PrEParing for the next phase of COVID-19: Protective layers for immunocompromised patients
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Suboptimal COVID-19 vaccination rates in the general population and poor vaccine response in the immunocompromised have forced the rheumatology community to look beyond the specialty in trying to protect vulnerable individuals from the virus.
The natural place to look was infectious diseases. Specifically, the focus zeroed in on pre-exposure prophylaxis (PrEP), a decades-old standby of the infectious diseases community for protecting those at risk. The principle is straightforward: Individuals in certain high-risk categories are treated with a drug or drugs that reduce the likelihood of infection or transmission.
Source: Washington University School of Medicine.
“PrEP is given most commonly in the United States for people at substantial risk of acquiring HIV,” Paul Sax, MD, clinical director of the division of infectious diseases at Brigham and Women’s Hospital and Harvard Medical School, told Healio Rheumatology. “It is also given as malaria prophylaxis to travelers in endemic regions.”
Sax painted a clear picture of who is at risk for COVID-19. “This is particularly the case for those on anti-CD20 agents, such as rituximab [Rituxan, Genentech], regardless of whether for autoimmune conditions or lymphoma,” he said. “Other populations include transplant recipients on anti-rejection therapy, especially those on mycophenolic acid, or certain hematologic malignancies, such as chronic lymphocytic leukemia.”
Additional evidence has shown impaired vaccine response in individuals being treated for other cancers or those on hemodialysis, Sax added. “Taking preventive therapy for COVID-19 would enable many of them to lead a more normal life,” he said.
Two COVID PrEP products are hurtling toward FDA approval and offering options for these at-risk groups. One is a combination of casirivimab and imdevimab (REGEN-COV, Regeneron) and the other is AZD7442 (AstraZeneca); both are monoclonal antibodies that target the spiked protein that is the hallmark of coronaviruses.
“When given as pre-exposure prophylaxis, they prevent infection in the first place” Cassandra Calabrese, DO, an assistant professor of medicine in the department of rheumatic and immunologic disease and the department of infectious disease at the Cleveland Clinic Foundation, said in an interview.
REGEN-COV is currently FDA-authorized for post-exposure prophylaxis (PEP) and being considered for PrEP, while AZD7442 is already authorized for emergency use for PrEP in Europe. AstraZeneca has requested FDA authorization for the same indication in the U.S.
While there is hope in these two products, and the others like them that are expected to follow, it might be a misnomer to call them game changers. COVID-19 is too dynamic, too politicized and too complicated in terms of disease manifestation. But these products may matter in rheumatology.
“I am not sure what overall impact PrEP will have on the course of the pandemic, but its use in the high-risk population will be important,” Alfred H. J. Kim, MD, PhD, assistant professor of medicine at Washington University School of Medicine, told Healio Rheumatology. “Within this population, it will certainly reduce the risk of infection and thus poor outcomes from COVID-19, which is a big win.”
Any development that could be described as a “big win” is welcome at this stage of the pandemic. The addition of PrEP to the armamentarium could be one more small step on the road back to “normal.”
Two Drugs, One Goal
The application for approval for AZD7442 came in the wake of findings from the phase 3 PROVENT trial. According to data on Clinicaltrials.gov and a press release from AstraZeneca, the analysis included 5,197 participants randomly assigned intramuscular injection of AZD7442 or placebo. The primary endpoint was reduction in incidence of symptomatic infection. Results showed a 77% reduction in the risk for the primary outcome for the study drug compared with placebo (95% CI, 46-90).
Further data showed no cases of severe COVID-19 infection or associated mortality in the AZD7442 group, compared with three serious infections and two fatalities in the placebo arm. Safety data showed balance in adverse events between the two groups.
“Unlike many other monoclonal antibodies, this product has a long half-life and could provide up to 12 months of protection,” Jeffrey Sparks, MD, MMSc, associate physician at Brigham and Women’s Hospital and Harvard Medical School, said in an interview. “This interval is important since some studies suggest that vaccine response after rituximab may not be expected until 1 year after previous infusion.”
It is important to note that the benefits offer protection from severe COVID-19 if administered early in the disease course, according to Sparks. “Thus, the rationale is that if given as PrEP, this would help neutralize the virus at the earliest stage of infection to mitigate clinical symptoms and severity,” he said. “The risks are minimal and related to infusion/injection reactions.”
Yet AZD7442 is not without its drawbacks. “A potential downside to giving monoclonal antibodies as PrEP is that they do not generally stimulate other parts of the immune system, such as T cells, so they may not give as robust protection as the vaccine,” Sparks said. “Also, the current guidelines suggest that individuals should not get vaccinated until at least 90 days after monoclonal antibody administration. For this long-acting drug, it may require an even longer delay until people who receive it can get vaccinated.”
The key study for REGEN-COV was published in the New England Journal of Medicine by Weinreich and colleagues. They randomly assigned 1,355 patients with outpatient COVID-19 a subcutaneous injection of REGEN-COV or placebo and followed them for 29 days. Results showed that 1.3% of patients treated with a 2,400-mg dose of REGEN-COV experienced hospitalization from COVID-19 or all-cause mortality, compared with 4.6% of patients in the placebo arm. The researchers noted that this was a relative risk reduction of 71.3% (P < .001). For a REGEN-COV dose of 1,200 mg, the hospitalization or all-cause mortality rate was 1.0%, compared with 3.2% for placebo. The relative risk reduction was 70.4% (P = .002).
“This monoclonal antibody cocktail clearly reduces risk of severe COVID-19 if given as post-exposure prophylaxis,” Sparks said. “I would expect it to also work as PrEP in selected populations and trials are ongoing to test this. This generally is thought to last up to 90 days.”
Further data from the Weinreich study showed that both REGEN-COV doses bested placebo in terms of duration in achieving the resolution of COVID symptoms, as well (10 days vs. 14 days; P < .001 for both comparisons).
“There are great data from both the AstraZeneca and Regeneron products supporting use as PrEP,” Cassandra Calabrese said. “They have both shown pretty impressive efficacy in preventing infection in high-risk patients.”
As these drugs move toward approval, that “impressive efficacy” will surely provide benefit for many patients in immunosuppressed categories. However, some fine-tuning will be required to maximize the utility of these drugs, and that will come with the understanding of who is most likely to benefit, and why.
The Other 3%
Leonard H. Calabrese, DO, director of the RJ Fasenmyer Center for Clinical Immunology at the Cleveland Clinic, likes to look at the big picture, or the “30,000-foot view,” as he calls it.
“The framework is that the COVID-19 pandemic is certainly not over,” he said in an interview. “Based upon the approximations of most epidemiologists, this virus will persist in some form. It may be a more muted version, given the mounting immunity in the general population, they will still likely be afforded protection from serious disease; however, for immunosuppressed people, which is about 3% of the population, it is a completely different story.”
At the heart of the story is that patients who are being treated with steroids or B-cell depleting therapies respond poorly to most vaccines, including the COVID-19 products. In this case, PrEP may offer at least a temporary solution in the form of passive immunity.
“While humoral immunity after vaccination is clearly impaired for those on B cell-depleting therapies such as rituximab, the jury is still out on whether repeated doses of vaccine may offer sufficient protection from T-cell response,” Sparks said. “The early data suggests rituximab-treated patients are also at higher risk of breakthrough infections, so I suspect the T-cell response might not be enough. Perhaps PrEP could bridge that gap and bring them closer to the protection of the general population.”
Drugs that deplete the B cells are not the only therapies of concern, according to Kim. “Our data shows that while TNF inhibitor users have detectable antibodies, those antibodies do not neutralize the delta variant well,” he said.
The ability to assess antibodies would answer these questions and allow rheumatologists to understand who is likely to mount a reasonable vaccine response and who is not. There is just one issue. “No commercial test can assess this, particularly for the variants such as Delta,” Kim said.
Thus, rather than targeting only the most vulnerable patients, a broad-based application of PrEP will have to suffice for now. “This example continues to emphasize the lack of utility of checking antibody levels, and that the use of PrEP will need to be broadly applied to immunosuppressed people,” Kim said.
Looking beyond patients being treated with immunosuppressive drugs, there are additional high-risk groups to consider, according to Leonard Calabrese. “Of course, patients with IBD or multiple sclerosis are also at risk,” he said. “There are also groups in places like nursing homes or jails who have ongoing exposure to the virus. We need strategies for them as well.”
Kim added that PrEP is likely to have benefit in the aged population. “It has been long established that vaccine responses are substantially reduced in older individuals,” Kim said. “In other vulnerable populations, if they are vaccinated and generate good responses, the benefit may not be as substantial as they already have good immunity.”
ID specialists like Sax have decades of experience in targeting and strategizing for high-risk populations. He provided some straightforward advice for the rheumatology community to that end. “While I mentioned that some patients who are afraid to get COVID-19 since they are immunocompromised, the opposite is also true,” he said. “Some who are high risk do not realize it. Clinicians need to be aware of those conditions likely to make someone a vaccine non-responder or more vulnerable to severe COVID-19.”
While the general picture of who is at risk and who may benefit from COVID-19 PrEP comes into shape, it is also important to understand that further questions remain.
Why PrEP?
If there is a key consideration for rheumatologists, it is to understand why an intervention like PrEP can be so beneficial.
One part of the story is that immunosuppressed patients with COVID-19 have long-lived infection, according to Kim. “It is often longer than 3 months,” he said.
The other part pertains to public health. “Variants of interest and concern have been identified in these immunocompromised patients despite being infected by the common variant, indicating the permissive environment for the evolution of the virus,” Kim said. “The possibility of variants and mutations emerging from these patients emphasizes the need to provide additional layers of protection for this group.”
At the moment, PrEP is clearly an attractive option to offer this protection. But there are still hurdles to consider. “COVID has been very interesting in that many of the recommendations that come down can be — and have been — interpreted a bit differently depending on where you are practicing,” Cassandra Calabrese said.
This is another key component in the case for monoclonal antibody use in the PrEP setting, according to Calabrese. For example, while it is clear that B cell-depleting therapies and steroids place rheumatic disease patients in the higher risk category for poor COVID-19 outcomes, there may be some ambiguity about sulfasalazine. “When the authorization for monoclonal antibodies as PrEP arrives, there will be verbiage for who should receive these medications for PrEP,” she said. “Those recommended to receive monoclonals as PrEP are likely to be the same group indicated for treatment with monoclonals, including those aged 65 years and older, those younger than 65 years with high risk comorbidities like diabetes and chronic lung disease, and then patients with immune mediated inflammatory diseases on certain immunosuppressive medications.”
She added: “We see the biggest role for monoclonal antibodies as PrEP in rituximab-treated patients who are unlikely to mount a humoral immune response after COVID-19 vaccination.”
The use of PrEP in pregnancy and women of childbearing age is another area that will require guidance, Calabrese added. “There are a lot of details that will need to be worked out.”
If there is another thing that physicians need to know, it is exactly why these drugs are able to do what they do.
Understanding the Mechanism
In a paper published in Nature, Zost and colleagues conducted an analysis of a large panel of human monoclonal antibodies that target the spike glycoprotein. They found that a number of these antibodies can neutralize and fully block the receptor-binding domain of the S protein (SRBD) from interacting with human angiotensin-converting enzyme 2 (ACE2).
In models using mice with the SARS-CoV-2 virus, they observed that passive transfer of two antibodies — COV2-2196, COV2-2130 or a combination of both — yielded two outcomes of interest. One was protecting mice from weight loss, while the other was a reduction of viral burden and levels of inflammation in the lungs. “These results identify protective epitopes on the SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents,” they wrote.
Dong and colleagues reached similar conclusions in a paper published in Nature Microbiology. They noted that two monoclonal antibodies, AZD8895 and AZD1061, which form the basis for the AZD7442 cocktail, work in tandem to prevent infection. “AZD8895 forms an ‘aromatic cage’ at the heavy/light chain interface using germ line-encoded residues in complementarity-determining regions (CDRs) 2 and 3 of the heavy chain and CDRs 1 and 3 of the light chain,” they wrote. “AZD1061 has an unusually long LCDR1; the HCDR3 makes interactions with the opposite face of the RBD from that of AZD8895.”
The result is the capacity to neutralize not only SARS-CoV-2 infection, but some of the emerging variants with antigenic substitutions in the RBD, as well, according to the findings.
This information may be beyond the comprehension of most patients. It is with gray areas like these in mind that the Calabreses have placed a premium on education of both patients and providers about all things related to COVID and immunosuppression that may ultimately be important considerations for PrEP usage and labeling.
Focus on Education
The Cleveland Clinic is developing materials outlining a cross-section of issues pertaining to PrEP, from the parameters of poor vaccine response and other risk factors to the necessity of home test kits.
“We want patients to know when to call their doctor, and which doctor to call, with issues pertaining to COVID,” Cassandra Calabrese said. “We want physicians to know when and how to get monoclonal antibodies for their patients.”
The good news is that many rheumatologists have their high-risk patients on the radar and are primed to try methods to protect them. The next step is to intervene, according to Sax. “It is important to counsel them on risk reduction and, once approved, how monoclonal antibodies might be useful as PrEP,” he said.
However, advice from a clinician about the use of PrEP is just one part of the equation. “Presumably, when the monoclonals gain approval for PrEP, there will be clear guidance about the eligible populations,” Sax said.
If there is a particular consideration for rheumatologists, it pertains to vaccine response. “It is important to note that just because a vaccine response is impaired does not mean that it is worthless,” Sax said. “There is evidence for the vaccines providing some protection even in immunocompromised people, and hence I would still strongly recommend they be vaccinated.”
The problem is that there are still many individuals — immunosuppressed and non-immunosuppressed alike — who remain unvaccinated for one reason or another. This raises questions for the rheumatology community that extend beyond the clinic or mechanism of action. Should a patient who has refused the vaccine have priority for treatment with a product like AZD7442 or REGEN-COV that is potentially costly, or in short supply, when there are others who are vaccinated but have not mounted a response?
There are no easy answers to issues surrounding the vaccine hesitant. But there are some certainties, according to Sparks. “From a societal and cost perspective, PrEP involves much more logistics related to production, transport, and storage of the monoclonal antibody,” he said. “It involves research and development to make sure it neutralizes all current and future variants of the virus, and administration in an infusion center or other facility with specialized equipment/nursing care.”
For rheumatologists who do encounter vaccine-hesitant patients, Sparks suggested that a simple message may be most effective. “It is clear that vaccination offers much more robust protection against COVID-19 than PrEP,” he said. “Vaccination will prime the entire immune system to defend against the virus, while PrEP only provides some neutralization against the spike protein. I cannot envision a scenario where PrEP would be beneficial over vaccination for the general population or vaccine hesitant.”
In closing, Sparks highlighted the importance of fundamental primary prevention. “These patients have to be very vigilant about masking and social distancing,” he said. While this seems simple enough, he was forthright about how these approaches have become increasingly more difficult with each passing month of the pandemic. “This can really wear down on mental and physical health.”
Like most health care professionals, Leonard Calabrese understands the toll the pandemic has taken, because he sees it in the clinic every day. “We are extremely concerned about our compromised patients,” he said. “But the approval of one or both of the PrEP products, which we are expecting soon, could offer reason for hope.”
- References:
- Dong J, et al. Nat Microbiol. 2021;doi:10.1038/s41564-021-00972-2.
- PROVENT trial: https://clinicaltrials.gov/ct2/show/NCT04625725.
- Weinreich DM, et al. NEJM. 2021;do:10.1056/NEJMoa2108163.
- Zost SJ, et al. Nature. 2020;doi:10.1038/s41586-020-2548-6.
- For more information:
- Cassandra Calabrese, DO, can be reached at 9500 Euclid Ave., Desk A50, Cleveland, OH 44195; email: calabrc@ccf.org.
- Leonard H. Calabrese, DO, can be reached at 9500 Euclid Ave., Cleveland, Ohio 44195; email: calabrl@ccf.org.
- Alfred H. J. Kim, MD, PhD, can be reached at 660 S Euclid Ave., MSC 8045-0020-10, St. Louis, MO 63110; email: akim@wustl.edu.
- Paul Sax, MD, can be reached at 75 Francis St., PBB-A-4, Boston MA, 02115.
- Jeffrey Sparks, MD, MMSc, can be reached at 60 Fenwood Rd., Suite 6016U, Boston, MA 02115; jsparks@bwh.harvard.edu.
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