Vaccination, Booster Shots, and COVID-19

Oliver and I are from Mount Sinai in New York. As many of you may know, Mount Sinai was the center of the pandemic last year. We saw over 5,000 patients in a span of a few months in the first wave and our whole hospital was converted into a giant ICU and all the doctors essentially took part as COVID physicians and we learned a lot through that experience, not just in managing COVID, but also in managing myeloma patients and how to make their treatment safer, save them trips to the clinic or infusion center unless absolutely necessary and so on and so forth. What also happened at that time is we connected with the other scientists at Sinai that were experts in virology, immunology and other infectious disease related fields that had existing studies and protocols on understanding antibody and cellular response to viral infection and then as the vaccines came about, we worked with them and through their protocols were able to study myeloma patients and their response and what was interesting is at the same time we were studying our patients, we as a group, the physicians, nurses and other healthcare workers were in a parallel study as healthy controls so we were also giving our blood and saliva and nasal swabs and things like that every month and followed longitudinally since the beginning of the pandemic so we could actually compare the difference in antibody production or T cell response and things like that. Oliver actually recently published a paper based on a large analysis, actually when we published it was the largest to date of myeloma patients with over 320 patients in that study that were being treated at the institution and enrolled on these protocols and they were compared to healthy controls as I explained to you. So why don't you explain the results that you found Oliver? In early 2021 when the vaccine got its emergency authorization, I think we all had seen the data in healthy controls and how effective it was but an obvious question for us as myeloma physicians was is this going to translate to the same effectiveness in our patients and what we saw was somewhat surprising. The first observation was that the level of anti-spike or anti-COVID IgG which is a type of antibody was significantly lower in the myeloma patients even after two shots of the mRNA vaccine but importantly we saw that there was a significant fraction about 15 or 16 percent in our data set that had no detectable levels of IgG at all. That group obviously was the biggest worry to us because antibody levels we don't routinely measure antibody levels for other pathogens in the past so that might be something that is also true for other vaccines but obviously patients that have no detectable antibodies these were the ones that we were worried about then that might develop COVID-19 even after their vaccination and that's why we studied their characteristics we tried to figure out what made this group special and we saw that there were some factors related to their disease having a lot of prior treatment lines was a risk factor for not having antibodies as well as being lymphopenic having very low white blood cell counts of a specific type was a predictor as well but the most important factors were actually treatment factors we saw that patients that were being treated with either anti-CD38 monoclonal antibodies or BCMA targeted treatments at the time of their vaccination they were at the highest risk much higher than myeloma patients on other treatments not to develop the antibodies. So there were some surprises in there as well one was the patients that had natural COVID infection and then got immunized actually had comparable antibody levels to healthy controls the patients that were having lower antibody levels were the patients had that had gotten two doses of vaccines without having previously seen COVID as an infection and across the board their levels were a little bit lower than healthy controls in the paper we actually describe 10 patients that had breakthrough infections that is infections after getting one or even both vaccinations the study was was spurred by a patient of mine who had a breakthrough infection after both doses and he had been vaccinated after CAR T. Unfortunately the CAR T cured his myeloma but made him susceptible to COVID and he ultimately ended up very sick going to the ICU and didn't make it so this spurred us to do this study and expand it to our entire population of patients we have been subsequently following this up not just looking at the antibody responses to the two doses but now we're looking at the booster dose or the third dose that patients are getting we have also looked at T cell responses because there is this notion or assumption in healthy patient in healthy volunteers that has led some people to believe that even if you don't have antibodies you will have some protection from T cells therefore you know patients can ease up the restrictions and masking but in our cohort at least we've analyzed about 60 or so patients and the patterns are strikingly similar that the patients that don't have antibodies also don't have T cells so this is a surprise to even the immunologist and virologists and really has implications for the patients because they remain the vaccinated vulnerable so if your antibody levels are low or zero our advice to the patients are the following you know keep social distancing or physical distance physical distancing masking vaccinate your family members to create a environment of vaccinated people and you know talk to their myeloma physicians about what would be the best way to protect them until they actually can develop some protection themselves we have been talking to drug companies as well that are making monoclonal antibodies against covid and there's a study that's going to start very soon at our institution and others that is being led by Regeneron that will give the monoclonal anti-covid antibody prophylactically very much like patients receive IVIG. Protection against a virus like covid or SARS-CoV-2 is not depends on a lot of different factors it's relatively easy to measure the levels of antibody and that is a type of protein that is circulating throughout the blood and that recognizes targets on the surface of the virus binds to it and then makes it easier for other parts of the immune system to filter out the covid particles and kill them our body doesn't exclusively rely on those antibodies in fact there are other cells called T cells that are also circulating throughout the bodies and they exist in many different flavors they also have receptors on their surface that specifically recognize targets on the surface of the virus like the spike protein for example and they go around throughout the tissues and they find cells that have been infected with covid can be in the upper respiratory tract or in the lungs or wherever in the body and they have an effect they either produce cytokines that sort of signal through the to the immune system that there's an infection going on and that we should fight it or in some cases they actually have the ability to kill off virally infected cells and so it is the ensemble of all these factors together that really leads to a good immune response historically it's been relatively easy to determine the level of antibodies as it is a simple blood test and determining a particular protein we have assays for that it is much more tricky i think to do assays to measure T cell levels that being said we have the tools and we are using them in the lab but expanding them on a scale to offer it to to patients as a as a test on the market is much more standardizing them standardizing is very difficult so typically the way T cell responses are measured is that we take the patient's blood we take T cells from the blood and then we expose them to covid peptides if the T cells recognize the covid peptides they produce substances called cytokines and we can detect them and we then know that the patient's blood had T cells that are capable of recognizing and mounting a response against covid but this assay currently you know takes about two days and requires a lot of sophistication and technical expertise to run it's not a quick test like we do even now the antigen tests at this conference are being done in 10 minutes and it's really easy so these are more involved it will take some initiative from researchers regulatory agencies and so on so forth to make a standardized T cell assay but i think it will be an important complement to the antibody testing that is widely being done by both physicians and patients i think that's a very good question the question as to what level of antibodies are enough to be protected i don't think there is the one right answer to that and the reason for that there's multiple reasons for that one of the reason is that not all the tests are identical and so not all the lab measurements can be directly compared that's why i think it's most useful if patients repeatedly go to the same lab or make sure that their labs come are are being managed in the same lab so that they can at least compare their own results longitudinally and another important factor or an important factor that that comes in here is that the virus itself has changed as well and so levels that might have been protective in the beginning of this year now that there's variants of the virus might not offer the same degree of protection and so that makes it even harder to answer that question for for us that's why we focused i think heavily on the group of patients that had undetectable levels because that i think was there was a lot of consensus that those were at the highest risk but thankfully that's a very small number of patients yes and we also have now data longitudinal data over six or more months now because the vaccine has been around since the beginning of this year to see how the longitudinal trajectory of the antibody level changes in myeloma patients versus healthy controls and there too we saw that the levels have a tendency to decline more rapidly that's why i think it is timely now that they've that they've approved or at least advised to get the they give the third dose of the vaccine it's still too early to tell i think that we are measuring this at the moment we are recommending all our patients to go ahead and get the booster i think it's very important and we hope by now all patients have gotten at least their initial vaccines and can freely avail of the booster what i would also recommend if possible is that patients also check whether they are responding both to the initial vaccination and to the booster in antibodies and if they see no response then they may actually be eligible for other ways of protection like the regeneron antibody study and things like that i wanted to say i think we owe it to a lot of the patients because i know a lot of them have been exceedingly cautious and understandably so and they've been been doing all they can to make sure they don't get infected and so that's why we have always argued for measurement of the antibodies despite there being sort of the general idea that it wasn't useful i think people are coming back from that and understanding that in a subgroup of people namely people with serious conditions like myeloma it is definitely useful to know if you're at a higher risk so that you can protect yourself and do all these non-pharmacological interventions and make sure that you're you're safe so for patients that have unknown exposure to somebody that has covid or if they're in the same room for any amount of time things they should definitely consider getting the monoclonal antibodies there are two of them that have been approved for this and they should try to get them as soon as possible they are fairly easy to access at most centers so they should make them they should make that effort i think they are definitely useful to protect patients further in the setting of exposure i think they are working on that and they're definitely trying to make vaccines that are for example delta protective and so on so forth from what we've seen so far you know we have to learn to live with this infection and you know myeloma patients are very comfortable with getting their yearly vaccines and flu vaccines and they're good about that i think this might become one of the repertoire of protective things that we do for our patients including ivig and vaccination that may have to be repeated on a timely basis as more information the past year or the past two years were a unique a unique time in the sense that we were confronted with this new pathogen that nobody had ever been exposed to before and this has triggered as we said previously a lot of collaboration on our side with people from virology or microbiology i definitely hope that some of that work would also could be translated to other infections because we know that myeloma patients are vulnerable to other viruses and to other other pathogens i definitely hope and i expect that we will use some of the lessons that we learned from this unique pandemic and translate it and try to figure out how to deal with other pathogens that have a seasonal course like flu and and other viruses so i'm hopeful that we we can do that for sure it's a good question i think one of the things we learned to through our studies is that the disease myeloma and some of the treatments that we are giving affect the cells that are the factory that produces antibodies to their stimuli whether they're vaccines or natural infections so if the factory is compromised it is indeed possible that you know the protection against a variety of influences may be uh diminished i think it just underscores the need to understand what is critical in terms of level of antibody producing cells or t cells these thresholds can only be set by patients participating in studies and being followed longitudinally to see if they are responding not just in terms of numbers but actually getting infected and that will be the ultimate proof as i mentioned earlier we have recommended all our patients to go ahead and get their third or booster shots regardless of whether they were on cd38 antibodies or not i think that um especially if the patients changed from a cd38 antibody to another one there's a greater likelihood that they may mount a response of course acknowledging that every drug has its own half-life and depending on when they discontinue the treatment the body may take less or more time to recover from it an important question i think for patients is what to do after a transplantation or after car t treatment i think currently we're advising to do to redo all vaccinations and i think that will definitely also account for the covid vaccine in terms of car t treatment i think there's no right answer at this point i think the the standard has been to wait at least three months for the covid vaccine that is we actually find that patients that wait longer mount better responses it depends more when the patients recover immunologically rather than a fixed number because i think if you have the ability to produce antibodies you have the b cells in sufficient amount you will mount a response as far as the post autologous transplant vaccination is concerned there's an ongoing national study run by the bmtctn that's looking at this so we should have an answer from that study those are simpler ways of looking at immune function definitely very useful looking at lymphocyte counts we found has some correlation so that's something that can be done in cbc i think more sophisticated tests like looking at number of b cells or covid specific b or t cells are beyond the reach of most outpatient clinics and you know small oncology offices they will still be available in research setting i think your suggestion of using immunoglobulin levels or b cell counts or lymphocyte counts as surrogate would be a good first step and and definitely measuring the actual antibody is more widespread now so that should be recommended go get your third shot i think that's our message right now get get your boosters