Editorial: Factors Driving New Variants of SARS-CoV-2, Immune Escape, and Resistance to Antiviral Treatments as the End of the COVID-19 Pandemic is Declared

In 2009, The World Health Organization (WHO) established definitions of epidemiological phases of pandemic viral infections based on pandemic influenza [1]. The WHO has identified that in the post-pandemic period, the activity of influenza returns to the levels expected for seasonal influenza [1]. However, although there is speculation that COVID-19, due to infection with SARS-CoV-2, will become an endemic and seasonal viral infection, the SARS-CoV-2 virus has several unique pathogenic features, and it may be too premature to make such assumptions.

On January 30, 2020, the WHO first declared that COVID-19 was a public health emergency of international concern (PHEIC) [2]. On May 5, 2023, the WHO Director-General advised the transition to long-term management of the COVID-19 pandemic and that COVID-19 is now an established and ongoing health issue that is no longer a PHEIC [2]. The WHO decision was based on an analysis of the decreasing trend in mortality, the decline in hospital admissions and intensive care unit (ICU) admissions from COVID-19, and the increasing levels of population immunity to SARS-CoV-2 [2].

Since January 2020, the WHO has estimated that the true death toll from COVID-19 is at least 20 million and has warned countries to remain vigilant and that infection surveillance remains a priority [2]. Also, 13.3 billion doses of COVID-19 vaccines have been given worldwide, and >80% of health workers and >8% of adults >60 years of age have received a primary vaccine course [2]. The WHO advises countries to transition from emergency mode to long-term management of COVID-19 and other infectious diseases [2]. Long-term recommendations for COVID-19 are in development [2]. The WHO has recently published the fourth edition of its global strategic preparedness and response plan, which covers surveillance, clinical management, community disease prevention, access to countermeasures, and emergency response co-ordination for COVID-19 [3].

On April 10, 2023, the US President signed resolution H.J.Res. 7, which terminated the national emergency status related to the COVID-19 pandemic, and the public health emergency status ended one month later [4]. In September 2022, the US President had previously declared that the COVID-19 pandemic was over, although during that month, more than 10,000 Americans had died from COVID-19 [5]. By the end of 2022, several European countries declared an end to the emergency restrictions associated with the COVID-19 pandemic [6,7].

A recent review article by Abi-Rached and Brandt of the medical history of pandemics and how they end has given a timely reminder of how social, economic, and political factors have influenced declarations made regarding the end of outbreaks and pandemics of infectious diseases [6]. For example, at the time of the outbreak of bubonic plague in 18th century France, which brought the economy to a standstill, King Louis XV (1710–1774) pronounced that there should be public celebrations and market trading should recommence even though people were still dying of the plague [6]. This disease persists in some parts of the world and has not been eradicated [6]. Pandemics end when a certain number of infections are tolerated or endemicized, like influenza and HIV/AIDS [6]. Historically, the factors involved in determining the end of a pandemic include conclusions from a public authority that the public health crisis is no longer a threat to the economic productivity of society [6].

However, the pathogenesis and behavior of SARS-CoV-2 is unique, and previous history of viral pandemics, including influenza pandemics, may not have relevance [7]. Looking back only three years, the Omicron (B.1.1.529) variant of SARS-CoV-2 became the dominant variant from the beginning of the COVID-19 pandemic, with many sublineages due to mutations in the spike (S) protein that allows the virus to adhere to and enter cells [8]. The BA.2 subvariant of the Omicron (B.1.1.529) variant of SARS-CoV-2, also known as the ‘stealth’ subvariant, was dominant in early 2022 [9]. More recently, from August 2023, the BA.2.86 Omicron subvariant was identified in small numbers of patients in Denmark, Israel, the UK, and the US [10,11]. This subvariant is descended from the BA.2 (stealth) subvariant of SARS-CoV-2 [9]. The S protein of the BA.2.86 subvariant has 34 additional mutational changes relative to BA.2, which resulted in the World Health Organization (WHO) designation of BA.2.86 as a variant under monitoring (VUM) [10,11]. BA.2.86 has been named ‘Pirola,’ a combination of the Greek letters Pi and Rho, and has more than 30 mutations to its spike protein compared to the XBB.1.5 (Kraken) subvariant, which was dominant in the US before the EG.5 (Eris) subvariant [10–13]. The geographical distribution of this subvariant remains unexplained, as the BA.2.86 (Pirola) cases are not linked or associated with international travel [10,11]. Now that the BA.2.86 (Pirola) subvariant has been reported in 11 countries, it may already be widespread due to community transmission [10,11]. A further concern is that many of the BA.2.86 (Pirola) mutations are in S protein regions that are targeted by neutralizing antibodies, indicating that infection by the BA.2.86 (Pirola) subvariant could escape some of the neutralizing antibodies triggered by current vaccine boosters or by previous SARS-CoV-2 infections [14]. Surveillance continues on the effects of possible immune escape by the BA.2.86 (Pirola) subvariant, which may require the development of new SARS-CoV-2 booster vaccines, which are currently developed from the S protein sequence of the XBB.1.5 (Kraken) subvariant [10,11,14].

SARS-CoV-2 is a unique pandemic virus with a rapid mutation rate that was not predicted during 2020, the first year of the pandemic [14]. The effects of the rapid evolution of SARS-CoV-2 due to multiple adaptive mutations have resulted in new variants and subvariants with enhanced transmission rates relative to previous variants and changes in virus antigenicity [14]. Mutations involve the S protein, the furin spike cleavage site, and non-spike proteins [14]. The emerging variants and subvariants may evade the immune response even in changing immunity due to prior infection and vaccination [14]. The immune response to viral infection involves an interaction between innate and acquired humoral and cellular immunity and population (herd) immunity, which is poorly understood for SARS-CoV-2 variants and subvariants [14,15]. Also, a complex relationship exists between virus antigenicity, virulence, and transmission [14]. Currently, these elaborate immune escape and virulence factors have unpredictable implications for future local and global trajectories of COVID-19 [16].

Some repurposed antiviral agents have been effective for SARS-CoV-2 infection and have undergone regulatory approval. However, some antiviral agents have been associated with rebound viral infection following treatment cessation, and a more worrying effect has been to drive viral mutations. One of the first antiviral agents to be approved was molnupiravir, which was granted Emergency Use Authorization (EUA) by the US Food and Drug Administration (FDA) on December 23, 2021, for adults >18 years of age with mild-to-moderate COVID-19 at increased risk for progression to severe COVID-19 [17]. The antiviral effects of molnupiravir include the induction of inducing mutations in the virus genome during replication [18]. Although most random mutations will be lethal to the virus, some patients with COVID-19 do not fully clear the virus [18]. An early indication of a lack of viral clearance was the finding of rebound COVID-19 in some patients following cessation of antiviral treatment [19]. Recent studies have also shown that onward transmission of molnupiravir-mutated SARS-CoV-2 may occur [18].

In May 2023, nirmatrelvir-ritonavir (Paxlovid) received full FDA approval and is now the most frequently prescribed SARS-CoV-2 antiviral in the US [20]. Paxlovid is also associated with rebound SARS-CoV-2 infection following treatment cessation [19,20]. Paxlovid targets the main protease (Mpro) of SARS-CoV-2 [20]. Although SARS-CoV-2 variants with mutations in Mpro have been reported following the treatment of patients with COVID-19 with Paxlovid, the main concern is with the development of antiviral drug resistance rather than the production of SARS-CoV-2 mutation variants with increased pathogenicity [21].

A recent European Centre for Disease Prevention and Control (ECDC) report analyzed 258 publications on four approved therapeutic monoclonal antibodies and 23 publications on antiviral drugs [21]. According to these studies, the ORF1ab mutations nsp5: Q189K, nsp5: S144A, nsp5: H172Y, nsp5: F140A, and nsp5: E166A conferred a moderate to high reduction in virus susceptibility to Paxlovid [21]. The report identified a reduced neutralization capacity of Ronapreve (casirivimab/imdevimab) for all Omicron sublineages [21]. The sublineages BA.1, BA.2, and BA.5 showed a significantly reduced susceptibility to Regkirona (regdanvimab) and Xevudy (sotrovimab) [21]. The ECDC report identified significantly reduced neutralization activity for the BQ.1 and BQ.1.1 sublineages with the use of Evusheld (tixagevimab/cilgavimab) [21]. The ECDC recommends that a global SARS-CoV-2 antiviral resistance surveillance system follows the example set by the existing influenza antiviral resistance surveillance system [21]. The ECDC also suggests that this global surveillance system includes clear criteria for evaluating antiviral susceptibility and combines clinical data with in vitro data for COVID-19 antiviral therapies [21].

The University of Harvard and the University of Oxford have recently jointly developed the EVEscape database (https://evescape.org), which provides antibody escape predictions for all SARS-CoV-2 strains in the Global Initiative on Sharing All Influenza Data (GISAID) viral genome database [22]. The EVEscape artificial intelligence (AI) tool flags potentially concerning viral variants as they emerge and provides data on the three factors that determine the variant’s immune escape potential: a mutation that favors viral fitness; disrupts antibody binding; or occurs in a region accessible to neutralizing antibodies [22]. As of Oct 23, 2023, the Eris sublineage, EG.5.1, remains the most frequently recorded lineage in GISAID, and BA.2.86 (Pirola) has the highest predicted immune escape potential [22].

Conclusions

Although emergency restrictions associated with the COVID-19 pandemic have now ended, continued surveillance of mutations in SARS-CoV-2 and emerging variants are required, as these are related to changes in viral transmission and pathogenicity, immune escape from previous infection and vaccines, and resistance to antiviral treatments. Therefore, in addition to monitoring new variants of SARS-CoV-2, resistance to antiviral treatments of circulating new variants of SARS-CoV-2 should also be monitored, with discontinuation of the use of ineffective treatments for emerging SARS-CoV-2 viral variants.