Emerging Infectious Diseases
Coronaviruses (CoVs) are a large family of viruses that cause respiratory illness in humans, ranging from mild common cold symptoms to the potentially fatal Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and, of course, COVID-19. The intermediary hosts and zoonotic source of human infection by MERS-CoV are dromedary camels, while SARS-CoV is transmitted by palm civets; however, the natural reservoir for both CoVs is thought to be bats.
MERS infection can occur either through contact with infected dromedaries or upon ingestion of camel products; nosocomial infection of MERS is also possible, although sustained human-to-human transmission is limited. SARS is spread from human-to-human through respiratory droplets. The symptoms of MERS and SARS are non-specific, and both may include headache, fatigue, fever, sore throat, runny nose, and diarrhoea; and, in severe cases, pneumonia, respiratory failure and death.
MERS-CoV was first detected in 2012 in the Kingdom of Saudi Arabia (KSA). Since 2012, there have been at least 2,499 confirmed MERS cases and 861 deaths (34% case fatality ratio) across 27 countries, the vast majority from the KSA. Outside of the Middle East, MERS has been detected in North America, Europe and Asia, where a 2015 nosocomial outbreak in South Korea resulted in 186 cases and 38 deaths.
SARS-CoV-1 was first detected during the 2002-2003 epidemic in China – its first and last outbreak – which spread to 26 countries, resulting in 8,098 cases and 774 deaths (10% case fatality ratio).
Currently, there are no approved drugs or vaccines targeting MERS-CoV or SARS-CoV-1 infections. Research and development for SARS has largely stalled in the absence of further outbreaks and of Target Product Profiles (TPPs) to align R&D activities. An overarching challenge impeding all aspects of MERS research is the weakness of the available animal models in accurately mimicking the disease and severe infections in humans.
The WHO recommends the development of three MERS-CoV vaccine categories: a single dose vaccine for reactive use in outbreak settings, a two-dose vaccine for long-term protection for those at continual high risk (such as healthcare workers and camel handlers), and a reservoir-targeted vaccine for juvenile dromedaries to reduce or prevent viral shedding. Various candidates based on DNA and viral-vector are in the early stage of clinical development. Only two SARS vaccine candidates have ever been tested in humans and no candidate has yet passed Phase I trials.
Based on the current understanding of MERS pathogenesis, a combination antiviral and antibody therapy would help avoid viral escape, while enabling researchers to learn more about the virus’ evolution and immune response in survivors. Based on this approach, a combination of a repurposed drug (lopinavir/ritonavir) and a biologic (IFN-β1b) completed Phase IIb/III trials in 2020. Additionally, a human polyclonal antibody (SAB-301) and a cocktail of human monoclonal antibodies (REGN3048-3051) have completed Phase I trials, while remdesivir, a novel broad-spectrum antiviral with a proven safety profile, is in pre-clinical evaluation.
Creation of an accurate, rapid test to diagnose MERS is rendered challenging by the need for specimens taken from the lower respiratory tract. Consequently, there are currently no point-of-care molecular tests or RDTs available for use outside of research, requiring suspected samples to be sent to a laboratory with biosafety capabilities. Development of a sensitive, specific, and easily administered diagnostic assay is needed for case confirmation as well as surveillance, epidemiological studies and efficacy assessments in clinical trials.
In 2021, Inovio commenced Phase II trials of their DNA vaccine INO-4700 in Jordan and Lebanon, supported with funding from CEPI. Ardis Pharmaceuticals announced preclinical efficacy of a pan-coronavirus mAb cocktail (AR-701) showing broad reactivity against COVID-19 variants, SARS and MERS in December 2021. A new ultra-rapid real-time RT-PCR test using a mobile PCR device demonstrated a similar sensitivity and specificity to conventional real-time PCR instruments, detecting MERS-CoV RNA within 20 minutes.