SILVER SPRING, MD—Middle East respiratory syndrome emerged first in Saudi Arabia in 2012 before spreading to several other countries, including a major outbreak in South Korea.
In total, the MERS coronavirus infected more than 2,200 people, and nearly 40% of those infected died from the disease. Initial symptoms include fever, cough and shortness of breath.
While the U.S. military is always concerned about the threat of infectious disease to the health and readiness of servicemembers, the identification of MERS-CoV with the Middle East, where hundreds of thousands of troops had been deployed since 1991, made it especially worrisome.
That’s one reason DoD took a lead in trying to develop a vaccine. Now, a Phase 1 first-in-human trial conducted by the Walter Reed Army Institute of Research has demonstrated safety and ability to induce an immune response for a MERS-CoV vaccine. Results of the trial were published in The Lancet.1
Six coronaviruses infect humans. Four of them are responsible for many cases of the common cold and some instances of pneumonia. The two most recently identified coronaviruses, however, cause severe respiratory disease and significant mortality. Severe acute respiratory syndrome, or SARS, started in China in 2002 and spread rapidly to 37 countries, where it infected more than 8,000 individuals and caused 774 deaths. The last reported case of SARS occurred in 2004.
The World Health Organization identified MERS as a priority disease and the U.S. National Institutes of Health classified MERS coronavirus as a Category C biodefense agent, meaning it could be engineered in the future for mass dissemination with the potential for high morbidity and mortality rates.
“The world witnessed the emergence and devastation of SARS in 2002 and then MERS 10 years later. MERS hasn’t gone away, and there’s every indication that the family of viruses to which SARS and MERS belong, coronaviruses, are here to stay,” said Kayvon Modjarrad, MD, PhD, director of WRAIR’s Emerging Infectious Diseases Branch, the principal investigator of the study and first author on the publication.
“Theoretically MERS, SARS or another coronavirus could be weaponized, if it were mutated to be more communicable between humans. Currently MERS does not transmit easily from person to person,” Modjarrad told U.S. Medicine. “Additionally, a weaponized coronavirus would have to be stable enough to be transported before being released and delivered by a device that maximizes dissemination in a way that mimics or supersedes natural transmission.”
That method of transmission is not yet fully understood. It could be aerosolized, might ride on large droplets or be transmitted through contact with surfaces on which it has been sitting, he noted. “If this were all worked out, the impact would be devastating, given that available estimates of MERS mortality hover around 40%, with no licensed treatments or vaccines available yet.”
“In the aftermath of the Korea MERS outbreak in 2015, the U.S. Army deemed MERS a priority threat and invested funds into supporting the advancement of a vaccine candidate,” Modjarrad said.
Responsibility for researching a MERS CoV vaccine fell to WRAIR’s Emerging Infectious Diseases Branch. The branch plays a critical role in the U.S. Army’s readiness and ability to respond to pathogens that threaten U.S. and allied forces by uniting subject matter expertise, operational platforms and research and development capabilities to develop vaccines, drugs and diagnostics. In addition to its work on MERS, the branch has tested more Ebola vaccines than any other organization in the world, developed and manufactured a Zika vaccine and is testing vaccine candidates for Lassa hemorrhagic fever.
Previous MERS CoV vaccine candidates had been tested in camels. At the time Modjarrad joined WRAIR from the National Institutes of Health, where he had worked extensively on MERS immunology and vaccine development, GeneOne LifeSciences Inc. had demonstrated efficacy in mice, camels and monkeys for its DNA vaccine candidate for MERS coronavirus, GLS-5300. Applying WRAIR’s capabilities to test GeneOne LifeScience’s new product under Modjarrad’s guidance made sense to all parties, Modjarrad explained.
“Military personnel are at particular risk for MERS, given the deployments to the Middle East and South Korea where the largest MERS outbreaks have occurred,” Modjarrad said. “This study is, therefore, an important advancement for the U.S. Army, the military community as a whole and global stakeholders in the research and development of both MERS and corona virus countermeasures.”
The study enrolled 75 healthy volunteers, aged 18 to 50 years. Researchers randomized participants to three equal groups to receive a single intramuscular injection of 0.67 mg, 2 mg or 6 mg of the vaccine at baseline, Week 4 and Week 12. Co-localized intramuscular electroporation followed each injection to enhance cellular entry of plasmid DNA. Follow up continued until 48 weeks after the third injection.
After two injections, 86% of participants demonstrated seroconversion, and 71% had detectable T-cell response. After the third injection, the seroconversion rate rose to 94%, and the T-cell response increased to 76%. Half of participants developed neutralizing antibodies.
Immune response did not differ by dosage after six weeks. The vaccine generated an immune response of similar magnitude to that seen in survivors of natural MERS CoV infection from the South Korean outbreak. The response persisted throughout the study. At 60 weeks, 77% of participants showed humoral response and 64% had detectable cellular response.
No vaccine-associated serious adverse events occurred. Common adverse events included reactions at injection site, headache, malaise or fatigue and creatine phosphokinase increases.
Building on the Results
Based on the favorable outcomes seen in the study, GLS-5300 will advance to a Phase Ib/IIa trial in South Korea and a Phase II study in the Middle East.
While this vaccine could not protect against other coronaviruses, “having data on this vaccine will inform the design and development of vaccines for other coronaviruses, both unknown and yet to emerge,” Modjarrad said. “We at WRAIR are also working on developing vaccines that are more universal for the whole family of coronaviruses. The information gathered from this trial and the follow up studies from it will inform that research.”
Developing other coronavirus vaccines could take a number of paths, according to Modjarrad. “Sometimes we develop our own products from discovery through preclinical testing, manufacturing and early phase clinical testing and then partner with industry to take vaccine candidates forward through advanced phases of clinical testing (Phase II and Phase III clinical trials).
“Other times we work with industry vaccine developers to test their products in our animal models or in humans at our domestic or international sites. Sometimes we collaborate on the immunologic endpoints for these vaccine candidates,” he said. “The model varies depending on the required and available expertise for that particular product at our own institute and with the industry partner.”
- Modjarrad K, Roberts CC, Mills KT, Castellano AR, et. Al. Safety and immunogenicity of an anti-Middle East respiratory syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial. Lancet Infect Dis. 2019 Jul 24. pii: S1473-3099(19)30266-X.
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