Abstract:
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4 and BA.5 variants caused
major waves of infections. Here, we assess the sensitivity of BA.4 to binding, neutralization, and antibodydependent
cellular cytotoxicity (ADCC) potential, measured by FcgRIIIa signaling, in convalescent donors
infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections
(BTIs) caused by Delta or BA.1. We confirm that BA.4 shows high-level neutralization resistance regardless
of the infecting variant. However, BTIs retain activity against BA.4, albeit at reduced titers. BA.4 sensitivity to
ADCC is reduced compared with other variants but with smaller fold losses compared with neutralization and
similar patterns of cross-reactivity. Overall, the high neutralization resistance of BA.4, even to antibodies
from BA.1 infection, provides an immunological mechanism for the rapid spread of BA.4 immediately after
a BA.1-dominated wave. Furthermore, although ADCC potential against BA.4 is reduced, residual activity
may contribute to observed protection from severe disease.
