A third round of booster immunization with the SARS-CoV-2 vaccine is currently under
consideration. Our data suggest that repeated immunization with the wild-type spike may not be
effective in controlling the newly emerging Delta variants. We demonstrated that immunization by
Delta spike induces antibodies that neutralize not only the Delta variant but also wild-type and the
Delta 4+ variant without enhancing the infectivity. Although mRNA vaccination may yield
different results from our animal model, development of mRNA vaccine expressing the Delta spike
might be effective for controlling the emerging Delta variant. However, epitopes of the enhancing
antibodies, not neutralizing antibodies, are well conserved in most SARS-CoV-2 variants,
including the Delta variant. Therefore, additional immunization of the spike protein derived from
SARS-CoV-2 variants may boost enhancing antibodies more than the neutralizing antibodies in
individuals who were previously infected with wild-type SARS-CoV-2 or immunized with
vaccines composed of wild-type spike protein. Immunization using the RBD alone, which will not
induce anti-NTD enhancing antibodies, could be a strategy for a vaccination. However, anti-NTD
neutralizing antibodies that protect against SARS-CoV-2 infection similar to anti-RBD-
neutralizing antibodies are not induced by immunization by RBD alone (Chi et al., 2020; Li et al.,
2021 ; Liu et al., 2020; Suryadevara et al., 2021; Voss et al., 2021). Whole spike protein containing
RBD mutations observed in major variants but lacking the enhancing antibody epitopes may need
to be considered as a booster vaccine.