A series of recent emerging infectious disease outbreaks, including the 2014 Ebola virus disease (EVD) epidemic in West Africa and the continuing Zika virus disease epidemic in the Americas, have underlined the need for better understanding of which kinds of pathogens are most likely to emerge and cause disease in human populations. Many, although not all, emerging infectious diseases are caused by viruses, and these frequently emerge from nonhuman host reservoirs (1–3). The enormous diversity (4) and high rates of evolution (5) of viral pathogens discourage attempts to predict with any precision which ones are most likely to emerge in humans. However, there is some consensus, at least in general terms, regarding the kinds of traits that are most essential in determining the capacity of a virus to infect, cause disease, and spread within human populations (Table 1). We focus on one of these traits, the capacity of a virus to spread from one human to another (by any transmission route other than deliberate laboratory exposure), a key determinant of the epidemic potential of a virus.

A theoretical framework for studying the dynamics of infectious disease outbreaks is well established (6). The capacity of an infectious disease to spread in a host population can be quantified in terms of its basic reproduction number, R 0 . R 0 is defined as the average number of secondary cases generated by a single primary case in a large, previously unexposed host population, and its value tells us a great deal about the epidemiology of a pathogen. R 0 = 0 indicates no spread in that population; this value would apply to zoonotic infections that do not spread between humans. R 0 in the range 0<R 0 <1 indicates that chains of transmission are possible but that outbreaks will ultimately be self-limiting. R 0 >1 indicates that major epidemics can occur or that the disease may become endemic in that host population. A higher value of R 0 also indicates that a greater reduction in transmission rates must be achieved to control an epidemic (6). R 0 values have been estimated for >60 common human pathogens (7), including human influenza A virus (R 0 <2), measles virus (R 0 <18), and dengue virus (R 0 <22).

R 0 is determined by a combination of pathogen traits, such as its transmission biology, which is itself a complex interplay between the within-host dynamics of the pathogen and the host response to infection, and host traits, such as demography, behavior, genetics, and adaptive immunity. Consequently, for any given infectious disease, R 0 can vary between host species and between host populations. Infectious diseases with R 0 close to 1 are a particular concern because small changes in their epidemiologies can lead to major changes in the threat they pose to public health (8).

R 0 is closely related to another conceptual approach to disease emergence, the pathogen pyramid. There are different versions of this scheme (3,9). We consider a pyramid of 4 levels (Figure 1). Level 1 represents the background chatter of pathogens to which humans are continually or sporadically exposed but most of which are not capable of causing infection. Other levels can be considered in terms of the R 0 of the pathogen in humans: level 2 corresponds to R 0 = 0, level 3 to 0<R 0 <1, and level 4 to R 0 >1.

Data and Analysis

Identifying and Characterizing Level 3 and 4 Viruses We updated our previous systematic literature review (10) of the capacity of virus species to transmit between humans (i.e., level 3 and level 4 viruses; Technical Appendix). Such viruses are found in 25 of 29 families containing viruses that infect mammals or birds (discounting 2 reports of family Nodaviridae species in mammals/birds). The 4 exceptions comprise 2 families that have no known human-infective viruses (Arteriviridae and Birnaviridae) and 2 with species that have been reported in humans but only at level 2 (Asfarviridae and Bornaviridae). A total of 22 of these families contain level 4 viruses with epidemic potential in humans (sometimes described as human-adapted viruses) (11). This finding indicates that this capability is widely distributed among virus taxa. The 3 families with level 3 viruses but no level 4 viruses are the Arenaviridae, Bunyaviridae, and Rhabdoviridae. A list of 37 presumptive level 3 virus species is provided in Table 2. These species cover a wide taxonomic range and a variety of transmission routes, including vectorborne. Several level 3 viruses have historically been associated with sizeable outbreaks (>100 cases) in human populations: Bwamba, Oropouche, Lake Victoria Marburg, Sudan Ebola, and o’nyong-nyong viruses. For some other viruses, including Guanarito, Junin, lymphocytic choriomeningitis, and Sabia (all arenaviruses); simian virus 40; Titi monkey virus; and influenza A(H5N1) virus, human-to-human transmission is rare or merely suspected. In addition, several viruses are only known or believed to transmit between humans by iatrogenic routes or vertical transmission; this group (Table 2) might be regarded as unlikely epidemic threats. When a virus is transmitted by a vector, it can be particularly difficult to confirm or exclude the infectiousness of human cases, as with Semliki forest, Barmah forest, and Rift Valley fever viruses. Similarly, even when human–vector–human transmission is believed to occur, it is often difficult to quantify its contribution to a given outbreak, as with Venezuelan equine encephalitis virus. Level 2 viruses are those that can infect humans (>100 species) but have never been reported to be transmitted by humans (10). In at least some instances, such as influenza A(H5N1) virus (12), this finding is attributable to tissue tropisms during human infection that are incompatible with onward transmission. Shifts in pyramid level equate to shifts in the public health threat posed by a virus. We consider possible shifts in the following sections.

Level 1 to Levels 3 and 4 Virus species of mammalian and, more rarely, avian origin are sometimes observed to be transmissible between humans when first found in humans, which constitutes a jump from level 1 straight to level 3 or 4 (Figure 1), and events of this kind have been reported regularly. Recent examples that appear on the basis of available evidence to fit this model include severe acute respiratory syndrome coronavirus (first reported in humans in 2003), Bundibugyo Ebolavirus (2008), Lujo virus (2009), severe fever with thrombocytopenia syndrome virus (2011), and Middle East respiratory syndrome coronavirus (MERS-CoV) (2012). We still have incomplete knowledge of the diversity of viruses that infect mammals and birds; the few hundred recognized species (4) surely represent only a small fraction of the total (3). Moreover, we have few predictors of potential human-to-human transmissibility. One possible indicator is emergence from nonhuman primates, with suggestions that primate viruses are more likely to be able to, or to acquire the ability to, spread in human populations (13,14). However, emergence of human transmissible viruses from bat (e.g., severe acute respiratory syndrome coronavirus) or bird (e.g., influenza) reservoirs indicates that this trait is associated with a wide range of reservoirs.

Level 2 to Levels 3 and 4 The possibility that level 2 viruses might acquire the capacity to be transmitted between humans (i.e., move into level 3 or 4) is a major concern, especially in the context of influenza A(H5N1) virus and other avian influenza virus subtypes. However, there are few examples of this transition throughout the entire recorded history of human viruses going back to 1901. One possible example involves the simian immunodeficiency virus (SIV) and HIV. A SIV smm -derived laboratory strain of SIV has been reported to infect humans, but without onward transmission (15). SIV smm is related to HIV-2. SIV cpz , which is related to HIV-1, has not been directly observed in humans. However, different HIV-1 lineages, independently derived from SIV cpz , are variably transmissible in humans, and the pandemic HIV-1 M lineage was the only virus to overcome a key host restriction factor (human tetherin) (16). The only other examples of viruses newly transmitted between humans relate to rare instances of iatrogenic transmission (e.g., Colorado tick fever or rabies viruses). Epidemiologic and phylogenetic considerations routinely inform our assessment of the likelihood of human-to-human transmission being observed in the future. For example, there is markedly less concern about rabies virus than about avian influenza virus, and we suggest 2 reasons for this observation. First, rabies virus has a much longer history of and a much higher incidence of human infection, but human-to-human transmission is extremely rare. Second, there is no evidence that other rhabdoviruses viruses (with the possible exception of Bas-Congo virus, which represents a novel genus) are transmissible in humans (or primates more generally).

Level 3 to Level 4 Level 3 viruses can also become level 4 viruses. We note that virus evolution is not (necessarily) required for R 0 to become >1 in human populations. Differences in host (or vector) behavior, ecology, or demography might be sufficient (8). Instances of shifts from level 3 to level 4 in recent times have been infrequent. Three candidates are Ebolavirus, Zika virus, and chikungunya virus. However, although these viruses have caused epidemics of unprecedented size in humans populations in the past decade, the condition R 0 >1 in human populations might had been previously met for all 3 viruses (17–19). For Ebola virus, the epidemic in West Africa in 2014 constituted the first appearance of this virus in high-density, urban populations, which is expected to correspond to a higher value of R 0 . The chikungunya virus epidemic in the Indian Ocean region in 2005 was associated with a vector species jump (from Aedes aegypti to Ae. albopictus mosquitoes) that has been linked to a mutation in the virus envelope 1 protein gene (18). The chikungunya virus epidemic in the Caribbean region in 2013 followed the first appearance of chikungunya in the Americas and infected populations that had no history of exposure to the virus. The current Zika virus epidemic in South America appears to be another example of a transition from a level 3 to a level 4 arbovirus associated with geographic spread into areas with high densities of vectors (19). Occasional Zika virus transmission directly from infected humans to other humans are of considerable interest, but probably contribute little to R 0 . Chikungunya, Zika and the other level 4 arboviruses (yellow fever and dengue viruses) illustrate that, for arboviruses, a high potential for spread in human populations is linked to carriage by anthropophilic vector species, particularly mosquitoes of the genus Aedes. In contrast, no tick species are regarded as anthropophilic, and there are no level 4 and few level 3 tickborne arboviruses.

Epidemiologic Patterns The preceding sections illustrate that identifying transitions of viruses between level 2 and level 3 or between level 3 and level 4 is not always straightforward. Standard epidemiologic theory can help clarify our expectations. Figure 2 As we discussed, pyramid level is related to the basic reproduction number R 0 in human populations. In turn, the value of R 0 is indicative of expected outbreak dynamics. Some key results (Figure 2) are the probability that a single primary case will generate >1 secondary cases (for any value of R 0 ), the expected average size of an outbreak generated (over the range 0<R 0 <1), and the probability that an epidemic will spread in the human population (for R 0 >1). These results strictly apply to homogeneous infections in a homogeneous host population, although more general frameworks can accommodate host or pathogen heterogeneity (20–22). Nonetheless, the key predictions that secondary cases do not always occur even if R 0 >0 and that major epidemics do not always occur even if R 0 >1 are robust. Figure 3 From an epidemiologic perspective, our confidence that a putatively level 2 virus is truly incapable of human-to-human transmission is thus a function of the number of index cases observed. The transition between level 3 and level 4 can be studied in terms of the expected distribution of outbreak sizes (23). In the range 0<R 0 <1, an overdispersed distribution of outbreak sizes is expected: most outbreaks are small (often just single cases) with a long tail of larger outbreaks. This pattern has been reported for a range of emerging viral diseases (Figure 3). As the critical threshold R 0 = 1 is approached, this value is signaled in the outbreak size distribution (Figure 3). This framework has been used successfully to monitor the epidemiology of measles virus in the United Kingdom after a decrease in childhood vaccination rates in the late 1990s and indicated the approach to the critical threshold that corresponded to loss of herd immunity (23). Outbreak size distribution analysis has been applied to human case data for Andes virus (24), monkeypox virus (20), and MERS-CoV (25) (Figure 3). For EVD up to 2013, data are clearly inconsistent with theoretical expectation for R 0 <1 (Figure 3), which suggests that large numbers of small outbreaks have remained undetected or that R 0 was already >1 in at least some settings. Either way, R 0 ≈1 for EVD in humans implies that small differences in the biology or epidemiology of the virus would lead to large changes in scale of outbreaks (8), which could make events such as the EVD epidemic in 2014, if not predictable, then much less unexpected.

Evolution Changes in pyramid level might be mediated by virus evolution or changes in virus ecology (28). A major issue is whether the capacity of a virus to spread in human populations arises as a result of adaptation (evolution of transmissibility that occurs during human infection) or preadaptation (genetic variation within nonhuman reservoirs that predisposes a virus not only to infect humans but also transmit between humans, noting that RNA viruses often show high levels of genetic variation such that they are sometimes described as quasi-species [29]). These alternatives have been characterized as tailor-made and off-the-shelf, respectively (28). The first alternative implies a progression from no or low transmissibility between humans to moderate or high transmissibility. The second alternative implies moderate or high transmissibility at first infection of humans. We consider that our survey of documented changes of pyramid level is most consistent with the off-the-shelf model of virus emergence. In particular, we can find no convincing examples of level 2 viruses becoming level 3 or 4 viruses, which suggests that, if this happens at all, it typically happens sufficiently rapidly (i.e., requires a sufficiently small number of introductions) that we fail to observe the level 2 phase. In contrast, we regularly observe viruses at levels 3 or 4 the first time they are detected in human populations. Nonetheless, the possibility of virus evolution of transmissibility in a new host has been demonstrated experimentally for influenza A(H5N1) virus in ferrets (30). A theoretical study (31) suggested that the fact that this virus subtype has been circulating widely in poultry populations, with frequent human exposure and sporadic human infection for almost 20 years, provides little or no reassurance about its future evolutionary trajectory. HIV lineages show clear evidence of adaptation to humans (16), but as discussed earlier, it is not clear whether the SIV lineages that gave rise to HIV-1 or HIV-2 were capable of transmission between human hosts. We speculate that extended infection times make tailor-made emergence more likely for retroviruses.

Transmission Demonstrating that an infected human has the potential to transmit the infection to another human is not always straightforward. High virus titers in body secretions and excretions, blood, or skin are considered indicative. Case clusters are suggestive, but if persons occupy the same environment (e.g., household), then it might be difficult to rule out common exposure. Case clusters must be epidemiologically plausible (i.e., delimited in space and time in a manner consistent with the known or assumed epidemiology of the virus). Genotyping techniques are useful tools for confirming a cluster but do not resolve the source of infection. For several of the viruses we studied (e.g., Bas-Congo, Lujo, Nelson Bay, and severe fever with thrombocytopenia syndrome viruses) (Table 2), the evidence for human-to-human transmission is best regarded as tentative, particularly where putative clusters were small. Such assessments can be even more difficult for vectorborne viruses. In many situations, the best evidence for the human-to-human transmission will come from analysis of virus genome sequences.