Vaccinations in Patient with Chronic Lymphocytic Leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by immune dysfunction resulting in heightened susceptibility to infections and elevated rates of morbidity and mortality. A key strategy to mitigate infection-related complications has been immunization against common pathogens. However, the immunocompromised status of CLL patients poses challenges in eliciting an adequate humoral and cellular immune response to vaccination. Most CLL-directed therapy disproportionately impairs humoral immunity. Vaccine responsiveness also depends on the phase and type of immune response triggered by immunization. In this review, we discuss the immune dysfunction, vaccine responsiveness, and considerations for optimizing vaccine response in patients with CLL.

Introduction

Immunosuppression is a well-studied outcome in patients with chronic lymphocytic leukemia (CLL) [1]. Defects in immune cells including B and T cells, natural killer (NK) cells, neutrophils, and macrophages have been described [1–3]. In addition to disease-related immunocompromise, some CLL-directed therapies further dampen immunity [4–7]. As a result, CLL patients have an increased susceptibility to bacterial, viral, and fungal infections [8], which account for more than half of the deaths in this population [9–11].

Although vaccine registration trials have generally excluded patients with hematologic malignancies, several smaller studies have investigated vaccine efficacy in patients with CLL [11,12]. Vaccinations in CLL patients have yielded suboptimal results [7,9,13]. Despite impaired vaccine responsiveness, immunization remains a cornerstone of infection prophylaxis in CLL because of its favorable risk-benefit profile relative to other interventions such as antimicrobials and immunoglobulin replacement. In this review, we will discuss disease and treatment-related factors contributing to blunted vaccine response and outline optimal immunization strategies in patients with CLL.

Infections Among CLL Patients

CLL is one of the most common leukemias, amassing approximately 30% of all leukemias [14]. Serious infectious complications develop in up to 80% of CLL patients [15] and account for up to 60% of all deaths [11,16,17]. Patients are at increased risk of bacterial infections, in particular to Staphylococcus aureus and encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus pneumoniae [13,18–20]. Due to reduced T-cell immunity [21], patients are also susceptible to viral infections, most commonly influenza [22–25], leading to 25–37% of deaths [22,25,26], and varicella zoster virus (VZV). Treatment-related opportunistic infections have also been well-documented [3,16]; for example, Pneumocystis jirovecii pneumonia (PJP) has been associated with corticosteroids, purine analogs, and monoclonal antibodies [11,27]. Other rare opportunistic infections among actively treated patients include invasive fungal infections with Aspergillus sp. [28], CMV reactivation [29], and EBV-associated lymphoproliferative disorders [30,31].

Immune Dysfunction

Optimal immune response against pathogens and vaccines involves cooperative interactions between the innate and adaptive immune systems. The innate immune system provides fast short-term protection and comprises physical barriers (e.g., skin), complement, and immune cells, including NK cells, dendritic cells, neutrophils and macrophages [32]. In contrast, the adaptive immune system, which includes T cells and B cells, provides a highly specific, delayed response that, when stimulated optimally, can produce immunologic memory [32]. CLL patients experience a complex immune dysfunction that encompasses elements of both adaptive and innate arms [17] (Figure 1).

Figure 1: Immune dysfunction affecting vaccine response.

Components of the innate and adaptive immune system are defective in CLL, and collectively impair the immune response to vaccines. Abnormalities in antigen presentation, B cells, plasma cells, and T cells directly affect humoral and cellular vaccine responses. The function of NK cells, which activate APCs, and the levels and activity of complement, which enhance the neutralizing effect of antibodies, are also diminished.

CLL is a hematologic malignancy of mature B cells which clonally expand and accumulate in the peripheral blood, bone marrow, lymph nodes, and spleen [5]. While these clonal B cells are numerous, the normal B-cell pool is significantly contracted, and normal B-cell function is suppressed. In addition, plasma cell survival and dysfunction results in hypogammaglobulinemia, which worsens with CLL progression [9]. In early-stage CLL, one immunoglobulin class may be decreased, but in advanced-stage CLL, all immunoglobulin classes are eventually affected [2,33]. Antibodies recognize and bind pathogens, marking them for destruction by other members of the immune system, such as complement and phagocytic cells, or neutralizing the pathogen, preventing it from entering or infecting the host cell. Notably, in addition to facilitating phagocytosis and lysis, complement can boost the neutralizing effect of antibodies [34]. Complement proteins in CLL patients are diminished in number and are unable to bind and activate effectively [35]. Understandably, vaccines relying on humoral immunity yield attenuated responses in the CLL population [7].

For some vaccines, antibody production is dependent not only on B cells, but also on interactions between B cells and T cells. Research into T-cell characteristics in CLL has revealed a broad spectrum of changes including alterations in numbers, differentiation, activity and specificity [36]. Increased regulatory T cells [37,38], reduced T-helper cell activity, diminished levels of functionally naïve T cells, skewing of the T-cell repertoire [39,40], and compromised T-cell immunologic synapse formation, which hinder interactions with antigen presenting cells (APCs) [41], are some documented abnormalities that could adversely affect the immune response to vaccines.

The development of immunologic memory requires presentation of engulfed antigens by phagocytic antigen presenting cells, such as dendritic cells and macrophages, to cells of the adaptive immune system. In CLL, dendritic cells demonstrate impaired maturation and antigen presentation [9]. CLL macrophages favor an immunosuppressive M2 rather than an M1 phenotype [42,43], Neutrophils produce high amounts of reactive oxygen species, which is suspected to inhibit the cytotoxic activity of T cells and NK cells [9,44]. NK cells produce cytokines that activate APCs, leading to improved antigen presentation to T cells [45,46], promote type 1 T-helper (Th1) differentiation [47], and possibly influence B-cell response, including isotype class switching [48], thus contributing to the coordinated effectiveness of the adaptive immune system [46]. The cytotoxic machinery is defective in NK cells in patients with CLL [49–51], although recent studies have noted restoration of NK-cell function upon stimulation by cytokines [52,53] and anti-CD20 monoclonal antibodies (mAb) [54].

Vaccine Response in CLL Patients

Patients with hematologic malignancies typically encounter more pronounced immune dysfunction compared to patients who have solid tumors [55], leading to a predictable decrease in their vaccine response, which is further impaired by treatment [56]. In a meta-analysis of 170 studies, patients with lymphoid malignancies exhibited reduced seroconversion to the coronavirus disease 2019 (COVID-19) vaccine compared to myeloid malignancies [56]. Among lymphoid malignancies, patients with CLL and non-Hodgkin lymphoma (NHL) had the lowest seroconversion rate [56]. CLL and NHL patients also have lower humoral response to the herpes zoster vaccine compared to other hematologic malignancies [21]. This is, in part, attributed to B-cell depletion from receipt of anti-CD20 monoclonal antibodies, which is commonly given to CLL and NHL patients [21].

Monoclonal B-cell lymphocytosis (MBL) is a precursor condition characterized by the presence of circulating monoclonal B cells below the diagnostic threshold for CLL [57]. Only a subset of individuals with MBL eventually develop CLL [57]. Similar to CLL, however, MBL is also marked by immune dysfunction, which renders patients susceptible to infections and hinders their ability to mount an optimal response to vaccines, albeit to a lesser extent [17,57,58]. However, in some instances, such as the herpes zoster vaccine, the humoral response did not statistically differ between patients with CLL and MBL [59]. Better vaccine responses have also been appreciated among patients with early-stage CLL compared to advanced-stage CLL [13,60]. Furthermore, previously treated CLL patients in clinical remission were noted to have a higher seroconversion rate to COVID-19 vaccination than treatment naïve (TN) CLL patients [61], suggesting restoration of immune function after disease control is achieved.

Seroconversion rates among CLL patients are highest to COVID-19 mRNA vaccines (0–79%) [61–63], recombinant zoster vaccine (36–59%) [59,64], and conjugate polysaccharide pneumococcal vaccines (0–100%) [65–68]. Conversely, seroconversion rates are lower to inactivated influenza vaccines (0–26%) [17,69–71], recombinant hepatitis B vaccine (3.8–28%) [64], and polysaccharide pneumococcal vaccine (26%) [68].

Immune Response to Different Vaccine Subtypes

Vaccination is a form of active immunity whereby patients are exposed to antigen that stimulates a Th1 and/or a type 2 T-helper cell (Th2) response, facilitating cellular and humoral immunity, respectively. The predominant response elicited depends on the antigenic material (Figure 2) and vaccine adjuvants. Vaccines can either contain whole pathogen or pathogen component(s). Whole pathogen vaccines include live-attenuated vaccines and inactivated vaccines. Component parts include proteins, capsule polysaccharides, exotoxins and mRNA [72].

Figure 2: Recommended vaccines and responses by vaccine subtype.

The immune response generated by a vaccine is dependent on the antigenic material processed by APCs. The antigenic material, recommended vaccines, and range of seroconversion rates for each vaccine subtype are provided. In contrast to other vaccine subtypes containing antigenic material, the mRNA lipid particle is delivered to the recipient’s cells where transcription and translation synthesize the final antigenic proteins.

CLL patients are routinely advised to receive vaccinations against bacteria and viruses. Antibacterial vaccinations focus on antibody production and the induction of humoral immunity rather than cell-mediated immunity. Conversely, antiviral vaccinations produce variable adaptive immune responses. For instance, attenuated vaccines yield an antibody and cell-mediated response, recombinant vaccines will largely produce antibodies specific to the antigen but also cell-mediated immunity with the appropriate adjuvant, and inactivated vaccines primarily produce an antibody response. With this in mind, the means by which vaccine response is measured can be contextualized.

Several vaccine subtypes and formulations may be available against a single pathogen. There are six vaccine subtypes against COVID-19 (e.g., mRNA, viral vector, protein subunit), at least nine vaccine subtypes and formulations against influenza (e.g., live attenuated, adjuvanted, recombinant and high dose formulations), and two vaccine subtypes against Streptococcus pneumoniae (e.g., conjugate, polysaccharide). Selection of vaccine subtypes and formulations may enhance immune response in patients with CLL.

Standard-dose and high-dose inactivated influenza vaccines have been individually examined in CLL patients. Regrettably, each study selected a unique study population, complicating the ability to directly compare formulations. Among those using standard-dose formulations, the rate of seroconversion was low (0–15%) in both untreated patients and patients receiving a Bruton tyrosine kinase inhibitor (BTKi) [69,71]. The seroconversion rate (0–26%) was slightly higher among TN and ibrutinib-treated CLL patients receiving the high-dose formulation [17,70]. An adjuvanted influenza vaccine, which is currently recommended for patients ≥65 years of age due to its increased immunogenicity, has not been tested in patients with CLL.

Another key example of varied response based on vaccine subtype is the pneumococcal vaccine. Polysaccharide vaccines are less immunogenic than polysaccharide-protein conjugate vaccines because naked polysaccharides cannot stimulate a T-cell activated B-cell response. Rather, the polysaccharide stimulates B-cell differentiation and proliferation independently, creating a predominance of lower affinity IgM rather than higher affinity IgG antibodies and limited memory development [68]. In theory, each vaccination will restart the cycle of creating new plasma cells to synthesize IgM anew [73]. In keeping with this established understanding, the seroconversion rate among CLL patients immunized with the pneumococcal polysaccharide vaccine PPSV23 was less than that achieved with pneumococcal conjugate vaccine PCV13 [68]. To optimize immune response, prior pneumococcal vaccination schedules recommended administration of PCV13 first and then PPSV23 6 to 12 months later. It should be noted that in October 2021, two new conjugate pneumococcal vaccines (PCV15, PCV20) were added by the Advisory Committee on Immunization Practices (ACIP) and are favored over PPSV23 in both the general population and the immunocompromised (Table 1). An ongoing study of PCV20 followed by PPSV23 will evaluate the vaccine response rate specifically in patients with CLL (NCT05183854).

Table 1. Recommended routine vaccinations in CLL.

Travel vaccines are not included.

Vaccine	Recommendation
Influenza	Single dose of any of the following:  • Quadrivalent high-dose inactivated vaccine (HD-IIV4)  • Quadrivalent recombinant vaccine (RIV4)  • Quadrivalent adjuvanted inactivated influenza Vaccine (aIIV4)
COVID-19	Unvaccinated:  • 3 doses of Moderna or Pfizer-BioNTech (2023–2024 formula)  • 2 doses of Novavax (2023–2024 formula) Previously vaccinated:  • Single dose of 2023–2024 formula vaccine
Pneumococcal	Unvaccinated:  • Single dose of PCV15 or PCV20 Previously vaccinated:  • PCV7 → PCV15 or PCV20  • PCV13 → PCV20 or PPSV23  • PPSV23 → PCV15 or PCV20  • PCV13 and PPSV13 → PCV20 or PPSV23
Zoster	2 doses of recombinant zoster vaccine
Respiratory syncytial virus	Single dose of RSVPreF3 or RSVpreF
Tetanus	Td or Tdap every 10 years
Hepatitis B*	2 to 4-dose series depending on vaccine administered

COVID-19: coronavirus disease 2019; PCV: polysaccharide conjugate vaccine; PPSV: pneumococcal polysaccharide vaccine; Td: tetanus, diphtheria; Tdap: tetanus, diphtheria, and acellular pertussis

^*Administer to patients with risk factors of hepatitis B virus infection or upon request.

De Novo Versus Recall Immune Response to Vaccination

A de novo vaccine response refers to the immune system’s first encounter with a new pathogen or vaccine, resulting in the development of protective antibodies and immunological memory. In contrast, a recall vaccine response is triggered when the immune system reencounters a previously encountered pathogen or vaccine, leading to a rapid and targeted immune reaction by memory immunity that mitigates the severity of infection and lowers the risk of severe illness.

De novo response in the CLL population appears to diminish as the disease progresses and when receiving treatment. In a prospective study of COVID-19 vaccination in CLL patients with no prior exposure to COVID-19, de novo immune responses were limited to TN patients, while recall responses inducing cross-reactive B cells against endemic coronaviruses were preserved in patients on active treatment [74]. In a second study, the de novo immune response to the recombinant hepatitis B vaccine was nearly absent in CLL patients receiving BTKi (seroconversion rate of 3.8%) and impaired among TN patients (seroconversion rate of 28%) [64]. These observations are consistent with the recognized decline in key mediators of de novo response, such as naïve B cells [74] and CD4+ T-cell function [39,40], as CLL progresses.

Vaccines which likely evoke a recall response include those against COVID-19, influenza, and herpes zoster. A reliance on recall response and diminished de novo response in immunocompromised persons have been observed with the influenza vaccine [17,75,76] and may in part explain the higher seroprotective rate (0–83.3%) and lower seroconversion rates (0–26%) observed in the CLL population [17,69–71]. The seroconversion rate to recombinant zoster vaccination was notably higher among both TN patients (59%) and patients receiving BTKi (41.5%) than to hepatitis B immunization [77].

Cellular Response to Vaccination

Cellular immunity is essential for the recognition and control of intracellular pathogens as well as for the immune modulation necessary for antibody synthesis and action [78]. Assessment of T-cell response is more complex than assessing humoral response for many reasons including T-cell diversity and HLA restriction [78]. There are also different molecular and cellular assays, and limited standardization between laboratories [79,80]. Despite these caveats, assessing T-cell responses in conjunction with humoral responses provides a more comprehensive appreciation of immune reactions triggered by vaccination [81].

In the CLL population, cellular responses to the recombinant zoster vaccine (RZV) and the COVID-19 mRNA vaccine have been evaluated. Cellular rather than humoral immunity is the dominant adaptive response required to reduce the severity of herpes zoster infection [82]. There have been three studies that assessed T-cell response to RZV, each utilizing a different method to measure and define T-cell response [59,77,83]. Overall, patients with CLL demonstrated a diminished cellular response to RZV compared to the general population. However, a higher rate of cellular response among patients treated with a BTKi was observed by Zent et al. (78.1% vs 32 – 41.3%), which set a relatively lower threshold for T-cell response [59,64,77,83]. In contrast to the general population where there is coordination between humoral and cellular vaccine responses [84,85], these responses can be discordant in patients with CLL. Some CLL patients mount a cellular response following vaccination without a concomitant humoral response [77]. It is unclear if this discordance reflects disease-related immune dysfunction, treatment-related impairments, or both [77].

Like RZV, CLL patients also exhibit a diminished cellular response to the COVID-19 vaccine compared to the general population [74]. Interestingly, COVID-19 specific T cells from convalescent patients with CLL or MBL may produce IFNγ and IL-2 comparable to convalescent patients without a hematologic malignancy [58]. A stronger T-cell response has been associated with higher anti-spike antibody titer after multiple boosters [86]. Further, CLL patients unable to form neutralizing antibodies have decreased naïve CD4 T cells and increased CD8 effector memory T cells [74].

Treatment Effects on Vaccine Response

Treatment for CLL includes BTKi, B-cell lymphoma 2 inhibitors (BCL-2i), anti-CD20 mAb, and to a lesser extent, chemoimmunotherapy. Although the immunological effects differ between therapies, there appears to be an overall trend of decreased vaccine responsiveness among CLL patients actively receiving treatment [87,88] (Figure 3). Other factors are the timing of treatment relative to vaccination and lines of therapy.

Figure 3: Vaccine response in different treatment settings.

Humoral vaccine responses are generally decreased in patients treated with BTKi, BCL-2i and anti-CD20 mAb compared to TN patients. In patients treated with BTKi, cellular responses to COVID-19, recombinant zoster, and seasonal influenza vaccines are also impaired. Cellular responses are detectable in patients treated with BTKi after hepatitis B vaccination and in patients treated with anti-CD20 mAb after COVID-19 and seasonal influenza vaccine. Data comparing these cellular responses to untreated patients are limited.

BTK Inhibitors

BTKi, such as ibrutinib and acalabrutinib, disrupt B-cell receptor signaling and inhibit APCs, dampening the humoral response to vaccination. Given the severe hypogammaglobulinemia caused by loss-of-function mutations in BTK, the first vaccine studies in BTKi-treated patients sought to determine whether antibody responses to vaccination were permissible during treatment. Seasonal influenza vaccination in patients on ibrutinib significantly increased the geometric mean antibody titer against all immunized strains and resulted in a seroprotective rate of up to 74% [70]. The antibody response to influenza vaccination was lower in ibrutinib-treated patients who had received multiple lines of prior therapy [69].

For the recombinant zoster vaccine, a lower rate of antibody response was observed among patients on BTKi therapy compared to TN patients [89]. Interestingly, although treatment with BTKi has been associated with improvement in some aspects of T-cell function [59], patients on BTKi therapy also had a lower rate of cellular response to vaccination compared to TN patients. As with seasonable influenza vaccination, the response to RZV was more robust in patients receiving ibrutinib in the front-line setting [83].

The rate of antibody response to COVID-19 mRNA vaccine response has been consistently lower in patients treated with a BTKi compared to untreated patients [61]. During earlier stages of the COVID-19 pandemic when fewer patients had been exposed to the virus, vaccination was more likely to trigger a de novo immune response. Indeed, in Israel, one of the first countries to launch a national immunization program, only 16% of patients on a BTKi developed an antibody response to COVID-19 mRNA vaccine [61]. This low rate of response is consistent with the recombinant hepatitis B vaccine experience in BTKi-treated patients [64]. Repeated antigenic exposure with booster vaccination increases the proportion of patients with seroprotective titers. In the absence of an antibody response to the primary vaccination series, patients with IgA ≥85 mg/dL and age ≤60 years were more likely to respond to booster vaccination [90].

T-cell response to the recombinant zoster and COVID-19 vaccines are lower in BTKi-treated patients compared to TN patients [77,90]. While both T-cell and antibody responses are impaired, they do not appear to be correlated with each other. In addition to the effects of treatment, actively treated patients likely have more pronounced immune dysfunction due to advanced disease compared to their TN counterparts.

BCL-2 Inhibitors

Drugs that target BCL-2 displace pro-apoptotic proteins from BCL-2 to initiate apoptosis. Venetoclax is the only approved BCL-2i for the treatment of CLL [91]. In CLL patients treated with venetoclax, T- and NK-cell counts normalize, the percentage of tumor-supportive T-cell subsets decrease, PD-1+ CD8+ T cells are reduced, and NK-cell function is restored [52]. Notably, in patients with breast cancer, treatment with venetoclax also depletes circulating B cells [92]. Since venetoclax is often administered with anti-CD20 mAb for CLL, data regarding the effect of venetoclax alone on vaccine responses are limited.

In CLL patients treated with single-agent venetoclax, the rate of seroconversion following COVID-19 vaccination ranges from 25% to 52% [86,90,93,94]. A retrospective study found that CLL patients treated with venetoclax monotherapy had a significantly higher response rate to COVID-19 vaccination compared to patients on a BTKi (52% vs. 22%, P<0.001) [95]. Other studies with fewer venetoclax-treated patients have not reported this difference.

Anti-CD20 Monoclonal Antibodies

Monoclonal antibodies (mAb) against CD20, including rituximab and obinutuzumab, are often incorporated into combination therapies for CLL. Treatment with anti-CD20 mAb results in B-cell depletion that can persist for up to 12 months [96]. Seroconversion after COVID-19 vaccination is lower in patients with lymphoproliferative disorders treated with rituximab and improves 12 months after the last dose of anti-CD20 mAb [94]. In CLL patients receiving anti-CD20 mAb, the rate of antibody response ranges from 0% to 27% [63,86,97]. Notably, patients who do not respond to the primary vaccine series may still seroconvert after a booster dose when administered at least 12 months after completion of anti-CD20 mAb [98]. In contrast, T-cell response, while reduced in patients treated with anti-CD20 mAb, does not appear to be influenced by the length of time between treatment and COVID-19 vaccination [99]. In addition to COVID-19 vaccination [61], exposure to anti-CD20 mAb within 6 to 12 months of immunization also reduces the response to seasonal influenza and pneumococcal polysaccharide vaccines [100].

Strategies to Improve Vaccine Response

Patients with CLL should follow vaccination guidelines for immunocompromised persons, such as the immunization schedule recommended by the CDC (Table 1). Live vaccines are contraindicated due to an increased risk of reactivation of the attenuated virus and potential for disseminated infection [12,101]. Recognizing the blunted vaccine response in individuals with CLL, considerations should be made to maximize response for patients with CLL.

The timing of vaccination is an important and relatively modifiable parameter to influence vaccine response. Patients with early-stage CLL are more likely to mount a protective response to vaccination because their immunity is still relatively intact [86,102,103]. Since most patients with CLL are under active surveillance for years before starting treatment, immunizations early in the disease course, ideally at diagnosis, are typically possible. Vaccination is recommended at least 2 weeks prior to the start of treatment but should be deferred at least 6 months after anti-CD20 mAb administration to increase the likelihood of an antibody response [12].

Selection of more immunogenic vaccine types is advised if more than one exists against a particular pathogen. Vaccine adjuvants are added to enable or improve the delivery of antigen, or potentiate the immune response, often by activating Toll-like receptor signaling [104]. Vaccines containing higher doses of antigenic material (e.g., influenza) can also enhance immunogenicity.

Booster vaccination or revaccination can increase the rate of seroprotection in patients with CLL. Administration of up to 6 sequential doses of COVID-19 vaccine resulted in seroconversion of all individuals with MBL and 94.2% of patients with CLL [86]. Unfortunately, not all boosters yield such a response, as seen with the influenza vaccine [71]. In addition, close proximity between receipt of the polysaccharide pneumococcal vaccine and booster has been shown to lead to tolerance [72].

Herd immunity of household and other close contacts can protect CLL patients without an adequate vaccine response. Therefore, vaccination of family members and close contacts is a safe and complementary measure to protect patients against infection.

Recent studies have evaluated the effect of BTKi interruption on antibody vaccine responses. In both CLL [90] and Waldenström macroglobulinema [105], BTKi interruption at the time of COVID-19 vaccination resulted in higher anti-spike Ab titers than BTKi continuation. Upon BTKi reinitiation in patients with CLL, anti-spike Ab declined at the same rate in the treatment interruption and continuation groups. Since patients who interrupted treatment achieved a higher titer after vaccination, they maintained higher titers throughout the follow-up period [90]. Given these results, a randomized study of BTKi interruption versus continuation around the time of vaccination has been initiated (NCT05170399).

Conclusion

Developing methods to protect CLL patients against infection has proven to be challenging. The overall immune response to vaccination is inadequate in CLL patients, but many variables, including disease stage, CLL-directed treatment, vaccine type, and vaccine schedule, affect this response. Further, humoral and cellular responses to vaccine may be discordant, and laboratory parameters are only correlates of clinical efficacy often with limited validation. Current recommendations to optimize vaccine response, while important, are insufficient because these strategies do not improve the underlying immune dysfunction in CLL. Clinical trials in CLL that incorporate immunological measurements and infection-driven endpoints are needed to tackle the challenge of restoring vaccine responsiveness and more broadly, immunocompetence.