Resistance of SARS-CoV-2 Omicron BA.1 and BA.2 Variants to Vaccine-Elicited Sera and Therapeutic Monoclonal Antibodies

Abstract

The recent emergence of the Omicron BA.1 and BA.2 variants with heavily mutated spike proteins has posed a challenge to the effectiveness of current vaccines and to monoclonal antibody therapy for severe COVID-19. After two immunizations of individuals with no history of previous SARS-CoV-2 infection with BNT162b2 vaccine, neutralizing titer against BA.1 and BA.2 were 20-fold decreased compared to titers against the parental D614G virus. A third immunization boosted overall neutralizing titers by about 5-fold but titers against BA.1 and BA.2 remained about 10-fold below that of D614G. Both Omicron variants were highly resistant to several of the emergency use authorized therapeutic monoclonal antibodies. The variants were highly resistant to Regeneron REGN10933 and REGN10987 and Lilly LY-CoV555 and LY-CoV016 while Vir-7831 and the mixture of AstraZeneca monoclonal antibodies AZD8895 and AZD1061 were significantly decreased in neutralizing titer. Strikingly, a single monoclonal antibody LY-CoV1404 potently neutralized both Omicron variants.

Epistasis lowers the genetic barrier to SARS-CoV-2 neutralizing antibody escape

“…Consecutive waves of SARS-CoV-2 infection have been driven in part by the repeated emergence of variants with mutations that confer resistance to neutralizing antibodies[1-8] Nevertheless, prolonged or repeated antigen exposure generates diverse memory B-cells [9-14] that can produce affinity matured receptor binding domain (RBD)-specific antibodies that likely contribute to ongoing protection against severe disease. RBD-specifiic antibodies are the dominant source of neutralizing activity in the plasma of infected or vaccinated individuals[15, 16] and can be broadly grouped into 4 prototype classes[17, 18].…”

“…1a), while class 3 and 4 antibodies bind outside the ACE-2-binding site on opposite sides of the RBD. The emergence of viral variants, particularly omicron BA.1 and BA.2 with numerous RBD substitutions has reduced the effectiveness of neutralizing antibodies as components of the convalescent and vaccine-elicited immune response and as therapeutics [3][4][5][6][7][8]. However, the retention of activity against emergent variants, such as BA.1 and BA.2 and derivatives thereof [4,14,19,20], by a subset of plasma and memory antibodies likely contributes to the residual effectiveness of ancestral variant-based vaccines, and the partial protection afforded by exposure to antigens from earlier variants.…”

Potential Benefit of Early Treatment with Sotrovimab in Patients With High Risk for Severe COVID-19 Carrying BA.2 Infection

“…BA.2 exhibits significant in vitro resistance to most of the neutralizing monoclonal antibodies approved, including sotrovimab [23,34]. Sotrovimab has a 77-fold increase in the IC 50 against BA.2 vs only 7.8-fold for BA.1.…”

Converting non-neutralizing SARS-CoV-2 antibodies into broad-spectrum inhibitors

“… 10 ), was initially isolated from a survivor of SARS-CoV-1, so its epitope in the RBD is more highly conserved 11 , although in vitro escape mutations have been identified 5 . Moreover, since this article has been in review, sotrovimab has lost significant activity against the recent BA.2 variant 12 . This has necessitated authorization of a new mAb, bebtelovimab, which is capable of neutralizing BA.2 (ref.…”