key: cord-0845011-x95jxwzk
authors: Morawska, Marta
title: Reasons and consequences of COVID‐19 vaccine failure in patients with chronic lymphocytic leukemia
date: 2021-12-05
journal: Eur J Haematol
DOI: 10.1111/ejh.13722
sha: 941e0247491167bdabcf59d0467f83801d6854ca
doc_id: 845011
cord_uid: x95jxwzk

People with hematologic malignancies are at a high risk of morbidity and mortality from COVID‐19. The response to vaccination is highly limited in patients with chronic lymphocytic leukemia. Less than half of the patients develop antibody response, suggesting that they remain at risk of SARS‐CoV‐2 infection even after the vaccination. Reasons for inadequate response to COVID‐19 vaccination in chronic lymphocytic leukemia are multifactorial and attributed to disease‐related immune dysregulation and patient‐ and therapy‐related factors. The negative predictors of response to vaccination include hypogammaglobulinemia, advanced age, current active treatment, and past treatment anti‐CD20 monoclonal antibodies. Despite using booster doses and heterologous immunization to improve humoral and cellular immunity, some patients with chronic lymphocytic leukemia will fail to respond. Active treatment at the time of vaccination and a recent history of anti‐CD20 monoclonal antibodies use are the strongest predictors of the non‐response. Current data support informing patients with chronic lymphocytic leukemia and other hematologic malignancies about the risk of infection regardless of vaccination. These individuals and members of their households should continue extreme preventive actions despite relaxed local regulations. Other emerging non‐vaccine preventive strategies include passive and post‐exposure prevention with monoclonal antibodies.

Since the beginning of the coronavirus disease-2019 (COVID- 19) pandemic, cancer patients have been regarded as a vulnerable population. Elderly, frail, and affected by significant comorbidities cancer patients were especially susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection and are more likely to develop severe disease, with a high risk of death than in the general population. [1] [2] [3] [4] The mortality estimated in the meta-analysis in adult onco-hematological patients with COVID-19 was 34%. Every three out of four patients required hospitalization. 5 Multicenter studies showed that patients with chronic lymphocytic leukemia (CLL) had a high risk of morbidity and mortality from COVID-19. 6, 7 This strongly supported the recommendation to prioritize COVID-19 vaccination for patients with hematologic cancer. 8 National and international healthcare institutions adapted guidelines regarding priority vaccination against COVID-19 in this vulnerable patient population. [9] [10] [11] [12] [13] [14] 

In the absence of efficacious treatment of COVID-19, registration of first vaccines was the greatest promise to end the pandemic.

Whether COVID-19 vaccination will be protective in the population of patients with hematologic malignancies, particularly in patients in advanced age and profoundly immunosuppressed due to disease and cytotoxic cancer treatments, was the primary concern of hematologists during the development of vaccines. Patients with CLL are burdened with these factors and already in past showed compromised responses to different immunizations.

More specifically, serological response to pneumococcal, haemophilus, hepatitis B, zoster or influenza vaccines was adequate typically in patients at the early stage of the disease, before chemotherapy and the development of hypogammaglobulinemia. [15] [16] [17] [18] [19] [20] [21] It indicates it would be more advantageous to vaccinate early after CLL diagnosis. Attempts to optimize seroconversion by alternative vaccination schemes like booster doses and sequencing different vaccines had mixed results. 20, 22, 23 Comparison of efficacy of pneumococcal conjugate and polysaccharide vaccines revealed differences in immune response 24 ; it highlights the role of type of vaccine; however, adequate response to the more beneficial conjugate vaccine was still lower than in healthy controls. 25 Immune enhancement of the response to vaccination with lenalidomide or granulocyte-macrophage-colony-stimulating factor was not significant 23, 26 ; however, ranitidine stimulated antibody response to the polysaccharide vaccines. 27 The finding requires further studies.

Pivotal clinical trials evaluating efficacy and safety of the SARS-CoV-2 vaccines 28-31 did not provide information about the effectiveness of vaccinations in patients in immunosuppressive or immunodeficient states or receiving systemic immunosuppressants or immune-modifying drugs since they were excluded from studies. Approved in Europe vaccines against SARS-CoV-2 are mRNA or vector-based and can be used in patients with CLL without risk of dissemination of attenuated virus from a vaccine. 32, 33 In addition, a large study confirmed safety of BNT162b2 mRNA COVID-19 vaccine in patients with CLL. 34 Concerns about efficacy of COVID-19 vaccines in patients with CLL occurred justified. Immune response to vaccination was severely impaired in patients with CLL. The proportion of patients with antibody response to COVID-19 vaccines varied from 23% to 47% (Table 1) [34] [35] [36] [37] [38] and was lower compared to patients with other hematologic malignancies and healthy controls. [37] [38] [39] [40] Agha et al. 37 showed that patients with CLL were significantly less likely to develop SARS-CoV-2 antibodies than patients with other hematologic malignancies (23.1% vs. 61.1%, p = .01). This, in combination with advanced age and other comorbid conditions, put patients with CLL at increased risk of morbidity and mortality from SARS-CoV-2 infection, despite the protective role of vaccines in the broad population.

It should be noted that the SARS-CoV-2 vaccine induces both humoral and cell-mediated immunity; however, most of the studies involving patients with hematologic malignancies focus on the production of neutralizing antibodies against the spike protein only.

The serologic response is considered a surrogate endpoint of immunity. The response to the vaccination itself is more complex than only the titer of antibody, e.g., the seropositivity after vaccination may not equal virus neutralization capability in patients with B cell malignancies. 41 

CLL affects <1 to 5.5/100,000 of the population at any time.

Patients with CLL represent from 22 to 30% of all patients with leukemia. 49 Because of lack of functional B cells and impaired humoral immunity, they are prone to infections, a cardinal feature of CLL. 50 Also, poor humoral response to different vaccinations was well-documented within this population. 16, 17, 21, 24 Reasons for poor response to COVID-19 vaccination are multifactorial and attributed to disease-related immune dysregulation and patient-and therapyrelated factors ( Table 2 ).

Infections are the major disease-specific feature of CLL, and the tumor burden is a leading factor influencing immune function.

Tumor cells slowly replace immune cells in lymphoid tissues; however, impairment of immune function occurs even during an earlystage disease, at relatively small tumor infiltration. 51 Although the severity of immune suppression in CLL increases with time from diagnosis, the risk of infection had a constant pattern in over ten years of observation of 125 patients with CLL. 52 Tumor cells suppress natural immune function by release of interleukins, cytokines, chemokines, 53 and presenting surface proteins 54 which modify the function of normal B and T cells leading to characteristic changes of their phenotype and impaired signaling between B and T cells. 43, 51, [55] [56] [57] The clinical and molecular heterogeneity of CLL patients is well-known. 58 Since the production of antibodies against the S protein depends on proper T and B cell interaction, both quantitative and qualitative humoral and cellular defects in immune cells reduce response to vaccines.

Hypogammaglobulinemia correlates with infection risk 59 and has been an independent factor associated with poor humoral response to COVID-19 vaccines. 34 ( Table 2 ). The normal concentration of IgA was a predictor of good response after the second vaccine in multivariate analysis. 60 

The median age at the time of the CLL diagnosis is 64 years. 61

Both COVID-19 fatalities 62 and impaired vaccine responses 63 are more common in older adults. In all studies evaluating response to COVID-19 vaccines, the older age was an unfavorable prognostic factor 34, 35, 37, 38, 64 (Table 2) . However, the observed lack of even minimal antibody response to the COVID-19 vaccine cannot be explained purely by age. As mentioned before, immune dysfunction develops with the duration of the disease, thus is associated with disease-specific humoral defects.

Typically, females develop higher antibody responses following vaccination than males. 65 This was also true in patients with CLL 35 (Table 2 ).

The treatment options, such as anti-CD20 antibodies and Bruton (Table 2) . It is consistent with earlier meta-analysis findings; response to different vaccinates improves incrementally after anti-CD20 therapy. 68 Fox T. et al. 38 found that patients who completed any anti-CLL treatment more than six months before vaccination were more likely to develop antibodies in comparison with the period shorter than six months between treatment and vaccination. Note: Data from three studies involving only patients with chronic lymphocytic leukemia were reviewed to list the number of patients exposed to a risk factor, the proportion of vaccine responders, and non-responders, and the result of multivariate or univariate analysis (Odds ratio (OR) with 95% confidence interval (CI) and p-value). If a factor was not included in the multivariate analysis ( m ) or analysis was not performed, the result of the univariate analysis was presented ( u ). If a study presented factors associated with favorable serologic response, the result was recalculated to present an odds ratio with 95% confidence interval for the negative outcome. (Table 1) . However, a long interval between doses is justified at the time of pandemic.

There were controversies about the rationale of using the third booster dose of vaccines in the general population. 65 Nowadays, many countries recommend using a third dose in vulnerable populations, including immunosuppressed patients and healthcare practitioners. 74, 75 The evidence about the effectiveness of booster dose in patients in CLL is nowadays limited only to 17 cases. 47, 48 Patients without antibodies before the third dose remained antibodynegative; patients with antibodies increased their titers after the third dose. Moreover, the booster dose can induce T cell response and interferon secretion; however, the effect largely depends on treatment during the vaccination sequence. These preliminary data support early use of the third dose; however, some patients will still face vaccine failure. 47 Results of the second study, with only two patients, are promising to patients who did not seroconvert after the mRNA-base vaccine. The use of Ad26.COV2.S vaccine let to antibody response in one patient and boost of T cell response in both patients. 48 The proper timing of vaccination of patients with CLL after recovery from COVID-19 is unknown. Similar to the vaccination, antibody response after recovery from COVID-19 is also diminished in patients with CLL. Only two of three patients had detectable anti-SARS-CoV-2 IgG within 2 months after the infection, and hypogammaglobulinemia was negatively associated with the seroconversion. 36 The Since patients with CLL may be at a high risk of COVID-19 infections, 6 including the time after complete vaccination, 35 

The patients are eligible to receive the third dose of vaccine. 78 The third dose is administrated early, from 3 to 4 weeks after the second. 47 Another helpful approach may include heterologous vaccination (use of mRNA and adenovirus-based vaccines in the vaccination cycle); however, it seems to be a safe and effective way of immunization in the general population, 79 and preliminary report in patients with CLL was promising and did not raise safety concerns. 48 Finally, passive immunization via monoclonal antibodies or hightiter convalescent plasma has been shown to reduce viral load and reduce COVID-19 complications. 80 Neutralizing antibodies and convalescent plasma were of particular interest for therapeutic purposes but also for prophylactics. Passive immunization has established preventive applications. 81 In the USA, the monoclonal antibodies cocktail, casirivimab and imdevimab, was authorized for post-exposure prophylactics for COVID-19. The cocktail of two antibodies against the SARS-CoV-2 spike protein reduced the risk of developing symptomatic COVID-19 by 92.6% compared to placebo in the group persons received the treatment within 96 hours after household contact with an infected person. 82 When the product becomes available, it may be useful for the post-exposure protection of people at high risk for progression to severe COVID-19, hospitalization and death, like patients with CLL.

The combination of disease-, patient-, and treatment-related factors makes people with CLL extremely vulnerable to SARS-CoV-2 infection and low-responsive vaccination. We are at the period of rapid learning about predictors of an unfavorable response to vaccination and new approaches to overcome the current care limitations.

Despite a high level of non-response in patients with hematologic malignancies, vaccines remain a cornerstone of COVID-19 prevention. Until the achievement of herd immunity or the end of the COVID-19 pandemic, patients with CLL need to adhere to strict preventive measures, regardless of their vaccination status.

Marcin Balcerzak of Medink provided medical writing support.

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Marta Morawska https://orcid.org/0000-0001-6836-2903

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How to cite this article: Morawska M. Reasons and consequences of COVID-19 vaccine failure in patients with chronic lymphocytic leukemia