What is Passive vaccination? Does Convalescent Plasma work? What is IVIG?

Passive Vaccination

How can we help the immune system know how to fight the virus it has never seen before? You might have already read my post “How the immune system works” in which I put forward the illustration of Spitfires as an model of the role of antibodies. In that example I explained that somehow the body has to come up with the design for the perfectly matched response to an infection during the alien invasion itself.

We imagined a frantic competition where millions of designers (the lymphocytes) looked for the perfect type of airplane to fight off the enemy. Then when identified that design would somehow be manufactured at break neck speed. The rate of production in antibodies during an infection is astronomical. But sometimes it is not fast enough.

So, in today’s article we will look at one solution to the shortage of antibodies – simply import them. This was where we left off in the last post which asked the question “Could your blood save a life?“

Of course during World War 2 the Brits did not have any other country to turn to for help who had just successfully fought off the Nazis. So they couldn’t suddenly import hundreds of Spitfire planes. But with convalescent plasma that is essentially what we are doing.

For over a hundred years people have been drawing blood from people who have recently recovered from an illness (called “convalescent“) , and infusing it into other sick people with the hope they too will recover. We now use just the plasma (having removed the blood cells) to transfer antibodies to a sick person, or in some cases for prophylaxis to prevent an infection.

Theres been a recent American web conference explaining this in more detail as regards to COVID19. It makes an interesting viewing, at an intermediate level of knowledge base. It explains how American doctors are making this treatment available to as many people as possible and encouraging those recovering to donate plasma.

A report has been published online of the USA Covid19 plasma access scheme which has given plasma to a remarkable number of people. From April 3 to May 11, 2020, a total of 14,288 patients with severe or life-threatening COVID-19 or who were judged by a healthcare provider to be at high risk of progression to severe or life-threatening COVID-19 were enrolled in the scheme. In that time, a total of 8,932 enrolled patients received a COVID-19 convalescent plasma transfusion. Data from the first 5,000 transfused patients were included in this report.

“…we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5,000 hospitalized adults with severe or life threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma. Results: The incidence of all serious adverse events (SAEs) in the first four hours after transfusion was <1%, including mortality rate (0.3%).
Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n=4), transfusion-associated circulatory overload (TACO; n=7), transfusion-related acute lung injury (TRALI; n=11), and severe allergic transfusion reactions (n=3). However, only 2 (of 36) SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician.”
“Although this study was not designed to evaluate efficacy of convalescent plasma we note with optimism the relatively low mortality in treated patients.”
https://www.medrxiv.org/content/10.1101/2020.05.12.20099879v1.full.pdf
https://www.medrxiv.org/content/10.1101/2020.05.12.20099879v1.full.pdf

The evidence based doctor and fan of research in me regrets that the USA did not implement a randomised controlled trial (RCT) to prove whether this approach helps, and to identify whether late in the disease or early in the disease makes the most difference. It is interesting to note that they clearly didnt have enough plasma to treat everyone they wanted to so to assign people to a random group could have also been fair and equitable.

Some might argue it is unethical to withold a treatment that might work from patients who are very sick. But isn’t it also unethical to give them a treatment that we do not know for certain does work? Or at least to do so outside of a clinical trial context where we can identify as quickly as possible if the intervention really does work.

In the UK we are also asking people to donate plasma. The doctors are especially interested in those who have tested positive to the antigen, but if they have space they may test some people for the antibody who have had classic symptoms and then enrol them too. The Brits have decided that where the Americans and others might just give a treatment in hope it would work we would do a full randomised controlled clinical trial, however.

Information about the UK’s convalescent plasma clinical trial

The Americans are also now also studying convalescent plasma more systematically.

There are some side effects to the use of plasma. Part of this is that plasma may contain white blood cells and this could lead to certain side effects. These are listed as follows:

Risks commonly associated with plasma transfusion include transfusion related acute lung injury (TRALI), transfusion associated circulatory overload (TACO), and allergic transfusion reactions (ATR) while more rare complications include infectious disease transmission, leukocyte-associated risks [related to the white blood cells that remain in the plasma], and red-cell alloimmunization. [developing antibodies to red blood cells]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356109/

Patients with some blood cancers (Hodgkins lymphoma) and who have received certain chemotherapy drugs including Fludarabine are advised to have irrradiated blood products for life. This may include convalescent plasma, although if the plasma has been frozen the irradiation is not considered necessary. It is definitely worth asking the question, “should this be irradiated first for me?”.

As of right now 17% of Londoner and 5% of the rest of the UK have antibodies to COVID19. So we should be able to harvest lots of convalescent plasma.

My hope would be that any excess convalescent plasma could be further processed to make additional supplies of Intravenous immunoglobulin (IVIg). This is essentially a further purified form of antibodies. It is taken from a pooled sample of thousands of donors and in theory recipients become immune to whatever infections any of the donors have been exposed to.

We have not been making IVIG ourselves in the UK for a number of years, and I wonder if the current drive to collect convalescent plasma might lead to a resurgence of production and a widening of access which is currently severely rationed.

Why some blood cancer patients need your plasma

Some people some types of blood cancer are unable to make enough antibodies of their own. The ability to make new antibodies to infections we have not seen tends to be lost before the ability to make antibodies for those infections we have seen even decades before. This is because healthy lymphocytes are required to create new antibodies. Many blood cancers arise from the lymphocytes and effectively seem to crowd them out. This is often true even during periods of watch and wait or remission.

When they are selected as helpful and multiply some of the resulting cells become plasma cells. Plasma cells are less vulnerable to the effects of blood cancer and its treatment although they are essentially wiped out entirely in a stem cell transplant.

Impaired immune response is present at all stages of most blood cancer. This is why the advice is that all patients with blood cancer at any stage should be considered extremely clinically vulnerable to COVID19 infection. Someome might simply have been lucky in avoiding other infections so we cannot assume that if a patient doesn’t get regular infections they are not immune compromised. In practice of course some patients with blood cancer will be able to create antibodies despite this, we just are not able to predict which at the moment.

Already many people with blood cancer are given this purified form of plasma antibodies. It is done typically in hospitals, which at the moment is problematic due to COVID19 exposure. At the beginning of the epidemic many patients have had their IVIG suspended. This puts them at increased risk of bacterial infections, but the hope is it protects them from exposure to COVID19 in hospital settings. Here are the current UK criteria for IVIG use in blood cancer patients. The USA criteria seem to be similar but perhaps not quite as restrictive.

UK Criteria for IVIG treatment in Blood Cancer

Recurrent or severe bacterial infection despite continuous oral antibiotic therapy for 6 months
IgG <4 g/L (excluding paraprotein)
Documented failure of serum antibody response to unconjugated pneumococcal or other polysaccharide vaccine challenge

It is recognised that vaccine challenge may be of limited value in patients with very low serum IgG (< 3g/L). In these circumstances vaccine challenge may be omitted if it is considered inappropriate clinically.
It is acknowledged that not all of the above criteria will need to be fulfilled for an individual patient.

Source: https://www.england.nhs.uk/wp-content/uploads/2019/03/PSS9-Immunoglobulin-Commissioning-Guidance-CQUIN-1920.pdf

It shouldn’t be necessary for people to come to hospital to have antibody replacement treatment. We hope we will now see an acceleration in the adoption of SCIg Therapy (Subcutaneous Immunoglobulin) this is given at home through a needle that goes into the fatty layer (see the video below). It has not been widely taken up in the UK or USA up until now, but the epidemic may well accelerate the change in practice. Some IVIG products can be used subcutaneously and other specific products exist.

If a vaccine is found to work and large numbers of the population are vaccinated, or indeed have caught the disease and developed antibodies, eventually IVIG or SCIG would presumably become protective against COVID19.

There would surely a need at that point for those blood cancer patients who did not respond to a vaccine to be offered passive immunisation with either IVIG or SCIG. I have not seen any evidence so far that this is being considered by the powers at be but I really hope it is being prepared for behind the scenes. I am certainly hoping that at some point I will either be vaccinated and perhaps somehow manage to produce my own antibodies, or instead be given antibodies by the kindness of strangers.

Friends and family of blood cancer patients: please donate your blood, stem cells and plasma

But no mater how many people give their plasma there will not be enough for everyone. And receiving plasma can have side effects. This is why they instead give IVIG or SCIG to those who need long term antibody replacement therapy. This takes time to purify and make and is very expensive.

Assuming the body has working factories for antibodies itself, then it is surely much easier to give the body the blueprint to make more of the antibodies (the spitfires) than it is to try and export enough spitfires from other countries. That is what vaccination is all about. We therefore hope vaccination will play a major role in our fighting back against COVID19.

It is surely much easier to give the body the blueprint to make antibodies (the Spitfires) than it is to try and export enough Spitfires from other countries. We will ask teh question in our next post in this series: How do vaccines work?