Fc effector activity and neutralization against SARS-CoV-2 BA.4 is compromised in convalescent sera, regardless of the infecting variant

Abstract

The SARS-CoV-2 Omicron BA.1 variant, which exhibits high level neutralization resistance, has since evolved into several sub-lineages including BA.4 and BA.5, which have dominated the fifth wave of infection in South Africa. Here we assessed the sensitivity of BA.4 to neutralization and antibody dependent cellular cytotoxicity (ADCC) 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 resistance to neutralization, regardless of the infecting variant. However, breakthrough infections, which trigger potent neutralization, retained activity against BA.4, albeit at reduced titers. Fold reduction of neutralization in BTIs was lower than that seen in unvaccinated convalescent donors, suggesting maturation of neutralizing responses to become more resilient against VOCs in hybrid immunity. BA.4 sensitivity to ADCC was reduced but remained detectable in both convalescent donors and in BTIs. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infections, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC activity against BA.4 was reduced, residual activity may nonetheless contribute to the protection from disease.

Vaccine- and BTI-elicited pre-Omicron immunity more effectively neutralizes Omicron sublineages BA.1, BA.2, BA.4 and BA.5 than pre-Omicron infection alone

“…In contrast, they were unable to neutralize BA.1, in agreement with previous reports (42,57,75). This observation somehow mirrors the restricted cross-neutralizing ability of BA.1elicited antibodies against pre-Omicron and other Omicron lineages (3,20,30,42,50,63,66,73,(75)(76)(77)89), and highlights that BA.1 is antigenically very distant from all other VOCs and triggers strongly imprinted immune responses. Accordingly one study found that BA.1 booster triggers the activation of naïve B-cells rather than memory B-cells (74), while others record a small proportion of naïve B-cell activation (2,63,67,87).…”

“…Hybrid immunity conferred by vaccination and infection together was reported to be superior to immunity elicited by infection or vaccination alone (3,20,37,38,65,66,70,73,76,(82)(83)(84)(85). We therefore further investigated the susceptibility of the four Omicron sublineages to sera from 16 Despite distinct neutralization profiles, all but one BTI sera had antibodies against S, the RBD and the NTD (Fig 3M).…”

“…BA.2.75, BA.4 and BA.5 also resist antibodies elicited by Omicron BA.1 and BA.2 infection (2, 3, 16, 30, 31, 50, 63–66).…”

“…Immune imprinting can however obstruct the generation of new, better adapted antibodies, either by neutralizing the antigen which is supposed to boost immunity (thus decreasing the impact of booster doses), or by skewing immunity to continue to produce antibodies against the past virus, impairing the generation of antibodies better suited to neutralize the new variant (2, 63, 72, 73). Imprinting has been beneficial up to Delta, but the completely different Omicron lineages evade antibodies and T-cells elicited by prior immunogens (2, 3, 20, 34, 66, 72–74). Conversely, studies on the cross-protection elicited by Omicron BA.1 infection alone against pre-Omicron and other Omicron sublineages consistently document poor cross-neutralization, highlighting the strong immune imprinting of this sublineage (3, 20, 30, 42, 50, 63, 66, 73, 75, 76).…”

“…Imprinting has been beneficial up to Delta, but the completely different Omicron lineages evade antibodies and T-cells elicited by prior immunogens (2, 3, 20, 34, 66, 72–74). Conversely, studies on the cross-protection elicited by Omicron BA.1 infection alone against pre-Omicron and other Omicron sublineages consistently document poor cross-neutralization, highlighting the strong immune imprinting of this sublineage (3, 20, 30, 42, 50, 63, 66, 73, 75, 76). Obstructive immune imprinting has been described for BA.1, BA.2 and BA.5 breakthrough infections after vaccination with first generation vaccines as well (2, 18, 63, 73, 74).…”