SARS-CoV-2 pandemic: on its way to becoming an endemic disease?

We analysed the impact of Alpha, Delta and Omicron SARS-CoV-2 lineages throughout the three sequential waves of these variants in the UK. In summary, the cumulative vaccination rate increased by over 12-fold throughout the study period, while the odds of coronavirus disease 2019 (COVID-19) related hospitalizations declined by 78% and 83% from Alpha to Delta and Alpha to Omicron periods. Likewise, COVID-19 related deaths declined by 93% and 95% from Alpha to Delta and Alpha to Omicron periods. Widespread vaccination and SARS-CoV-2 mutation seem thus to have combined to modify the scenario, with early signs of endemicity. Omicron SARS-CoV-2


1.Introduction
Although the number of cumulative deaths remains considerably lower than those caused by the Spanish flu pandemic in 1918-1919 (i.e., around 50 millions) [1], the ongoing worldwide outbreak sustained by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing unprecedented consequences on healthcare, society and economy. As observed in the past for other infective agents, deadly pandemics have emerged throughout the recorded human history, but have then disappeared or have become endemic disease over time by concurrent impact of herd immunity (which can be achieved by either natural infection or vaccination) and virus attenuation [2]. Influenza A virus H1N1 is a paradigmatic example of a pathogen that has so much mutated its genome (by introducing over 300 non-synonymous changes, i.e., around 7% of all codons) [3], such that it has now become endemic, whilst SARS-CoV(-1) and Middle East respiratory syndrome coronavirus (MERS-CoV) have instead progressively disappeared [4].

2.Materials and Methods
We carried out an electronic search in the official UK Government website for data and insights on coronavirus (COVID-19) [6], to retrieve official information on nationwide volume of SARS-CoV-2 testing, numbers of new SARS-CoV-2 daily cases, Software Ltd., Ostend, Belgium). Statistical significance was set at p<0.05. The study was carried out in accordance with Helsinki Declaration, under terms of relevant local legislation. This research was based on publicly available data, thus Ethical Committee approval was unnecessary.

3.Results
The main outcome of our analysis is shown in  Figure 1). With respect to the clinical endpoints, the SARS-CoV-2 positivity rate of testing was 10.7% in the SARS-CoV-2 Alpha prevalent period, decreasing to 1.7% in the SARS-CoV-2 Delta prevalent period, but then increasing to 11.7% in the SARS-CoV-2 Omicron prevalent period. Such trend of SARS-CoV-2 positivity was not mirrored by the rate of COVID-19 related hospital admissions and deaths, as shown in Table 2. More specifically, the odds of COVID-19 related hospitalizations declined by 78% and 83% from Alpha to Delta and from Alpha to Omicron prevalence periods, respectively, decreasing also by 22% from the Delta to Omicron periods ( Figure 1). A similar trend could be noted for COVID-19 related deaths, which declined by 93% and 95% from Alpha to Delta and from Alpha to Omicron periods, respectively, also decreasing by 24% between the Delta and Omicron periods ( Figure 1).

4.Discussion
The results of our analysis pave the way to some important reflections. The first and perhaps most important consideration is that both COVID-19 related variant, which has become endemic at the end of 2021 throughout UK and Europe, our analysis confirm that it apparently retains moderately higher infectivity compared to the Alpha lineage (+10%), though its spread has been associated with considerably enhanced (up to 8-fold) rate of positive SARS-CoV-2 tests compared to the rate found during the Delta strain prevalence. This finding confirms previous evidence that have attributed a considerably enhanced reproduction number (between 3 to 4 higher) to this new strain compared to the formerly endemic Delta lineage [8,9]. Nonetheless, such increased infectivity has not been mirrored by exponential increase of COVID-19 related hospitalizations and deaths in the UK, which were actually found to be 83% and 95% lower compared to the Alpha variant period, but also 22% and 24% lower compared to the Delta strain period. These findings are in keeping with recently published evidence, which would seemingly portrait the Omicron lineage as a less pathogenic virus compared with the Delta variant despite its immune escape capacity.

Garrett et al. recently reported that the rate of asymptomatic SARS-CoV-2 cases among
persons living in South Africa was over 12-fold higher during the recent Omicron outbreak compared to the former Delta wave [10]. In accordance with these findings,

Maslo et al. explored the clinical outcome of South African patients hospitalized for
COVID-19 during the Omicron wave [11], revealing that the number of patients needing oxygen therapy, mechanical ventilation, intensive care and even the death rate progressively declined over time, becoming the lowest during the period of prevalence of the Omicron strain. Similar data were preliminary reported in Canada by Ulloa et al. [12], who evidence an over 50% reduction of COVID-19 related hospitalizations and deaths in patients testing positive for the Omicron lineage compared to those with infection sustained by Delta variant. Additional preliminary evidence comes from a Californian study carried out by Lewnard et al. [13], who concluded that the number of COVID-19 related hospitalizations, intensive care unit (ICU) admissions and deaths decreased by 50-90% by comparing Omicron and Delta variant infections.
The fact that infection with the highly mutated SARS-CoV-2 Omicron variant (this lineage has accumulated over 30 non-synonymous mutations in the spike protein, 15 of which within the receptor binding domain) [14] is seemingly less severe than with other strains (i.e., Alpha or Delta) fits with early scientific findings regarding its intrinsic viral properties. Evidence attests that this lineage seems to have magnified affinity for its human host cell receptor (i.e., angiotensin converting enzyme 2; ACE2) [15], while more prevalently infecting and more efficiently replicating in the upper respiratory tract [16][17], thus having attenuated pulmonary and systemic virulence.
According to this and other previous evidence, SARS-CoV-2 may have started a (predictably long) journey to gradually becoming an endemic disease, with which humanity will need to for better or worse must live with [18]. However, the position of Omicron is the progressive evolution of the virus has yet to be fully understood and the future remains unpredictable, especially with much of the world still unvaccinated, leaving high potential for emergence of new variants. Moreover, the potential individual and population health impacts of Omicron on post-acute sequelae of COVID-19 and long COVID remain to be seen and the consequences of endemicity remain unknown.
Irrespective of the ostensibly lower pathogenicity attributed to the SARS-CoV-2 Omicron lineage compared to previous variants, it is noteworthy that the exiting evidence garnered so far on the so-called "Omicron wave" around the world, including that provided in this UK-based study, has emerged from highly vaccinated populations.
It is hence not easy to discriminate to what extent the considerable decline observed in the number of COVID-19 hospitalizations and deaths may be attributed to SARS-CoV-2 mutations versus widespread vaccination, since the efficacy of COVID-19 vaccines against the risk of developing a vast array of COVID-19 related complications needing hospital care is now almost unquestionable [19][20]. Although the Omicron variant appears more resistant versus antibody-mediated neutralization (e.g., neutralization can be however efficiently restored by administering COVID-19 vaccine booster doses) [21], the protection garnered by T cells against severe disease appears largely intact [22].
Thus, the most likely scenario encompasses that both increasing population immunity and changes in intrinsic viral properties may have combined to modify the current pandemic scenario. Thus, the path to a future where SARS-CoV-2 is endemic may be occurring. Regardless of the pathogenic attenuation, Omicron is still associated with substantial morbidity and mortality and widespread transmission could potentially lead to further mutation and variant emergence, thus physical preventive measures and widespread vaccination and boosters must still be advocated, especially in developing countries, as nobody should forget that we are still facing one of the worst pandemics in human history.