Immunocompromised patients and COVID-19: how do we protect those most at risk?

KEYWORDS:

• COVID-19
• immunosuppression
• risk for severe COVID-19

1. Introduction

Population immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has increased during the pandemic because of vaccination campaigns and convalescence, resulting in declining coronavirus disease (COVID-19) morbidity and mortality [1]. While the global case fatality rate has declined from more than 5% to below 1% in the general population, this is not the case in vulnerable populations [1]. Immunocompromised individuals still face a significant risk of experiencing symptomatic COVID-19 with severe disease outcomes owing to their diminished protective immune responses.

2. Outcomes of COVID-19 in immunocompromised patients

The immunocompromised population is extremely heterogeneous and encompasses a wide spectrum of individuals, including those with autoimmune disorders, solid organ transplant recipients, cancer patients undergoing active chemotherapy, with human immunodeficiency virus (HIV) infection, and who rely on extended periods of immunomodulating medication. Consequently, the risk of severe COVID-19 varies considerably within this group [2]. Even among solid organ transplant recipients, the outcome of COVID-19 varies significantly, with the highest fatality rate observed in lung transplant recipients [3]. Like the immunocompetent population, the outcomes of immunocompromised individuals are significantly influenced by factors such as comorbidities and age, in addition to the underlying causes of immunosuppression and immunomodulation [2]. With the progression of the pandemic, the decrease in in-hospital mortality has occurred at a slower rate among immunocompromised than among immunocompetent patients [2].

3. Vaccination in immunocompromised patients

Vaccination has become a game-changer that has had a major impact on leading us out of the pandemic. For immunocompromised individuals, several nuances must be considered, and vaccinations need to be strategically planned to attain an optimal vaccine response. Immunosuppressed patients exhibit less robust humoral and cellular vaccine responses than do immunocompetent patients, resulting in a higher incidence of breakthrough infections and a more severe disease course. Correspondingly, the titers of vaccine-generated antibodies vary greatly, depending on the type of immunosuppression. Remarkably, patients undergoing CD20-depleting treatment may not develop an adequate humoral immune response; therefore, ideally, they should be vaccinated before the initiation of CD20-depleting therapy. However, the existence of B cell-depleting therapy should not deter people from the implementation of active immunization because immunosuppressed patients with inadequate humoral immune responses can still develop T cell immunity [4]. Cellular immunity protects against severe COVID-19, whereas humoral immune competence reduces the likelihood of infection. To enhance the vaccine response, a reduction in immunosuppressive dosage should be considered if clinically feasible [5]. Evaluating the vaccine response using neutralizing antibody surrogate marker assays could aid in determining the necessity for additional booster vaccinations; however, precise cutoff values for protective immunity do not exist and may not be relevant in the evolving landscape of viral variants. Therefore, the current guidelines stress the importance of intensified vaccination schedules for immunocompromised patients to enhance vaccine response rates.

4. Benefits of early COVID-19-specific treatment

COVID-19-specific treatments currently consist of either direct antiviral agents, such as neutralizing monoclonal antibodies (nMABs) or convalescent plasma, or antiviral agents that interfere with the viral life cycle and inhibit replication. Both treatment approaches have been demonstrated to reduce the risk of severe COVID-19 in immunocompromised individuals with early SARS-CoV-2 infection [6]. Prior to the occurrence of the Omicron surge, early antiviral treatment significantly reduced hospitalization and mortality rates among high-risk patients. Depending on the specific agents and registration studies, the number needed to treat (NNT) to prevent defined endpoints, mainly hospitalization, ICU admission, and/or death, ranged between 19 and 35 patients. Following increased immune competence because of vaccination and/or convalescence, the NNT for COVID-19-specific early antiviral treatment was significantly higher during the Omicron surge. In addition to changes in immune competence, the reduced virulence of Omicron may also have supported declining morbidity and mortality, resulting in an increased NNT for antiviral treatment outcomes in the general population. In contrast to antivirals, the immune escape and variance of SARS-CoV-2 result in a decreased or complete loss of neutralization activity of current licensed monoclonal antibodies (MABs) [7].

4.1. Antivirals

Agents that inhibit viral replication, such as remdesivir and nirmatrelvir/ritonavir, are highly effective in preventing severe COVID-19 in individuals without sufficient immunity during the early phase of infection, whereas data regarding molnupiravir is controversial [8–10]. In a retrospective single-center study involving solid organ recipients diagnosed with COVID-19 in an outpatient setting during the Omicron surge, the rate of hospital admission within 30 days for patients treated with molnupiravir was 16% [10]. In February 2023, the European Medicines Agency advised against granting marketing authorization for molnupiravir, arguing that the available data did not demonstrate the clinical benefit of molnupiravir in treating adults with COVID-19 who were at higher risk of developing severe COVID-19 but were not receiving supplemental oxygen.

Remdesivir interferes with viral RNA polymerase, causing cessation of virus replication inside infected cells by inducing chain termination during RNA replication. In contrast to nirmatrelvir/ritonavir, remdesivir does not exhibit significant drug interactions, especially not with calcineurin inhibitors such as tacrolimus or cyclosporine. Therefore, it is the preferred choice for solid organ transplant recipients. Meanwhile, approval has been expanded for use in patients with severe renal insufficiency (GFR <30 mL/min, including those requiring hemodialysis) without the need for dose adjustment. The need for parenteral administration of remdesivir raises logistical issues and restricts its use in outpatient settings, requiring specialized outpatient centers for intravenous infusions.

Nirmatrelvir, a protease inhibitor, interrupts SARS-CoV-2 replication. It is coformulated with ritonavir, which acts as a booster, inhibiting the CYP3A-mediated degradation of nirmatrelvir, resulting in elevated plasma levels that amplify the potency of nirmatrelvir. Numerous drug-drug interactions are caused by ritonavir, primarily constraining the use of nirmatrelvir/ritonavir in elderly and immunosuppressed patients, in whom polypharmacy is prevalent.

4.2. Neutralizing SARS-CoV-2 monoclonal antibodies

Current nMABs target the spike protein of SARS-CoV-2, preventing the virus from entering the target cell through the angiotensin-converting enzyme (ACE) receptor, thus inhibiting its replication. The neutralization properties of nMABs strongly depend on their binding affinity to the spike protein. Driven mainly by spike mutations, the evolution of the SARS-CoV-2 virus resulted in a significant decline in the neutralization activity of all nMABs – bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, tixagevimab/cilgavimab, and bebtelovimab – within a few months of market availability. By the end of August 2023, no market-authorized MAB was available that possessed potent (and therefore, likely clinically relevant) neutralizing activity against the prevailing circulating Omicron variants of SARS-CoV-2 (including XBB and EG.5). Whether sotrovimab retains sufficient neutralization activity against BQ1.1 and XBB remains highly controversial, as postulated in animal experimental studies [11].

5. What is in the next available (antiviral) pipeline?

Promising drug developments are underway for antiviral treatments that avoid the limitations of remdesivir and nirmatrelvir/ritonavir. Obeldesivir, a chemically modified version of remdesivir designed for oral bioavailability, provides more convenient use of remdesivir in outpatient settings. A randomized, double-blind, placebo-controlled phase 3 study (OAKTREE trial, NCT05715528) to assess the efficacy and safety of obeldesivir for the treatment of COVID-19 in non-hospitalized participants is still ongoing. Ensitrelvir, a novel 3C protease inhibitor, eliminates the need for a booster and thereby presents considerably fewer interactions than nirmatrelvir/ritonavir, also making it a viable choice for transplant patients who use calcineurin inhibitors. A randomized phase 2/3 study [12] revealed favorable antiviral effectiveness and potential clinical advantages while maintaining an acceptable safety profile. AZD3152 is a newly developed nMAB that binds to a highly conserved epitope region on the receptor-binding domain of the SARS-CoV-2 spike protein; therefore, it is expected to have a broad-spectrum effect against all circulating variants. A phase 1/3 trial (SUPERNOVA, NCT05648110) is currently recruiting immunocompromised individuals globally.

6. How to manage prolonged SARS-CoV-2 and/or relapsing COVID-19?

Immunocompromised individuals are vulnerable to prolonged viral shedding that can last for several weeks to months. Patients with depleted B cells or those with hematologic malignancies of the B cell lineage seem to be particularly at risk of persistent viral shedding [13]. This not only raises hygiene concerns and delays medical treatment but also increases the risk of relapse of symptomatic COVID-19, necessitating hospital readmission. Identifying the ideal timing for solid organ transplantation or the continuation of active cancer chemotherapy in patients with persistent viral shedding who require urgent treatment is a significant challenge. Quantitative SARS-CoV-2 PCR viral load can offer guidance in this decision-making process, as the likelihood of detecting viable viruses diminishes with increasing CT values. The effects of COVID-19-specific treatments on the duration of viral shedding in immunocompromised patients remain controversial. A case series report [14] indicated that combination therapy, including two antivirals (mainly remdesivir and nirmatrelvir/ritonavir) and nMABs, was associated with a high rate of virological clearance and clinical response in immunocompromised patients with prolonged or relapsed COVID-19 during the Omicron era. Based on our center’s experience and other case reports, viral clearance was predominantly attributed to highly effective neutralizing antibodies [15].

7. Conclusion

In contrast to the general population, COVID-19 poses substantial challenges to immunocompromised individuals. Intensified vaccine protocols can reduce the overall infection and symptomatic and/or disease progression toward COVID-19. Fully active early antiviral treatment may offer additional benefits in preventing severe COVID-19. Further research is needed to develop pragmatic and effective prevention strategies for patients at an increased risk of severe COVID-19.

Declaration of interest

JS reports grants, personal fees, and non-financial support from AbbVie, Gilead Sciences, Janssen-Cilag, GSK/ViiV Healthcare, MSD, Dr. Falk Pharma GmbH, Diasorin, Deutsche Forschungsgemeinschaft (DFG) and the Central Innovation Programme for small and medium-sized enterprises (ZIM) outside the submitted work. CDS reports grants and personal fees from AbbVie, grants, fees, and non-financial support from Gilead Sciences, grants and personal fees from Janssen-Cilag, grants and personal fees from MSD, grants from Cepheid, personal fees from GSK, grants and personal fees from ViiV Healthcare, during the conduct of the study; fees from AstraZeneca, other from Apeiron, grants, personal fees, and non-financial support from BBraun Melsungen, grants and personal fees from BioNtech, personal fees from Eli Lilly, personal fees from Formycon, personal fees from Moderna, personal fees from Molecular partners, personal fees from Novartis, grants and personal fees from Eli Lilly, personal fees from Roche, personal fees from SOBI, personal fees from Shionogi, and personal fees from Pfizer.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contribution statement

JS, JE, LR, and CDS contributed substantially to the conception and design of the review article and the interpretation of the relevant literature. CDS has revised the review for intellectual content.

Additional information

Funding

This paper was not funded.