During 2002-2003, when severe acute respiratory syndrome-1 (SARS-CoV-1) first emerged in China, it triggered a global alert, including in Nepal. I was then working as a junior medical officer, where I mostly provided care to patients suspected of having SARS-CoV-1 cases at Sukraraj Tropical and Infectious Disease Hospital, although none were laboratory-confirmed. According to the World Health Organisation (WHO), SARS-CoV-1 was reported in 29 countries and resulted in 774 deaths due to its complications. No cases of SARS-CoV-1 have been reported since 2004.

Likewise, SARS-CoV-2, which emerged in 2019 and caused coronavirus disease 2019 (Covid-19), was first reported in Wuhan, China, as a SARS-like pneumonia, resulting in hundreds of thousands of deaths worldwide. In Nepal, the first laboratory-confirmed case was identified in a 32-year-old male student who had returned from Wuhan, China. Although this index patient was managed uneventfully in Sukraraj Tropical and Infectious Disease Hospital, Nepal experienced a substantial disease burden during successive waves of Covid-19. Nearly 12,000 deaths were reported due to Covid-19-related complications, with the highest mortality observed during the second wave dominated by the Delta variant. In addition, hundreds of patients continue to suffer from post Covid-19 syndrome despite successful acute illness management.

Research has demonstrated that bats are the primary reservoir of coronaviruses (SARS-CoV-1 and 2). While Covid-19 has transitioned towards a seasonal infection pattern, there remains grave concern regarding the potential emergence of a novel coronavirus arising from genetic mutations over time, here referred to as ‘SARS-CoV-3’. This concern is particularly more relevant in South Asia, where recent increases in Nipah virus cases reported in India and Bangladesh suggest more frequent human-bat interactions in the region.

Covid-19 has demonstrated the capacity to generate multiple variants within a relatively short period, with each variant exhibiting differing transmissibility and fatality rates across regions. For instance, during the first wave, the variant initially identified in China was associated with substantial mortality in China, Europe and the United States, while its impact appeared comparatively lower in South Asia, including Nepal. In contrast, the second wave, dominated by the Delta variant that first emerged in India, resulted in devastating losses of human life, particularly in India and Nepal. However, the third wave, driven by the Omicron variant, first identified in South Africa, was generally associated with less severe disease but greater transmissibility than the Delta variant. At present, Omicron variant sub-lineages continue to emerge globally. If this evolutionary trend persists, the possibility of the emergence of a novel coronavirus, here dubbed as ‘SARS-CoV-3’, cannot be ruled out, particularly given that SARS-CoV-2 emerged approximately 16 years after the appearance of SARS-CoV-1 (2003-2019).

One of the widely debated issues concerns the identification of an intermediate host for coronaviruses (SARS-CoV-1 and 2). Previous studies have reported detection of SARS-CoV-1 in masked palm civets (wild animal) sold in local markets in Guangdong, China, indicating that transmission may have occurred during handling or trading of these animals, although clinical signs and symptoms in this animal were not documented at the time. Nevertheless, there is no definitive evidence establishing masked palm civets as the true intermediate host for SARS-CoV-1.

SARS-CoV-2 may have arisen through genetic drift, characterised by slow, gradual genetic mutations over an extended period, originating from SARS-CoV-1. SARS-CoV-2 emerged approximately 16 years after the initial appearance of SARS-CoV-1, raising the hypothesis that related viruses may have continued to circulate silently in human populations during this interval before re-emerging with enhanced transmissibility and increased pathogenicity. Thus, the potential emergence of SARS-CoV-3 with increased pathogenicity over the coming years cannot be overlooked, particularly as new Omicron sublineages of SARS-CoV-2 continue to emerge in human populations.

The most controversial hypothesis regarding the origin of SARS-CoV-2 is the laboratory leak theory, which suggests that the virus may have been unintentionally released from a research laboratory through various routes into human populations. Although this hypothesis remains highly debated and has been dismissed by the majority of the scientific community, it cannot categorically be excluded. Advances in state-of-the-art laboratory technology have made it possible to manipulate viruses for research purposes, underscoring the importance of stringent biosafety measures. Historical examples of laboratory-developed biological agents highlight the potential risks associated with inadequate handling or containment.

Recently, the Chinese government has proposed a ‘cold-chain’ hypothesis, suggesting that SARS-CoV-2 may have been introduced into China through imported frozen food; however, this conclusion has been met with scepticism by many scientists. Although extensive research has focused on post-infection outcomes in humans and viral behaviour, it is crucial to understand how the virus crossed species barriers and which intermediate animal hosts facilitated transmission to human populations. Without clearly elucidating the link between bat reservoirs and human infection, it will be extremely difficult to implement effective preventive measures against the potential emergence of SARS-CoV-3.

In summary, although the emergence of SARS-CoV-3 may currently seem unlikely, the increasing incidence of zoonotic diseases such as the Nipah virus in India and Bangladesh highlights the rising frequency of close human-bat interactions, suggesting that the risk of emerging SARS-CoV-3 cannot be ignored in South Asia. Given the devastating impact of SARS-CoV-2 in modern history, it is critical to identify the definitive intermediate hosts, which could help prevent the emergence of the next SARS-related coronavirus. Simultaneously, close monitoring of viral evolution is essential to evaluate potential threats and prepare for a possible SARS-CoV-3 pandemic.