Don’t tell me what proportion of blood cancer patients get a COVID19 vaccine response. Tell me if it has worked for me! How do I get tested? Which test do I need? What do the results mean?

We are now entering a critically dangerous phase of the pandemic for those of us with blood cancer.

At least in Israel and the UK (see also this study) vaccination levels are rising fast and deaths are falling rapidly as the vaccines are shown to have a fantastic safety profile and to work far better than we ever hoped at reducing the risk of hospitalisation and death (close to 100% even in the elderly if they have a relatively healthy immune system!). Even after just a few weeks real world data has seen reductions of over 80% after just one dose.

Vaccines also reduce the risk of symptomatic infection, and even transmission from asymptomatic infection. This effect is not quite as strong and so some people will still get infected but for the population as a whole the reduction in spread of COVID19 appears to be remarkable. I am not known for being foolishly over-optimistic and have written on here about the tyranny of the positive. But I do believe that in countries that are vacccinating rapidly the threat of COVID19 is going to shrink to a very low level in the coming months.

In the UK the background infection rates are already coming down. Random samplying by the ONS shows 1/340 people are currently infected with COVID19 at the moment. At the worst in parts of London it was around 1/20. As that number drops the risk of us catching the disease falls. And so at some point in the not too distant future we become safe even if the vaccine didn’t work for us personally.

The benefits to us of the vaccine are not just in its response in our own bodies. But also in the way it will turn millions into human shields for us.

But right now the infection rate is still relatively high right now in most areas and certainly in many other countries. Vaccines can be expected to help drive the R value down allowing the end of many social distancing protocols. But those with blood cancer may well need to continue to be cautious for longer than others. Increasingly clinical data and anecdotal experience is showing that many with blood cancer will not respond well to the vaccines.

This means that even though in the UK the end of shielding is now be imminent these decisions are being based on the whole clinically extremely vulnerable group and not the needs of blood cancer patients and others who are immune compromised. The blood cancer charites are advising we continue to be cautious and indeed the government highlighted that for us the furlough scheme can be used until September.

Even for those identified as Clinically Extremely vulnerable but who do not have a low immune system official advice is still “keep social contacts at low levels, work from home where possible and stay at a distance from other people.”

For sure we need to be very very cautious about crowded poorly ventilated rooms for some time to come.

So I feel I need to say to is that we need to be patient a little longer and not do anything we might feel puts us at too much risk. We are all adults and can work this out for ourselves, but my concern is that some of us might assume the vaccine has worked and relax our precautions too rapidly.

The risk is that we assume we are safe following vaccination when we may well not be.

What can we do to get an indication of whether we have responded to the vaccines and how can we keep ourselves safe whilst the rates continue to drop?

Why antibodies matter

There are two ways that we know the COVID19 vaccines work. And they do it in a remarkably similar way to the virus itself. As the virus enters the body it is looking for cells to infect and turn into virus factories. Most of the vaccines that are currently available do the same thing but turn a few cells into factories to produce only the spike protein. You can see the spikes in the illustration of the virus at the top of this article. Those spikes allow the virus to bind to receptors on the cell membrane and enter the cells.

When you are infected with COVID19 if your immune system is working well antibodies will be produced to the nucleus of the virus (often referred to as the N protein) and to the Spike protein (the S protein). Antibody tests look for one or other of these types of antibodies so it is crucial to have the right test as will become clear.

Spike protein antibodies seem to be crucial in preventing the virus from even entering the cells in the first place. The vaccines are therefore focused on producing so-called neutralising antibodies which will bind to the virus destroying it and also tag any cells producing viruses for destruction.

There is growing evidence that antibodies are crucial in the immune response to COVID19 and in people who do not make antibodies there is believed to be a much greater risk of serious prolonged infection, hospitalisation, and death. In the Regeneron monoclonal antiboty trial it was noted that

“While seronegative patients [those who do not make their own antibodies] comprised less than half of the trial population, based on placebo rates they account for approximately two-thirds of the deaths in the absence of antibody cocktail treatment”

https://www.genengnews.com/covid-19-candidates/regeneron-pharmaceuticals/

It is also believed that such prolonged infections in those who are immune compromised are the main cause of new mutated super-strains. Those who do not make their own antibodies are dramatically helped when sick with COVID19 by being given monoclonal man-made antibodies to the spike protein, and these are now being tested as a preventative measure.

T-Cells are also involved in the immune response presumably in helping to kill the infected cells. We know that both B-lymphocytes (which make antibodies) and T-lymphocytes learn how to specifically identify coronavirus after vaccination in a healthy person.

Israeli study of 167 Patients confirms poor response among CLL patients

We already know that patients with certain types of blood cancer do not respond as frequently to vaccines as healthy populations. An Israeli CLL expert has now published research detailing the poor level of response to COVID19 vaccines seen in people with CLL specifically. These results may not generalise to all blood cancer types and the estimates may still not be 100% accurate due to the size of the study. But the critical take home message is that as an individual you cannot predict whether you will have responded, which makes the message of check your own response all the more critical. Here are some crucial messages from the study:

• 167 patients with CLL were studied, the overall antibody response rate was 39.5%. This compares poorly to the close to 100% response rate seen in this study and others with healthy controls.
• 79.2% of patients in clinical remission responded
• 55.2% of treatment-naïve patients responded
• Only 16% of patients under treatment at the time of vaccination responded with similarly low rates seen in those taking ibrutinib or Venetoclax.
• None of the patients exposed to anti-CD20 antibodies (Rituximab or obinituzimab) less than 12 months prior to vaccination responded.
• A multivariate analysis revealed predictors of response were younger age, females, lack of currently active treatment, IgG levels ≥550 mg/dL and IgM levels ≥40mg/dL.

This data adds weight to an earlier small UK study showed only 13% of the blood cancer patients tested produced antibodies in response to the vaccine.

There are reasons to believe that these early estimates will turn out to be too low, and that the percentage of people who make antibodies will vary at different stages and with different types of blood cancer.

Crucially some patients with blood cancer did make normal levels of antibodies but some made none.

But it is certainly expected that relatively fewer people with any blood cancer at any stage will create antibodies than healthy individuals. The observed rate of antibody production in blood cancer patients compared unfavourably to the 97% response rate of healthy individuals. In several other studies close to 100% of those with a healthy immune system make antibodies three weeks after the first dose of a COVID19 vaccine. The following image is another way of visualising the results:

There is a helpful brief video explaining the results from one of the investigators filmed by the Blood Cancer UK charity:

So the vaccine does not help all of us to a lesser extent than healthy people. Rather that, at least in terms of antibody production, some of us make the same number of antibodies as healthy people. But some make zero response whatsoever.

What is proven is that it won’t work for SOME of us. What we don’t know is how many of us or who. But anecdotal evidence of those who are doing the antibody test in online forums shows some are getting antibodies but a larger number are not. This seems to be true for blood cancer patients at all the different stages including watch and wait, on treatment, and post treatment.

Do not assume you have responded to the vaccine if you have blood cancer. Spike antibodies are the best available indicator. It’s medical negligence that the NHS and health services in other countries are not routinely offering this to every blood cancer patient.

Clearly the antibodies is not 100% predictive of your level of protection but since almost 100% of those with a healthy immune system make them in response to the vaccine it is currently the best way for an individual with blood cancer to know if they responded to the vaccine or not.

Whilst it is probably true that those early in the disease and who haven’t been treated are probably more likely to make antibodies that doesn’t really help you unless you know if you yourself have made them or not.

I am not trying to be a kill joy because the other side of all this is that becuse rhe vaccines are working so well for others and the rates are going down it won’t be too long hopefully before we can start to feel that we are safe due to the “herd immunity “ and when the infection rate gets low enough we can honestly start to relax.

It now seems likely that in the autumn in the UK all clinically extremely vulnerable patients will be offered a third vaccine shot, possibly modified to give better cover to the new variants. It is currenly the expectation that at higher blood antibody levels, even if obtained from the current vaccines, there will still be protection against severe illness from all the currently widespread varients, however.

It is surely imperative that all blood cancer patients are tested to see if they created antibodies to help them in their personal risk assessment as society begins to open up.

How do I get tested?

Start by asking your primary care doctor (GP) or consultant to please request a blood test called the “quantitative covid19 spike protein antibodies”. This may be described as a type of COVID19 serology. But your doctor must be careful not to request a nuclear antibody test by mistake as this will be negative unless you have been infected with COVID19.

Qantitative simply means that it measures the number of antibodies and not just whether they are present or not. Some tests are descirbed as semi-quantitative which is also fine. Expect that your doctor will be impressed by your knowledge but be prepared for some push back from some doctors.

Clinical trials are available in both the USA and UK (see below). In the UK a private not for profit provider offers approved Roche antibody tests through the mail. They are also collecting a voluntary survey to help explain the reasons behind the results they are reporting.

Do not take no for an answer.

I honestly think we should all be campaigning on this issue with our family doctors, consultants, writing formal complaints to hospials if turned down, and contacting members of parliament. Think about the benefits not just for you but for other blood cancer patients who may not be as well informed and may therefore take risks assuming they are safe.

In the UK the Green book of official vaccine advice states (on page 15 of the COVID19 chapter)

“Individuals with immunosuppression may not make a full immune response to vaccination . . . The small number of patients who are about to receive planned immunosuppressive therapy should be considered for vaccination prior to commencing therapy (ideally at least two weeks before), when their immune system is better able to make a response. Where possible, it would also be preferable for the 2-dose schedule to be completed prior to commencing immunosuppression . . . Although the immune correlates of protection are currently unknown, post-vaccination testing may be considered. Until further information becomes available vaccinated patients with immunosuppression should continue to follow advice to reduce the chance of exposure.” [emphasis added, note this comment in this official book indicates that such testing may be considered as part of routine medical practice]

https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/961287/Greenbook_chapter_14a_v7_12Feb2021.pdf

Objections and replies

• “Why would you want to know if you have responded to the vaccine what difference would it make?” This was a genuine comment from a doctor which shows zero empathy to the fear that those of us living with blood cancer for the last year of pandemic have been facing. With scary data talking about an increased death rate and the news that many of us do not respond to a vaccine of course we want to know. The test is worth it just for the psychological reassurance that a positive result would give us, or if negative providing the amunition to help us persuade employers, friends and family that we still need to take signifciant precautions to stay safe.
• “This test is only available in clinical research“. This is simply untrue. Your doctor may not realise this, and the test may not be available in their hospital, but it definitely is elsewhere. In the UK some hospitals including UCLH, Leeds, Southampton and Oxford are already offering this test and there is no reason why other hospitals couldn’t contract send blood samples to them to run it on their behalf. That is what already happens with other antibody tests. In the USA all the major laboratory groups have this test available for any doctor to order. Other vaccine trials are common routine practice and are used to help determine if patients require IVIG.
• “We don’t know if antibodies are important. What about T cells?” This is not an argument for not doing the antibody test but rather for also doing specific T cell tests which are currently still rather experimental. In the absense of being able to do both tests it is certainly better than dooing none! It should be possible to do a lymphocyte sub type test to see how many CD4 T cells you have. This may be an indicator of how likely your T cells are to respond (hard for them to respond if you do not have any). I will write another article soon about other tests your doctor may decide to order to have your immune system tested.
• “Nobody else is doing this” As we have said this is simply not true. Doing an antibody test after vaccination is meant to be part of routine clinical practice in people with CLL and there is a strong argument for saying we should have specific antibody tests after any vaccination for which they are avaible.
• “I don’t want you taking extra risks if positive” Of course it is sensible even for blood cancer patients who have a positive antibody test to continue to follow all government precautions. But if you test negative you will probably want to go further than the official recommendations. Surely there is a greater risk of people taking too many risks if they just assume the vaccine worked.
• “I don’t want you to be too depressed if you test negative” There is no need for us to be depressed with a negative result. Hopefully the background infection rate will drop to safe levels soon. And hopefully the monoclonal antibodies may ultimately become available and have a similar effect to IVIG/SCIG. Having your failure to respond to a vaccine clearly documented may help you qualify for this if it is approved. In the mentime this is useful medical information that can help to inform your personal risk assessments. It is possible that if something bad happeend to you becasue you did not know this information legal liabilty may fall on your healthcare provider.

Ultimately remember even if you are not directly paying for your healthcare your employer or taxes are. If you are not happy with the response you are given you are well within your rights to put in a formal complaint or even to ask your family doctor to organise a second opinion with a true specialist site where you know the test is done.

Join a clinical research project

If you are in the USA and you have ever been diagnosied with any blood cancer you can get your antibodies tested after Covid19 vaccines FREE by joining a study supported by blood cancer charities. You can find your nearest labcorp where the tests are done, even if it is a bit of a drive it is well worth it. The research allows you to see your own results immediately.

A second study is also underway for past or present Mayo Clinic patients: Immunogenicity and Safety of Commercially Available Vaccines Against SARS-CoV-2 (COVID-19) in Patients With Hematologic Malignancies. Contact Julianne Lunde, MA (507)266-2657  lunde.julianne@mayo.edu

Some similar UK research projects are also avaialble but in some cases are not providing individuals with their own results! By all means participate to help the community but you will still need to get your own results elsewhere in some cases. Please email or visit the webapges for more information according to your diagnosis (ask if you will get your own results). If there are additional studies please email us at bloodcanceruncensored@gmail.com and we will add them to the list.

• CLL (Birmingham) haematologyengagement@contacts.bham.ac.uk
• Myeloma (Oxford) https://prepare.oxford-myeloma.org.uk/ Note that people with other blood cancers can join the Ruby study to help collate fatigue and qualtity of life data, but that COVID19 antibody tests will be done only on Myeloma patients.
• An informal survey is being carried out by Testing for All a private company offering mail order spike protein antibody testing for purchase at a not for profit price. Results updated regularly here but please note it is perhaps not surprising that many people concerned enough to pay for their own test have tested negative.

Which test do I need?

An example of the test you need is made by Roche and described as “Immunoassay for the quantitative determination of antibodies to the SARS-CoV-2 spike protein”

The two key words are quantitative which means it estimates the quantity or number of antibodies and not just their presence or absence (this would be called qualitative). In the USA these tests are called semi-quantitative. If you are in the USA the CPT code is 86769, but that can also apply to the qualitative test which is less ideal. Have your doctor write on the request “Semi-quantitative Covid19 Spike Protein Antibodies”

In the USA it seems that the maximum reading the semi-quantitative test will give is over 250 U/ml. In the UK many labs will be using the identical test as in the USA but if the level is higher they tend to dilute the sample ten fold and run the test again and so can identify with more precision the higher levels. But perhaps this is not that important as if your level is at least 250 it seems that is a very good result.

Here are direct links to information from two of the main USA blood laboratories. This test can be ordered in the USA by any doctor, and so it may be easiest to ask your primary care doctor. To obtain approval from your insurance company you may need to explain that you are concerned that your immune response to the vaccine will be poor due to blood cancer.

• Labcorp test number 164090 (NB this test is performed by Labcorp free for volunteers in the blood cancer charity supported study.
• Quest test code 39820

In the UK your first port of call should be your NHS GP or consultant. Some may claim it is not possible, but you should push them and may wish to submit a complaint if they refuse to organise the test for you. Remember that the barriers may well be adminstrative rather than your doctor not wanting to help.

Do ensure your doctor is definitely ordering the quantitative spike protein antibody test and not the nuclear protein (which until recently was the only test avaiable). If you get a negative result it is worth confirming again that you have had the right test.

It is my strong view that the NHS should be offering antibody testing free to all blood cancer patients and helping us interpret the results.

Unfortunately on both sides of the Atlantic many tests are advertised without clarity of what they test see for example this Lloyds Pharmacy test is testing the nuclear antibodies and therefore will ONLY be positive if you have been infected with COVID19. The page does mention this but only in small print.

Abingdon Health is a UK company which is offering tests but not direct to the public. Their information page is helpful, however.

In the UK we have been able to identify a private company called Testing for All which offers two tests priced on a not for profit basis. If you decide to order through them you want the Immunity Tracker. The recommendation is this may be performed at least 21 days after either the first or second vaccine. If desired, you could repeat the test to track your antibody levels. This company uses the Roche test mentioned earlier. It is believed that a finger prick sample of blood will be sufficient. Note that this is a new private company seeling on a whilst a number of our UK readers report being satisfied with their results we cannot make any guarentees about this organisation, though it seems to have forged some links with the NHS.

What does the test results show?

If you have selected a quanitative test you will be given a number in units per ml. We do not know for sure what antibody level is required to prevent infections, but the assumption is that the higher the level the better. Tests taken after a first vaccine are perhaps more likely to be lower than those taken after both doses. if you have both tests done the nuclear / nucleocapsid antibodies and the spike (s) protein antibodies you can figure out if you had an infection (if recent) or vaccine response or both. .

If you have both tests done you can usually figure out if you had an infection or vaccine response.

Neucleocapsid / Spike

• Negative / negative means no infection and no vaccine response
• negative / positive means vaccine response but no infection
• Positive / positive means probably just an infection but if the spike is much higher than the nuclear it may well mean you were vaccinated but also had an infection previously.

The UK’s Testing for All is reporting the distribution of their customers levels. The following graph indicates that the higher levels are relatively uncommon. In a number of cases the people obtained these levels if they had previously been infected with COVID19 and were then vaccinated.

Note that the high number of negative results may indicate that people willing to pay to be tested are more likely to have a reason to be concerned about their immune system.

They have also been surveying their customers to put the results into context. The link is regularly updated as they perform more tests. You may want to contact them if you bought the test but were not sent the survey link.

The following graph is based on a small number of people who have completed the survey and took the test at least 21 days after a vaccine. Many of the negative results had some form of immune compromise including blood cancer.

What should I do if the result is positive?

If you test positive for spike protein antibodies you know that your immune system has responded more similarly to someone without immune compromise. If the level is high then there is probably more protection than if the level is low. There are no guarentees, however, and you may well wish to discuss your test results with your specialist to help put it into context of the rest of your own clinical condition.

This is one data point among others that help us know just how good or bad our own immune system is. So for example someone with a healthy CD4 T lymphocyte count and a low positive antibody response might possibly be safer than someone with a moderate positive antibody response but who has a really low total CD4 T lymphocyte count (eg post treatment) and so perhaps may have been unlikely to generate a T cell response. There are other tests which can help indicate how well your immune system is likely to work.

It is vital that you continue to follow your government and doctor’s social distancing guidelines even if your result is positive.

We do not know for certain that blood cancer patients immune systems will definitely be able to fight off the virus even in the presence of antibodies. It is not yet widely possible to test for T cells specific to COVID19 and so you cannot currently know if you responded in such a way.

You will obvisouly have to make your own informed choices about how much you relax your own personal restrictions as the area around you opens up. Pay attention to local infection rates and be more careful if hospitalisations and deaths are low due to vaccines but infections are still high.

Remember the basics of keeping your distance from people, covering your face, and crucially improving ventilation by opening windows.

What should I do if the result is negative?

It is important to manage your emotions in the event of a negative test. This does not mean that you will permanently be consigned to remaining trapped in your own house unable to see others. Yes, you will probably want to be much more cautious than the general advice in your area. But it remains the case, for example, that meeting one person outside and keeping 6 feet away from them is not as likely to pass on the disease as meeting people indoors.

Yes it is a set back. Yes it means you continue at the moment to not be safe from COVID19. Yes you should consider not working outside of the home (and in the UK even if shielding stops the furlough scheme may allow you to be paid despite not working). BUT, once the background infection levels in your area have dropped sufficiently everyone else who has been vaccinated will effectively act as a human shield for you. Each of us will have to do our own personal risk assessment and this is why I advocate getting as much information as possible about the function of YOUR personal immune system to help you make these judgement calls.

Please double check a few things. Are you certain it was the right test (do not assume your doctor ordered correctly!) When did you take the test?

In theory you’d be hoping to havd got antibodies by 3-4 weeks post your first dose. If you don’t have antibodies it is still possible you may still have triggered some T cells. But you should assume the vaccine simply didn’t work.

It’s certainly possible to ask for a differential test to see how many T cells you have in general (even with a high lymphocyte count that may sadly still sometimes be low) and if your overall lymphocyte count post treatment is below 1 the chances are high you don’t have many CD4 lymphocytes. Sadly I’m in that boat and was told I have the T lymphocyte count of an AIDS patient so the vaccine is unlikely to work for me as I also don’t make enough antibodies and failed totally my last vaccine test. I still had my jab though just in case it helped me. In a later article I will talk about other blood tests to assess your immune system.

Right now in the UK each person you meet has around a 1/340 chance of having COVID right now even if they don’t know it. At the worst some areas of London that number was around 1 in 20! When it drops a lot more you might feel that you can do a lot more things (as allowed by the goverment). But even as the rate drops dramatically you may still want to be cautious about crowded poorly ventilated environments.

Nobody dares to use the word any more because of the negative connotations but it’s herd immunity from a combination of vaccine and natural immunity will ultimately lead to the end of this pandemic. When we reach herd immunity even if one person catches the disease it can’t start spreading exponentially through the population any more. It may not take that long since at least in healthy people the vaccines are astonishingly good much, they are much better then flu vaccines for example and here in the UK we are getting through our adults really quickly. Other countries will also speed up the roll out.

Foreign travel, especially to areas that are not vaccinated should definitely be avoided by blood cancer patients without antibodies to COVID19.

My main personal hope is that sooner rather than later the background infection rate will drop so low we can stop worrying about COVID19 altogether even if some of us do not respond to the vaccine personally. Essentially if a combination of natural immunity from those already infected, vaccines and driving the rate down by lockdown and social distancing gets us to the point where each person we meet has the boy a tiny chance of having the disease at some point we just relax and realise the risk is now really low.

If you are negative for antibodies I suspect you may decide to wait a longer before stopping shielding than the general government advice and continue to work from home or be furloughed if possible.

Also if the monoclonal antibodies do become available following trials then that would be an option for this group either prevention or even post exposure.

Some blood cancer patients will no doubt decide to continue some infection prevention measures even after the pandemic is over to avoid catching other infections such as flu. Some of us might continue wearing masks on public transport, or if possible avoid it altogether. The disappearance of flu has been real and it’s because it’s actually harder to catch than Covid19. So simple measures may well help us avoid it. I was mini shielding since a horrid flu in jan 2019 and managed to avoid catching it right up to the start of shielding just by keeping away from sick family members and avoiding crowded places. I am not sure I will ever want to go back into busy shopping centres again. But I have a particularly bad immune system at the moment and yours may well be stronger.

Most of us already feel comfortable walking outside with a friend more than 2 m or 6 feet away (possibly masked for extra assurance). Meeting people outside as the weather warms up and local restrictions allow will also remain much lower risk than meeting inside, particularly if your indoor venue is crowded and/or poorly ventilated. A simple measure like opening windows can greatly reduce the risk of transmission.

Cinemas, theatres, churches, public transport, indoor pubs bars or restaurants, shops, offices are all going to remain higher risk for longer. Having all your shopping and medicines delivered may feel like it should become the new normal especially if you have a poor immune response in general.

The risk of indoor buildings will remain especially high if they have recirculating air conditioning (no obvious fan units on the outside) and no way of opening windows.

The Crucial thing for those who work is if you are currently furloughed you can definitely apply to your employer for that to continue past the end of shrielding on the basis of a risk assessment and your diagnosis. Obviously it does require discretion but especially if you had a negative antibodies test I am sure most sensible employers who are currently furloughing will be willing to continue this. And if you can work from home right now it would be hard for them to argue you can’t continue that a bit longer as a reasonable adjustment for the disability that a cancer diagnosis automatically gives you legally.

This pandemic will not last forever. Even if you have not responded to the vaccine, when the rate in the population is really low you will be safe. Monoclonal antibodies to COVID19 may also become available if trials are successful.

Volunteering for a monoclonal antibody COVID19 clinical trial

• Blood Cancer UK COVID19 Vaccine Page

• Blood Cancer UK page on the recent small vaccine response study

• CLL Society COVID19 Resource Page (USA)

• Patient Power COVID19 Vaccine Video

• LLS Covid19 Vaccine FAQ

• Testing for all results summary – UK private test provider (updated regularly)

• Roche Spike Protein Antibody test

• Abbingdon Health Vaccine test information

• Study showing COVID-19 antibodies remain for at least 6 months by UK Biobank

• Coronavirus antibody tests: what we know so far by The Crick’s George Kassiotis

• Immune responses and immunity to SARS-CoV-2  by the European Centre for Disease Prevention and Control