New emerging SARS-CoV-2 variants and antiviral agents

Dear Editor,

The continuous emergence of new Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) variants forces the health-care sector and the scientific world to constantly monitor the evolution, pathogenicity, virulence, and transmissibility of the virus in different countries. In parallel, there is a growing need for the rapid preparation of new diagnostic instruments and methods that may increase sensitivity and specificity in the detection and identification of CoronaVirus Disease (COVID-19) infections caused by the new SARS-CoV-2 variants/subvariants, which may present some difference in their clinical manifestations (SARS-CoV-2 variants of concern as of 1 June 2023 (europa.eu), Fernandes et al., 2022, Vitiello et al., 2022). Vaccines remain the main weapon available for health prevention of COVID-19 infection, to reduce mortality and severe cases of infection (Hadj Hassine, 2022, Vitiello et al., 2022). Recently, the European Medicine Agency (EMA) Committee for Medicinal Products for Human Use (Chmp) recommended the authorization of an adapted bivalent vaccine that therapeutically targets the induction and stimulation of antibody response against Omicron subvariants BA.4 and BA.5 in addition to the original SARS-CoV-2 strain (〈https://www.ema.europa.eu/en/news/adapted-vaccine-targeting-ba4-ba5-omicron-variants-original-sars-cov-2-recommended-approval〉), and monovalent vaccines against reccombinant subvariants regoing to be developed. As of 3 March 2023, the European Centre for Disease Prevention and Control (ECDC) removed BA.2. BA.4 and BA.5 from the list of SARS-CoV-2 variants of concern (VOC), as these parental lineages no longer have a significant impact on the epidemiological situation in terms of transmissibility and severity. To date, the list of variants of interest (VOI) includes all variants with available preliminary evidence on genomic, and epidemiological properties that could have a significant impact on transmissibility and epidemiological severity. To date, the list of VOI includes Omicron variant BA.2.75 with spike mutations of interest W152R, F157L, I210V, G257S, D339H, G446S, N460K, Q493, Omicron variant BQ.1 with spike mutations of interest K444T, N460K, Omicron variant XBB with spike mutations N460K, F490S, Omicron variant XBB.1.5 with spike mutations of interest N460K, S486P, F490S (SARS-CoV-2 variants of concern as of 1 June 2023 (europa.eu)). And finally, the latest variants identified and under close monitoring, and with very little evidence available, are Omicron variant CH.1.1 with spike muttions of interest K444T, L452R, Omicron variant XBB.1.16 with spike mutations of interest E180V, T478R, F486P and Omicron variant FE.1 with spike mutations of interest Q183E, F456L, F486P, F490S. In light of these emerging new variants of SARS-CoV-2, current challenges pose the need to periodically produce updated vaccines that can stimulate an appropriate antibody immune response that can effectively counter and prevent COVID-19 infection caused by these new variants. In addition, the efforts of the scientific community must always be directed in researching and developing new pharmacological therapeutic strategies that can effectively inhibit viral replication and lower the circulating load with new antiviral agents directed against the new variants and immunomodulating agents to manage the hyperinflammatory response of the individual that may develop in some cases. The various subvariants followed each other at different times as dominant variants in different countries around the world: first BA.1, then BA.2, and finally BA.5. All of the Omicron subvariants, including the latest emerging subvariants BQ.1.1 and XBB, have mutations of interest in the receptor binding domain of the spike(s) protein, the main target of vaccines and therapeutic monoclonal antibodies for coronavirus disease 2019 (Covid-19). These subvariants may therefore exhibit increased resistance and evasion from currently available pharmacological therapeutic strategies, with particular regard to monoclonal antibodies. In fact, an interesting recent study (Imai et al., 2022) showed that the efficacy of therapeutic monoclonal antibodies against the emerging subvariants of Omicron, namely BQ.1.1 and XBB, may not be effective in the clinical setting. Different is the case of antiviral drugs, such as Remdesivir (inhibitor of Rna-polymerase), Molnupiravir ( inhibitor of RdRp) whose efficacy has been recently questioned, and Nirmatrelvir (a major protease inhibitor of SARS-CoV-2), where current in vitro evidence shows good antiviral activity even against the latest BQ.1.1 and XBB, with decreased resistance rates. Another recent study demonstrated the antiviral activity of remdesivir, molnupiravir and nirmatrelvir against Omicron's new subvariants (Cho et al., 2023). Thus, the drugs are likely to retain their antiviral activity against newly emerging Omicron subvariants. Whether the new subvariants are less resistant to some antiviral drug treatments and more resistant to others should be better investigated (Cao et al., 2022, Takashita et al., 2022). This implies that the continued evolution of Omicron variants supports and reinforces the need to test new antiviral therapeutic strategies, and most importantly, clinicians must use currently available drugs always following the indications, dosages, and timing of administration reported in the summary of product characteristics. The development of better diagnostic tests, targeted and updated vaccines, and new antiviral therapeutic agents is a clear urgent need for the scientific world, which must know how to evolve in step with the pace of SARS-CoV-2 mutation. Continuous and ongoing research is needed to increase scientific knowledge on the emerging new variants of SARS-CoV-2, in order to rapidly implement effective preventive and therapeutic antiviral strategies.

CRediT authorship contribution statement

Antonio Vitiello: conceptualization; methodology; supervision; validation; writing – original draft; writing – review and editing; Andrea Zovi: methodology; validation; writing – original draft; writing – review and editing. Giovanni Rezza: Editing.

Declaration of Competing Interest

The authors declare no competing or financial interests. The authors declare that they have no known competing financial interests or personal relationships that could appear to have influenced the work reported in this paper. The authors declare that the opinions expressed are of a personal nature and do not in any way commit the responsibility of the Administrations to which they belong.