Enhancing SARS-CoV-2 Surveillance through Regular Genomic Sequencing in Spain: The RELECOV Network.

Millions of SARS-CoV-2 whole genome sequences have been generated to date. However, good quality data and adequate surveillance systems are required to contribute to meaningful surveillance in public health. In this context, the network of Spanish laboratories for coronavirus (RELECOV) was created with the main goal of promoting actions to speed up the detection, analyses, and evaluation of SARS-CoV-2 at a national level, partially structured and financed by an ECDC-HERA-Incubator action (ECDC/GRANT/2021/024). A SARS-CoV-2 sequencing quality control assessment (QCA) was developed to evaluate the network's technical capacity. QCA full panel results showed a lower hit rate for lineage assignment compared to that obtained for variants. Genomic data comprising 48,578 viral genomes were studied and evaluated to monitor SARS-CoV-2. The developed network actions showed a 36% increase in sharing viral sequences. In addition, analysis of lineage/sublineage-defining mutations to track the virus showed characteristic mutation profiles for the Delta and Omicron variants. Further, phylogenetic analyses strongly correlated with different variant clusters, obtaining a robust reference tree. The RELECOV network has made it possible to improve and enhance the genomic surveillance of SARS-CoV-2 in Spain. It has provided and evaluated genomic tools for viral genome monitoring and characterization that make it possible to increase knowledge efficiently and quickly, promoting the genomic surveillance of SARS-CoV-2 in Spain.

RNA loads of severe acute respiratory syndrome coronavirus 2 in patients with breakthrough coronavirus disease 2019 caused by the Delta and Omicron variants.

OBJECTIVES: To compare the RNA loads of severe acute respiratory syndrome coronavirus 2 in nasopharyngeal specimens collected from patients with breakthrough coronavirus disease 2019 (COVID-19) caused by the Delta variant with those in specimens collected from patients with breakthrough COVID-19 caused by the Omicron variant. METHODS: A retrospective, observational study was conducted, including 240 consecutive adult out-patients, of whom 121 (74 females; median age, 40 years) had COVID-19 due to the Omicron variant and 119 (65 females; median age, 48 years) had COVID-19 caused by the Delta variant. The viral RNA load was quantitated using the TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific, Waltham, MS, USA). The viability platinum chloride reverse transcription-PCR assay was used to discriminate between potentially infectious viral particles and free (encapsidated) viral RNA. RESULTS: Overall, the viral RNA loads were significantly higher (p 0.003) for the Omicron variant (median, 8.1 log10 copies/mL; range, 4.0-10.9 log10 copies/mL) than for the Delta variant (median, 7.5 log10 copies/mL; range, 3.0-11.6 log10 copies/mL). A trend towards higher viral loads was noticed for Omicron compared with that for Delta across the following time frames since vaccination: 16-90 days (median, 6.83 vs. 5.88 log10 copies/mL, respectively; range, 3.91-10.68 vs. 3.67-9.66 log10 copies/mL, respectively; p 0.10), 91-180 days (median, 8.09 vs. 7.46 log10 copies/mL, respectively; range, 4.30-10.92 vs. 3.03-11.56 log10 copies/mL, respectively; p 0.003) and 181-330 days (median, 8.56 vs. 8.10 log10 copies/mL, respectively; range, 6.51-10.29 vs. 3.03-10.61 log10 copies/mL, respectively; p 0.11). The platinum chloride treated or untreated reverse transcription-PCR cycle threshold ratio for the nucleocapsid gene as the target was slightly higher for Omicron than for Delta (median, 0.62 vs. 0.57, respectively; range, 0.57-0.98 vs. 0.61-0.87, respectively), although statistical significance was not reached (p 0.10). CONCLUSION: The time elapsed since vaccination has a major impact on the RNA loads of severe acute respiratory syndrome coronavirus 2 in nasopharyngeal specimens, particularly for the Omicron variant. The Omicron variant may be better adapted for replication in the upper respiratory tract than the Delta variant, in which this is unlikely given its more efficient generation of viral particles.

Epidemiological and Genomic Analysis of a Large SARS-CoV-2 Outbreak in a Long-Term Care Facility in Catalonia, Spain.

Limiting outbreaks in long-term care facilities (LTCFs) is a cornerstone strategy to avoid an excess of COVID-19-related morbidity and mortality and to reduce its burden on the health system. We studied a large outbreak that occurred at an LTCF, combining methods of classical and genomic epidemiology analysis. The outbreak lasted for 31 days among residents, with an attack rate of 98% and 57% among residents and staff, respectively. The case fatality rate among residents was 16% (n = 15). Phylogenetic analysis of 59 SARS-CoV-2 isolates revealed the presence of two closely related viral variants in all cases (B.1.177 lineage), revealing a far more complex outbreak than initially thought and suggesting an initial spread driven by staff members. In turn, our results suggest that resident relocations to mitigate viral spread might have increased the risk of infection for staff members, creating secondary chains of transmission that were responsible for prolonging the outbreak. Our results highlight the importance of considering unnoticed chains of transmission early during an outbreak and making an adequate use and interpretation of diagnostic tests. Outbreak containment measures should be carefully tailored to each LTCF. IMPORTANCE The impact of COVID-19 on long-term care facilities (LTCFs) has been disproportionately large due to the high frailty of the residents. Here, we report epidemiological and genomic findings of a large outbreak that occurred at an LTCF, which ultimately affected almost all residents and nearly half of staff members. We found that the outbreak was initially driven by staff members; however, later resident relocation to limit the outbreak resulted in transmission from residents to staff members, evidencing the complexity and different phases of the outbreak. The phylogenetic analysis of SARS-CoV-2 isolates indicated that two closely related variants were responsible for the large outbreak. Our study highlights the importance of combining methods of classical and genomic epidemiology to take appropriate outbreak containment measures in LTCFs.

SARS-CoV-2 RNA load in nasopharyngeal specimens from outpatients with breakthrough COVID-19 due to Omicron BA.1 and BA.2.

This retrospective observational study compared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA load in nasopharyngeal specimens (NPs) from patients with breakthrough coronavirus disease 2019 (COVID-19) caused by the Omicron BA.1 or BA.2 sublineages. The convenience sample was composed of 277 outpatients (176 female/112 male; median age, 48 years; range, 12-97) with breakthrough COVID-19 (n = 130 due to BA.1 and n = 147 due to BA.2). All participants had completed a full vaccination schedule and 56% had received a booster vaccine dose at the time of COVID-19 breakthrough microbiological diagnosis. NPs were collected within 7 days (median 2 days) after symptom onset. The TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific) was used to estimate viral loads in NPs. Overall, viral RNA loads in NPs were comparable (p = 0.31) for BA.1 (median, 7.1 log10 copies/ml; range, 2.7-10.6) and BA.2 (median, 7.5 log10 copies/ml; range, 2.7-10.6), yet peak viral load appeared to be reached sooner for BA.2 than for BA.1 (Day 1 vs. Days 3-5; p = 0.002). Time elapsed since last vaccine dose had no significant impact on SARS-CoV-2 RNA loads in the upper respiratory tract (URT) for either BA.1 or BA.2. The data presented do not support that the transmissibility advantage of BA.2 over BA.1 is related to generation of higher viral loads in the URT early after infection.

A Genomic Snapshot of the SARS-CoV-2 Pandemic in the Balearic Islands.

Objective: To analyze the SARS-CoV-2 genomic epidemiology in the Balearic Islands, a unique setting in which the course of the pandemic has been influenced by a complex interplay between insularity, severe social restrictions and tourism travels. Methods: Since the onset of the pandemic, more than 2,700 SARS-CoV-2 positive respiratory samples have been randomly selected and sequenced in the Balearic Islands. Genetic diversity of circulating variants was assessed by lineage assignment of consensus whole genome sequences with PANGOLIN and investigation of additional spike mutations. Results: Consensus sequences were assigned to 46 different PANGO lineages and 75% of genomes were classified within a VOC, VUI, or VUM variant according to the WHO definitions. Highest genetic diversity was documented in the island of Majorca (42 different lineages detected). Globally, lineages B.1.1.7 and B.1.617.2/AY.X were identified as the 2 major lineages circulating in the Balearic Islands during the pandemic, distantly followed by lineages B.1.177/B.1.177.X. However, in Ibiza/Formentera lineage distribution was slightly different and lineage B.1.221 was the third most prevalent. Temporal distribution analysis showed that B.1 and B.1.5 lineages dominated the first epidemic wave, lineage B.1.177 dominated the second and third, and lineage B.1.617.2 the fourth. Of note, lineage B.1.1.7 became the most prevalent circulating lineage during first half of 2021; however, it was not associated with an increased in COVID-19 cases likely due to severe social restrictions and limited travels. Additional spike mutations were rarely documented with the exception of mutation S:Q613H which has been detected in several genomes (n = 25) since July 2021. Conclusion: Virus evolution, mainly driven by the acquisition and selection of spike substitutions conferring biological advantages, social restrictions, and size population are apparently key factors for explaining the epidemic patterns registered in the Balearic Islands.

SARS-CoV-2 Omicron BA.1 variant breakthrough infections in nursing home residents after an homologous third dose of the Comirnaty® COVID-19 vaccine: Looking for correlates of protection.

We investigated whether peripheral blood levels of SARS-CoV-2 Spike (S) receptor binding domain antibodies (anti-RBD), neutralizing antibodies (NtAb) targeting Omicron S, and S-reactive-interferon (IFN)-γ-producing CD4+ and CD8+ T cells measured after a homologous booster dose (3D) with the Comirnaty® vaccine was associated with the likelihood of subsequent breakthrough infections due to the Omicron variant. An observational study including 146 nursing home residents (median age, 80 years; range, 66-99; 109 female) evaluated for an immunological response after 3D (at a median of 16 days). Anti-RBD total antibodies were measured by chemiluminescent immunoassay. NtAb were quantified by an Omicron S pseudotyped virus neutralization assay. SARS-CoV-2-S specific-IFNγ-producing CD4+ and CD8+ T cells were enumerated by whole-blood flow cytometry for intracellular cytokine staining. In total, 33/146 participants contracted breakthrough Omicron infection (symptomatic in 30/33) within 4 months after 3D. Anti-RBD antibody levels were comparable in infected and uninfected participants (21 123 vs. 24 723 BAU/ml; p = 0.34). Likewise, NtAb titers (reciprocal IC50 titer, 157 vs. 95; p = 0.32) and frequency of virus-reactive CD4+ (p = 0.82) and CD8+ (p = 0.91) T cells were similar across participants in both groups. anti-RBD antibody levels and NtAb titers estimated at around the time of infection were also comparable (3445 vs. 4345 BAU/ml; p = 0.59 and 188.5 vs. 88.9; p = 0.70, respectively). Having detectable NtAb against Omicron or SARS-CoV-2-S-reactive-IFNγ-producing CD4+ or CD8+ T cells after 3D was not correlated with increased protection from breakthrough infection (OR, 1.50; p = 0.54; OR, 0.0; p = 0.99 and OR 3.70; p = 0.23, respectively). None of the immune parameters evaluated herein, including NtAb titers against the Omicron variant, may reliably predict at the individual level the risk of contracting COVID-19 due to the Omicron variant in nursing home residents.

The International Virus Bioinformatics Meeting 2022.

The International Virus Bioinformatics Meeting 2022 took place online, on 23-25 March 2022, and has attracted about 380 participants from all over the world. The goal of the meeting was to provide a meaningful and interactive scientific environment to promote discussion and collaboration and to inspire and suggest new research directions and questions. The participants created a highly interactive scientific environment even without physical face-to-face interactions. This meeting is a focal point to gain an insight into the state-of-the-art of the virus bioinformatics research landscape and to interact with researchers in the forefront as well as aspiring young scientists. The meeting featured eight invited and 18 contributed talks in eight sessions on three days, as well as 52 posters, which were presented during three virtual poster sessions. The main topics were: SARS-CoV-2, viral emergence and surveillance, virus-host interactions, viral sequence analysis, virus identification and annotation, phages, and viral diversity. This report summarizes the main research findings and highlights presented at the meeting.

SARS-CoV-2 Delta-variant breakthrough infections in nursing home residents at midterm after Comirnaty® COVID-19 vaccination.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant breakthrough infections in nursing home residents following vaccination with Comirnaty® COVID-19 vaccine were characterized. In total, 201 participants (median age, 87 years; range, 64-100; 133 female) from two nursing homes in the Valencian community (Spain) were included. SARS-CoV-2-Spike (S) antibody responses were determined by a lateral flow immunocromatography (LFIC) assay and by quantitative electrochemiluminescent assay in LFIC-negative participants. SARS-CoV-2-S-IFNγ T cells were enumerated by flow cytometry in 10 participants. Nasopharyngeal SARS-CoV-2 RNA loads were quantified by real-time polymerase chain reaction assays. Vaccine breakthrough COVID-19 due to the Delta variant occurred in 39 residents (median age, 87 years; range, 69-96; 31 female) at a median of 6.5 months after vaccination (nine requiring hospitalization). Breakthrough infections occurred at a higher rate (p < 0.0001) in residents who had not been previously infected with SARS-CoV-2 (naïve) (33/108; 18%) than in those with prior diagnosis of SARS-CoV-2 infection (experienced) (6/93; 6.4%), and were more likely (p < 0.0001) to develop in residents who tested negative by LFIC (20/49) at 3 months after vaccination as compared to their LFIC-positive counterparts (19/142). Among LFIC-negative residents, a trend towards lower plasma anti-RBD antibody levels was noticed in those developing breakthrough infection (p = 0.16). SARS-CoV-2 RNA loads in nasopharyngeal specimens were lower in SARS-CoV-2-experienced residents (p < 0.001) and in those testing positive by LFIC (p = 0.13). The frequency of SARS-CoV-2-S-reactive T cells at 3 months was similar in LFIC-negative residents with (n = 7) or without (n = 3) breakthrough infection. Prior history of SARS-CoV-2 infection and detection of S-reactive antibodies by LFIC at 3 months is associated with a lower risk of Delta-variant breakthrough infection in nursing home residents at midterm after Comirnaty® COVID-19 vaccination.

Systematic Genomic and Clinical Analysis of Severe Acute Respiratory Syndrome Coronavirus 2 Reinfections and Recurrences Involving the Same Strain.

Estimates of the burden of severe acute respiratory syndrome coronavirus 2 reinfections are limited by the scarcity of population-level studies incorporating genomic support. We conducted a systematic study of reinfections in Madrid, Spain, supported by genomic viral analysis and host genetic analysis, to cleanse laboratory errors and to discriminate between reinfections and recurrences involving the same strain. Among the 41,195 cases diagnosed (March 2020-March 2021), 93 (0.23%) had 2 positive reverse transcription PCR tests (55-346 days apart). After eliminating cases with specimens not stored, of suboptimal sequence quality, or belonging to different persons, we obtained valid data from 22 cases. Of those, 4 (0.01%) cases were recurrences involving the same strain; case-patients were 39-93 years of age, and 3 were immunosuppressed. Eighteen (0.04%) cases were reinfections; patients were 19-84 years of age, and most had no relevant clinical history. The second episode was more severe in 8 cases.

Evolutionary and Phenotypic Characterization of Two Spike Mutations in European Lineage 20E of SARS-CoV-2.

We have detected two mutations in the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at amino acid positions 1163 and 1167 that appeared independently in multiple transmission clusters and different genetic backgrounds. Furthermore, both mutations appeared together in a cluster of 1,627 sequences belonging to clade 20E. This cluster is characterized by 12 additional single nucleotide polymorphisms but no deletions. The available structural information on the S protein in the pre- and postfusion conformations predicts that both mutations confer rigidity, which could potentially decrease viral fitness. Accordingly, we observed reduced infectivity of this spike genotype relative to the ancestral 20E sequence in vitro, and the levels of viral RNA in nasopharyngeal swabs were not significantly higher. Furthermore, the mutations did not impact thermal stability or antibody neutralization by sera from vaccinated individuals but moderately reduce neutralization by convalescent-phase sera from the early stages of the pandemic. Despite multiple successful appearances of the two spike mutations during the first year of SARS-CoV-2 evolution, the genotype with both mutations was displaced upon the expansion of the 20I (Alpha) variant. The midterm fate of the genotype investigated was consistent with the lack of advantage observed in the clinical and experimental data. IMPORTANCE We observed repeated, independent emergence of mutations in the SARS-CoV-2 spike involving amino acids 1163 and 1167, within the HR2 functional motif. Conclusions derived from evolutionary and genomic diversity analysis suggest that the co-occurrence of both mutations might pose an advantage for the virus and therefore a threat to effective control of the epidemic. However, biological characterization, including in vitro experiments and analysis of clinical data, indicated no clear benefit in terms of stability or infectivity. In agreement with this, continuous epidemiological surveillance conducted months after the first observations revealed that both mutations did not successfully outcompete other variants and stopped circulating 9 months after their initial detection. Additionally, we evaluated the potential of both mutations to escape neutralizing antibodies, finding that the presence of these two mutations on their own is not likely to confer antibody escape. Our results provide an example of how newly emerged spike mutations can be assessed to better understand the risk posed by new variants and indicate that some spike mutations confer no clear advantage to the virus despite independently emerging multiple times and are eventually displaced by fitter variants.

Complete Analysis of the Epidemiological Scenario around a SARS-CoV-2 Reinfection: Previous Infection Events and Subsequent Transmission.

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. Our objectives were to perform a complete analysis of the sequential infections and community transmission events around a SARS-CoV-2 reinfection, including the infection events preceding it, the exposure, and subsequent transmissions. Our analysis was supported by host genetics, viral whole-genome sequencing, phylogenomic viral population analysis, and refined epidemiological data obtained from interviews with the involved subjects. The reinfection involved a 53-year-old woman with asthma (Case A), with a first COVID-19 episode in April 2020 and a much more severe second episode 4-1/2 months later, with SARS-CoV-2 seroconversion in August, that required hospital admission. An extended genomic analysis allowed us to demonstrate that the strain involved in Case A's reinfection was circulating in the epidemiological context of Case A and was also transmitted subsequently from Case A to her family context. The reinfection was also supported by a phylogenetic analysis, including 348 strains from Madrid, which revealed that the strain involved in the reinfection was circulating by the time Case A suffered the second episode, August-September 2020, but absent at the time range corresponding to Case A's first episode. IMPORTANCE We present the first complete analysis of the epidemiological scenario around a reinfection by SARS-CoV-2, more severe than the first episode, including three cases preceding the reinfection, the reinfected case per se, and the subsequent transmission to another seven cases.

Overlapping of Independent SARS-CoV-2 Nosocomial Transmissions in a Complex Outbreak.

SARS-CoV-2 nosocomial outbreaks in the first COVID-19 wave were likely associated with a shortage of personal protective equipment and scarce 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 3 health care workers. Patients had stayed in one of three neighboring rooms in the ward. The severity of the infections in six of the cases and a high fatality rate made the clinicians suspect the possible involvement of a single virulent strain persisting in those rooms. Whole-genome sequencing (WGS) of the strains from 12 patients and 1 health care 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. IMPORTANCE We report a complex epidemiological scenario of a nosocomial COVID-19 outbreak in the second wave, based on WGS analysis. Initially, standard epidemiological findings led to the assumption of a homogeneous outbreak caused by a single SARS-CoV-2 strain. The discriminatory power of WGS offered a strikingly different perspective consisting of five introductions of different strains, with only half of them causing secondary cases in three independent overlapping clusters. Our study exemplifies how complex the SARS-CoV-2 transmission in the nosocomial setting during the second COVID-19 wave occurred and leads to extending the analysis of outbreaks beyond the initial epidemiological assumptions.

Different Within-Host Viral Evolution Dynamics in Severely Immunosuppressed Cases with Persistent SARS-CoV-2.

A successful Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant, B.1.1.7, has recently been reported in the UK, causing global alarm. Most likely, the new variant emerged in a persistently infected patient, justifying a special focus on these cases. Our aim in this study was to explore certain clinical profiles involving severe immunosuppression that may help explain the prolonged persistence of viable viruses. We present three severely immunosuppressed cases (A, B, and C) with a history of lymphoma and prolonged SARS-CoV-2 shedding (2, 4, and 6 months), two of whom finally died. Whole-genome sequencing of 9 and 10 specimens from Cases A and B revealed extensive within-patient acquisition of diversity, 12 and 28 new single nucleotide polymorphisms, respectively, which suggests ongoing SARS-CoV-2 replication. This diversity was not observed for Case C after analysing 5 sequential nasopharyngeal specimens and one plasma specimen, and was only observed in one bronchoaspirate specimen, although viral viability was still considered based on constant low Ct values throughout the disease and recovery of the virus in cell cultures. The acquired viral diversity in Cases A and B followed different dynamics. For Case A, new single nucleotide polymorphisms were quickly fixed (13-15 days) after emerging as minority variants, while for Case B, higher diversity was observed at a slower emergence: fixation pace (1-2 months). Slower SARS-CoV-2 evolutionary pace was observed for Case A following the administration of hyperimmune plasma. This work adds knowledge on SARS-CoV-2 prolonged shedding in severely immunocompromised patients and demonstrates viral viability, noteworthy acquired intra-patient diversity, and different SARS-CoV-2 evolutionary dynamics in persistent cases.

Proper Assignation of Reactivation in a COVID-19 Recurrence Initially Interpreted as a Reinfection.

A 77-year-old man (case R) with previous diagnosis of a mild COVID-19 episode was hospitalized 35 days later. On day 23 postadmission, he developed a second COVID-19 episode, now severe, and finally died. Initially, case R's COVID-19 recurrence was interpreted as a reinfection due to the exposure to a SARS-CoV-2 RT-PCR-positive roommate. However, whole-genome sequencing indicated that case R's recurrence corresponded to a reactivation of the strain involved in his first episode. Case R's reactivation had major consequences, leading to a more severe episode, and causing subsequent transmission to another 2 hospitalized patients, 1 of them with fatal outcome.

Spread of a SARS-CoV-2 variant through Europe in the summer of 2020.

Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3-5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant's success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes.

One year into the pandemic: Short-term evolution of SARS-CoV-2 and emergence of new lineages.

The COVID-19 pandemic was officially declared on March 11th, 2020. Since the very beginning, the spread of the virus has been tracked nearly in real-time by worldwide genome sequencing efforts. As of March 2021, more than 830,000 SARS-CoV-2 genomes have been uploaded in GISAID and this wealth of data allowed researchers to study the evolution of SARS-CoV-2 during this first pandemic year. In parallel, nomenclatures systems, often with poor consistency among each other, have been developed to designate emerging viral lineages. Despite general fears that the virus might mutate to become more virulent or transmissible, SARS-CoV-2 genetic diversity has remained relatively low during the first ~ 8 months of sustained human-to-human transmission. At the end of 2020/beginning of 2021, though, some alarming events started to raise concerns of possible changes in the evolutionary trajectory of the virus. Specifically, three new viral variants associated with extensive transmission have been described as variants of concern (VOC). These variants were first reported in the UK (B.1.1.7), South Africa (B.1.351) and Brazil (P.1). Their designation as VOCs was determined by an increase of local cases and by the high number of amino acid substitutions harboured by these lineages. This latter feature is reminiscent of viral sequences isolated from immunocompromised patients with long-term infection, suggesting a possible causal link. Here we review the events that led to the identification of these lineages, as well as emerging data concerning their possible implications for viral phenotypes, reinfection risk, vaccine efficiency and epidemic potential. Most of the available evidence is, to date, provisional, but still represents a starting point to uncover the potential threat posed by the VOCs. We also stress that genomic surveillance must be strengthened, especially in the wake of the vaccination campaigns.