Three large observational studies attempted to quantify the increased risk and severity of COVID-19 in immunocompromised populations, COVID-19–Associated Hospitalization Surveillance Network (COVID-NET), Emerging Populations and Outcomes associated with COVID-19-Health Conditions (EPOCH-US), and INFORM (1, 7, 8).

COVID-NET monitored cases from March 1, 2020, through February 28, 2022, and included a representative sample of 22,345 adults aged ≥18 years in the United States hospitalized with COVID-19. Data from this population-based active surveillance suggested that immunocompromised people were overrepresented, accounting for 12% of adult hospitalizations (8). Furthermore, among vaccinated adults, those with immunocompromised status had higher risks of intensive care unit (ICU) admission (adjusted odds ratio 1.40) and in-hospital death (1.87) compared with those with competent immune function.

The EPOCH-US study included a cohort of over 16 million people registered in the Healthcare Integrated Research Database from April 1, 2018, through March 31, 2022. Of this cohort, 3% (n=458,049) were identified as immunocompromised (1). Overall, 13.5% (n=61,865) of this immunocompromised cohort developed COVID-19, with the largest prevalence among people with end-stage renal disease (20%), followed by primary immunodeficiency, hematopoietic stem cell transplant and solid organ transplant recipients (all 16%), immunosuppressive treatment (14%), and hematologic or solid tumor malignancy (9%). Of the immunocompromised cohort who developed COVID-19, 23.5% had hospitalizations associated with their first COVID-19 diagnosis, with a mean length of stay of 15.4 days. The mean cost for these events was estimated at nearly $1 billion US dollars in 2021, with a mean cost of $64,029 per patient.

INFORM, an ongoing retrospective cohort and electronic health data study in England (7), compared COVID-19–related outcomes (hospitalization, ICU admission, and death) among different groups of immunocompromised individuals and the general population. The study population comprised a random sample of 25% of all individuals aged ≥12 years (almost 12 million) registered in the National Health Service databases on January 1, 2022. Of this sample, 4% (470,910) were immunocompromised. Initial results from January 1 through December 31, 2022, showed that immunocompromised individuals disproportionately accounted for approximately 25% of COVID-related outcomes, including 22% (4585/20,910) of COVID-19 hospitalizations, 28% (125/440) of ICU admissions, and 24% (1145/4810) of deaths. Among the highly vaccinated population (≥3 doses of a COVID-19 vaccine), immunocompromised individuals accounted for approximately 25% of COVID-19 hospitalizations, 36% of ICU admissions, and 25% of deaths. In this group, the risks of COVID-19 hospitalization and ICU admission (incidence rate ratios adjusted for age, sex, and number of comorbidities) were 2.17 (95% CI 2.09–2.26) and 4.66 (95% CI 3.56–6.11), respectively. Individuals with the highest risk for COVID-19 hospitalization were solid organ and hematopoietic stem cell transplant recipients and those undergoing treatment for hematological malignancy.

Contracting COVID-19 can have additional negative consequences, including interrupted treatment for cancer or other underlying disease, potential adverse drug-drug interactions (DDIs) with COVID-19 treatments, loss of work productivity, social isolation, and emotional and financial burden ( Figure 1 ). Furthermore, the initial infection could lead to a syndrome called “long COVID” with negative consequences in a person’s quality of life (14).

The emotional and psychological impact of COVID-19 on immunocompromised people, their families, and caregivers cannot be underestimated. A survey conducted at the beginning of the pandemic revealed high levels of fear/anxiety among 70% of adults with primary immunodeficiencies (15). These individuals were most afraid of exposure from contact with strangers, especially in public places. Qualitative analyses conducted among parents of children with cancer (16) revealed similar negative sentiments associated with COVID-19, while healthcare providers struggled with responsibility around inadvertently transmitting COVID-19 to their immunocompromised patients (17).

Immunocompromised individuals with COVID-19 may suffer from persistent infection with prolonged viral shedding (18), and even viral rebound following treatment with antivirals (19), which carries significant public health implications. In a comprehensive review, DeWolf and colleagues (4) summarized the current understanding of how altered host immunity in individuals with cancer and other immunocompromising conditions impacts the prevention, clinical course, and long-term sequelae of SARS-CoV-2 infection. Multiple mechanisms contribute to the increased vulnerability of this population, depending on the type and severity of immunosuppression, including compromised epithelial barrier, impaired innate and adaptive T-cell immune responses, and altered tissue-resident immune cells (4). While antibody responses have been the primary clinical marker to prevent infection, T-cell responses also play a valuable role in controlling infection. Overall, the data suggest that neutralizing antibodies, CD4 T cells, and CD8 T cells work together in controlling COVID-19, and a deficiency in any one of the three immune measures is a risk factor for severe outcomes (20–23).

While immunocompetent individuals typically recover from COVID-19 within 5–7 days, immunocompromised people are at risk of prolonged infection due to slower clearance of the virus. People with hematologic malignancies and transplant recipients may shed viable virus for a median of 4 weeks (24–26). Moreover, SARS-CoV-2 may persist for an even longer period of time with proven infectivity (>8 months) (27), or progress into a chronic infection (long COVID-19) (28), increasing the opportunity for the emergence of mutant variants (29–31). A detailed analysis of an immunocompromised cohort with COVID-19 (18) showed that SARS-CoV-2 clearance and evolution varied by type and severity of immunosuppressive condition; suppression of both B- and T-cell responses resulted in the highest risk of persistent infection. Expectedly, individuals with hematological malignancies or hematopoietic stem cell transplantation were at increased risk of delayed viral clearance. Next-generation sequencing of available viral samples revealed that 39% of participants in the immunocompromised group had nucleotide changes in the spike protein vs. 12% of participants in the non-immunocompromised group, highlighting their potential as a source for mutant variants.

Indeed, the continuous rapid evolution of SARS-CoV-2 has had a substantial impact on the prevention and treatment of COVID-19. It has been challenging to predict how the virus may mutate, not only because of its unique biological signature as an RNA virus, but also because of its interactions with human and animal hosts (32, 33). Emergent variants have had different transmission patterns, virulence, and incubation periods (32, 34). Infections caused by Omicron variants are known to lead to less severe disease (35), but the short incubation period compared with previous variants (Omicron variant: 3.42 days [95% CI 2.88–3.96] vs. Alpha variant: 5.0 days [95% CI 4.94–5.06]) (36) could have contributed to faster and more widespread transmission. The JN.1 variant became dominant across the globe, with only one additional receptor-binding domain (RBD) mutation compared to its predecessor, BA.2.86 (37). Moreover, mutations at the N-terminal and RBD of the spike protein have led to a reduction or loss of the neutralizing activity of monoclonal antibodies (mAbs) against Omicron and its subvariants (38).

The BA.2.87.1 variant is now being closely tracked because it has over 30 changes in the spike protein of the virus when compared to XBB.1.5, the variant that the 2023–2024 vaccine was designed to protect against (39). The potential public health impact of these variants on the durability of vaccine and therapeutic coverage make it essential to address most, if not all, of the reservoirs of virus mutagenesis.

Immunocompromised people respond to COVID-19 vaccination to different degrees but generally have a suboptimal response to vaccination and, consequently, less protection against severe outcomes (40). This is due to multiple factors, including reduced T-cell–specific or humoral-specific responses, which leads to low seroconversion rates post-vaccination, generation of antibodies with low neutralization activity against SARS-CoV-2 (41–43), and a short duration of protection. Studies have shown that although alterations in the B-cell compartment correlate with decreased humoral responses to COVID-19 vaccines, some degree of T-cell–mediated protection from severe disease might be conserved (23, 44, 45). A meta-analysis of 82 studies (46) showed that after one vaccine dose, people with hematological cancers, immune-mediated inflammatory disorders, and solid cancers were half less likely to seroconvert, while transplant recipients were 16 times less likely to seroconvert (risk ratio 0.06 [95% CI 0.04–0.09]) compared with immunocompetent controls. After a second dose, seroconversion remained least likely in transplant recipients. Parker et al. (47) identified 23 studies (2 clinical trials and 21 observational studies) reporting on vaccination outcomes for 1722 people with immunocompromised status. For participants with responses after the standard primary series, the median antibody response rate increased modestly from 41% (IQR 23–58) to 67% (55–69), while for low or non-responders, the median antibody response rate increased to 44% (32–55).

Waning of vaccine-induced protection is a major concern. Vaccine effectiveness decreases among individuals with comorbidities and those aged ≥55 years (48); this begins as early as the first month after full vaccination (defined as one or two vaccine doses, depending on vaccine type) (49). In immunocompromised individuals, the impact of waning is even more evident. During the Omicron period, vaccine effectiveness (defined as protection against COVID-19 requiring hospital admission following three doses of mRNA vaccines) in immunocompromised people waned to 48% (40–55%) by months four to five (50). By comparison, effectiveness in immunocompetent individuals decreased to 71% (68–74%). For the 2023–2024 (monovalent XBB.1.5) COVID-19 vaccine, effectiveness among adults aged ≥18 years with immunocompromising conditions was 38% in the 7–59 days after receipt of an updated vaccine dose and 34% in the 60–119 days after receipt of an updated dose (51).

In May 2023, COVID-19 stopped being regarded as a global health emergency (52). The non-pharmacological interventions that had a positive impact on the course of the disease, such as free at-home rapid diagnostic tools, social distancing, and wearing masks, became less frequently implemented (53).

Additionally, uptake of the recommended vaccine boosters has decreased. As of March 31, 2024, only 23% (95% CI 22.1–23.1%) of adults in the United States reported having received an updated 2023–2024 COVID-19 vaccine (54). In particular, data from the VISION Network showed that only 18% of adults with immunocompromising conditions had received the updated COVID-19 vaccine (51).

A preventive strategy briefly available during the pandemic was the use of mAbs for pre- and post-exposure prophylaxis. This approach of passive transfer of immunity offered a more immediate and reliable level of neutralizing titers (55), especially for people who are unable to develop their own endogenous antibodies from vaccination or natural infection. In December 2021, the US Food and Drug Administration (FDA) granted emergency use authorization for tixagevimab-cilgavimab as pre-exposure prophylaxis in adults and children (≥12 years, weighing ≥40 kg) (56, 57). Real-world evidence studies (58–60) demonstrated the benefits of mAb prophylaxis in people with immunocompromised status. However, in January 2023, the emergency use authorization was retracted in the United States because of loss of neutralization activity against the Omicron XBB and subsequent variants (61, 62). Following that, until recently, there were no authorized mAbs for pre-exposure or post-exposure prophylaxis of COVID-19. On March 22, 2024, the US FDA authorized the emergency use of pemivibart (formerly VYD222) for pre-exposure prophylaxis among adolescents and adults with moderate-to-severe immune compromised status. The emergency use authorization was based on the totality of scientific evidence available, including demonstration of in vitro neutralizing activity against major SARS-CoV-2 variants, such as JN.1 (63), and immunobridging data from the ongoing CANOPY clinical trial (NCT06039449). Anaphylaxis was seen in four trial participants.

Therapeutic mAbs (e.g., bamlanivimab, bamlanivimab-etesevimab, casirivimab-imdevimab, sotrovimab, and bebtelovimab) are no longer authorized for the treatment of COVID-19 because of the loss of neutralizing activity against Omicron subvariants (64–66). This has limited the treatment options for some immunocompromised people who have impaired ability to mount an immune response to natural infection, especially those with CD20 depletion (67). Currently, there are limited data on potential future mAb therapies and their capacity to reduce the risk of disease progression in people with immunocompromised status.

Antiviral drugs available to treat high-risk individuals include remdesivir, nirmatrelvir/ritonavir, and molnupiravir (68). However, clinicians need to consider many factors when prescribing one of the three options. For example, nirmatrelvir/ritonavir and molnupiravir treatment must be initiated early (<5 days after diagnosis) (69, 70). Additionally, the use of ritonavir-boosted nirmatrelvir is associated with myriad of potential DDIs (71). Interestingly, there is reluctance among physicians in prescribing this antiviral combination drug for the immunocompromised population (72). Barriers to antiviral use among eligible patients with COVID-19 also include access, logistics, and lack of perceived effectiveness. Remdesivir is administered intravenously over a three-day treatment course (73), which could pose logistical challenges to the care team, while molnupiravir may not be as effective in reducing COVID-19 hospitalizations in patients at high risk of severe outcomes (74).

Another issue with antivirals for treatment of COVID-19 is the phenomenon of virologic rebound, characterized by recurrence of symptoms and reversion to SARS-CoV-2 test positivity after initial recovery with treatment. Estimates of viral rebound have varied; however, in a recent multicenter observational study of 127 participants (19), virologic rebound with shedding of replication-competent virus occurred in approximately 21% of people taking a 5-day course of nirmatrelvir-ritonavir and 2% of those who were not using therapy.

The use of convalescent plasma with high titers of anti–SARS-CoV-2 antibodies appeared to be a safe and effective way to treat severe COVID-19 at the onset of the pandemic. Although meta-analysis studies concluded that convalescent plasma was not associated with lower all-cause mortality or improved disease progression (75, 76), some National Institutes of Health panel members recommend the use of high-titer COVID-19 convalescent plasma, with or without antiviral therapy, for immunocompromised patients with prolonged, symptomatic disease (77). However, this treatment option is not widely available because of limited supply.

Vaccination remains the cornerstone of prevention; however, since vaccination response is dependent on the individual’s immune system, an optimized strategy is needed for the immunosuppressed population. Depending on the COVID-19 vaccination history, different vaccination plans are subsequently recommended. People with immunocompromised status usually receive additional COVID-19 doses to boost their immune response at two or more months after the last recommended COVID-19 vaccine. The CDC developed specific guidance on COVID-19 vaccines for people who are moderately or severely immunocompromised (79), which are further endorsed by the National Institutes of Health (68). Improving the durability of vaccine response should also be prioritized. Considering that administration of the updated 2023–2024 COVID-19 vaccine resulted in only modest effectiveness (80), more research is needed in terms of dosing and frequency. Since there are different levels of immune compromise status and vaccine responses, it is suggested that dosing and frequency be individualized, as guided by underlying immune status and vaccine response.

There is an urgent need for the development of mAbs as prophylaxis for COVID-19 in people with immunocompromising conditions. This strategy is intended to provide passive immunity that complements the suboptimal vaccine response. Several mAbs are being studied in response to the emerging variants; two such long-acting mAbs (81, 82) are being evaluated for pre-exposure prophylaxis of COVID-19 in immunocompromised participants. Novel mAbs should be broad spectrum with a prolonged half-life and potential to treat emerging variants. New technologies that could predict emerging variants should be sought to guide the development of mAbs with a durable therapeutic lifespan.

Oral drugs are a preferred convenient approach to treatment, but they should be highly effective and without DDI potential. In addition, further consideration of the dose, timing, and duration of treatment with antiviral drugs is needed to inform optimal use and reduce the potential for viral rebound and infectivity. Various combination antiviral-antiviral drug or antiviral-antibody treatments have been explored. Small studies in B-cell–depleted patients with persistent SARS-CoV-2 infection showed better outcomes with combination therapy than monotherapy (83, 84). Mikulska et al. (85) investigated the combination therapy of remdesivir plus nirmatrelvir/ritonavir, or molnupiravir in case of renal failure, with mAbs in 22 immunocompromised patients with prolonged/relapsed COVID-19. The group observed significant increases in the rate of virological response when the combination treatment included mAbs, both at early stage (P=0.032) and after 30 days of treatment (P=0.046). However, controlled clinical trials are needed to advance these observations beyond case series and provide solid evidence for optimized antiviral treatment strategies.

Healthcare systems, policymakers, and regulators need to work together and develop population-based health measures that focus on people with compromised immunity. Harm-reduction measures to prevent the spread of SARS-CoV-2 to the highest-risk individuals, such as masking and adherence to the CDC isolation guidelines, are known to be effective. A declaration of health emergency that is centered around immunosuppressed people will allow for more funding to develop new vaccines, diagnostics, and therapeutics for this vulnerable population.