COVID-19 pandemic shows a rapid succession of dominant viral SARS-CoV-2 variants [3], probably caused by intrinsically high mutation rates in RNA viruses [4]. New variants are seemingly always more infective than the previous, enabling the pandemic to move around the globe in waves directed by the local availability of susceptible individuals among contacts of COVID-19 patients.

For microbes and viruses, the decisive survival challenges are within their hosts. Individual immune response and other intrinsic settings force pathogens to change or to be eliminated, often replaced by a more resilient pathogen. Probable survival and spreading challenges for new SARS-CoV-2 variants in different population settings are listed in Table 1. The initial idea is that mutated viral variants can emerge only during the infection of a host that was susceptible to previously present SARS-CoV-2 variants. In other words, any mutation that promotes a new SARS-CoV-2 variant occurs in COVID-19 patients during the infection.

Survival challenges for the new, mutated viral variant within the initial host can be divided in phases (Table 1): the replication challenge requires sufficient viral multiplication in normal ACE2 expressing cells, while the excretion challenge requires sufficient viral presence in respiratory and digestive fluids [5]. Both challenges depend on two relations: competition with the coexisting unmutated viral variant and on the emerging immune response of the initial host against both variants.

Competition between the mutated and the unmutated variant for replication and excretion forces the new SARS-CoV-2 variant to remain ACE2 dependent.  Otherwise, it would lose the ability to compete with the unmutated variant for cellular replication in ACE2 expressing cells of the initial host.  Replications of all new viral variants thus seem inevitably linked to the dysfunction of the renin-angiotensin system, more often and severe in older patients with stress-related comorbidities [6].

The third survival challenge for the new viral variant is to infect other persons, beside the initial host. This challenge is easily reduced by various epidemiological and social measures, presence of already immune persons (convalescent or vaccinated) among available contacts, and other viral variants.

In the early phase of local epidemic, the challenge of infectivity favours increased spreading among susceptible persons (unvaccinated or not convalescent persons, or those with already diminished previous immune response to this virus). Specific immune response against the previous SARS-CoV-2 variant can also prevent clinical disease by some new variants [7], although often not completely.

If one of the emerging new variants can evade the prevailing immune response [8, 9], it can probably easily spread to other persons, despite their vaccination or convalescence. The emergence of a “stealth” SARS-CoV-2 variant is a critical scenario that leads to self-sustained COVID-19 pandemic.

It is here proposed that in areas approaching the herd immunity, the speed of viral spreading might become unimportant, due to very few susceptible persons. In this setting, new cases are often clustered and this allows several viral variants to coexist in the same population and evolve separately. The infection starts to imitate an endemic disease with stable total numbers of new cases, since this setting forces the emerging viral variant to evolve toward reduced recognition by the prevailing immune response in the population (Figure 1).

This hypothetical endemic setting can last until an immunologically different viral variant emerges, less detectable by available immune responses. When this “stealth” variant occurs, it can spread like a new disease that requires new vaccines and social measures.

This interpretation suggests that the COVID-19 pandemic have a potential to initiate slow cycles of ever returning new SARS-CoV-2 variants (Figure 1), thus leading to a perpetuating Corona pandemic.

Table 1: Three proposed survival challenges for the new viral variant within the initial host that acquired infection with the previous SARS-CoV-2 variant: a/ the replication challenge is sufficient viral multiplication in ACE2 expressing cells; b/ the excretion challenge is sufficient viral presence in respiratory and digestive fluids; c/ infecting other persons in contact with the initial host.