prevalence just before the lockdown. Employing Bayesian phylodynamic analysis, we inferred a reduction in the effective reproductive number of these two SECs from around 2.5 to below 0.5 after the implementation of strict public-health interventions in mid March. The effects of lockdown on the genetic variants of the virus are reflected in the general replacement of preexisting SECs by a new variant at the beginning of the summer season. Our results reveal a significant difference in the genetic makeup of the epidemic in Spain and support the effectiveness of lockdown measures in controlling virus spread even for the most successful genetic variants. Finally, earlier control of SEC7 and particularly SEC8 might have reduced the incidence and impact of COVID-19 in our country.
Subject(s)
COVID-19ABSTRACT
The first descriptions of reinfection by SARS-CoV-2 have been recently reported. However, these studies focus exclusively on the reinfected case, without considering the epidemiological context of the event. We present the first complete analysis of the epidemiological scenario around a reinfection by SARS-CoV-2, including three cases preceding the reinfection, the reinfected case per se, and the subsequent transmission to another seven cases. Our analysis is supported by host genetics, viral whole genome sequencing, phylogenomic population analysis, and refined epidemiological data obtained from in-depth interviews with the involved subjects. The reinfection involved a 53-year-old woman with asthma, with a first COVID-19 episode in April 2020 and a much more severe second episode four months and a half later, with COVID-19 seroconversion in August, and requiring hospital admission.