Thursday, April 17, 2014

MERS-CoV: The Long Road To A Pharmacological Solution

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# 8485

 

Three years ago, in the movie `Contagion, a MERS-like virus (dubbed MEV-1) emerged in China and spread quickly around the globe while scientists at the CDC (and elsewhere) worked frantically to find a vaccine. Unlike most summer blockbusters, this film endeavored to portray the science as accurately as possible  (see my review here).

 

One area where the movie took some dramatic license was in portraying the development (and deployment) of a vaccine for this never-before-seen virus as happening over a matter of months, rather than years.

 

As with most novels, TV shows and movies that deal with an epidemic outbreak, there is a need to `wrap up’ the story in the last 15 minutes.  The standard solution therefore is for valiant scientists to come up with a last-minute cure, and for it to be dispensed immediately on a global scale in order to save civilization. 


It’s a nice fantasy, but with today’s technology, that’s about all it is.

 

A quick vaccine – and by quick, I mean available any time in the next several years – to the MERS virus seems unlikely, given the realities of vaccine development, testing, and production.  The cost of development could run into the hundreds of millions of dollars, and  given that researchers have been working for more than a decade on creating SARS vaccine – success is far from assured.

 

Nevertheless,the Saudi Ministry of Health made a big point to  assure the public yesterday that they were going to `invite international companies to the vaccine industry to conduct research to find cures for the virus’.

 

One possible hitch to creating a vaccine – at least for use in camels –was revealed earlier this week in EID Journal: MERS Coronavirus In A Saudi Dromedary Herd, where we learned that elevated antibody titers from previous exposures don’t appear to be very protective against reinfection with the MERS virus.

 

That doesn’t mean there aren’t some avenues of research that might produce – if not a vaccine – some form of treatment for MERS infection.  So today, a brief review of some of the pharmacological options, and the obstacles that must be overcome,before they can be used.

 

With no coronavirus-specific antiviral in our arsenal, treatment for infection has basically been supportive (e.g. fluids, vasopressors, ventilators and/or ECMO, dialysis, and antibiotics for secondary infections).  While many people only suffer mild (or asymptomatic) infection, among those most severely affected, the mortality rate runs over 50%.

 

During the SARS epidemic a decade ago, the early administration of Ribavirin was associated with a better outcome (see CMAJ Ribavirin in the treatment of SARS: A new trick for an old drug?), but the number of patients treated in this way was fairly small and the results far from conclusive.

Although Ribavirin use has been associated with significant side effects, it has the decided advantage of already being approved for human use.


Last summer, in Nature: Animal Testing Of Drug Combo Shows Potential For Treating MERS, we looked at early work that suggested a combination of Interferon-α2b & ribavirin – which showed promise earlier that year in in-vitro experiments -  `reduced virus replication, moderated the host response, and improved the clinical outcome’ of rhesus macaques experimentally infected with the MERS coronavirus.

. At the time I cautioned that, while encouraging, the following caveats should be kept in mind:

  • First, the macaque model is not a perfect substitute for humans, as they tend not to be as severely impacted by the MERS virus. 
  • Second, treatment was initiated 8 hours post infection, which is an earlier pharmacological intervention than most humans could hope to see. 
  • And third, most severe human infections have been seen in people with co-morbidities like COPD, cancer, diabetes, asthma . . . variables this study does not attempt to replicate.

 

Fast forward to January of this year (see JID: Early Observational Study On Ribavirin & Interferon Treatment of MERS-CoV) and the results from treating humans with this drug combo were far from encouraging: The authors wrote:

Conclusions

While ribavirin and interferon may be effective in some patients, our practical experience suggests that critically ill patients with multiple comorbidities who are diagnosed late in the course of their illness may not benefit from combination antiviral therapy as preclinical data suggest. There is clearly an urgent need for a novel effective antiviral therapy for this emerging global threat.

Not exactly a rousing success, but then these were critically ill patients (all on ventilators) with profound comorbidities (4 on maintenance dialysis), and treatment was begun (on average) 19 days into their illness

 

Essentially, at that stage of their illness, attempts to use this, or any other antiviral therapy, was pretty much a long shot.  It remains to be seen whether further testing will bear out its value.

An investigational drug – BCX4430 – was the subject of a letter in the Journal Nature last month, that holds some promise as a treatment for filovirus infections (Ebola, Marburg).  As an aside, the manufacturer – Biocryst –stated in their press release

 

In addition, BCX4430 was shown to be active in vitro against a broad range of other RNA viruses, including the emerging viral pathogen Middle East Respiratory Syndrome Coronavirus (MERS-CoV).

 

Still, this drug is a long way from being approved for human use, and its effect on the MERS virus – for now - is speculative at best.


The therapeutic option with perhaps the most promising future is the use of Convalescent Plasma, taken from patients who have already recovered from infection. Three years ago , in CID Journal: Convalescent Plasma Therapy For Severe H1N1, I described the process:

 

Blood is collected from people that have been infected and have recovered, and through a process called plasmapheresis, the blood cells are removed leaving only blood plasma.

This is done by passing the blood through a special filter, or by using a centrifuge. The remaining blood plasma will contain antibodies that could then be injected into severely ill patients.

Convalescent plasma could, theoretically, be used as either a treatment for someone already infected, or as a temporary prophylactic, to prevent infection.

There is more to it, of course.

The donor must be checked for a variety of blood borne diseases (i.e. hepatitis B, hepatitis C, Syphilis, and HIV), and then the plasma is usually heated to inactivate other possible pathogens.

 

The idea of using convalescent serum for MERS goes back almost a year; This is from the World Health Organization Novel coronavirus summary and literature update – as of 8 May 2013.

An international network of clinical experts has been convened to discuss therapeutic options. It concluded that in the absence of clinical evidence for disease-specific interventions, convalescent plasma is the most promising therapy. A memo containing advice for setting up international or regional serum centers, to obtain and share convalescent plasma, has been circulated by WHO to ministries of health in affected countries. WHO and the International Severe Acute Respiratory and Emerging Infection Consortium have developed and shared a set of research protocols and case report forms to help clinical investigators establish studies of pathogenesis and pharmacology. These are available at http://www.prognosis.org/isaric/.

 

Last month the WHO released a Position Paper on Collection and Use of Convalescent Plasma or Serum as an Element in Middle East Respiratory Syndrome Coronavirus Response Pdf, 70kb, which concluded:

 

The WHO Blood Regulators Network recommends that scientific studies on the feasibility and medical effectiveness for collection and use of convalescent plasma or serum be explored through clinical trials.  In particular, an opportunity exists to study the feasibility, safety and effectiveness  of convalescent plasma or serum and possibly other passive immunotherapies  in MERS-CoV.  Acting within their mandates, regulatory agencies can play an essential role to enable progress in this area.  Countries which want  to engage in this type of  practice should take all necessary steps to establish appropriate  regulatory conditions for the collection of convalescent plasma or serum, the conduct of clinical studies and the monitoring and reporting of patient outcomes. 

Programmes conducted at the national level should ensure the use only of convalescent plasma or serum collections that meet the safety, quality and efficacy criteria consistent with established  regulatory standards.  The feasibility of production on a large scale, possibly including a specific immunoglobulin, should be considered based on the outcome of studies, the course of the epidemic, and the available infrastructure for manufacturing under GMP. 

 

Making headlines, and sparking a great deal of Arabic twitter traffic, have been the claims of a Saudi researcher Dr Faten Khurshid, who proposes that serum antibodies could be harvested from camels, along with camel milk immune proteins, and then used to treat human infections.

Although equine serums have been used for more than a century (and still are), their use has declined in recent years due to concerns over adverse reactions, which according to the FDA, may include:

    1. Anaphylactic reactions have been reported following administration of equine sera.
    2. Thermal Reaction: When this reaction occurs, it usually develops in from twenty minutes to one hour after the injection of serum or antitoxin. It is characterized by a chilly sensation, slight dyspnoea and a rapid rise in temperature.
    3. Serum Sickness: The symptoms of serum sickness include fever, urticaria, or maculopapular rash, arthritis or arthralgia, and lymphadenopathy. These symptoms may appear individually, or in combination, within fourteen days after the administration of a serum or antitoxin.

 

While likely an abundant source of serum antibodies, it is also likely that a camel derived product could suffer some of these same (and perhaps, other) adverse reactions.

 

So far, the Saudi MOH doesn’t appear to be terribly receptive to Dr.Khurshid’s proposal.

 

Additionally, research is ongoing into ways to block the receptor cells for MERS; Dipeptidyl peptidase 4 (DPP4).  But once again, this avenue of research is in its infancy, and it may take years before an effective drug can be developed.

 

While the lack of a vaccine, or drug therapy, against the MERS virus is a serious concern, we are not exactly helpless in the face of this emerging virus.

 

Eleven years ago the SARS virus was far more widespread – and more transmissible – than the MERS virus of today, and yet it was quickly brought under control without the aid of a vaccine.

 

What it took was a recognition of the seriousness of the threat, a coordinated global public health response, stringent infection control protocols, and the effective use of quarantines and isolation (see SARS And Remembrance).

 

Solutions that are available today, but that will only work when there is full disclosure and broad cooperation between the various national and international entities charged with containing this virus. 

 

A lesson learned the hard way by China with SARS in 2003, and one that hopefully won’t have to be relearned by other nations with MERS in 2014.

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