Traditional passive immune therapy for emerging Ebola infection

I am highly sympathetic with the views that Dr Shan Lu expresses in his paper “Using convalescent whole blood or plasma as passive immune therapy for the global war against Ebola”.¹ He makes an excellent case for rapidly putting in place procedures for harvesting convalescent plasma and urges World Health Organization (WHO) to take a lead. Indeed, I take the view that it is regrettable that WHO had not prepared stores of convalescent immunoglobulins against Ebola and Marburg disease in anticipation of an epidemic. These are diseases for which there are no vaccines yet available and no effective antiviral therapy, so that passive immunotherapy for those who are exposed or who are in the pre-symptomatic stage of infection is likely to be the most promising and plausible therapeutic approach.

It is as long ago as 1999 that Maruyama et al.² from the group of Dennis Burton in La Jolla produced monoclonal antibodies from a convalescent Ebola subject and identified an antibody to the envelope glycoprotein that neutralised the virus, thereby demonstrating that humans do produce neutralising antibodies after infection. Slightly disturbingly, the same group,³ then produced some data showing that such a neutralising monoclonal antibody did not affect the course of Ebola infection in macaque monkeys. They interpreted this finding as showing that the Ebola virus can be infective even in the presence of a neutralising antibody by some unknown mechanism. This may have discouraged the development of passive immunotherapy.

However, the explanation they give is by no means the only one that may account for their findings. In spite of some considerable literature of possible receptors that the Ebola virus uses to infect cells,⁴ the actual receptor remains unknown although there is some evidence that glycosaminoglycans are important. However, it is quite possible that the Ebola virus uses a different receptor when infecting cells in-vitro from those which it does when infecting monkeys in vivo. There is a parallel with the measles virus which uses CD46 as its receptor very frequently in-vitro but where another major receptor is CD150 (SLAM). It is therefore quite possible that a monoclonal antibody that neutralises that part of the envelope glycoprotein that reacts with the in-vitro receptor may fail to neutralise a different receptor being used in-vivo. This would suggest that using polyclonal convalescent immunoglobulins could be a good approach and there is indeed anecdotal evidence in the present outbreak that this has been effective, as has a mixture of three monoclonal antibodies known as Zmapp.

Another great advantage of using convalescent immunoglobulin is that this is not a novel product and does not require to go through multiple stages of testing before being made available.

Dr Shan Lu discusses the use of whole plasma or serum from individual convalescent patients.¹ There are disadvantages to this in as much as the infusion of substantial amounts of individual plasmas is associated with about a 5% possibility of producing an anaphylactoid reaction due to the presence of heterophile antigens and antibodies to them. This can be largely avoided by using pools of plasma where these alloantigens and alloantibodies tend to neutralise each other. It is also probably preferable to fractionate the immunoglobulins which are much easier to store over the long term and whose sterilisation from known viruses is well understood. Furthermore having a large pool would allow dose estimates to be made once that would otherwise need doing for each plasma.

I would therefore enthusiastically support the sort of enterprise where a hospital ship equipped to do plasmaphoresis on a substantial scale is anchored off the coast of one of the affected countries and where convalescent donors are paid for allowing their blood to be taken and are transported by air to these ships where they are plasmaphoresed. Pools of these plasmas can then be made, their immunoglobulins fractionated and sterilised as is the case with immunoglobulins made for treating other infectious diseases or indeed treating the immunodeficient. These could then be made available for treating those who are in close contact with infected subjects and those in the earliest stages of infection. It is clearly not known without testing what the minimal effective dose would be and there will have to be both neutralisation tests done in-vitro and some dose escalation experiments to see what dose is effective in stopping early infection from taking hold.

However, as Dr Lu points out,¹ it should be possible with relatively modest outlays to produce such protective immunoglobulins in large enough amounts to make a real difference. I very much hope that those responsible for the anti-Ebola campaign will take this route as part of their procedures.