Why are there so few (or so many) circulating coronaviruses?

Abstract

Despite vast diversity in non-human hosts and conspicuous recent spillover events, only a small number of coronaviruses have been observed to persist in human populations. This puzzling mismatch suggests substantial barriers to establishment. We detail hypotheses that might contribute to explain the low numbers of endemic coronaviruses, despite their considerable evolutionary and emergence potential. We assess possible explanations ranging from issues of ascertainment, historically lower opportunities for spillover, aspects of human demographic changes, and features of pathogen biology and pre-existing adaptive immunity to related viruses. We describe how successful emergent viral species must triangulate transmission, virulence, and host immunity to maintain circulation. Characterizing the factors that might shape the limits of viral persistence can delineate promising research directions to better understand the combinations of pathogens and contexts that are most likely to lead to spillover.

Keywords: antigenic space; cross-reactivity; landscape of immunity; viral ecology.

Figure 1

Coronaviruses and the pathway to endemism. (A) In this schematic, a subset of pathogens in the diverse reservoir pool enters the emergent pool via spillover, and a subset of emergent pathogens attain sufficiently stable transmission to enter the pool of persistently circulating endemic pathogens. Owing to incomplete sampling, a fraction of each pool remains unobserved (lighter colors). (B) Depicted are the reservoir, emergent, and endemic pools for coronaviruses, and again a fraction of each remains unobserved. Classification follows the International Committee on Taxonomy of Viruses (ICTV) [6]. (C) Spillover and cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a likely bat reservoir, to a possible intermediate host, to humans, and then to secondary human–animal transmission. Bats have been hypothesized to be unusually prolific hosts for pathogens [111], but many other hosts are also noted (including non-human primates, wild and domestic carnivores, and ungulates). Note that human–mink–human transmission is suspected from fur farms, and susceptibility based on angiotensin-converting enzyme 2 (ACE2) receptor sequence variation was predicted, but unconfirmed, for some non-human primates [15., 16., 17., 18.]. Abbreviation: est. n ya, established n years ago; MERS, Middle East respiratory syndrome.

Figure 2

Key figure. Possible hypotheses to explain the limits of endemic viral diversity. (A) An increase in spillover over time leads to the movement of more pathogens (shown as pink circles) from the emergent pool to the endemic pool. The filters or barriers to establishment as an endemic pathogen (shown as a gray bar with gaps) are constant; in other words the probability of an emergent pathogen being established remains fixed over time. (B) Host susceptibility increases over time such that a greater proportion of emergent pathogens can exploit widening gaps in immunity. (C) Emergent pathogens are numerous and diverse but the probability of establishment is small owing to narrow requirements for host and pathogen factors that are compatible with persistent transmission. (D) Opportunities for viral emergence depend on previously established pathogens that block or partially block immune niches or gaps via cross-reactive immune responses (e.g., for coronaviruses [84]).

Figure 3

The landscape of variable immune responses against coronaviruses and the concept of 'free antigen space'. 'Antigenic space' can be represented in 2D [112]. Above, a large proportion of possible antigenic phenotypes are within areas of antigenic space featuring some degree of cross-reactivity to existing endemic pathogens. The potential for transmission (e.g., in terms of R₀) of a novel pathogen situated near an existing pathogen can vary from low (white) to high (green), and the proportion of 'occupied' space where transmission is strongly reduced can vary from small (group A) to large (group B). Below, for different pathogen groups, each existing pathogen generates an immune response that occupies a smaller proportion of antigenic space, either because of more specific immunity or a larger possible antigenic space. As a result, a greater proportion of antigenic space is 'free' (group C) or more pathogens can occupy the antigenic space without much overlap (group D).