COVID-19 PrEP for immunosuppressed patients: The time is now
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For some time now, we have been discussing COVID-19 as two epidemics. One is the tragic and unnecessary epidemic among those unwilling to be vaccinated who are pushing our fragile health care system to the limit, unnecessarily spreading the infections throughout the community, including to the most vulnerable. The other is one of breakthrough infections in those who have done what they can to protect themselves by being partially or fully vaccinated.
I have previously commented that I am among this latter breakthrough epidemic, although I am fortunate that both myself and my wife, who are otherwise healthy, experienced mild COVID-19. While not fun, the vaccine did its job and we are fine. There is, however, a third epidemic that is not in the limelight, occurring among the 3% or so of the population who are immunosuppressed or otherwise unable to be immunized who are highly vulnerable to COVID-19, despite vaccinations.
Recent studies from Israel and the U.S. have demonstrated that among the few percent of breakthrough infections that wind up hospitalized with severe disease, approximately 30% to 40% have immunocompromising conditions, including autoimmune disease, transplantations, primary and secondary immunodeficiency states, cancer and other disorders that collectively limit their ability to mount a protective vaccine response.
The clinical outcomes of breakthrough infections in autoimmune patients can be severe and even fatal and have been recently documented. In our department at the Cleveland Clinic, we have unfortunately confirmed this and witnessed this clinically with fatal breakthrough infections, especially among those treated with B-cell depleting agents. Since we are unable to predict the end of the pandemic, I assert without hesitancy that strategies are needed now to mitigate risk in this vulnerable group.
Monoclonal antibodies have become a valuable tool in our armamentarium for patients with COVID-19 and have been granted emergency use authorization for patients early in their course with mild (non-hospitalized) infection. The data are clear that prompt therapy with such agents reduces the likelihood of hospitalization and death. This summer, the FDA revised and extended the EUA for REGEN-COV (casirivimab and imdevimab, administered together) beyond such treatment to include use as PEP or post-exposure prophylaxis for COVID-19 in adults and pediatric individuals who are unlikely to mount a robust response to vaccination and are at high risk for progression to severe disease. This preventive EUA also endorsed a lower dose ongoing regimen for these same vulnerable patients who are subjected to “repeated exposure.”
While most have interpreted this ongoing strategy for residents of endemic infected facilities (ie, nursing homes, jails, etc.), I asked immediately why this is not appropriate for these same immunosuppressed patients who must live their lives in this recent surge. This includes the teachers, bus drivers, health care workers, or anyone who really wants their life back but is unfortunate to be incapable of mounting a vaccine response that provides the reasonable assurances that the healthy vaccinated patient population enjoy.
Recently, AstraZeneca issued a press release regarding their combination monoclonal AZD7442, which is being investigated for both prevention and treatment demonstrating a significant protective effect in a study of more than 5,000 patients defined as having “increased risk for inadequate response to active immunization or having increased risk of SARS-CoV-2 infection.” Similar studies are underway for other monoclonals, as well.
At the Cleveland Clinic, we are organized around our Rheumatology-Infectious Disease Clinic and training program and have a unique vantage point of this third epidemic. We, like many other clinical immunologists – defined as any clinician engaged in the application of immunologic diagnostic and/or therapeutics – are already engaged in early battles to get ongoing COVID-19 PrEP approved for our patients.
I recognize that there are obstacles to instituting such a strategy, including our lack of standardized biomarkers for protective immunity. While regulatory agencies strongly advise against the use of serologic and cellular testing as an index of immunity in the general population, I would argue that there may be clinical merit of such in the most immunosuppressed patients. I assert that in patients with severe immunosuppression who are fully vaccinated, a complete absence of anti-S response is a source of clear concern.
In addition, while the costs of such a program are not insignificant, this is a relatively small part of our population in whom we are already investing large amounts of money for immune-based and other advanced therapeutics (ie, biologics, IVIG, etc.).
Coupled with the high costs of treating hospitalized COVID-19 patients – a likely outcome for those who didn’t mount immune responses following vaccination – the financial burden of this therapy would be comparatively small. I believe for many of my most severely immunocompromised patients (ie, patients on B-cell depleting agents, CVID, others) there are ample data to make these agents available on a compassionate use basis and the barriers should and must come down now. To delay further, particularly for the most vulnerable, will be fatal.
Perspective
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Professor Calabrese raises an interesting strategy to prevent severe COVID-19 in patients who are immunosuppressed—the prophylactic use of monoclonal antibodies against SARS-CoV2 even before known infection. Typically, the three products available under emergency use authorization are used in patients with known COVID-19 and at least one risk factor for severe illness and are used to prevent hospitalization or death. They are quite effective in this regard, with relative risk reductions ranging from 70% to 85% for severe COVID-19. In vaccinated patients with immune-mediated inflammatory diseases who are severely immunosuppressed, could these antibodies be used pre-emptively to prevent death? How would this work in gastroenterology among our inflammatory bowel disease patients? It’s interesting to note that in studies of vaccine response among the immunosuppressed, there is variability among medication classes with respect to impact on mounting an antibody response. For example, in one systematic review of 25 studies, the rates of seroconversion following two doses of mRNA vaccine were over 90% among patients receiving anti-TNF agents, anti-integrins, or anti-IL-12/23 agents (Jena A et al, Autoimmun Rev 2021 Aug 30:102927). With rituximab and abatacept, the rates of seroconversion were below 70%. And with steroids, JAK inhibitors, and mycophenolate, seroconversion rates were between 70% and 90%. Since the vast majority of our IBD patients are not on rituximab or abatacept, we can probably breathe a sigh of relief. This strategy is certainly deserving of more study. However, given governmental constraints on availability of the monoclonal antibodies, my advice for gastroenterologists is to await more data before pursuing a strategy of prophylactic use before known infection.
Perspective
Back to TopAnita Afzali, MD, MPH
I read this article on COVID PreP for immunosuppressed patients with great interest. The third epidemic described of the immunosuppressed who is highly vulnerable to COVID-19 despite vaccinations may apply to some of our patients with inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. Similar to other immune-mediated inflammatory diseases (IMIDs) as described by Dr. Calabrese, some IBD patients treated with TNF antagonists may have a decreased immune response to COVID-19 mRNA vaccine with a lower anti-S observed as early as 4 weeks after the second dose of the vaccination, as reported in a recent prospective, controlled, multicenter Israeli study. However, it is important to note that other studies, including COVID-19 vaccination registries from the United States and Europe, have not reported lower antibody titers among IBD patients, and immune responses with COVID-19 vaccines were comparable to the general population regardless of treatment including biologics such as TNF antagonists, anti-cytokine and anti-trafficking agents. This may suggest differences in dose and medication effect, or perhaps a difference in the underlying immunology of the diseases themselves, which render varying responses to vaccinations among patients with IMIDs.
There may be a blunted immune response among some IBD patients, particularly older patients, those also on high dose corticosteroids, or those on combination therapy with TNF antagonists and an immune modulator. As such, based on the recent CDC recommendations, these patients may also benefit from third or additional SARS-CoV2-2 mRNA vaccine dose.
All in all, because vaccine response is multi-factorial and there remains only a fair understanding between serologic or cellular immunity and correlation with vaccine protectiveness, at this time, based on the numerous real-time, clinical practice experiences we have, the majority of IBD patients do not need COVID PrP.
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Alfred H. J. Kim, MD, PhD
Ben Ryan recently wrote a piece in The Guardian where one of my patients with systemic lupus erythematosus expressed her trepidation of contracting COVID-19, as she found out through our COVaRiPAD study that her humoral responses following the initial series of SARS-CoV-2 vaccine was essentially absent due to her immunosuppression.
Immunosuppressed patients like her are increasingly fearful and frustrated. They are fearful because despite their efforts to mitigate their risk of getting COVID-19 by being vaccinated, some are still at high risk of developing severe COVID-19 due to inadequate immune responses. They are frustrated that while the rest of society opens up, they remain sheltered in place and cannot re-engage with others without exposing themselves to possible infection.
The immediate solution is straightforward: PrEP with monoclonal antibodies to the spike protein of SARS-CoV-2, which is exactly what is generated in immunocompetent people that translates to protective responses. While the hard work to identify ways to induce more durable immunity following vaccination continues, these patients — and our health care system — cannot afford to wait.
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Jeremy L. Warner, MD, MS, FAMIA, FASCO
People with autoimmune diseases and with hematologic malignancies share a great deal in common, including underlying immunosuppression and a treatment armamentarium that includes agents that deplete cellular and humoral immunity — to damp down the autoimmune response in the former, and to kill cancer cells in the latter. It is therefore not too surprising that they share the burden of severe outcomes from COVID-19 and have a less-than-robust response to vaccination. Besides avoiding infection, what to do?
Convalescent plasma may improve outcomes in patients with hematologic malignancies, but the data overall for plasma is mixed. Monoclonal antibodies have had encouraging results for infected patients, and it is natural to wonder if pre-exposure prophylaxis (PrEP) would save lives. At the same time, states such as Tennessee are restricting monoclonals, adopting NIH guidance in a time of shortage. Before we can have a serious conversation about PrEP, we need to solve the supply shortages that we currently confront. In a time of plenty, PrEP should be seriously considered for the most vulnerable.
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