JVI: Investigating Dromedary Immune Serum As MERS-CoV Treatment

Credit FAO

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We’ve a study, published  in the Journal of Virology (JVI), that uses the mouse model to explore the possibility of using camel antibodies as a treatment option for MERS-Cov infection.

 

As we discussed last year in MERS-CoV: The Long Road To A Pharmacological Solution, with no coronavirus-specific therapy in our arsenal, treatment for infection has basically been supportive (e.g. fluids, vasopressors, ventilators and/or ECMO, dialysis, and antibiotics for secondary infections).

 

We’ve seen some limited testing of Ribavirin & Interferon Treatment of MERS-CoV, but he results from treating humans with this drug combo were far from encouraging.  Other drugs are under investigation, like Biocryst’s experimental antiviral BCX4430, but  it is too early to know how effective it might be.

 

The therapeutic option with perhaps the most promising future is the use of Convalescent Plasma, taken from patients who have already recovered from infection, but here again, there have been roadblocks, Many MERS survivors – due to advanced age, general health, or low antibody titers – are poor donors.

 

The idea of using convalescent serum for MERS goes back nearly two years; 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/.

 

Making headlines last year, and sparking a great deal of Arabic twitter traffic,  was talk that serum antibodies might be harvested from camels, along with camel milk immune proteins, and then used to treat human infections.

It is not that far-fetched, as horse serums have been used for treating humans for more than a century, although their use has declined in recent years due to concerns over adverse reactions and other available options.

 

As nearly all adult camels in Saudi Arabia have been infected with MERS-CoV, they carry specific antibodies against the virus (see Lancet: Camels Found With Antibodies To MERS-CoV-Like Virus), and could theoretically be an abundant source for convalescent serum.

 

Fast forward to today, and we have a study in the Journal of Virology (JVI)  and an accompanying press release, that looks at using dromedary convalescent plasma to treat (or protect against) MERS-CoV infection in mice.

Mice are not a perfect analog for humans, and normally are not even susceptible to the MERS virus (nor are most lab animals, including non-human primates, making studies difficult).  Transgenic mice, however, can be rendered susceptible to the virus, and this study found that camel sera was shown to be protective against a MERS-CoV challenge.

 

The caveat being that what works on mice may not necessarily work in humans. 

 

But as a `proof of concept’  this is a pretty good start.   Follow the link to the study, and the press release below: 

 

Passive Immunotherapy With Dromedary Immune Serum In An Experimental Animal Model For MERS Coronavirus Infection.

Jincun Zhao1, Ranawaka A.P.M. Perera2, Ghazi Kayali3, David Meyerholz4, Stanley Perlman1* and Malik Peiris2*

ABSTRACT

The Middle East Respiratory Syndrome (MERS) is a highly lethal pulmonary infection. Sera from MERS convalescent patients may provide some benefit but is not readily available. In contrast, nearly all camels in the Middle East were previously infected with MERS-CoV. Here, we show that sera obtained from MERS immune camels augment the kinetics of MERS-CoV clearance, and reduce the severity of pathological changes in infected lungs, with efficacy proportional to MERS-CoV neutralizing serum antibody titers.

 

 

Could antibodies from camels protect humans from MERS?

American Society for Microbiology

Antibodies from dromedary camels protected uninfected mice from Middle East Respiratory Syndrome (MERS), and helped infected mice expunge the disease, according to a study published online March 18th in the Journal of Virology, a journal published by the American Society for Microbiology. MERS, which emerged in humans last year in the Saudi Arabian peninsula, causes severe respiratory disease, with a high mortality rate of 35-40 percent. No specific therapy is currently available.

"Our results suggest that these antibodies might prove therapeutic for MERS patients, and might protect uninfected household members and healthcare workers against MERS," says corresponding author Stanley Perlman, MD, PhD, a professor in the Departments of Microbiology and Pediatrics, the University of Iowa, Iowa City.

Passive immunization, a procedure where you inject a former patient's antibodies into a new patient to fight the disease, has been used in the past, including last year in a small number of cases of Ebola, but in the case of MERS, few former patients are available to donate antibodies. Additionally, their antibody titers are often too low, and many former patients are not healthy enough to donate.

Suspecting that humans and dromedaries were likely infected by the same virus, first author Malik Peiris, D. Phil., Professor of Medical Science, School of Public Health, the University of Hong Kong, SAR, China suggested that camel sera might be used to combat MERS. The vast majority of dromedaries on the Arabian peninsula are infected, and many have high antibody titers. The investigators decided to test dromedary antibodies against virus taken from humans. They tested the antibodies in mouse models infected with the latter virus.

 (Continue . . .)

WHO Ebola Situation Assessment: Investigating Convalescent Therapies

Credit Wikipedia

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Three weeks ago, in WHO Statement: Consultation On Potential Use of Ebola Therapies & Vaccines, we looked at the recommendations of an expert committee who had met to discuss potential experimental therapies and preventatives for the Ebola epidemic. Topping their list of recommendations:

 

• There was consensus that the use of whole blood therapies and convalescent blood serums needs to be considered as a matter of priority.

Although still in limited use today, human and animal serum therapy was used extensively during the first half of the 20th century to treat a variety of infectious diseases, including anthrax, scarlet fever, measles, tularemia, diphtheria and rabies.

 

Plagued by a relatively high percentage of adverse reactions (serum sickness), and largely replaced by antibiotics or other drugs, its use has declined over time.

 

Convalescent serum is something we’ve discussed in the past for both novel flu and MERS (see MERS-CoV: The Long Road To A Pharmacological Solution).  Results, most recently in China for treatment of novel flu, have been mixed (Shanghai: Serum Treatment For H1N1), and so no one really knows how useful it would prove for Ebola. 

 

The idea is fairly simple, though. Blood is collected from patients that have been infected and have recovered from a viral infection, and through a process called plasmapheresis, blood cells are removed (using filters or a centrifuge) and the remaining antibody-rich plasma or serum is then used to treat ill patients. 

 

Technically, whole blood transfusions (correctly typed and cross-matched), plasma, or serum could be used. Serum is essentially blood plasma without Fibrinogen. 

There are significant challenges for all of these methods, particularly in very low resource medical environments , as described in the following panel from the WHO  BACKGROUND DOCUMENT POTENTIAL EBOLA THERAPIES AND VACCINES.

 

 

Today’s WHO statement (sent via email, not yet posted) explores the promise, and the challenges, of convalescent therapy, and telegraphs the release of a set of guidelines next week for its implementation.

 

Ebola situation assessment
26 September

Experimental therapies: growing interest in the use of whole blood or plasma from recovered Ebola patients (convalescent therapies)

Background
Ebola virus disease currently has no vaccines or medicines approved by national regulatory authorities for use in humans save for the purpose of compassionate care.

To date, the virus has infected 6242 people and killed 2909 of them. These figures, which are far greater than those from all previous Ebola outbreaks combined, are known by WHO to vastly underestimate the true scale of the epidemic.

The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long.

On 11 August, a group of experts convened by WHO reached consensus that the use of experimental medicines and vaccines under the exceptional circumstances of the Ebola epidemic is ethically acceptable.

Following that advice, WHO convened (from 4–5 September) a consultation on potential Ebola therapies and vaccines.
The meeting was attended by more than 200 experts from around the world, including West Africa, though bans and restrictions on international flights to and from that region diminished the numbers significantly.

The meeting aimed to identify the most promising candidate vaccines and experimental therapies and map out the next most urgent steps to take.

The experts agreed to prioritize convalescent blood and plasma therapies for further investigation. That decision further stimulated already intense interest, with the result that new knowledge is expected to grow fairly quickly.
This assessment looks at what is known about the efficacy of convalescent therapies and the potential role they might play in improving clinical care and reducing the unacceptably high number of deaths.

The current evidence base: limited data – from 1976 up to now

Convalescent therapy was first used for a young woman infected with Ebola in the Democratic Republic of Congo (then Zaire) in 1976 – the year the virus first emerged. The woman was treated with plasma from a person who survived infection with the closely-related Marburg virus. She had less clinical bleeding than other Ebola patients, but died within days.

During the 1995 Ebola outbreak in Kikwit, Democratic Republic of Congo, whole blood collected from recovered patients was administered to eight patients. Seven of the eight recovered.

However, as the study did not include a control group, no firm conclusions could be reached concerning whether the treatment alone was responsible for the favourable clinical outcome or even contributed to this outcome in some way.
In the current outbreak, convalescent therapies have been used in a few patients. The numbers are too small to support any conclusions about efficacy.

In one well-known case, an American doctor, who became infected while working in Monrovia, Liberia, received whole blood from a recovered patient while still in Monrovia.

He likewise fully recovered, though it is not possible to determine whether that recovery can be attributed to convalescent therapy, the administration of the experimental medicine, ZMapp, or the excellent supportive care he received in the United States.

In another well-documented case, a foreign medical doctor, who was infected in Sierra Leone, has been improving following outstanding supportive care. He did not receive treatment with any experimental therapy.

In yet another case, an American doctor, who became infected while working in Liberia, was subsequently treated in the US. As part of that treatment, he received a transfusion of convalescent plasma from blood donated by the first case mentioned above. The infusion was well-tolerated.

Yesterday, he was declared by his attending physicians and the US Centers for Disease Control and Prevention (CDC) to be “virus-free”. He is weak but fully recovered.

Again, as he also received the experimental medicine TKM-EBV, together with outstanding supportive care, it is impossible to know which component of care contributed most – or at all – to his recovery.

The hospital where he was treated will share clinical lessons learned with doctors working in West Africa.

As the epidemic worsens, interest in convalescent therapies grows

WHO has been encouraged by the growth of interest in convalescent therapies as an already bad epidemic gets worse.

In the three hardest-hit countries, Guinea, Liberia, and Sierra Leone, health systems have begun to buckle under the pressure of closed or overflowing hospitals, the difficulties of staffing newly opened treatment centres, and the exceptionally large number of Ebola deaths among health care workers.

The number of cases continues to grow exponentially. The number of treatment beds is grossly and visibly inadequate. Good supportive clinical care is becoming increasingly difficult to implement.

The need to expand the current very limited arsenal of clinical tools is self-evident.

WHO has been approached by several donors, foundations, public health agencies, and development partners seeking guidance and advice.

Major questions need to be answered about the safety and efficacy of convalescent therapies, and the feasibility of implementation in countries with shattered health systems and an acute shortage of medical staff.

WHO is also being asked to assess whether rapid scaling up of convalescent therapy is feasible to an extent that could begin to reduce the estimated 70.8% case fatality rate seen consistently across the three outbreak sites.

Some partners and donors are asking for rough estimates of what needs to be in place to support rapid implementation on the largest possible scale. They have questions about the number of staff needed and their training requirements, safety risks and how to manage them, laboratory capacities and how to enhance them, specific needs for equipment and supplies, and what all of this might cost.

As initial supplies of these therapies will inevitably be limited, questions about which groups should have priority access also need to be addressed.

WHO is currently holding discussions with health experts in the Democratic Republic of Congo, Guinea, Liberia, Nigeria, and Sierra Leone. These discussions aim to identify practical needs for implementation and potential bottlenecks that could stand in the way.

One great appeal of this drive to assess and introduce convalescent therapies is the opportunity to strengthen basic public health infrastructures by helping these countries develop good quality blood services.

The list of common and severe health problems that could benefit from safe and well-functioning blood services is long – ranging from malaria, dengue, Lassa fever, and yellow fever to complications of childbirth and injuries following accidents and traffic crashes.

The current situation is so dire that, in several areas that include capital cities, many of these common diseases and health conditions are barely being managed at all.

 
Technical guidance for experts

Early next week, WHO is issuing new interim guidance on Use of convalescent whole blood or plasma collected from patients recovered from Ebola virus disease for transfusion during outbreaks.

The document is addressed to national health authorities and blood transfusion services.