The Ebola “Secret Serum” – what is it and how does it work?

The news that both the American aid workers who have contracted Ebola have been treated with a secret serum and appear to be making a recovery will answer many calls for why there is no treatment for Ebola. I wish both patients the best possible outcome. But what is this secret serum, why hasn’t it been used before and how does it work?

In fact the “serum” is a mixture of 3 humanised monoclonal antibodies previously selected for inhibiting Ebola replication and shown to protect monkeys from Ebola infection[1]. Crucially, a study last year showed that the antibody mixture could be given post-exposure, that is once someone was already infected, and still result in about 50% protection[2]. “Serum” is an inaccurate description of the product as a naturally occurring serum, for example taken from an animal or someone who has been previously vaccinated (or infected), would contain many antibodies, only some of which would be effective in blocking virus infection. This product is much more defined; it is made of ONLY antibodies that block virus infection so the potency per volume is far higher. An added twist, although it doesn’t relate to how the antibodies work, is that each antibody was produced by expression of the protein in plants, a technology that has the possibility of cheap manufacture.  

mabs

Making the secret serum. Mice are immunized with Ebola virus, to which they mount a normal immune response. In this case the mice are transgenic and make human not mouse antibodies so down the line, if they are used in man, the antibodies themselves will not cause a reaction. The antibodies are screened for those that inhibit Ebola virus growth and those that show inhibition are isolated. The genes that encode those antibodies are isolated and put into plant cells in such a way that they make human antibodies as part of the growth of the plant. Plants are harvested and crushed and the human antibody in the sap is purified. Now, when infused into infected patients the antibody slows Ebola growth giving the patient a chance to recover. It is not a cure but a very supportive helping hand for a natural recovery. The treatment is part of the field of “therapeutic antibodies” and is already an accepted clinical practice.     

 

Will this now be rolled out in Africa? Alas probably not. Firstly, no-one knows how late in an infection the products would still work. Both aid workers were in the very centres set up to deal with Ebola so couldn’t have been in a more appropriate place. They were diagnosed very quickly and surrendered themselves for treatment. That is not the case in the rural population of western Africa. The product is not FDA approved and was used under a special “compassionate grounds” clause. This would probably not apply in Africa were local consent would need to be sought. And despite the manufacture in plants, which in theory could be growth on almost limitless scale, the product will not be cheap or plentiful in the short term. All of these facts will limit the application of therapeutic antibodies in a real outbreak situation. However, assuming a good outcome an important principle will have been proved and stockpiling of the product for use in future outbreaks may be a realistic possibility.

 

[1] Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques.Olinger GG Jr, Pettitt J, Kim D, Working C, Bohorov O, Bratcher B, Hiatt E, Hume SD, Johnson AK, Morton J, Pauly M, Whaley KJ, Lear CM, Biggins JE, Scully C, Hensley L, Zeitlin L.Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18030-5. doi: 10.1073/pnas.1213709109. Epub 2012 Oct 15
[2] Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail.Pettitt J, Zeitlin L, Kim do H, Working C, Johnson JC, Bohorov O, Bratcher B, Hiatt E, Hume SD, Johnson AK, Morton J, Pauly MH, Whaley KJ, Ingram MF, Zovanyi A, Heinrich M, Piper A, Zelko J, Olinger GG.Sci Transl Med. 2013 Aug 21;5(199):199ra113. doi: 10.1126/scitranslmed.3006608

MERS – a bioterrorist plot?

Two publications from Raina MacIntyre of the School of Public Health and Community Medicine, University of New South Wales[i] suggest that bioterrorism or accidental lab release could explain the origin of the MERS coronavirus. Is this a possibility? For me the answer is a very firm NO.

 

In essence the authors use standard epidemiology parameters to assess the pattern of MERS infections to date. The methodology is fine but the dataset used is not. The accepted problem for any modelling is the quality of the data used for the predictions, cynically termed the GIGO problem (garbage in, garbage out), a minor change in which can have a disproportionally big outcome. Think about the numbers that were predicted to have nvCJD (human BSE) or to die in the last influenza pandemic – both hugely overestimated early on in the epidemics. The issue with MERS is the dataset is small and much of it uncertain (the number of cases increased sharply following the change of Saudi health minister in June but these cases were mostly anecdotal as the patients are all dead. The precise details of the cases and technical proof of MERS infection are lacking). It is true that the exact origin and route to man is still unclear but there are no grounds to invoke bioterrorist or accidental release. For bioterrorism the virus clearly doesn’t work well in man so is hardly going to change the course of anything – it is a poorly transmitting virus so why would it be released? And who is it targeted at? Similarly, accidental release would require a local lab working on the virus or a very similar virus – none known, especially in the Middle East. In the latter case the epidemiology would also clearly trace back to the originating lab instead of being all over the place.

Death

 Pieter Bruegel’s “The Triumph of Death” is a favourite accompanying picture for bioterrorism texts. But is it a realistic scenario for the Middle Eastern Respiratory Syndrome coronavirus?   

The latest molecular studies show that the virus is able to infect camel, goat, cow, and sheep cells, which would fit the idea of a zoonotic origin (probably bats) that gets across to domestic livestock, likely as a silent infection that is not reported. Occasionally and via circuitous routes it gets to man where it can lead to severe respiratory distress, especially if the patient is already compromised in some way. The age and male predominance of cases to date fits with typical social roles that would interface with livestock. My own view is that low level contamination of food is also a possibility and the recent finding that the virus can survive for several days in unpasteurised milk shows this is a realistic possibility. Overall however the data are too fragmentary to offer a clear answer.

 

The papers from UNSW do not offer any direct evidence for a deliberate or accidental release of MERS-CoV. With our present state of knowledge you might as well drag up viruses from outer space (nonsense that was wrongly invoked to explain the SARS outbreak). It is none of these things. MERS CoV is a newly recognised and rare zoonotic infection whose pattern of spread will only become clear when more case controlled studies like those recently initiated by the new Saudi health minister have been completed. Science will get to the bottom of MERS, not speculation.


[i]

  1. MacIntyre CR. The discrepant epidemiology of Middle East respiratory syndrome coronavirus (MERS-CoV). Environment Systems and Decisions. Formerly The Environmentalist. 2014 10.1007/s10669-014-9506-5
  2. Gardner LM, MacIntyre CR. Unanswered questions about the Middle East respiratory syndrome coronavirus (MERS-CoV). BMC Res Notes. 2014 Jun 11;7:358. doi: 10.1186/1756-0500-7-358.