Dr. Whitt is a Professor and Chair in the Department of Microbiology, Immunology and Biochemistry at The University of Tennessee Health Science Center (UTHSC) in Memphis, Tennessee. His expertise is molecular virology, with a particular focus on the cell biology of virus entry, replication and assembly of nonsegmented negative-strand RNA viruses. He also has a long-standing interest in the cellular machinery involved in regulating immune responses to viral antigens for vaccine development and the general mechanisms involved in innate immune responses of the host to viral infections. His laboratory was one of the first to develop a reverse genetic system for a prototypic negative-strand RNA virus called vesicular stomatitis virus (VSV) and his laboratory has recovered hundreds of recombinant viruses, some of which have been used as platforms to develop vaccines for viral diseases, including Ebola virus hemorrhagic fever. Dr. Whitt also hold two patents for use of recombinant VSV as cell targeting and cytolytic/oncolytic agents in which VSV is retargeted to cancer cells. From 2001-2005 he served as the Director of Viral Cytolytics and Vector Development at a biotech company to develop these recombinant VSVs as therapeutic agents, and he continues that work in his laboratory at UTHSC today. The following interview was conducted on the 2nd of July 2015.
Lin: The first case of MERS-CoV infection was reported in Saudi Arabia, and it has spread across different continents. But why has MERS been so deadly in Korea?
Whitt: The case-fatality rate in Korea is actually similar to, or possibly lower than that of the earlier outbreaks in Saudi Arabia and other countries in the Arabian Peninsula. According to a recent report from the World Health Organization (www.who.int/mediacentre/factsheets/mers-cov/en/) approximately 35% of people who contract MERS die of complications from the infection. As of June 30th, 33 people have died in Korea from MERS and 182 have been confirmed to have been infected via diagnostic tests. This calculates to only an 18% fatality rate. The initial higher mortality rate in the Arabian Peninsula was likely due to under-reporting of total infections prior to development of a diagnostic test for MERS-CoV. It is also important to recognize that MERS-CoV does not cause severe disease in most patients, but primarily affects the very young, the elderly and people with other underlying health problems.
Lin: Apart from MERS, are there other respiratory or infectious diseases that have shown to spread differently across sub-groups of populations (with naïve immune system to pathogen of interests)?
Whitt: Yes. In 2003 we saw the emergence of SARS (Severe Acute Respiratory Syndrome), which is caused by another coronavirus (SARS-associated CoV) that was introduced into the human population in China and rapidly spread to other countries. We could include new strains of influenza virus in this group as well. Influenza is constantly changing and a big concern right now is the potential introduction of a strain of avian influenza (bird flu) that can easily spread from human-to-human. Fortunately, none of the bird flu strains have that capability, but it is likely just a matter of time until sufficient mutations occur which allow a bird flu strain to circulate between people.
Lin: The development of a drug takes years, and this is often nerve-wracking when the treatment is available, but it is not permitted for treatment till all clinical trials have been conducted. In simple explanation, it is helpful to describe the procedures of a drug development, and the approximate time require for each stage in the United States.
Whitt: It can take up to 15 years to develop and test a new drug for use in humans and often costs between $800 million to $1 billion for development through human testing. The process can be divided into 5 different steps. The first step (Discovery) can be relatively fast (1-2 years) provided you have a way to identify a good drug for the disease. This requires that you have a reliable model system that allows you to screen 1,000’s to 100,000’s of compounds to find out which ones are effective against the disease. An example would be a drug to inhibit the replication of a virus. Most viruses can replicate in certain types of cells that can be grown in a culture dish. An easy screen would be to see which drugs would prevent replication of the virus, but would not harm the cell in which it’s growing. This is easier said than done since most drugs that inhibit virus replication also end up killing cells due to toxicity. Once several “candidate drugs”, are identified, these move into the next stage, which is called Preclinical Testing. Here, the candidate drugs are first tested in small animals (such as mice or hamsters) that are susceptible to the disease. During this phase, the candidate drugs are also evaluated to see how long they remain in the animal’s system and whether the drugs are stable, or are rapidly inactivated or metabolized to other compounds that may be toxic. Preclinical testing can take up to 5-6 years depending on the animal systems used. Before a drug can be tested in humans, it must be evaluated in at least two animal systems with the last preferably being in a non-human primate (monkey). After preclinical testing, companies will typically move forward with a single drug which now enters into Human Clinical Trials. There are typically 3 sub-stages of Clinical Trials simply called Phase I-III. Phase I trials test whether healthy adults exhibit any adverse reactions when given the drug. This is why Phase 1 trials are also referred to as Safety trials. Next, the drug is given to a small number of patients who have the disease in a Phase II efficacy trial. Here there are two groups of patients. One will receive the drug and the other group does not. The idea is to see if the drug helps reduce symptoms of the disease, reduce duration of the disease, or some other measure to test the effectiveness of the drug. If the drug looks like it works, then a large scale Phase III trial is performed, generally by recruiting thousands of patients to test whether the drug works on a large population of people, and whether anyone develops an adverse reaction that was not identified in the smaller Phase II trial. Completion of Phase I-III trials for a new drug can take between 2-5 years. If the drug passes all of the tests, shows efficacy and does not cause problems in people taking the drug, it next goes to the Federal Drug Administration (FDA) for review, which can take another 1-2 years. Only after approval by the FDA can a drug be sold in the U.S.
Lin: What are the current therapies or treatment available for MERS?
Whitt: There are currently no approved antiviral drugs to treat MERS or vaccines to prevent MERS-CoV infections. The only treatment is to provide supportive care to relieve the fever and to minimize the respiratory distress resulting from the infection. The best practice to prevent infection is to follow good hygiene practices. The practices recommended by the Centers for Disease Control include: 1) Washing your hands often with soap and water for 20 seconds. If soap and water are not available, use an alcohol-based hand sanitizer; 2) Covering your nose and mouth with a tissue when you cough or sneeze, then throw the tissue in the trash; 3) Avoid touching your eyes, nose and mouth with unwashed hands; 4) Avoid personal contact, such as kissing, or sharing cups or eating utensils with sick people; 5) Clean and disinfect frequently touched surfaces and objects, such as doorknobs.
Lin: We have closed the chapter for SARS outbreak, what are the important lessons we have learned from the epidemic disease that may be applicable to MERS outbreak?
Whitt: To limit spread of SARS, health officials instituted strict quarantine rules for anyone exhibiting signs of infection. The same applies to the MERS outbreak and this seems to have helped. The fact that initially it was the health care workers in Korea who were exposed by a single individual, who visited 3 different hospital/emergency rooms before eventually being diagnosed with MERS, who then spread the infection to other contacts shows that if the disease had been recognized early and the patient put in quarantine, the outbreak in Korea likely would not have happened.
Lin: Any speculation that MERS-CoV may evolve to a subtype viral strain, and possibly cause another outbreak?
Whitt: MERS-CoV, like SARS-CoV most likely resides in an animal reservoir, probably in bats, and then spreads to other “incidental” hosts who exhibit disease symptoms. The fact that SARS-CoV has not evolved into a more infectious sub-type makes it unlikely that MERS-CoV will evolve in a similar way. However, there is a good likelihood that we will continue to see MERS-CoV infections since we really do not understand the epidemiology of this virus yet. Of greater concern is the spread of antibiotic resistant bacterial infections and the emergence of new influenza strains to which the general population does not have immunity.
Lin: To quarantine an individual whom has previous contact with a MERS-infected individual often provoke emotional stress to members of the public, and also fear for the individual to be quarantine. Are there any insights we should know about the quarantine process? The number of days and restrictions?
Whitt: The quarantine process for MERS-CoV infections is similar to other quarantine procedures for individuals with highly contagious or difficult to treat respiratory infections, such as multi-drug resistant tuberculosis. While it is true that being placed in quarantine can be emotionally stressful, the alternative, which has played out in Korea during the recent MERS outbreak, is much worse. Therefore, everyone should recognize that being placed in quarantine is a community-health duty and should not be stigmatized. The standard infection control procedures and protocols for any highly contagious respiratory infection require that hospitals, ERs, and minor medical clinics be prepared to minimize aerosol exposure as soon as a patient with any of the following symptoms arrives. A patient who might be infected with MERS-CoV, and who has a fever, cough and runny nose should call before arriving at the facility and be instructed to wear a facemask. The patient is then placed in an Airborne Infection Isolation Room (AIIR), which are single patient rooms in which air is sucked into the room (called a negative pressure room) and exhausted directly to the outside or be filtered through a high-efficiency particulate air (HEPA) filter before recirculation. Room doors should be kept closed except when entering or leaving the room, and entry and exit should be minimized. Facilities should monitor and document the proper negative-pressure function of these rooms. If an AIIR is not available, the patient should be transferred as soon as is feasible to a facility where an AIIR is available. Pending transfer, the patient needs to wear a facemask and remain isolated in an examination room with the door closed. The minimum amount of time a patient should remain in quarantine for potential MERS-CoV infections has not been well-established yet and generally is on a case-by-case basis. The factors that are considered include whether the patient continues to exhibit symptoms related to MERS-CoV, the date symptoms resolved, and the results of testing for other causes (e.g. influenza, tuberculosis, or other infectious agents).
Lin: Any preventative measures to lower our susceptibilities for MERS-CoV infection?
Whitt: Again, good hygiene practices are the best preventative measures for MERS-CoV, as well as any other respiratory type of infection. Thinking about not touching your nose and not rubbing your eyes without first thoroughly washing your hands with soap and water for at least 20 seconds will greatly reduce your risk of getting “colds” and other respiratory infections. Being aware of individuals around you who are coughing, sneezing, or who have a runny nose, and distancing yourself from them if possible will also reduce your risk. While we can never be assured that we won’t contract a respiratory infection, doing these two simple procedures will greatly minimize your chance of getting infected and becoming sick.