Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Abstract

Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Manaus, Brazil, resurged in late 2020 despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1 acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 (angiotensin-converting enzyme 2) receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7- to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

Fig. 1. SARS-CoV-2 epidemiological, diagnostic, genomic, and mobility data from Manaus.

(A) Dark solid line shows the 7-day rolling average of the COVID-19 confirmed and suspected daily time series of hospitalizations in Manaus. Admissions in Manaus are from Fundao de Vigilncia em Sade do Amazonas (66). Green dots indicate daily severe acute respiratory mortality records from the SIVEP-Gripe (Sistema de Informao de Vigilncia Epidemiolgica da Gripe) database (67). Red dots indicate excess burial records based on data from Manaus Mayors office for comparison (supplementary materials, materials and methods). The arrow indicates 6 December 2020, the date of the first P.1 case identified in Manaus by our study. (B) Maximum likelihood tree (n = 962 viral genomes) with B.1.1.28, P.1, and P.2 sequences, with collapsed views of P.1 and P.2 clusters and highlighting other sequences from Amazonas state, Brazil. Ancestral branches leading to P.1 and P.2 are shown as dashed lines. A more detailed phylogeny is available in fig. S3. Scale bar is shown in units of nucleotide substitutions per site (s/s). (C) Number of air travel passengers from Manaus to all states in Brazil was obtained from National Civil Aviation Agency of Brazil (www.gov.br/anac). The ISO 3166-2:BR codes of the states with genomic reports of P.1 [GISAID (68), as of 24 February 2021], are shown in bold. An updated list of GISAID genomes and reports of P.1 worldwide is available at https://cov-lineages.org/global_report_P.1.html. (D) Number of genome sequences from Manaus belonging to lineages of interest (supplementary materials, materials and methods). Spike mutations of interest are denoted.

Fig. 2. Visualization of the time-calibrated maximum clade credibility tree reconstruction for B.1.1.28, P.1, and P.2 lineages in Brazil.

Terminal branches and tips of Amazonas state are colored in brown, and those from other locations are colored in green (n = 962 viral genomes). Nodes with posterior probabilities of <0.5 have been collapsed into polytomies, and their range of divergence dates are illustrated as shaded expanses.

Fig. 3. Temporal variation in the proportion of sequenced genomes belonging to P.1, and trends in quantitative RT-PCR Ct values for COVID-19 infections in Manaus.

(A) Logistic function fitting to the proportion of genomes in sequenced infections that have been classified as P.1 (black circles, size indicating number of infections sequenced), divided up into time periods when the predicted proportion of infections that are due to P.1 is <1/3 (light brown), between 1/3 and 2/3 (green), and greater than 2/3 (gray). For the model fit, the darker ribbon indicates the 50% credible interval, and the lighter ribbon indicates the 95% credible interval. For the data points, the gray thick line is the 50% exact binomial CI, and the thinner line is the 95% exact binomial CI. (B) Ct values for genes E and N in a sample of symptomatic cases presenting for testing at a health care facility in Manaus (laboratory A), stratified according to the period defined in (A) in which the oropharyngeal and nasal swab collections occurred. (C) Ct values for genes E and N in a subsample of 184 infections included in (B) that had their genomes sequenced (dataset A).

Fig. 4. Estimates of the epidemiological characteristics of P.1 inferred from a multicategory Bayesian transmission model fitted to data from Manaus, Brazil.

(A) Joint posterior distribution of the cross-immunity and transmissibility increase inferred through fitting the model to mortality and genomic data. Gray contours indicate posterior density intervals ranging from the 95 and 50% isoclines. Marginal posterior distributions for each parameter shown along each axis. (B) As for (A), but showing the joint-posterior distribution of cross-immunity and the inferred relative risk of mortality in the period after emergence of P.1 compared with the period prior. (C) Daily incidence of COVID-19 mortality. Points indicate severe acute respiratory mortality records from the SIVEP-Gripe database (67, 69). Brown and green ribbons indicate model fit for COVID-19 mortality incidence, disaggregated by mortality attributable to non-P.1 lineages (brown) and the P.1 lineage (green). (D) Estimate of the proportion of P.1 infections through time in Manaus. Black data points with error bars are the empirical proportion observed in genomically sequenced cases (Fig. 3A), and green ribbons (dark = 50% BCI, light = 95% BCI) are the model fit to the data. (E) Estimated cumulative infection incidence for the P.1 and non-P.1 categories. Black data points with error bars are reversion-corrected estimates of seroprevalence from blood donors in Manaus (2). Colored ribbons are the model predictions of cumulative infection incidence for non-P.1 lineages (brown) and P.1 lineages (green). These points are shown for reference only and were not used to fit the model. (F) Bayesian posterior estimates of trends in reproduction number R_t for the P.1 and non-P.1 categories.