Spread of Gamma (P.1) sub-lineages carrying Spike mutations close to the furin cleavage site and deletions in the N-terminal domain drives ongoing transmission of SARS-CoV-2 in Amazonas, Brazil (preprint)

Summary 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 Δ 144 or Δ 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.

SARS-CoV-2 VOCs Immune Evasion from Previously Elicited Neutralizing Antibodies Is Mainly Driven by Lower Cross-Reactivity Due to Spike RBD Electrostatic Surface Changes (preprint)

Leveraging structural data and computer modelling techniques, we investigated the variation in the binding free-energy (𝛥𝛥𝐺) profile of VOCs and VOIs SARS-CoV-2 lineages with hACE2 and with a dataset of known human nAbs. In agreement with the available experimental data, our results show only a marginal impact of VOC RBD amino acid changes to hACE2 affinity. On the other hand, we found that VOCs RBDs have a significant unfavorable 𝛥𝛥𝐺 to nAbs that can be related to changes in the electrostatic potential surface profiles, hence identifying the molecular and thermodynamical components behind SARS-CoV-2 antibody evasion. In addition, our data suggests that a close attention should be given to lineage P.3, as it likely holds a high spreading potential in a human population with rising immunity. In summary, the current observed higher transmission of SARS-CoV-2 VOCs is likely associated with a partial or complete failure of the antibody recognition and neutralization in individuals previously exposed to SARS-CoV-2 non-VOC variants. These results have key implications on i. the basic understanding of VOCs emergence and maintenance; ii. on the rational design of antibody-based therapeutics; iii. vaccine efficacy and updates; and iv. may be exploited to rapidly screen immune scape worrisome lineages.