Review: Efficacy of Antiviral Agents Against Omicron Subvariant BA.2

The omicron (B.1.1.529) variant of SARS-CoV-2, has spread rapidly around the world and has already become the predominant variant circulating in many countries. Most circulating omicron variants belong to sublineage BA.1; however, in Denmark, India, and the Philippines, the sublineage BA.2 is now becoming dominant. The BA.2 and BA.1 variants share 12 of these 16 substitutions; however, BA.2 has four substitutions in the receptor-binding domain (i.e., S371F, T376A, D405N, and R408S) that differ from those in BA.1. These findings suggest that there may be differences in the effectiveness of monoclonal antibodies against these different omicron sublineages.

The current study examined the neutralizing ability of therapeutic monoclonal antibodies individually and in combination, against the omicron BA.2 subvariant. The results are as followed;

• A live-virus focus reduction neutralization test (FRNT) showed that both etesevimab and bamlanivimab, individually and in combination, lost neutralizing activity against omicron/BA.2.
• However, imdevimab was previously shown to lose neutralizing activity against omicron/BA.1 (NC928) and omicron/BA.1.1 (NC929), had neutralizing activity against omicron/BA.2 (NCD1288).
• In addition, the combination of imdevimab and casirivimab also inhibited omicron/BA.2 but did not inhibit omicron/BA.1 or omicron/BA.1.1.
• However, the FRNT50 (the titer of monoclonal antibodies required for a 50% reduction in the number of infectious foci) value of this combination therapy was higher by a factorof43.0 to 143.6 for omicron/BA.2 than for an ancestral strain and other variants of concern (i.e., the alpha [B.1.1.7], beta [B.1.351], gamma [P.1], and delta [B.1.617.2] variants).
• S309 (the precursor of sotrovimab), which has been shown to have lower neutralizing activity against omicron/BA.1 and omicron/BA.1.1 than against the ancestral strain and other variants of concern had even less neutralizing activity against omicron/BA.2.
• The susceptibilities of omicron/BA.2 (NCD1288) to remdesivir, molnupiravir, and nirmatrelvir were similar to those of the ancestral strain and other variants of concern.

Table: Efficacy of Monoclonal Antibodies and Antiviral Drugs against the Omicron/BA.2 Subvariant in Vitro

† The individual monoclonal antibodies were tested at a starting concentration of 50,000 ng per milliliter as a 50% focus reduction neutralization test (FRNT50) titer. The monoclonal antibody combinations were tested at a starting concentration of 10,000 ng per milliliter for each antibody. Shown is the factor increase in the FRNT50 titers of monoclonal antibodies against the omicron/BA.2 subvariant as compared with that against the ancestral strain, SARS- CoV-2/UT-NC002-1T/Human/2020/Tokyo (A.)

‡ In this category, the value is the 50% inhibitory concentration (Ic50) of the mean micromole value of triplicate reactions. The factor increase in the Ic50 of drugs against the omicron/BA.2 subvariant as compared with that against the ancestral strain, SARS-CoV-2/UT-NC002-1T/HUman/2020/Tokyo (A), are shown.

§ GS-441524 is the main metabolite of remdesivir, an RNA-dependent RNA polymerase inhibitor.

¶ EIDD-1931 is the active form of molnupiravir, an RNA-dependant RNA polymerase inhibitor.

|| PF-07321332 (also know as nirmatrelvir) is a protease inhibitor.

Reference:

Takashita E, Kinoshita N, Yamayoshi S, Sakai-Tagawa Y, Fujisaki S, Ito M, Iwatsuki-Horimoto K, Halfmann P, Watanabe S, Maeda K, Imai M, Mitsuya H, Ohmagari N, Takeda M, Hasegawa H, Kawaoka Y. Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2. N Engl J Med. 2022 Apr 14;386(15):1475-1477. doi: 10.1056/NEJMc2201933

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