Scientists have provided the first comprehensive analysis of human immune responses in survivors of Middle Eastern Respiratory Syndrome (MERS).
The results describe T cell responses that are specific to the MERS virus and may provide longer immunity than antibodies, the predominant immune response studied until now.
Jingxian Zhao, from State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangdong, China, and Department of Microbiology and Immunology, University of Iowa, Iowa City, and colleagues published their findings online August 4 in Science Immunology.
“These results will be useful for identifying previously infected patients with low or nil antibody titers in epidemiological studies of the infection and for establishing guidelines for therapeutic use of convalescent sera in patients and will complement measurements of virus load in predicting patient outcomes.” write the authors, a multinational group of researchers from China, Saudi Arabia, and the United States.
Results may also aid efforts to develop a vaccine, which does not yet exist. Both the World Health Organization and Coalition for Epidemic Preparedness Innovations have identified MERS as a prime candidate for vaccine development. Recent efforts at vaccine development have concentrated on antibody responses, which are usually not long-lasting. Understanding the human immune response to MERS is important for development of effective treatments and vaccines.
MERS is a newly emerged infectious disease that spreads mostly from camels (who carry the virus) to humans who live or travel in the Middle East. The MERS virus can also be transmitted in hospitals, both from direct contact with the infected person and through healthcare workers who do not take necessary precautions. Active transmission continues — about 140 new MERS cases have been diagnosed in Saudi Arabia this year — making MERS a public health threat.
“I think people are so worried about MERS because it’s being introduced into human populations very frequently…. We don’t know if this virus will continue to be a low-level infection in Saudi Arabia. We all worry that because it’s continuously transmitted from camels, it could get worse,” author Stanley Perlman, from the University of Iowa, said in an online video interview with Science Immunology.
A lot of mysteries surround MERS. Infection with the MERS virus can cause a highly lethal pneumonia, which kills about 35% of people who come down with it. But not everyone gets sick, and not everyone who becomes infected spreads the virus.
“We don’t understand the spread completely because there’s definitely cases of individuals who infected a lot of people, but other times, people go back from the Arabian Peninsula to their home and there’s no spread at all,” Dr Perlman said.
To shed more light on the issue, researchers analyzed blood samples from 21 patients with MERS in Saudi Arabia. Patients with a low neutralizing antibody response specific to MERS had less severe illness, while a high response correlated with more severe illness.
Then researchers transferred sera from patients to mice sensitized to MERS. Results confirmed the importance of neutralizing antibodies for clearing the virus and pointed to an antibody concentration that could be useful for treating MERS in clinical settings.
Next, they stimulated white blood cells from healthy individuals and MERS survivors using a set of proteins manufactured for the purpose. The idea was to see whether patients produce MERS-specific CD4+ (“helper” cells) and CD8+ (“killer” cells, some of which can become memory cells to protect against later infection with the same virus).
Healthy individuals did not produce MERS-specific CD4+ and CD8+ T cell responses. However, almost all survivors (even those with less severe illness) produced MERS-specific CD4+ and CD8+ T cell responses.
Analyses also showed that the percentage of CD8+ T cells did not correspond to the levels of neutralizing antibodies. Some patients with undetectable neutralizing antibodies still had MERS-specific CD8+ cells. The results suggest that the CD8+ response to MERS may help identify patterns of transmission and incidence of infection.
In addition, patients who fought MERS most effectively showed a prominent MERS-specific CD8+ response, suggesting that the CD8+ response could help establish prognosis in clinically ill patients.
Finally, researchers did experiments to identify target molecules called epitopes, which CD4+ and CD8+ cells recognize when responding to antigens. The goal was to identify specific epitopes that predict rapid recovery from initial infection and protection from later infection. Analyses in mice and humans pointed to several specific epitopes, which may be useful for vaccine development.
“Maybe this is more my opinion than fact, but I think a good MERS vaccine has to induce both an antibody response and a T cell response,” Dr Perlman emphasized, “A portion of the vaccines that scientists are studying induce mostly antibody responses, and these may well be transient. So they may work for today, tomorrow or 2 months from now, but for a disease like MERS, where it’s possible that we’ll have introduction of the disease into human populations for the next, say,100 years because almost all camels are infected, you want to have a vaccine that’s effective for a long, long period of time.”
The study was limited by small size, so larger studies are needed to confirm the findings. Studies over time will also be needed to see how long MERS-specific T-cell responses last compared with antibody responses. Efforts at vaccine development will also need to understand whether MERS-specific T cell epitopes cross-react with other molecules in the body, especially in the upper respiratory tract.
The authors have disclosed no relevant financial relationships.
Sci Immun. Published online August 4, 2017. Abstract
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