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Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans. This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18–50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 × 109 viral particles, the intermediate-dose group received 2·5 × 1010 viral particles, and the high-dose group received 5 × 1010 viral particles. The primary objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by interferon-γ-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov, NCT03399578. Between March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were available for follow-up at 6 months, but five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 × 1010 viral particles with no vaccine-related serious adverse events reported by 12 months. One serious adverse event reported was deemed to be not related to ChAdOx1 MERS. 92 (74% [95% CI 66–81]) of 124 solicited adverse events were mild, 31 (25% [18–33]) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5·83 [95% CI 2·11–17·42], p<0·0001) Laboratory adverse events considered to be at least possibly related to the study intervention were self-limiting and predominantly mild in severity. A significant increase from baseline in T-cell (p<0·003) and IgG (p<0·0001) responses to the MERS-CoV spike antigen was observed at all doses. Neutralising antibodies against live MERS-CoV were observed in four (44% [95% CI 19–73]) of nine participants in the high-dose group 28 days after vaccination, and 19 (79% [58–93]) of 24 participants had antibodies capable of neutralisation in a pseudotyped virus neutralisation assay. ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials. UK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research.

MERS-CoV is a respiratory pathogen with a case-fatality rate of 36%, and for which no vaccines are currently licensed. MVA-MERS-S is a candidate vaccine based on recombinant modified vaccinia virus Ankara (MVA). In this study, the safety, immunogenicity, and optimal dose schedule of MVA-MERS-S was assessed in individuals with previous exposure to SARS-CoV-2 infections and vaccines. We conducted a multicentre, double-blind, randomised controlled phase 1b clinical trial at two university medical centres in Germany and the Netherlands. Healthy volunteers aged 18–55 years were assigned by computer randomisation to receive three intramuscular injections of 107 or 108 plaque-forming units (PFU) of MVA-MERS-S, with two treatment groups each of either 28-day or 56-day intervals between the initial two doses, and one control arm that received only placebo, at a ratio of 2:2:2:2:1. The third dose was given after 224 days. The sponsor, clinical and laboratory staff, and participants were masked to both vaccine dose and dosing interval. The primary outcome was safety, assessed in the all participants who had received at least one injection; daily solicited vaccine reactions were recorded after each dose for 7 days, unsolicited adverse events for 28 days, and serious adverse events throughout the study. The secondary outcome was humoral immunogenicity, measured with vaccine-induced geometric mean antibody concentrations and seroconversion rates, analysed in all participants who received at least three allocated treatments. This study is registered at ClinicalTrials.gov (NCT04119440) and is completed. Between 26 July, 2021, and 3 March, 2022, 244 volunteers were screened, 177 of whom were eligible and 140 were randomly assigned either to the 28-day 107 PFU group (n=32), 56-day 107 PFU group (n=31), 28-day 108 PFU group (n=31), 56-day 108 PFU group (n=30), or placebo group (n=16). In total, 178 doses were administered of 107 PFU of MVA-MERS-S, 174 of 108 PFU, and 164 doses of placebo, and 139 participants received at least one injection. 73 (53%) were female and 66 (48%) were male. No serious vaccine-related adverse events occurred. Solicited local reactions were mild in 288 (93%, 95% CI 90–96) of 309 reports and consisted primarily of pain or tenderness. Pain or tenderness (of any severity) occurred after 69 (39%, 32–46) of 178 107 PFU injections, 138 (79%; 73–85) of 174 108 PFU injections, and 18 (11%; 7–11) of 164 placebo injections. Of 595 reported solicited systemic reactions, 479 (81%, 77–83) were graded as mild. Systemic reactions of any grade occurred after 77 (43%; 36–51) 107 PFU injections, 102 (59%; 51–66) 108 PFU injections, and 67 (41%; 34–49) of 164 placebo injections. At 28 days after the second dose, MERS-CoV neutralising antibodies were highest for participants assigned to 56-day 108 PFU, with geometric mean ratios of 7·2 (95% CI 3·9–13·3) for the 56-day 108 PFU group versus the 28-day 108 PFU group (p<0·0001), 3·9 (2·1–7·2) for the 56-day 108 PFU group versus the 56-day 107 PFU group (p=0·0031), and 5·4 (2·9–10·0) for the 56-day 108 PFU group versus the 28-day 107 PFU group (p=0·0003). MVA-MERS-S was safe and immunogenic in individuals with previous and concurrent SARS-CoV-2 exposure. The second vaccination with the 108 PFU dose of MVA-MERS-S elicited a stronger humoral immune response when administered 56 days after the first dose than a 28-day interval. Further studies are needed to verify these findings in groups at risk for MERS-CoV exposure, and at risk of severe disease, including older individuals and those with relevant comorbidities. Coalition for Epidemic Preparedness Innovations, the German Centre for Infection Research, and the German Research Foundation.

COVID-19 pandemic is currently relatively controlled, mainly due to effective vaccines. Preparedness for future outbreaks should include means for reducing transmission of SARS-CoV-2 and other coronaviruses like MERS-CoV. Approximately 72% of camels in Israel are seropositive for MERS-CoV and may exhibit cross-reactivity with serologically related SARS-CoV-2, suggesting therapeutic possibilities. Aims:To investigate the potential of camel-derived anti-MERS-CoV antibodies from camels colostrum for mucosal use in humans, as MERS-CoV prophylaxis and to control COVID-19 progression and infectivity. Methods:Using ELISA assay, we screened serum and colostrum of MERS-CoV seropositive camels for MERS-CoV antibody titers and neutralization potency and for cross-reactivity with SARS-CoV-2 spike. Next, we performed an open label placebo controlled randomized trial, comparing the effect of mucosal application of colostrum to placebo. Infectivity and viral load levels were evaluated daily up to 96 h. Results:Anti-MERS-CoV spike reactive antibodies with partial SARS-CoV-2 cross-reactivity were detected in 22 serum and 12 colostrum samples. While SARS-CoV-2 cross-neutralization was detected, its potency was significantly weaker than that of MERS-CoV. Neutralization of spike pseudotyped reporter viruses representing MERS-CoV reached ~ 1:500, while neutralization against SARS-CoV-2 wild type and variants was only at (NT50) ≤ 1:120. Forty-three COVID-19 patients were recruited to the randomized controlled trial. The primary endpoints did not differ between groups, with comparable decline in viral load ( p  = 0.311) and infectivity ( p  = 0.9641) after 24-h. Conclusions:In-vitro, camel colostrum-derived antibodies neutralize MERS-CoV, but a thin colostrum preparation did not reduce infectivity or viral load in SARS-CoV-2 infected individuals. The role of camel colostrum-derived antibody-concentrate and more viscous preparations merit further evaluation as potential prophylaxis and treatment against MERS-CoV.

Middle East respiratory syndrome coronavirus (MERS-CoV) poses an ongoing public health risk with a 36% case-fatality rate and no licensed vaccines. This Phase 2a, randomized, blinded, placebo-controlled, multi-center trial (MERS-201; NCT04588428) evaluated the safety, tolerability, and immunogenicity of INO-4700, a DNA vaccine against the MERS-CoV spike glycoprotein, in healthy adult volunteers. Participants received INO-4700 or placebo intradermally followed by electroporation upon enrollment into any one of five active treatment groups, resulting from three-dose levels (0.6 mg, 1 mg, and 2 mg total) during each of two dosing days or four placebo groups. Doses were administered as 1 or 2 concurrent injections to achieve the total dose level at Week 0 and at either Week 4 or 8. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs), their toxicity grading scale, seriousness, and relationship to study treatment and AEs of special interest (AESI). Immunogenicity endpoints included evaluation of humoral and cellular immune responses, assessed pre-dose (Screening and/or Week 0) and at Weeks 6 and 10. One hundred and ninety-two participants were randomized across the nine study groups and followed up between June 2021 and January 2023. Treatment with INO-4700 was well-tolerated and had a favorable safety profile with low incidence of TEAEs, which were overall similar between INO-4700 and placebo groups, with most of the TEAEs assessed as Grade 1 or Grade 2, non-serious, and unrelated to treatment. Group E, the highest INO-4700 dose tested (2 mg total), showed greater immune responses compared to other groups, with significantly elevated MERS-CoV receptor-binding domain (RBD) and spike-binding IgG levels, and seroreactivity at Week 10 peaking at 42% and 32%, respectively. Spike-specific T cell responses further contributed to INO-4700 immunogenicity, ranging from 29% in Group C to 50% in Group E. DNA vaccine INO-4700 was well-tolerated in healthy adults across all groups after each dose was administered and elicited humoral and cellular immune responses. These results warrant further evaluation of INO-4700 as a candidate vaccine for MERS-CoV outbreak preparedness and prevention. https://clinicaltrials.gov, .

Middle East respiratory syndrome (MERS) is a severe respiratory illness with an overall mortality of 35%. There is no licensed or proven treatment. Passive immunotherapy approaches are being developed to prevent and treat several human medical conditions where alternative therapeutic options are absent. We report the safety of a fully human polyclonal IgG antibody (SAB-301) produced from the hyperimmune plasma of transchromosomic cattle immunised with a MERS coronavirus vaccine. We did a phase 1 double-blind, placebo-controlled, single-dose escalation trial at the National Institutes of Health Clinical Center. We recruited healthy participants aged 18–60 years who had normal laboratory parameters at enrolment, a body-mass index of 19–32 kg/m2, and a creatinine clearance of 70 mL/min or more, and who did not have any chronic medical problems that required daily oral medications, a positive rheumatoid factor (≥15 IU/mL), IgA deficiency (<7 mg/dL), or history of allergy to intravenous immunoglobulin or human blood products. Participants were randomly assigned by a computer-generated table, made by a masked pharmacist, to one of six cohorts (containing between three and ten participants each). Cohorts 1 and 2 had three participants, randomly assigned 2:1 to receive active drug SAB-301 versus normal saline placebo; cohorts 3 and 4 had six participants randomised 2:1; and cohorts 5 and 6 had ten participants, randomised 4:1. Participants received 1 mg/kg, 2·5 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, or 50 mg/kg of SAB-301, or equivalent volume placebo (saline control), on day 0, and were followed up by clinical, laboratory, and pharmacokinetic assessments on days 1, 3, 7, 21, 42, and 90. The primary outcome was safety, and immunogenicity was a secondary outcome. We analysed the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02788188. Between June 2, 2016, and Jan 4, 2017, we screened 43 participants, of whom 38 were eligible and randomly assigned to receive SAB-301 (n=28) or placebo (n=10). 97 adverse events were reported: 64 adverse events occurred in 23 (82%) of 28 participants receiving SAB-301 (mean 2·3 adverse events per participant). 33 adverse events occurred in all ten participants receiving placebo (mean 3·3 adverse events per participant). The most common adverse events were headache (n=6 [21%] in participants who received SAB-301 and n=2 [20%] in those receiving placebo), albuminuria (n=5 [18%] vs n=2 [20%]), myalgia (n=3 [11%] vs n=1 [10%]), increased creatine kinase (n=3 [11%] vs 1 [10%]), and common cold (n=3 [11%] vs n=2 [20%]). There was one serious adverse event (hospital admission for suicide attempt) in one participant who received 50 mg/kg of SAB-301. The area under the concentration–time curve (AUC) in the 50 mg/kg dose (27 498 μg × days per mL) is comparable to the AUC that was associated with efficacy in a preclinical model. Single infusions of SAB-301 up to 50 mg/kg appear to be safe and well tolerated in healthy participants. Human immunoglobulin derived from transchromosomic cattle could offer a new platform technology to produce fully human polyclonal IgG antibodies for other medical conditions. National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Biomedical Advanced Research and Development Authority.

Despite high exposure to Middle East respiratory syndrome coronavirus (MERS-CoV), the predictors for seropositivity in the context of husbandry practices for camels in Eastern Africa are not well understood. We conducted a cross-sectional survey to describe the camel herd profile and determine the factors associated with MERS-CoV seropositivity in Northern Kenya. We enrolled 29 camel-owning households and administered questionnaires to collect herd and household data. Serum samples collected from 493 randomly selected camels were tested for anti-MERS-CoV antibodies using a microneutralisation assay, and regression analysis used to correlate herd and household characteristics with camel seropositivity. Households reared camels (median = 23 camels and IQR 16–56), and at least one other livestock species in two distinct herds; a home herd kept near homesteads, and a range/fora herd that resided far from the homestead. The overall MERS-CoV IgG seropositivity was 76.3%, with no statistically significant difference between home and fora herds. Significant predictors for seropositivity (P ⩽ 0.05) included camels 6–10 years old (aOR 2.3, 95% CI 1.0–5.2), herds with ⩾25 camels (aOR 2.0, 95% CI 1.2–3.4) and camels from Gabra community (aOR 2.3, 95% CI 1.2–4.2). These results suggest high levels of virus transmission among camels, with potential for human infection.

Coronavirus infections of multiple origins have spread to date worldwide, causing severe respiratory diseases. Seven coronaviruses that infect humans have been identified: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2. Among them, SARS-CoV and MERS-CoV caused outbreaks in 2002 and 2012, respectively. SARS-CoV-2 (COVID-19) is the most recently discovered. It has created a severe worldwide outbreak beginning in late 2019, leading to date to over 4 million cases globally. Viruses are genetically simple, yet highly diverse. However, the recent outbreaks of SARS-CoV and MERS-CoV, and the ongoing outbreak of SARS-CoV-2, indicate that there remains a long way to go to identify and develop specific therapeutic treatments. Only after gaining a better understanding of their pathogenic mechanisms can we minimize viral pandemics. This paper mainly focuses on SARS-CoV, MERS-CoV, and SARS-CoV-2. Here, recent studies are summarized and reviewed, with a focus on virus–host interactions, vaccine-based and drug-targeted therapies, and the development of new approaches for clinical diagnosis and treatment.

Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoVs) are zoonotic pathogens with high fatality rates and pandemic potential. Vaccine development focuses on the principal target of the neutralizing humoral immune response, the spike (S) glycoprotein. Coronavirus S proteins are extensively glycosylated, encoding around 66–87 N-linked glycosylation sites per trimeric spike. Here, we reveal a specific area of high glycan density on MERS S that results in the formation of oligomannose-type glycan clusters, which were absent on SARS and HKU1 CoVs. We provide a comparison of the global glycan density of coronavirus spikes with other viral proteins including HIV-1 envelope, Lassa virus glycoprotein complex, and influenza hemagglutinin, where glycosylation plays a known role in shielding immunogenic epitopes. Overall, our data reveal how organisation of glycosylation across class I viral fusion proteins influence not only individual glycan compositions but also the immunological pressure across the protein surface. Glycosylation plays a key role in shielding of immunogenic epitopes on viral spike (S) proteins. Here Watanabe et al. report that glycans of coronavirus SARS and MERS S proteins are heterogeneously distributed and do not form an efficacious high-density global shield which would ensure efficient immune evasion.

To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the SARS-CoV-2 coronavirus. Our literature and clinical trial survey showed that the whole virus, as well as the spike (S) protein, nucleocapsid (N) protein, and membrane (M) protein, have been tested for vaccine development against SARS and MERS. However, these vaccine candidates might lack the induction of complete protection and have safety concerns. We then applied the Vaxign and the newly developed machine learning-based Vaxign-ML reverse vaccinology tools to predict COVID-19 vaccine candidates. Our Vaxign analysis found that the SARS-CoV-2 N protein sequence is conserved with SARS-CoV and MERS-CoV but not from the other four human coronaviruses causing mild symptoms. By investigating the entire proteome of SARS-CoV-2, six proteins, including the S protein and five non-structural proteins (nsp3, 3CL-pro, and nsp8-10), were predicted to be adhesins, which are crucial to the viral adhering and host invasion. The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, the nsp3 protein has not been tested in any coronavirus vaccine studies and was selected for further investigation. The nsp3 was found to be more conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV than among 15 coronaviruses infecting human and other animals. The protein was also predicted to contain promiscuous MHC-I and MHC-II T-cell epitopes, and the predicted linear B-cell epitopes were found to be localized on the surface of the protein. Our predicted vaccine targets have the potential for effective and safe COVID-19 vaccine development. We also propose that an \"Sp/Nsp cocktail vaccine\" containing a structural protein(s) (Sp) and a non-structural protein(s) (Nsp) would stimulate effective complementary immune responses.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a new type of coronavirus that causes the Coronavirus Disease 2019 (COVID-19), which has been the most challenging pandemic in this century. Considering its high mortality and rapid spread, an effective vaccine is urgently needed to control this pandemic. As a result, the academia, industry, and government sectors are working tightly together to develop and test a variety of vaccines at an unprecedented pace. In this review, we outline the essential coronavirus biological characteristics that are important for vaccine design. In addition, we summarize key takeaways from previous vaccination studies of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), highlighting the pros and cons of each immunization strategy. Finally, based on these prior vaccination experiences, we discuss recent progress and potential challenges of COVID-19 vaccine development.