Middle East respiratory syndrome coronavirus first emerged in 2012 and outbreaks have continued ever since, in the Middle East and beyond. Dr Ben Neuman, a virologist at the University of Reading, explains how the infection is currently diagnosed and explains why a quicker and simpler test could be urgently required in the future.
Since Middle East respiratory syndrome (MERS) first emerged in Saudi Arabia in 2012, epidemiologists have been watching with mounting concern. The virus – which, as of October 2015, has infected 1,595 people in 26 countries and caused 571 deaths – still has no vaccine or specific treatment.
What is more, infection control measures have been patchy. According to the World Health Organization, until these improve, “individual countries and the global community will remain at significant risk for further outbreaks”.
The scale of the problem was underscored in May 2015 when an outbreak began in South Korea. Spreading quickly throughout the country, the outbreak had killed 36 people and caused a significant economic slowdown by the time its ‘de facto end’ was announced in July.
“The first patient in South Korea was likely what is known as a super-spreader – a person who, for reasons not fully understood, is much more able to pass the virus to others than normal. Super-spreaders are rare, but they played a big part in the initial spread of SARS as well,” explains Dr Ben Neuman, a virologist at the University of Reading.
Like SARS – and indeed the common cold – MERS is caused by a coronavirus, in this case MERS-CoV. A respiratory disease characterised by fever, shortness of breath and gastrointestinal symptoms, it can be spread from person to person or through contact with infected camels. Strains of the virus have been identified in dromedary camels in Egypt, Oman, Saudi Arabia and Qatar, which may explain the prevalence of the condition in the Middle East. It has been estimated that as many as one in 30 of the camels in Saudi Arabia are infected at any given time.
Since the condition is relatively new – and has not yet been classed by the WHO as a Public Health Emergency of International Concern – the healthcare community has plenty left to accomplish. One key area that has been flagged for improvement is diagnosis. While there is an accurate laboratory test available for MERS, this test may not prove ideal in the case of a pandemic.
This test was developed at warp speed, becoming available just a week after the virus’s genomic sequence was obtained. Developed by the US Centers for Disease Control (CDC), it was authorised for emergency use in June 2013, and distributed to various laboratories across the world. As a real-time reverse-transcription polymerase chain reaction (rRT-PCR) assay it can be used to detect viral RNA in clinical samples.
“First doctors take a sample from the patient’s lungs – a few cells, some sputum or a little bit of tissue is enough,” explains Neuman. “Technicians collect all of the RNA from the sample – coronaviruses are only made of RNA, so if the person is sick, some of the RNA will be from MERS. Then they convert the RNA to DNA. That is the reverse transcription part.
“Next, two small probes that match the sequence of the MERS genome are added, along with an enzyme that will make a copy of the sequence between the two probes if MERS is present. That is the polymerase chain reaction part.”
The assay looks for two different sections of the viral genome. One of these sections is considered unlikely to mutate, but it is similar to comparable strings of RNA on other viruses. The second section is more likely to mutate, but because it is unique to MERS-CoV, this reduces the risk of false positives. If used correctly, the test therefore achieves a high degree of specificity and sensitivity.
“This RT-PCR can tell MERS from other human coronaviruses and other lung infections, so the rate of false positives is very low,” says Neuman. “It will give an accurate positive result if there are more than 400 copies of the virus in the sample being tested.”
While the test has so far proven fit for purpose, it has several acknowledged limitations. Its success will depend heavily on how much virus was present in the sample, meaning it is sometimes necessary for the technician to go back and take further samples with more potentially infected cells. MERS infects some patches of cells while leaving others unscathed, meaning a sample from a different part of the lung could also come back as a false negative.
Even when optimum specimens are available, accurate diagnosis can still prove challenging. The tests are somewhat susceptible to contamination, meaning technicians need to be careful to follow strict protocols aimed at keeping the assay intact. Moreover, laboratories conducting the test are advised to partner with a qualified reference laboratory, such as the CDC. This should be able to confirm any positive results via genomic sequencing.
The CDC also performs serology testing, which is used to check for an immune response in people who may have been exposed to the virus. This allows them to assess whether MERS infection has occurred in the past.
“Serology tests look for antibodies, which would show that a person has had MERS at some point in their life. It can take a few weeks for a strong antibody response to develop, so this is a better tool for epidemiology than diagnosis – it can be used to trace the chain of virus transmission back to its animal source,” says Neuman.
However, this is not applicable on the frontline of MERS testing, where there is a pressing need for more straightforward diagnostic tools. This need could become greater still were the virus to mutate. Currently, MERS-CoV is relatively difficult to spread from person to person, unless there is close contact between the two (the South Korean ‘superspreader’ being a notable exception). A mutation, however, could increase its transmissibility and therefore the risk of a pandemic.
“Several labs are working on a test that would be quicker, more portable and not require the expensive equipment needed for RT-PCR. It would work like a pregnancy test, detecting the most abundant protein that the virus produces,” says Neuman.
Should a global pandemic occur, better diagnostic methods would only be half the battle. It might also be necessary to place restrictions on travel or trade, or provide screening at points of entry. And we would likely see a push to develop a vaccine that could inoculate the populations most at risk.
“There are several vaccine candidates that have been shown to protect small animals from infection, but to date, there have not been any big human trials,” says Neuman. “That requires a very large investment, and cooperation between governments and health agencies. If the MERS problem continues to grow, I expect that vaccine trials in healthy humans will begin.”
This vaccine might not be particularly far afield. In October, the US-based Inovio Pharmaceuticals, along with South Korean GeneOne Life Sciences, filed an application with the FDA to start human testing of Inovio’s MERS vaccine. It is hoped that phase I trials could begin by the end of 2015.
As MERS continues to generate headlines – and the death toll continues to climb – public heath bodies are monitoring the situation closely. In the meantime, it is imperative that healthcare systems have the right infection control measures in place. Accurate diagnosis is a critical part of containing the spread of this deadly virus.
Give camels the hump
MERS-CoV is a zoonotic virus that is believed to have originated in bats before being transmitted to camels at some point in the distant past. Today, camels are thought to be the primary animal source of infection in humans, with the virus extremely prevalent in certain parts of the Middle East and Africa. A recent study that surveyed 335 dromedaries in Kenya found that 47% tested positive for MERS antibodies (the authors suggested that MERS in camels is comparable to the common cold).
Because the virus is so damaging to humans, the World Health Organization recommends that anyone dealing with camels should take certain precautions:
- If visiting farms, markets, barns or other places where camels are present, it’s important to practice general hygiene measures, such as regular hand washing, and avoiding contact with sick animals.
- Consumption of raw and undercooked camel products – including milk and meat – should be avoided. Cooked or pasteurised products of this kind should also be handled with care.
- People with pre-existing health conditions are particularly vulnerable to severe forms of the infection. These people (including those with diabetes, renal failure, chronic lung disease and deficient immune systems) should avoid contact with camels and camel products altogether.
Since most of the human-to-human transmission of the virus has occurred in healthcare facilities (from one patient to another, or from patient to caregiver), hospitals are advised to have strong infection-control measures in place. Healthcare workers should be educated in preventative measures, and their training should be regularly refreshed.