Covid-19: Boosters, Antibodies, and Continued Risk for the Immunocompromised

On February 24^th, CareDx hosted a webinar with NYU’s Dr. Dorry Segev, one of the world’s leading experts on the impact of Covid-19 on immunocompromised patients. When the pandemic hit, Dr. Segev shifted his research to better understanding vaccines in the immunocompromised, for which he has received a Letter of Commendation from Dr. Anthony Fauci. His research has been published in JAMA, and featured on CBS, NBC, NPR, and the New York Times, among other publications. In recognition of his contributions to health care, Dr. Segev was recently elected to the National Academy of Medicine.

We adapted our webinar conversation with Dr. Segev for this article, editing only for clarity and length.

Transplant patients and two-dose mRNA vaccines

About 14 months ago, Brian Boyarsky helped me put together a large national observational study of vaccine immunogenicity in transplant patients. Very early on, even a few months into the vaccine rollout, we already knew that there was going to be a problem with immunogenicity of vaccines and transplant patients.

In his second paper in JAMA, Boyarsky reported that only 50% of transplant patients had any antibody response whatsoever to vaccination, and looking at the antibody levels (which we now know are really important) of the people who had detectable antibodies, about half of them did not have optimal levels of antibodies after two-dose vaccination.

So in transplant patients, two-dose vaccination meant ~50% had no antibodies, ~25% didn’t have enough antibodies, and only ~25% were anywhere close to what we were seeing in the immunocompetent general population.

Factors predictive of Covid-19 vaccine response in transplant patients

We have since then gotten into some detail in trying to determine who we predict will have good vaccine responses and who will not.

Jen Alejo and Sunjae Bae developed a machine learning algorithm and found four variables were predictive of vaccine response:

1. Being on mycophenolate (also known as“MMF”, “Myfortic”, or “CellCept”; an antimetabolite drug)
2. Amount of time since transplant (presumably as a surrogate for how much immunosuppression the patient is taking)
3. Age
4. Vaccine platform (i.e., Pfizer vs. Moderna vs. JNJ)

The authors created a web app that allows you to enter all this information and then tells you your probability of having a positive antibody response to two-dose vaccination. The lower your probability, the more you need third and fourth vaccine doses and better surveillance. So this will give everybody a sense of their risk profile based on clinical characteristics.

MMF dosing correlated with Covid-19 vaccine response in transplant patients

Jonathan Mitchell, from Johns Hopkins, looked more carefully at MMF dosing and Covid vaccines and showed a dose-response: the higher the dose of MMF that someone is on, the more likely they are to have a poor antibody response to the vaccine. Does that mean that everybody should stop their MMF today? Absolutely not. There’s a reason patients take MMF and there are risks when they stop. We’re actually doing an NIH-funded randomized trial to see if it is safe to do those sorts of things, but until then the study provides information about who is more likely to be at risk.

Caoilfhionn Conolly, from Johns Hopkins, did a study comparing the Moderna vaccine with the Pfizer vaccine and showed that for transplant recipients, even those not on MMF, but particularly those on MMF, there’s about a three-fold higher chance of getting an antibody response with the Moderna vaccine than with the Pfizer vaccine.

Antibody levels correlate with neutralization activity and clinical outcomes

Andrew Karaba, from Johns Hopkins, showed that antibody levels correlate with neutralization activity. That’s really important because it means that if you measure a certain antibody level, it correlates with how well your immune system can kill the virus if it happens to see the virus. This relationship held in the wild type of the Covid virus, as well as the alpha, gamma, and delta variants (things change with omicron).

There was a large study from the original Moderna trial recently published in Science, which showed that not only do antibody levels correlate with neutralization, but they also correlate with clinical protection. They showed that for every tenfold increase in any of these antibody biomarkers you get about a 30 to 40% decrease in the risk of breakthrough infection. So, we know that antibody levels generally correlate with neutralization which generally correlates with protection (again things change with omicron).

Carolyn Chin, from Johns Hopkin, gathered data from 17 hospitals and showed that the fact that the antibody levels were lower in transplant patients not only correlated with things like neutralization but also correlated substantially with breakthrough infections as well. Two-dose fully vaccinated transplant patients had 82 times higher risk of a breakthrough infection and 485 times higher risk of a breakthrough infection with associated hospitalization or death when compared to the two-dose fully vaccinated general population from CDC numbers. This showed, very clinically, the significance of the risk of breakthroughs to transplant patients.

Pediatric transplant recipients and vaccine response

Fortunately, pediatric patients actually have better responses to the vaccines. In a relatively small cohort of pediatric recipients, our team at Johns Hopkins showed^i. that antibody levels were much higher than in adults and that the likelihood of getting an antibody response was also much higher than in adults. We don’t have a very good explanation for this, however, we’re currently looking more into the biology.

Third vaccine dose in transplant recipients

This work motivated a study^ii. that Bill Werbel and I did looking at third doses in transplant patients and whether those who failed two doses (defined as failing to mount antibody response) might be responsive to a third dose and whether that was safe. The early data showed that, indeed, there was a benefit to an additional dose. That motivated the CDC and the FDA to recommend that for initial vaccination, immunocompromised people should actually get three doses of the mRNA vaccines. I want to emphasize that this is for initial vaccination – in order for an immunocompromised person to get the same level of response as a person with a normal immune system gets with two doses, three doses are needed. When vaccine effectiveness wanes because of limited durability, transplant patients can get a booster dose as well which would be dose number four.

I strongly recommend that patients familiarize themselves with the new recommendations and discuss them with their doctors. Remember that everyone is different – this is a one-size-fits-all kind of recommendation, but we all know that transplant patients are not one-size-fits-all by any means.

Another thing we learned is that even with three doses of the vaccine, some people still have an inadequate response. A lot of the work that’s been done recently is to try to figure out what to do in that scenario.

Fourth and fifth doses of Covid-19 vaccines

Work from Jen Alejo and Andrew Karaba looked at people who got fourth doses, and the impact of fourth doses on antibody levels and on neutralization, which is a surrogate for how well your immune system might be able to kill the virus. They found that antibody levels went up; so if you had three doses, unless you were off the charts to begin with, if you got a fourth dose your antibody levels went up.

An interesting finding was that neutralization increased dramatically for the alpha, beta, and delta strains of the virus. However, for omicron this did not happen. People were not in the range for neutralization to begin with and did not achieve high neutralization after the fourth dose. Now remember, this was a very highly selected group of people who failed their first three doses and were trying to get better immunogenicity with a fourth dose. The study showed an increase in the immune response, but not enough to fight omicron. I realize that this is frustrating for transplant patients; it’s frustrating for researchers and physicians as well.

Some people have gone on to get a fifth dose. I will emphasize that the CDC and the FDA do not recommend a fifth dose; a fifth dose is not approved right now. There are some people who have managed to get 5th doses (I’m not sure how), but we have studied those who have. We found that with every increasing dose, the antibody levels increased and there were even people with very, very low antibody response after a fourth dose who then had a major rise in their antibodies after a fifth dose.

So continued priming of the immune system is something that we are still looking into and we’re still trying to evaluate whether you can get a good vaccine response by continued priming of the immune system. But this is in the research domain, because remember that fifth doses are not yet approved in the United States.

Covid-19 antibody testing enables personalization of care

I recently published in the American Journal of Transplantation with Dr. Werbel on antibody testing for transplant recipients^iii.. Based on our research, we recommend that all solid organ transplant recipients be tested for anti-spike antibody after vaccination. The test results should then be used to personalize efforts to improve protection against Covid-19 for the most vulnerable, such as additional vaccination strategies and consideration of passive immunoprophylaxis (i.e., Evusheld and other pre-exposure monoclonal antibodies).

I will also say that nothing is binary. This will come up in probably 50% of my responses, there is no cut point that I can tell you that now you’re safe versus below this you’re not safe, there’s no cut point where I can say this is where the goalpost should be, there’s no cut point in antibodies for really anything that we can tell you 100% clinically. However more antibodies means more protection, less antibodies means less protection. I can certainly tell you, if your antibodies are negative you probably have very little protection compared to if your antibodies are off the charts positive but, again, nothing is binary with Covid, everything needs to be personalized. Everything is best done as a conversation between you and your medical team.

I want to re-emphasize the fact that nothing is binary. Some patients have very high exposure risks, some have very low exposure risks, some have a lot of co-morbidities, some have much fewer comorbidities and all of these things need to be taken into consideration when you make your clinical and behavioral decisions.

How can transplant patients stay safe without living in a bubble?

This has been and continues to be the million-dollar question. I’ll start by saying “safe” is not a binary and there are no absolutes – there is nothing that is 100% safe or unsafe. There are three things that patients should think about: 1) exposure risk; 2) disease risk; and 3) risk tolerance.

Exposure risk

Exposure risk is the likelihood you will be exposed to Covid and the likelihood that you will get infected if you are exposed. So, thinking about your day-to-day activities: do you work from home? Do you order your groceries and other essentials through a delivery service? Or are you on the front lines as a nurse taking care of Covid patients? Or are you somewhere in between? This is a spectrum. The people that you interact with on a regular basis are also a key influence on your risk level; hopefully, they are vaccinated and they are being safe as well.

The likelihood that you’ll get infected if you are exposed is related to your amount of immune protection. If your measured antibodies are zero, you don’t have nearly as much protection as someone who has detectable antibodies. If you’ve received pre-exposure monoclonal antibodies, they may offer added protection.

Disease risk

Disease risk is if you happen to get Covid, what is the likelihood that you will contract a severe case and need to be hospitalized or die. This is driven by factors including age (older patients are more likely to have severe cases) and co-morbidities (e.g., diabetes, obesity).

Risk tolerance

Risk tolerance is more of a philosophical dimension. How risk-averse are you? Are you one of those that says, “We all take some risks in life, I’m sick and tired of hiding in my basement and I need to go see my family” even if there may be some risk? Do you take other risks like adventure sports or rock climbing? We all consider and accept various risks in our lives, so you should consider your own risk tolerance in the context of your exposure and disease risk.

Is it safe to travel domestically or internationally?

There is a spectrum when it comes to the safety of travel. In general, the travel industry requires masks but does not require vaccines. So being on an airplane where everyone is masked is, to some extent, safe. It’s safer than being in a restaurant where everyone is sitting and eating without masks. However, it’s also less safe than being in your house – it’s somewhere in between. But it’s not ultra-safe, because there will be times where you are exposed to people who are unmasked when they’re eating on the airplane and masks are not 100% perfect and they don’t require vaccination for travel.

What role do you see for Evusheld in immunocompromised patients? What are the benefits and associated risks?

There is currently a limited amount of data on Evusheld, so these are difficult questions to answer. However here are some thoughts on pre-exposure monoclonal antibodies in general and on Evusheld in particular, based on the available evidence. With all of these treatments, there are benefits and risks.

If your antibodies are zero, you are more likely to benefit from Evusheld than if your antibodies are greater than 2500 (based on the Roche/Labcorp antibody test).

I’m not saying you won’t benefit if you have off-the-chart detectable antibodies because we don’t know what antibody level you need to defend yourself against omicron.

It used to be that if you had greater than 2500, I could say you’re probably protected from Delta, but now with omicron we don’t know. It’s probably an extra zero beyond that, but once you’re greater than 2500 on the test I can’t tell if you’re 2501 or 25,000. So, there are probably people who will benefit even if their antibody levels are high, but the benefit is likely of a lower magnitude than the benefit to people whose antibodies are negative.

This is why given the limited supply of Evusheld, a lot of transplant groups and centers have prioritized people with negative antibodies. Additionally, the observed cardiac and other side effects, while rare, change the risk/benefit calculation in patients with higher antibody levels.

The Omicron variant seems to be milder for most patients. What is your viewpoint on potential future variants?

I want to start by clarifying that omicron is not mild for all populations – I’ve had transplant patients hospitalized and die from omicron. So the idea that omicron is “benign”, “easy”, or “just a cold” just isn’t true for everyone. In general, the outcomes have been better in transplant patients who got omicron versus delta, for example, but caution still needs to be paid.

With mask mandates being lifted across the country, I want to state my opinion that this should not change the behavior of transplant recipients. I’m still wearing a mask even though I have a ton of antibodies and a lot of immunity, and I think that until we really see the infectivity rate drop dramatically, we still need to be quite careful.

What are the next variants that could be on the horizon? There’s an omicron sub-variant that seems to be potentially more infective than omicron, although we don’t know a whole lot about it, and we really don’t know anything about it in transplant patients. However, in my mind, Covid is Covid – you don’t want to get Covid, and you should take precautions to avoid getting it.

I believe that there will inevitably be new variants and waves. I think that every six to twelve months, there’ll be a new wave and we’ll need a new vaccine dose. Transplant patients might need two doses or might need more monoclonal antibodies. Hopefully, with enough cross-variant immunity, we won’t see things that look like the delta and omicron spikes in the United States.

As a high-risk population, how can transplant patients communicate their concerns with friends and family who potentially remain unvaccinated, or perhaps have a different risk tolerance?

The people you are exposed to most are the ones who put you at most risk, so to every extent possible, make sure they have immunity either through vaccination and/or prior infection. Transplant patients should be very reluctant to spend extended periods of time with people who are not fully up-to-date with the CDC guidelines for vaccination – meaning, not just two doses anymore, but three doses today (or if the guidelines are further revised in the future to recommend additional boosters).

As a transplant patient, it’s important to share with people that even though they might not be at high-risk for a severe case of Covid, they could be carrying the virus (they may not even know that they’re carrying it) and it could unintentionally make you very sick or even lead to your death. And I don’t think anyone would want that on their hands.

I’ve been asked by a number of patients whether they can spend time with a friend or family member who refuses to get vaccinated. I would say ultimately it will be fine to spend time with folks like that when community prevalence drops and when infectivity drops, but for the time being my answer is you should only spend time with him/her on zoom or in-person while outdoors and masked.

How does the type of transplant you have impact your response to the Covid vaccines?

In the machine learning exploration developed by Sunjae Bae and Jen Alejo, organ type had very little impact on Covid vaccine response. The differences between different types of transplants were driven by the type and level of immunosuppression.

Will transplant patients need life-long vaccine boosters?

I think everyone will need lifelong booster regimens of the vaccines, and as the virus evolves there will be variant-specific boosters. What this may look like is people with healthy immune systems need only one booster dose and transplant patients may need two booster doses or a higher booster dose. But just like we need a flu shot every year I think we’re also going to need a Covid booster every year, at least for several years until things really wash out. Transplant patients who don’t respond to vaccination at all might instead of a booster dose or in addition to a booster dose, also need monoclonal antibodies in perpetuity at some interval. We should get used to the fact that this thing isn’t going anywhere anytime soon.

But hopefully what that means is that as we have better boosters, better protection, and better treatments, transplant patients will be able to resume living as they did prior to the virus.

If a patient’s transplant center won’t check their antibody levels, should patients consider doing this on their own?

Every transplant patient should know their antibody levels. If you are in the United States, and you have access to Labcorp or Quest, you can walk in and get an antibody test without a doctor’s order or prescription. Most insurance will cover the test, and even if your insurance doesn’t cover it, the out-of-pocket cost is only around $50.

However, patients need the results to be interpreted in the context of their personal situation. I do worry that if your transplant center tells you that there’s no reason to get your antibodies tested, and then you come back to them with antibody test results, they’re not going to know how to interpret the results.

What you should know is that a negative result or a very low result is more informative than a very high result. If your antibodies are negative, I can say with a high degree of certainty that you have suboptimal protection and need additional protection. If your antibodies are off the chart positive, because antibodies only represent one dimension of the immune response, I cannot say with the same amount of confidence that you are protected.

Final thoughts:

• Don’t lose hope
• Do as much as you possibly can to regain a feeling of normalcy, even though the world is not normal right now
• Engage with people whom you’re worried about or know you might get exposed to, on Zoom. Continue wearing your masks when interacting with people outside. Keep trying to get vaccinated as much as you possibly can
• If you’re a candidate for pre-exposure monoclonal antibodies, talk to your doctor about getting this treatment
• Do everything you can to mitigate your risk, but also do everything you can to create a sense of normalcy in your life. While nothing is 100% safe, there are many things you can do while maintaining precautions.

The information in this article is not intended or implied to be a substitute for professional medical advice from your healthcare provider. Always seek the advice of your physician or medical team with any questions you may have regarding your specific medical condition.

i. Qin, C. et al. American Journal of Transplantation, Sept. 13, 2021. https://doi.org/10.1111/ajt.16841
ii. Werbel, B. et al. Annals of Internal Medicine, September, 2021. https://doi.org/10.7326/L21-0282
iii. Werbel, B. and Segev, D. American Journal of Transplantation, Feb. 4, 2022. https://doi.org/10.1111/ajt.16993