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1.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-22280193

Résumé

The SARS-CoV-2 variants of concern (VOCs) Delta and Omicron spread globally during mid and late 2021, respectively, with variable impact according to the immune population landscape. In this study, we compare the dissemination dynamics of these VOCs in the Amazonas state, one of Brazils most heavily affected regions. We sequenced the virus genome from 4,128 patients collected in Amazonas between July 1st, 2021 and January 31st, 2022 and investigated the lineage replacement dynamics using a phylodynamic approach. The VOCs Delta and Omicron displayed similar patterns of phylogeographic spread but significantly different epidemic dynamics. The Delta and Omicron epidemics were fueled by multiple introduction events, followed by the successful establishment of a few local transmission lineages of considerable size that mainly arose in the Capital, Manaus. The VOC Omicron spread and became dominant much faster than the VOC Delta. We estimate that under the same epidemiological conditions, the average Re of Omicron was [~]3.3 times higher than that of Delta and the average Re of the Delta was [~]1.3 times higher than that of Gamma. Furthermore, the gradual replacement of Gamma by Delta occurred without an upsurge of COVID-19 cases, while the rise of Omicron fueled a sharp increase in SARS-CoV-2 infection. The Omicron wave displayed a shorter duration and a clear decoupling between the number of SARS-CoV-2 cases and deaths compared with previous (B.1.* and Gamma) waves in the Amazonas state. These findings suggest that the high level of hybrid immunity (infection plus vaccination) acquired by the Amazonian population by mid-2021 was able to limit the spread of the VOC Delta and was also probably crucial to curb the number of severe cases, although not the number of VOC Omicron new infections.

2.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-21266109

Résumé

The rapid spread of the SARS-CoV-2 Variant of Concern (VOC) Gamma during late 2020 and early 2021 in Brazilian settings with high seroprevalence raised some concern about the potential role of reinfections in driving the epidemic. Very few cases of reinfection associated with the VOC Gamma, however, have been reported. Here we describe 25 cases of SARS-CoV-2 reinfection confirmed by real-time RT-PCR twice within months apart in Brazil. SARS-CoV-2 genomic analysis confirmed that individuals were primo-infected between March and December 2020 with distinct viral lineages, including B.1.1, B.1.1.28, B.1.1.33, B.1.195 and P.2, and then reinfected with the VOC Gamma between 3 to 12 months after primo-infection. The overall mean cycle threshold (Ct) value of the first (25.7) and second (24.5) episodes were roughly similar for the whole group and 14 individuals displayed mean Ct values < 25.0 at reinfection. Sera of 14 patients tested by plaque reduction neutralization test after reinfection displayed detectable neutralizing antibodies against Gamma and other SARS-CoV-2 variants (B.1.33, B.1.1.28 and Delta). All individuals have milder or no symptoms after reinfection and none required hospitalization. The present study demonstrates that the VOC Gamma was associated with reinfections during the second Brazilian epidemic wave in 2021 and raised concern about the potential infectiousness of reinfected subjects. Although individuals here analyzed failed to mount a long-term sterilizing immunity, they developed a high anti-Gamma neutralizing antibody response after reinfection that may provide some protection against severe disease.

3.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-21266251

Résumé

The SARS-CoV-2 Variant of Concern (VOC) Delta was first detected in India in October 2020. The first imported cases of the Delta variant in Brazil were identified in April 2021 in the Southern region, followed by more cases in different country regions during the following months. By early September 2021, Delta was already the dominant variant in the Southeastern (87%), Southern (73%), and Northeastern (52%) Brazilian regions. This work aimed to understand the spatiotemporal dissemination dynamics of Delta in Brazil. To this end, we employed a combination of Maximum Likelihood (ML) and Bayesian methods to reconstruct the evolutionary relationship of 2,264 of VOC Delta complete genomes (482 from this study) recovered across 21 out of 27 Brazilian federal units. Our phylogeographic analyses identified three major transmission clusters of Delta in Brazil. The clade BR-I (n = 1,560) arose in Rio de Janeiro in late April 2021 and was the major cluster behind the dissemination of the VOC Delta in the Southeastern, Northeastern, Northern, and Central-Western regions. The clade BR-II (n = 207) arose in the Parana state in late April 2021 and aggregated the largest fraction of sampled genomes from the Southern region. Lastly, the clade BR-III emerged in the Sao Paulo state in early June 2021 and remained mostly restricted to this state. In the rapid turnover of viral variants characteristic of the SARS-CoV-2 pandemic, Brazilian regions seem to occupy different stages of an increasing prevalence of the VOC Delta in their epidemic profiles. This process demands continuous genomic and epidemiological surveillance toward identifying and mitigating new introductions, limiting their dissemination, and preventing the establishment of more significant outbreaks in a population already heavily affected by the COVID-19 pandemic.

4.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-21265116

Résumé

The COVID-19 epidemic in Brazil experienced two major country-wide lineage replacements, the first driven by the lineage P.2, formerly classified as variant of interest (VOI) Zeta in late 2020 and the second by the variant of concern (VOC) Gamma in early 2021. To better understand how these SARS-CoV-2 lineage turnovers occurred in Brazil, we analyzed 11,724 high-quality SARS-CoV-2 whole genomes of samples collected in different country regions between September 2020 and April 2021. Our findings indicate that the spatial dispersion of both variants in Brazil was driven by short and long-distance viral transmission. The lineage P.2 harboring Spike mutation E484K probably emerged around late July 2020 in the Rio de Janeiro (RJ) state, which contributed with most ([~]50%) inter-state viral disseminations, and only became locally established in most Brazilian states by October 2020. The VOC Gamma probably arose in November 2020 in the Amazonas (AM) state, which was responsible for 60-70% of the inter-state viral dissemination, and the earliest timing of community transmission of this VOC in many Brazilian states was already traced to December 2020. We estimate that variant Gamma was 1.56-3.06 more transmissible than variant P.2 co-circulating in RJ and that the median effective reproductive number (Re) of Gamma in RJ and SP states (Re = 1.59-1.91) was lower than in AM (Re = 3.55). In summary, although the epicenter of the lineage P.2 dissemination in Brazil was the heavily interconnected Southeastern region, it displayed a slower rate of spatial spread than the VOC Gamma originated in the more isolated Northern Brazilian region. Our findings also support that the VOC Gamma was more transmissible than lineage P.2, although the viral Re of the VOC varied according to the geographic context.

5.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-21263755

Résumé

The SARS-CoV-2 has infected almost 200 million people worldwide by July 2021 and the pandemic has been characterized by infection waves of viral lineages showing distinct fitness profiles. The simultaneous infection of a single individual by two distinct SARS-CoV-2 lineages provides a window of opportunity for viral recombination and the emergence of new lineages with differential phenotype. Several hundred SARS-CoV-2 lineages are currently well characterized but two main factors have precluded major coinfection/codetection analysis thus far: i) the low diversity of SARS-CoV-2 lineages during the first year of the pandemic which limited the identification of lineage defining mutations necessary to distinguish coinfecting viral lineages; and the ii) limited availability of raw sequencing data where abundance and distribution of intrasample/intrahost variability can be accessed. Here, we have put together a large sequencing dataset from Brazilian samples covering a period of 18 May 2020 to 30 April 2021 and probed it for unexpected patterns of high intrasample/intrahost variability. It enabled us to detect nine cases of SARS-CoV-2 coinfection with well characterized lineage-defining mutations. In addition, we matched these SARS-CoV-2 coinfections with spatio-temporal epidemiological data confirming their plausibility with the co-circulating lineages at the timeframe investigated. These coinfections represent around 0.61% of all samples investigated. Although our data suggests that coinfection with distinct SARS-CoV-2 lineages is a rare phenomenon, it is likely an underestimation and coinfection rates warrants further investigation. DATA SUMMARYThe raw fastq data of codetection cases are deposited on gisaid.org and correlated to gisaid codes: EPI_ISL_1068258, EPI_ISL_2491769, EPI_ISL_2491781, EPI_ISL_2645599, EPI_ISL_2661789, EPI_ISL_2661931, EPI_ISL_2677092, EPI_ISL_2777552, EPI_ISL_3869215. Supplementary data are available on https://doi.org/10.6084/m9.figshare.16570602.v1. The workflow code used in this study is publicly available on: https://github.com/dezordi/IAM_SARSCOV2.

6.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-21263453

Résumé

The Amazonas was one of the most heavily affected Brazilian states by the COVID-19 epidemic. Despite a large number of infected people, particularly during the second wave associated with the spread of the Variant of Concern (VOC) Gamma (lineage P.1), SARS-CoV-2 continues to circulate in the Amazonas. To understand how SARS-CoV-2 persisted in a human population with a high immunity barrier, we generated 1,188 SARS-CoV-2 whole-genome sequences from individuals diagnosed in the Amazonas state from 1st January to 6th July 2021, of which 38 were vaccine breakthrough infections. Our study reveals a sharp increase in the relative prevalence of Gamma plus (P.1+) variants, designated as Pango Lineages P.1.3 to P.1.6, harboring two types of additional Spike changes: deletions in the N-terminal (NTD) domain (particularly{Delta} 144 or{Delta} 141-144) associated with resistance to anti-NTD neutralizing antibodies or mutations at the S1/S2 junction (N679K or P681H) that probably enhance the binding affinity to the furin cleavage site, as suggested by our molecular dynamics simulations. As lineages P.1.4 (S:N679K) and P.1.6 (S:P681H) expanded (Re > 1) from March to July 2021, the lineage P.1 declined (Re < 1) and the median Ct value of SARS-CoV-2 positive cases in Amazonas significantly decreases. Still, we found no overrepresentation of P.1+ variants among breakthrough cases of fully vaccinated patients (71%) in comparison to unvaccinated individuals (93%). This evidence supports that the ongoing endemic transmission of SARS-CoV-2 in the Amazonas is driven by the spread of new local Gamma/P.1 sub-lineages that are more transmissible, although not more efficient to evade vaccine-elicited immunity than the parental VOC. Finally, as SARS-CoV-2 continues to spread in human populations with a declining density of susceptible hosts, the risk of selecting new variants with higher infectivity are expected to increase.

7.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-21260508

Résumé

We report a genomic surveillance of SARS-CoV-2 lineages circulating in Parana, Southern Brazil, from March 2020 to April 2021. Our analysis, based on 333 genomes, revealed that the first variants detected in the state of Parana in March 2020 were the B.1.1.33 and B.1.1.28 variants. The variants B.1.1.28 and B.1.1.33 were predominant throughout 2020 until the introduction of the variant P.2 in August 2020 and a variant of concern (VOC), P.1, in January 2021. Phylogenetic analyses of the SARS-CoV-2 genomes that were previously classified as the VOC P.1 lineage by PANGO showed that some genomes from February to April 2021 branched in a monophyletic clade and that these samples grouped together with genomes recently described with the lineage P.1-like-II. An extended phylogenetic analysis, including SARS-CoV-2 genomes from all over Brazil, showed that the P.1-like-II lineage appears at a high frequency in the southern region of the country. The P.1-like-II lineage genomes share some, but not all, defining mutations of the VOC P.1. For instance, it has the previously described ORF1a:D2980H and N:P383 L unique mutations and the newly detected ORF1a:P1213 L and ORF1b:K2340N mutations. Additionally, a new mutation (E661D) in the spike (S) protein has been identified in nearly 10% of the genomes classified as the VOC P.1 from Parana in March and April 2021. We also report the identification of the S:W152C mutation in one genome from Parana, classified as the N.10 variant. Finally, we analyzed the correlation between the lineage and the P.1 variant frequency, age group (patients younger or older than 60 years old) and the clinical data of 86 cases from the state of Parana. This analysis does not support an association between the P.1 variant prevalence and COVID-19 severity or age strata. Our results provided a reliable picture of the evolution of the SARS-CoV-2 pandemic in the state of Parana characterized by the dominance of the P.1 strain, as well as a high frequencies of the P.1-like-II lineage and the S:E661D mutations. Epidemiological and genomic surveillance efforts should be continued to unveil the biological relevance of the novel mutations detected in the VOC P.1 in Parana.

8.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-21253946

Résumé

Mutations at both the receptor-binding domain (RBD) and the amino (N)-terminal domain (NTD) of the SARS-CoV-2 Spike (S) glycoprotein can alter its antigenicity and promote immune escape. We identified that SARS-CoV-2 lineages circulating in Brazil with mutations of concern in the RBD independently acquired convergent deletions and insertions in the NTD of the S protein, which altered the NTD antigenic-supersite and other predicted epitopes at this region. These findings support that the ongoing widespread transmission of SARS-CoV-2 in Brazil is generating new viral lineages that might be more resistant to neutralization than parental variants of concern.

9.
Preprint Dans Anglais | bioRxiv | ID: ppbiorxiv-434969

Résumé

The SARS-CoV-2 epidemic in Brazil was dominated by two lineages designated as B.1.1.28 and B.1.1.33. Two SARS-CoV-2 variants harboring mutations at the receptor-binding domain of the Spike (S) protein, designated as lineages P.1 and P.2, evolved within lineage B.1.1.28 and are rapidly spreading in Brazil. Lineage P.1 is considered a Variant of Concern (VOC) because of the presence of multiple mutations in the S protein (including K417T, E484K, N501Y), while lineage P.2 only harbors mutation S:E484K and is considered a Variant of Interest (VOI). Here we report the identification of a new SARS-CoV-2 VOI within lineage B.1.1.33 that also harbors mutation S:E484K and was detected in Brazil between November 2020 and February 2021. This VOI displayed four non-synonymous lineage-defining mutations (NSP3:A1711V, NSP6:F36L, S:E484K, and NS7b:E33A) and was designated as lineage N.9. The VOI N.9 probably emerged in August 2020 and has spread across different Brazilian states from the Southeast, South, North and Northeast regions.

10.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-21251809

Résumé

In late March 2020, SARS-CoV-2 arrived in Manaus, Brazil, and rapidly developed into a large-scale epidemic that collapsed the local health system, and resulted in extreme death rates. Several key studies reported that [~]76% of residents of Manaus were infected (attack rate AR[~=]76%) by October 2020, suggesting protective herd immunity had been reached. Despite this, in November an unexpected second wave of COVID-19 struck again, and proved to be larger than the first creating a catastrophe for the unprepared population. It has been suggested that this could only be possible if the second wave was driven by reinfections. Here we use novel methods to model the epidemic from mortality data, evaluate the impact of interventions, in order to provide an alternative explanation as to why the second wave appeared. The method fits a "flexible" reproductive number R0(t) that changes over the epidemic, and found AR[~=]30-34% by October 2020, for the first wave, which is far less than required for herd immunity, yet in-line with recent seroprevalence estimates. The two-strain model provides an accurate fit to observed epidemic datasets, and finds AR[~=]70% by March 2021. Using genomic data, the model estimates transmissibility of the new P.1 virus lineage, as 1.9 times as transmissible as the non-P1. The model thus provides a reasonable explanation for the two-wave dynamics in Manaus, without the need to rely on reinfections which until now have only been found in small numbers in recent surveillance efforts. SignificanceThis paper explores the concept of herd immunity and approaches for assessing attack rate during the explosive outbreak of COVID-19 in the city of Manaus, Brazil. The event has been repeatedly used to exemplify the epidemiological dynamics of the disease and the phenomenon of herd immunity, as claimed to be achieved by the end of the first wave in October 2020. A novel modelling approach reconstructs these events, specifically in the presence of interventions. The analysis finds herd immunity was far from being attained, and thus a second wave was readily possible, as tragically occurred in reality. Based on genomic data, the multi-strain model gives insights on the new highly transmissible variant of concern P.1 and role of reinfection.

11.
Preprint Dans Anglais | bioRxiv | ID: ppbiorxiv-158006

Résumé

Despite all efforts to control the COVID-19 spread, the SARS-CoV-2 reached South America within three months after its first detection in China, and Brazil became one of the hotspots of COVID-19 in the world. Several SARS-CoV-2 lineages have been identified and some local clusters have been described in this early pandemic phase in Western countries. Here we investigated the genetic diversity of SARS-CoV-2 during the early phase (late February to late April) of the epidemic in Brazil. Phylogenetic analyses revealed multiple introductions of SARS-CoV-2 in Brazil and the community transmission of a major B.1.1 lineage defined by two amino acid substitutions in the Nucleocapsid and ORF6. This SARS-CoV-2 Brazilian lineage was probably established during February 2020 and rapidly spread through the country, reaching different Brazilian regions by the middle of March 2020. Our study also supports occasional exportations of this Brazilian B.1.1 lineage to neighboring South American countries and to more distant countries before the implementation of international air travels restrictions in Brazil.

12.
Preprint Dans Anglais | medRxiv | ID: ppmedrxiv-20073007

Résumé

The SARS-CoV-2 rapidly spread around the world during 2020, but the precise time in which the virus began to spread locally is currently unknown for most countries. Here, we estimate the probable onset date of the community spread of SARS-CoV-2 from the cumulative number of deaths reported during the early stage of the epidemic in Western Europe and the Americas. Our results support that SARS-CoV-2 probably started to spread locally in all western countries analyzed between the middle of January and early February 2020, thus long before community transmission was officially recognized and control measures were implemented.

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