CIENCIASMEDICASNEWS: Ahead of Print - Sequential Emergence and Wide Spread of Neutralization Escape Middle East Respiratory Syndrome Coronavirus Mutants, South Korea, 2015 - Volume 25, Number 6—June 2019 - Emerging Infectious Diseases journal

The unexpectedly large outbreak of Middle East respiratory syndrome in South Korea in 2015 was initiated by an infected traveler and amplified by several “superspreading” events. Previously, we reported the emergence and spread of mutant Middle East respiratory syndrome coronavirus bearing spike mutations (I529T or D510G) with reduced affinity to human receptor CD26 during the outbreak. To assess the potential association of spike mutations with superspreading events, we collected virus genetic information reported during the outbreak and systemically analyzed the relationship of spike sequences and epidemiology. We found sequential emergence of the spike mutations in 2 superspreaders. In vivo virulence of the mutant viruses seems to decline in human patients, as assessed by fever duration in affected persons. In addition, neutralizing activity against these 2 mutant viruses in serum samples from mice immunized with wild-type spike antigen were gradually reduced, suggesting emergence and wide spread of neutralization escapers during the outbreak.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging zoonotic pathogen that causes an acute and fatal respiratory disease (1). The viral pathogen was first identified in September 2012 in an acute pneumonia patient in Saudi Arabia and has since been associated with 2,279 confirmed cases (with a death rate of ≈35.4%) in 27 countries as of March 2019 (https://www.who.int/emergencies/mers-cov). Although primary transmission of MERS-CoV to humans is linked to contact with dromedary camels, up to 50% of outbreak cases have been associated with human-to-human transmission, especially in healthcare settings (1). During May–July 2015, an unexpectedly large outbreak of MERS swept South Korea, resulting in 186 confirmed cases and 38 deaths (death rate 20.4%). This outbreak was initiated by an infected traveler from the Middle East region and amplified by several “superspreading” events (defined as >4 human-to-human transmissions) in healthcare settings (2). Three superspreaders (P001, P014, and P016) were epidemiologically linked to 73.1% of the human transmissions and infected 28, 85, and 23 subjects, respectively. Even though nosocomial superspreading might be facilitated by delayed diagnosis and poor infection control in healthcare facilities (1), the contribution of biologic factors, including host responses and virologic changes, have been poorly characterized. In addition, superspreading events continue to sporadically arise and lead to unexpectedly large outbreaks of MERS (2–4). Therefore, host–pathogen interactions driving virus evolution and human adaptation, which are potentially associated with rare superspreading events during host changes of the enzoonotic virus (5), need to be further investigated.

In previous studies, we reported the emergence and spread of mutant MERS-CoV bearing spike mutations (I529T or D510G) in receptor binding domain (RBD) with reduced affinity to human CD26 receptor during the South Korea outbreak (6). These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread might be driven by host immunologic pressure, such as neutralizing antibodies (7–9), that result in impaired virus fitness and virulence, rather than positive selection for a better affinity to CD26. A recent report also showed that changes D510G and I529T reduced spike protein binding to CD26 and diminished virus entry (10).

To assess the potential contribution of new emerging mutations to superspreading events, we collected virus genetic information reported during the South Korea outbreak and systemically analyzed its variations, especially spike sequences, in relationship to individual disease severity and epidemiology. We also attempted to confirm whether the spike mutations affect virus dynamics in an in vitro infection model and virus escape from neutralizing antibody responses by using serum samples from mice immunized with wild-type spike antigen and from MERS patients in South Korea who had been infected with wild-type virus. Systemic overview of clinical and virologic data obtained during the transient but large outbreak driven by unexpected superspreading events among humans might provide novel insight into understanding the evolutionary pathways of the emerging coronavirus during animal-to-human transmission.