Middle East respiratory syndrome (MERS) - Emerging treatments

Experimental therapies

There is no conclusive evidence at this time to recommend any virus-specific treatments for patients with suspected or confirmed infection. If investigational agents are used, the World Health Organization (WHO) recommends that these drugs only be used under standard research treatment protocols and occur in the context of research trials.[75] Further studies are needed to evaluate the safety and efficacy of these agents in people with MERS.

Interferon alfa

MERS-CoV has been found to be 50 to 100 times more sensitive to pegylated interferon alfa compared with severe acute respiratory syndrome (SARS) coronavirus.[104] The combination of interferon alfa-1b plus ribavirin has shown activity against MERS-CoV in vitro.[105] Infected rhesus macaques treated with this combination had lower viral loads, and a decreased incidence of respiratory distress and bilateral infiltrates on chest x-ray compared with infected controls.[106] However, the combination did not prove to be effective in a cohort of 5 confirmed human cases.[107] Pegylated interferon alfa-2a plus ribavirin was studied in a retrospective study in humans and compared with standard supportive treatment. This combination demonstrated significantly improved survival at 14 days; however, it did not reach statistical significance by 28 days.[27] Studies of this same combination in patients with various underlying conditions, including renal transplant, produced variable results.[72][108][109] The combination of interferon alfa and ciclosporin has also shown effectiveness at reducing MERS-CoV replication in a human in-vitro and ex-vivo culture model.[110]

Interferon beta

Interferon beta has been shown to have superior activity in vitro against MERS-CoV compared with interferon alfa-2b and alfa-2a.[111] The combination of interferon beta plus ribavirin was compared with pegylated interferon alfa-2a plus ribavirin in a retrospective study of 24 patients. The study found no significant difference in 28-day survival between the two patient groups.[5] In the 2020 MIRACLE Study, a randomised, double-blind, placebo-controlled, multi-centre trial from Saudi Arabia, adults with laboratory-confirmed MERS were randomly assigned to receive interferon beta-1b plus lopinavir/ritonavir (n = 43) or placebo (n = 52) for 14 days. The risk difference (RD) for the primary outcome of 90-day all-cause mortality favoured the intervention (RD: 19%, one-sided P = 0.024). The pre-specified subgroup analysis indicated that treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk 0.19; 95% confidence interval 0.05 to 0.75), whereas later treatment did not.[102] The results suggest that early initiation of interferon beta-1b in combination with lopinavir/ritonavir may reduce mortality in adults hospitalised with MERS.

Lopinavir/ritonavir

A protease inhibitor that has previously shown efficacy in treating SARS when used in combination with ribavirin.[112] It has been tested against MERS-CoV in in vitro studies; however, it has demonstrated suboptimal efficacy so far.[104] Superior clinical outcome and survival advantage have been reported compared with mycophenolate when tested in animal studies.[113] A case report has documented resolution of viraemia when used in combination with interferon and ribavirin.[114] Early initiation of lopinavir/ritonavir in combination with interferon beta-1b has been associated with reduced 90-day mortality.[102]

Ciclosporin

An immunosuppressant with known antiviral activity. Has demonstrated activity against MERS-CoV in vitro; however, the peak plasma levels needed for activity against the virus are not achievable with current approved doses.[115] Case reports of two patients, who were already receiving ciclosporin for other medical reasons and subsequently died of MERS, have been published.[17][109] Based on the limited evidence available, use of ciclosporin is questionable. The combination of interferon alfa plus ciclosporin has shown effectiveness at reducing MERS-CoV replication in a human in-vitro and ex-vivo culture model.[110]

Mycophenolate

An immunosuppressant with known antiviral activity. A number of in vitro studies have demonstrated activity against MERS-CoV.[104][111][116][117] It has not been used in animal studies. There is a case report of a renal transplant patient, who was already on mycophenolate plus prednisolone, surviving MERS. There is also a case report of a patient receiving mycophenolate plus ciclosporin and prednisolone who did not survive.[109][118]

Monoclonal antibodies

Monoclonal antibodies which target different epitopes in the receptor binding domain on the S1 subunit of the MERS-CoV spike (S) protein have been developed (e.g., Mersmab).[119][120][121][122] These antibodies have a higher affinity (i.e., 10 to 450 times higher) for the receptor binding domain compared with the functional receptor dipeptidyl peptidase-4 (DPP4; also called CD26) on the surface of host cells.[120][123][124][125]

Synthetic peptides

A synthetic peptide (HR2P) has been developed to block the HR1 domain on the S2 subunit of the MERS-CoV virus, and has demonstrated a potent antiviral effect in vitro.[3][61][126] An intranasal formulation of this drug (HR2P-M2) has been developed. One study showed that it was effective in mice and was enhanced by using in combination with interferon beta.[127] Enfuvirtide, a HIV fusion inhibitor, is a HR2 peptide and is therefore another potential option for treatment.[128]

Convalescent plasma

The safety and efficacy of convalescent plasma for the treatment of MERS-CoV infection is being investigated.[129] However, the feasibility of clinical studies is limited by the small pool of potential donors with sufficiently high antibody titers.[130] The WHO has published a position paper on this matter and does not recommend its use outside of a clinical trial.[131]

Other drugs

A cell-based enzyme-linked immunosorbent assay (ELISA) assay was used to screen a number of compounds for activity against MERS-CoV and found that 60 agents demonstrated activity, including chlorpromazine, tamoxifen, and chloroquine.[3] One study has evaluated the antiviral activity of chloroquine, chlorpromazine, and toremifene, and found that chloroquine was not active in primary cells, but chlorpromazine showed strong anti-MERS-CoV activity and toremifene had marginal activity.[132] However, both drugs were associated with high cytotoxicity.

Vaccines

The MERS-CoV spike protein is a target for vaccine development, as it plays a critical role in viral entry. One study used a recombinant chimpanzee adenovirus in a single intranasal immunisation of BALB/c mice and observed sustained neutralising antibody and T cell responses.[133] Immunisation against MERS-CoV, although not available for clinical use at present, appears to be possible.