MERS-CoV and the hypothesis of a camel source

This post was written in January 2014 and is now out of date. Since then a considerable amount of new evidence for the role of camels in the MERS-CoV epidemic has been published. A discription of some of the genetic data is here


In the abscence of any other hypotheses I think it is interesting to explore the idea that camels are the primary source of MERS-CoV and whether it can explain the known facts. I should add that these are (informed) speculations based on limited information and I admit there are other plausible hypotheses (but currently with even less evidence). At this stage it would still be reasonable to replace 'camel' with just about any other animal with which humans have exposure it is just none other have been implicated to date.

Here are the pieces of evidence that I think support this hypothesis.

I have posted a list (probably incomplete) of published evidence linking camels with MERS-CoV in humans.

1) Camels can be infected with MERS. A few studies have shown that some populations of camels have antibodies that strongly cross-react with MERS-CoV spike proteins but not with other related coronaviruses. The Qatar 3 patient in the study above, owned and looked after a herd of 14 camels and 3 of them were shown to be PCR positive for MERS-CoV with sequence isolated from one of them (Haagmans et al 2013). A patient in Jeddah, KSA, also owned camels one of which tested postive using PCR. To my knowledge no other livestock animal has tested positive for MERS-like antibodies and none of the Qatar case's other animals were positive. The camels have subsequently tested negative so have possibly cleared their viruses (suggesting this is a mild, acute virus in camels). 

2) Despite causing human cases for nearly 2 years, this virus has resolutely stayed geographically constrained to the Arabian Peninsula. The few cases outside this area can all be traced directly to the affected countries. There is clear evidence of chains of human-to-human transmission but these are not sustained. If the nearly 200 (mainly severe) cases represented the tip of a large sustained human transmission network, the virus would not likely remain so geographically constrained. Most other acute viral epidemics of humans travel the globe in airplanes. 

3) At least some of the human cases have had documented contact with camels. This information is not reliably reported so it is not possible to calculate if this is a risk factor (I also don't know what the denominator on this would be - i.e., the expected exposure to camels non-MERS patients with similar demographic profiles). 

4) The incidence of (apparently primary) cases does not seem to be growing over the last 6 months. This can be seen in the timeseries data here but this data is not reported with consistent clinical dates so it is difficult to test this formally. There is perhaps an increase in incidence from April last year but this may be due to increased awareness (perhaps due to the large nocosomal outbreak in Al-Hasa about that time). Or it may represent increased exposure due to an increase in prevalence in the reservoir host (I will come to this later).

Figure 1|The phylogeny of all unlinked human genome sequences to illustrate the idea of a source animal reservoir for human cases. The dark green lineages are chains of infections in the reservoir, the lighter yellow colour represents the points where the virus jumps into humans. Some of these cases represent extended (but ultimately terminating) chains of human to human infection - most notably Al-Hasa.

If the camel hypothesis was correct then this would mean that most of the diversification in the tree in Figure 1, in green above, would have taken place in camels. This could also explain the high rate of geographical movement (albeit strictly with in the Arabian Peninsula) apparent in the trees of Cotten et al (2013) because camels are widely transported in this area for sale, racing and festivals. So does the common ancestor in the tree represent the jump to camels (perhaps from bats)? Not necessarily. Meyer et al (2013) report very high prevalence of MERS-like antibodies in camel samples collected and stored in 2003. This might mean that the jump occurred decades ago and the virus has been circulating in camels endemically ever since. 
 

The questions that arise from this hypothesis:

If the common ancestor of the known cases existed after 2009, how could MERS-CoV-like antibodies be present in camels in UAE in 2003? One possibility is that there have been multiple jumps of related but different coronaviruses from bats to camels. If sufficiently related these could all be positive in serology tests. The alternative is that this virus has been circulating constantly in camels since long before 2003 but a short infection time and long lasting immunity means that multiple lineages exist, spread in naïve populations and either spread or go extinct. This may be similar to human childhood disease such as chicken pox where at anyone time a tiny fraction of the population is infected but over their lifetime most people will catch it. Such diseases rely on the replenishment of susceptible hosts through birth. Foot and mouth disease is endemic in cattle in many parts of the world. Another possibility is that the virus is adapting to existing immunity by mutations in the antigenic genes so that it can infect previously infected hosts again. This is the mode of evolution of human seasonal influenza but also has been shown to happen in influenza in horses
 
Why has there been an increase in human incidence since early 2012? This is a more tricky question to answer. A chance in recorded incidence in zoonotic infection could be the result in a change in surveillance and diagnosis, a change in exposure of humans to the virus or a change in infectivity of the virus in humans. For the first, it is possible that human cases were occuring but being misdiagnosed as other diseases or not being reported. The cluster of severe respiratory illness in a hospital in Jordan in April 2012, including 2 deaths, has been listed as unknown and was only retrospectively confirmed as MERS-CoV through PCR testing. For the second possibilty, it is possible that the virus got into a particular population of animals that is more connected to other susceptible populations (I have no knowledge of what this might be but for influenza the analogy would be race horses which are moved about and come into contact with many other horses). The third option would require that one particular lineage had evolved in such a way as to make humans more susceptable to infection. This would not be adaptation to humans but a chance event that may be related to antigenic evolution in camels and that just happens to help infect humans. 
 
How can this explain the human cases with no direct exposure to animals? There are a number of cases with no recorded exposure to animals (let alone camels) but these could be part of the limited chains of human to human transmission (ultimately connected to camel exposure). It is also possible there are some intermediate tranmission routes (this list could include environmental, vector borne, another animal or animal product such as the consumption of raw milk).
 
Why has MERS-CoV not been found in camels except those connected to human cases? It seems plausible that MERS-CoV infection in camels is acute and mild (the known cases in camels in Qatar and KSA were so) and at any point in time, the proportion of camels infected is small. Serology tests whether the animal has ever been infected so the very high positive rates in some populations suggest that most camels will have had the virus at some point in their life. But if infections only last days or weeks samples from healthy individuals or samples taken for other reasons are unlikely to be positive for viral RNA. Human cases are being detected when the virus causes a severe disease or through contact tracing of confirmed cases. Because the overall prevalence can be so low, to detect respiratory viruses in livestock it is generally necessary to bias sampling towards animals that are have been reported with symptoms. 
 

How could this hypothesis be tested?

One prediction of the camel-source hypothesis would be that people in contact with camels are more likely to be infected whereas if the virus is has been circulating primarily in humans this would not be true. A serological test of camel husbandry workers verses an age matched cohort of non-animal exposed people might provide evidence. 

If viral sequences were isolated from camels through mass random surveillance across the Arabian Peninsula (i.e., not through a followup of a known human case), we would expect some of these these viruses to intermingle with the human cases in the phylogenetic tree.  This is because, under the camel-source hypothesis the sequences from primary human cases are connected from the camel viral population by only a short chain of infections. However, this could still be compatible with the virus spreading in humans and causing sporadic tranmission chains in camels. We might also pick up lineages of greater diversity than the human cases, particularly if just one lineage is human-infectious. 

What are the alternative hypotheses?

Firstly, another animal could be acting as a reservoir source. From the phylogenetics of known coronaviruses, MERS-CoV almost certainly came from bats at some point in the past. It is also possible that another livestock or domestic animal is a source (or a mixture of animals) but to date no serological evidence has been reported. Any such hypothesis requires an explanation about the exposure of numerous human cases to this source (which perhaps puts bats lower on the list of possible direct source than other animals).
 
The other alternative is the emergence and sustained transmission within the human population. This only requires a single cross species transmission from the animal source (and thus possibly directly from bats as this need only be a rare event). The modelling work in Cauchemez et al (2013) suggests that even with modest growth in cases, human-to-human transmission could be sustained over the timescale estimated from the phylogenetic analysis. However, it requires a positive growth rate (although that large) and would require a considerable number of undetected clinical cases in the affected countries. However, even if this rate of growth was low it would still be exponential growth and Cauchemez et al (2013) estimate the viral population would double in 90 days.  If this were the case and the human epidemic continued to grow since this paper was written, then we would expect to start seeing the virus appear in other countries (beyond the Arabian Peninsula) because of the degree of international travel. These cases would be in individuals without any recorded travel history to the Middle East. These new epidemics would cause severe and fatal cases at similar rates to what we have seen thus far and thus would start to be detected. 
 

References

Cauchemez et al (2013), The Lancet Infectious Diseases14: 50 - 56.

Cotten et al. (2013) 'Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study', The Lancet382: 1993 - 2002.

Guery et al (2013), The Lancet  381: 2265 - 2272.

Haagmans et al (2013) "Middle East respiratory syndrome coronavirus in dromedary camels: an outbreak investigation" The Lancet Infectious Diseases.

Meyer B, Mueller MA, Corman VM, et al (2014) Antibodies against MERS coronavirus in dromedary camels, United Arab Emirates, 2003 and 2013. Emerg Infect Dis. Online access.

Reusken et al (2013) "Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study" The Lancet Infectious Diseases, 13: 859 - 866.

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