Infection-enhancing antibodies may limit the efficiency of Covid-19 vaccines. We analyzed the evolution of
neutralizing and facilitating epitopes in 1,860,489 SARS-CoV-2 genomes stored in the Los Alamos database
from June to November 2021. The structural dynamics of these epitopes was determined by molecular modeling
of the spike protein on a representative panel of SARS-CoV-2 variants. D614, which belongs to an antibody-dependent-enhancement (ADE) epitope common to SARS-CoV-1 and SARS-CoV-2, has mutated to D614G in
2020, which could explain why ADE has not been detected following mass vaccination. A second epitope
located in the N-terminal domain (NTD), specific of SARS-CoV-2, is highly conserved among most variants. In
contrast, the neutralizing epitope of the NTD showed extensive variations in SARS-CoV-2 variants. The balance
between facilitating and neutralizing antibodies is in favor of neutralization for the Wuhan strain, alpha and beta
variants, but not for gamma, delta, lambda, and mu. The recently emerging omicron variant is atypic as its
mutational profiles affects both neutralization and ADE epitopes. Overall, our data reveal that the evolution of
SARS-CoV-2 has dramatically affected the ADE/neutralization balance. Future vaccines should consider these
findings to design new formulations adapted to SARS-CoV-2 variants and lacking ADE epitopes in the spike
protein.