Effectiveness of vaccination against SARS-CoV-2 and the need for alternative preventative approaches in immunocompromised individuals: a narrative review of systematic reviews

ABSTRACT

Introduction

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including administration of booster doses, continues to be the most effective method for controlling COVID-19-related complications including progression to severe illness and death. However, there is mounting evidence that more needs to be done to protect individuals with compromised immune function.

Areas covered

Here, we review the effectiveness of COVID-19 vaccination in immunocompromised patients, including those with primary immunodeficiencies, HIV, cancer (including hematological malignancies), solid organ transplant recipients, and chronic kidney disease, as reported in systematic reviews/meta-analyses published over a 12-month period in PubMed. Given the varied responses to vaccination in patients with compromised immune function, a major goal of this analysis was to try to identify specific risk-factors related to vaccine failure.

Expert opinion

COVID-19 remains a global problem, with new variants of concern emerging at regular intervals. There is an ongoing need for optimal vaccine strategies to combat the pandemic. In addition, alternative treatment approaches are needed for immunocompromised patients who may not mount an adequate immune response to current COVID-19 vaccines. Identification of high-risk patients and the introduction of newer antiviral approaches such as monoclonal antibodies will offer physicians therapeutic options for such vulnerable individuals.

KEYWORDS:

• COVID-19
• COVID-19 vaccines
• immunocompromised patients
• monoclonal antibodies
• SARS-CoV-2

1. Introduction

The coronavirus disease 2019 (COVID-19) pandemic is a result of the rapid and almost unrestricted spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide [1]. This is highlighted by statistics presented by the World Health Organization (WHO), which recorded cumulative case numbers of 84.9 million (2020), 290.8 million (2021) and 733.3 million (2022), although this most recent case count is likely an underestimate of the true count by at least an order of magnitude [2]. The high morbidity and mortality from COVID-19 have resulted in large-scale economic disruption and an unprecedented focus on measures to reduce its impact, with vaccination at the forefront.

The benefits that can be attributed to medical care (especially vaccination) over the last 2 years can be ascertained from a review of the numbers included on the WHO COVID-19 Dashboard. While the number of cases has risen almost 10-fold from 2020–2022, over the time period, the total number of deaths has risen to a much lower extent (3.4-fold; from 1.97 to 6.70 million). This roughly equates to one death in 43 cases in 2020 compared with less than one death in 350 cases up to 2022 [2]. These numbers can be considered, at best, as rough estimates, since they only relate to confirmed cases. However, the magnitude of the improved death/case rate over the 2-year period endorses the positive impact of the global medical care response to COVID-19, including ready access to vaccines/other treatments/medical care facilities and availability of appropriate medical care.

Immunocompromised persons represent approximately 3% of the adult population [3]. They are of particular concern as this vulnerable group is both at increased risk of severe COVID-19 and is less well protected by vaccination [4]. This increased risk may be attributable to the underlying disease itself or as an inevitable consequence of treatment with immunosuppressant medicines. Patients with active cancer, HIV, transplant recipients requiring prolonged immunosuppression, and individuals requiring immunosuppressive treatment for autoimmune and inflammatory rheumatic diseases have been reported to be at increased risk of severe COVID-19 and poor outcomes/death [5–9].

A number of vaccines for SARS-CoV-2 have been approved at unprecedented speed. This includes mRNA vaccines such as BNT162b2 (Pfizer-BioNTech) and mRNA1273 (Moderna), viral vector vaccines such as AZD1222 [ChAdOx1 nCoV-19] (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson), and traditional inactivated whole virus vaccines such as CoronaVac (Sinovac Biotech) [10]. The number of vaccine doses needed to complete the primary immunization series was usually two, except the Janssen/Johnson and Johnson vaccine (Ad26.COV2.S), which required only one dose. High seroconversion and vaccine efficacy rates against SARSCoV-2 infection have been reported regardless of the type of vaccine used or previous infection status [11–14]. Despite this, vaccine trials generally excluded immunocompromised populations, resulting in a paucity of data on the efficacy and safety of vaccination in these groups that have an increased risk of developing severe COVID-19 (including intensive care unit (ICU) admission and death) [15]. Thus, there is a need for more information in these high-risk patients with respect to vaccine effectiveness and outcomes, and also alternative treatment approaches such as immunotherapies to treat the disease [16] and f monoclonal antibodies for pre-exposure prophylaxis of COVID-19 [17].

In this article, we will review the latest evidence related to COVID-19 vaccination in immunocompromised individuals, with an emphasis on response rates in some key patient groups that have been shown to be at increased risk. This includes:

• Persons with primary or secondary immunodeficiencies

• Cancer patients, especially those with hematological malignancies

• Solid organ transplant recipients

• Patients with chronic kidney disease.

Within these difficult-to-treat populations, the risk of severe COVID-19 disease is increased, and identification of such patients would make them potential candidates for prophylaxis with monoclonal antibodies such as the approved combination tixagevimab + cilgavimab. Thus, one of the goals of this review will be to try and identify specific risk-factors in the identified immunocompromised patient cohorts.

2. Search strategy

The primary search for this review was completed by 21 October 2022 in PubMed and included the terms COVID-19 and vaccination and was restricted to all systematic reviews published in the preceding 12 months involving any COVID-19 vaccination. This strategy identified 530 records and the titles/abstracts were screened for suitability to identify all articles involving vaccination strategies against SARS-CoV-2 virus in immunocompromised persons.

Inclusion criteria for selection of systematic reviews used the ‘Population, Intervention, Comparison, Outcomes, and Time’ (PICOT) format as a framework [18]. Study populations included adults with immunocompromised disease (and control groups in some studies). Interventions were any COVID-19 vaccine. Comparators were not often employed, but included healthy controls and ‘other disease groups’ on occasion. Outcomes focused on vaccine effectiveness against death, hospitalization, and development of more serious disease as reported. Time was the preceding 12 months so as to make it as current as possible.

This was augmented by searches involving the specific indications: immunodeficiency (primary and secondary), HIV, cancer, solid cancers, hematological malignancies, solid organ transplantation, chronic kidney disease, and dialysis. General reviews on the topic COVID-19 in immunocompromised persons with/without vaccination were also searched to identify the most recent concepts regarding treatment in this high-risk population and to identify any missing systematic reviews/meta-analyses. Based on these searches 41 suitable systematic reviews were found and formed the basis of this article.

3. COVID-19 in immunocompromised populations – General

From the outset of the COVID-19 pandemic, it was clear that certain subgroups such as immunocompromised individuals were at increased risk of severe disease, ICU admission, and potentially death [15]. At-risk groups were identified in an analysis of the OpenSAFELY health analytics platform involving 17,278,392 primary care records for adult NHS patients in England prior to the availability of vaccines [19]. A total of 10,926 COVID-19-related deaths were recorded, and the highest risk factors (Hazard Ratios [95%CI]) adjusted for age and sex) were as follows: advanced age (80+ years 38.29 [35.02–41.87]; 70–79 years 8.62 [7.84–9.46]; and 60–69 years 2.79 [2.52–3.10]), organ transplant (6.00 [4.73–7.61]), eGFR <30 ml min⁻¹ per 1.73 m² (3.48 [3.23–3.75]), other neurological disease (3.08 [2.85–3.33]), hematological malignancy within the last year (3.02 [2.24–4.08]) or 1–4.9 years (2.56 [2.14–3.06]), and other immunosuppressive diagnoses (2.75 [2.10–3.63]). A cluster of metabolic and related disorders were also shown to be potential risk factors for severe COVID-19 in unvaccinated subjects including obesity class III (2.66 [2.39–2.95]), diabetes [(HbA1c ≥58 mmol mol⁻¹) (2.61 [2.46–2.77]) or no recent HbA1c measurement (2.27 [2.06–2.50])], stroke or dementia (2.57 [2.46–2.70]), and liver disease (2.39 [2.06–2.77]).

Multiple studies/systematic reviews using multivariate adjustment have highlighted the potential role of metabolic syndrome, hyperglycemia, insulin resistance, and obesity, as well as cardiovascular disorders, as risk factors for severe COVID-19 (morbidity and mortality) [19–28]. Importantly, in a registry study involving 6457 consecutive patients, obesity, diabetes, and hypertension had an additive effect on COVID-19-related mortality, particularly in young and middle-aged patients, and the risk of COVID-19-related mortality in these younger patients was similar to that of older, but metabolically healthy patients [29].

The rapid introduction of COVID-19 vaccination programs has had a marked impact on the dynamics of the COVID-19 pandemic, reducing both the morbidity and mortality associated with the disease. However, some groups of patients such as immunocompromised patients were excluded from vaccine trials, leading to a paucity of data on the efficacy and safety of vaccines in these at-risk groups [14,16]. This situation is being rectified, and two recent systematic reviews are summarized in Table 1. In the first, COVID-19 vaccines (primarily the mRNA vaccines from Pfizer/BioNTech and Moderna) decreased symptomatic COVID-19 infection with a vaccine effectiveness of 70.4% in immunocompromised patients [30]. This number was lower compared to the vaccine effectiveness in the general population (94.1%) [12]. A wide range of anti-SARS-CoV-2 spike protein IgG levels was reported after two doses of COVID-19 vaccines in immunocompromised patients, and the rate of response was significantly lower compared to the control group [30]. Similar findings were reported by Lee and colleagues in a systematic review/meta-analysis involving 82 studies (14; Table 1). Again, seroconversion rates and antibody titers after COVID-19 vaccines were significantly lower in immunocompromised patients than in controls, with solid organ transplant recipients having the lowest rates of seroconversion and patients with solid cancers the highest. Notably, immunocompromised patients generally had lower antibody titers associated with seroconversion than immunocompetent controls [14]. The authors noted that antibody titers are an imperfect surrogate marker for vaccine effectiveness and, although neutralizing antibody levels are becoming more widely used, the search for a reliable correlate of protection continues [14]. Given the varied responses to COVID-19 vaccination in different groups of immunocompromised patients, the following sections will cover common diseases associated with compromised immune function to try to identify specific risk-factors related to vaccine failure.

Table 1. Summary of systematic reviews published in 2022 investigating immune responses to COVID-19 vaccination in immunocompromised patients (general), and those with primary immunodeficiency (PI) or human immunodeficiency virus (HIV) infection.

Ref	Number of studies and patients	Vaccination	Results	Patients responding poorly to COVID-19 vaccination (low seropositivity) and conclusions
Immunocompromised patients – general
Marra et al. 2022 [30]	20 studies evaluated vaccine response (2219 immunocompromised pts), and 4 studies (42,821 patients) evaluated VE	Pfizer/BioNTech, Moderna, AstraZeneca, CoronaVac	The pooled diagnostic odds ratio for symptomatic COVID-19 infection in immunocompromised pts was 0.296 [95% CI, 0.108–0.811] with an estimated VE of 70.4% [95%CI, 18.9%-89.2%]. When stratified by diagnosis, IgG antibody levels were much higher in controls vs. immunocompromised pts such as SOT pts (pOR 232.3 [95%Cl, 66.98–806.03]), cancer pts (pOR 42.0 [95 Cl, 11.68–151.03]), and those with inflammatory rheumatic diseases (pOR 19.06 [95%Cl, 5.00–72.62]).	COVID-19 mRNA vaccines were effective against symptomatic COVID-19 in immunocompromised patients, but had lower VE compared to the controls. The authors conclude that further research is needed to understand the discordance between antibody production and protection against symptomatic COVID19 infection.
Lee et al. 2022 [14]	82 studies (>12,000 immunocompromised/immunocompetent individuals)	77 mRNA vaccines (Pfizer/BioNTech, Moderna), 16 viral vector vaccines (AstraZeneca and J&J), and 4 inactivated whole virus vaccines CoronaVac).	Compared with immunocompetent controls, the pooled risk ratios for seroconversion after one dose of vaccine were lower among SOT recipients (RR 0.06) and patients with hematological malignancies (0.40), immune-mediated inflammatory disorders (0.53), and solid tumors (0.55). Antibody responses improved significantly after 2 doses of vaccine and pooled RRs increased to 0.39 in SOT recipients, 0.63 in pts with hematological malignancies, 0.75 in pts with immune-mediated inflammatory disorders, and 0.90 in pts with solid tumors.	Seroconversion rates and antibody titers after covid-19 vaccines were significantly lower in immunocompromised patients than in controls with SOT recipients having the lowest rates of seroconversion and patients with solid cancers the highest. Notably, immunocompromised pts generally had lower antibody titers associated with seroconversion than immunocompetent controls. The authors concluded that this raises concern about the adequacy of seroprotection, and additional strategies, such as the administration of a third vaccine dose to the conventional 2-dose regimen for mRNA covid-19 vaccines would be warranted to increase seroprotection in these at-risk pts.
Patients with Primary Immunodeficiency (PI)
Drzymalla et al. 2022 [34]	68 studies; 459 people with PI	Only 2 studies evaluated the impact of vaccines (Pfizer/BioNTech)	The overall case fatality rate in people with PI and COVID-19 was of 9% (42/448). In 1 study, excluding XLA pts, 18 of 21 vaccinated PI patients produced antibodies that were able to block binding of the SARS-CoV-2 spike protein to the ACE2 receptor in vitro. 19 pts had a T-cell response to the vaccine, measured by IL-2 and IFN-ɣ production, including patients with XLA. In the second study, most COVID pts had abnormal B- and T-cell responses to the vaccine and the authors suggested this might not be sufficient to be protective.	In 2 studies, 2 doses of mRNA vaccine produced an immune response in some people with PI, such as CVID. However, people with XLA, were found to have little to no antibody production following vaccination. Even in patients exhibiting an immune response, the concentration of neutralizing antibodies may be suboptimal. A better understanding of the effectiveness of vaccination, including boosters, in protecting patients with PI will be important for optimizing vaccine recommendations for people with PI. This will require determining the immune correlates of protection that provide the most accurate measure of vaccine effectiveness and immunity in people with PI.
People living with HIV (PLWH)
Kang et al. 2022 [35]	34 studies; 4517 PLWH (3432 having received 2 doses of vaccine)	Adenovirus vector vaccines, inactivated virus vaccines and mRNA vaccines	Pooled seroconversion rates among PLWH after 1 and 2 doses of vaccine were 67.5% [95%CI, 49.1-85.9%] and 96.7% [95%CI, 95.6–97.8%]. The seroconversion was similar between PLWH and healthy controls after the first (RR 0.89 [95% CI, 0.76–1.04]) and second (RR 0.97 [95% CI, 0.93–1.00]) dose. Mean titers were not different between PLWH and controls after the first (SMD 0.30 [95%CI, −1.11 to 1.70]) and second doses (SMD −0.06 [95%CI, −0.18 to 0.05]). Subgroup analyses found lower seroconversion rates in South America, in cross-sectional studies, and PLWH receiving inactivated virus vaccines.	The immunogenicity of COVID-19 vaccines in PLWH was acceptable. There was no significant difference in seroconversion rates between PLWH and healthy controls. The authors conclude that further studies on the immunogenicity, effectiveness and safety of COVID-19 vaccines should focus on various types of vaccines, PLWH with different CD4 + T cell counts, and booster vaccination, especially in countries and regions with heavy HIV burdens.
Yin et al. 2022 [36]	22 studies; 6522 participants (2068 PLWH and 4454 controls)	Adenovirus vector vaccines (J&J and AstraZeneca) mRNA vaccines (Pfizer/BioNTech and Moderna) Inactivated virus vaccines (CoronaVac and Sinopharm) Novavax	After 2 doses of vaccine seroconversion rates were lower in PLWH compared with controls (RR 0.92 [95%CI, 0.87 to 0.97]). Furthermore, no significant differences were found in seroconversion rates between mRNA vaccines (RR 0.96 [95%CI, 0.92–1.01]) and non-mRNA vaccines (RR 0.84 [95%CI 0.76–0.93]).	This meta-analysis shows that COVID-19 vaccines have a favorable immunogenicity and efficacy profile in PLWH compared with healthy controls. A second dose was associated with consistently improved seroconversion rates, although they were lower in PLWH compared with controls. The authors suggest that administration of a third (booster) vaccination with a mRNA COVID-19 vaccine, might be beneficial in these patients.

Abbreviations: BCL2 inhibitors, B-cell lymphoma 2 inhibitors; BTK inhibitors, Bruton tyrosine kinase inhibitors; CAR T-cell therapy, chimeric antigen receptor T-cell therapy; CI, confidence interval; CVID, common variable immunodeficiency; eGFR, estimated glomerular filtration rate; ES, effect size; HIV, human immunodeficiency virus (HIV) infection; J&J, Johnson & Johnson; MPA/MMF, mycophenolic acid/mycophenolate mofetil; mTOR, mammalian target of rapamycin; ND, no details; OR, odds ratio; pOR, pooled odds ratio; PC, plasma cell; PLWH, people living with HIV; PI, primary immunodeficiency; pts, patients; RD, risk-difference RD, risk-difference; RR, risk-ratio; RRT, renal replacement therapy; SI, secondary immunodeficiency; SMD, standardized mean difference; SOT, solid organ transplant, VE, vaccine effectiveness; XLA, X-linked agammaglobulinemia.

4. The impact of COVID-19 vaccination in specific immunocompromised patient groups

4.1. Patients with primary immunodeficiencies

A number of individual studies have reported higher morbidity and mortality in primary immunodeficiency (PI) patients with COVID-19 compared with the general population [31,32]. However, there is no universal agreement on this point, as was noted in a systematic review of 22 studies involving 109,326 patients with PIs or secondary immunodeficiencies such as HIV [33]. Firstly, the common view is that immunodeficient patients are at a higher risk of infection leading to a higher mortality rate. It has also been speculated that immunodeficiency might have a protective role and lower mortality rates by reducing the severity of the inflammatory response via inhibition of the cytokine storm and its consequences. It is important to note, however, that comorbidities, such as diabetes, hypertension, coronary artery disease, kidney disease, and history of lower respiratory tract infections, as well as demographic characteristics (obesity and age >70 years) might also play a role [33].

Regarding the impact of COVID-19 vaccination in patients with PI, information is limited at the present time. In two studies included in a systematic review of 68 studies and 459 patients with PI, 2 doses of mRNA vaccines were found to produce an immune response in PI patients with common variable immunodeficiency (CVID; Table 1) [34]. As expected, persons with X-linked agammaglobulinemia produced few or no antibodies following vaccination. Even in patients exhibiting an immune response, the concentration of neutralizing antibodies tended to be suboptimal [34].

4.2. People with human immunodeficiency virus

Systematic reviews in people living with human immunodeficiency virus (PLWH) and vaccinated against COVID-19 are summarized in Table 1 [35,36]. The two reviews reported favorable immunogenicity and efficacy for COVID-19 vaccines in PLWH after two doses of vaccine, and seroconversion rates were only slightly lower than those reported for healthy (immunocompetent) controls.

4.3. Patients with cancer

Unvaccinated cancer patients infected with SARS-CoV-2 have been reported to have a higher risk of COVID-19-related complications including severe/critical disease, ICU admission, and a worse prognosis (including death), and this is best evidenced in patients with hematological malignancies [19,37]. The increased risk in cancer patients has been attributed to, at least in part, complex immunodeficiency caused by the disease as well as treatment-related factors [38,39]. A higher risk of death in cancer patients, particularly those with hematological malignancies, was also reported in an evaluation of the QResearch database, which comprised 1205 GP practices and 8,256,156 registered adults (aged 19–100 years) [39].

Cancer patients with COVID-19, particularly those with B-cell malignancies, exhibit delayed or negligible seroconversion, prolonged viral shedding, and sustained immune-dysregulation, compared to individuals without cancer [40]. Such patients have an increased likelihood of being admitted into an ICU and a higher risk of dying than patients with COVID-19 without cancer. Furthermore, severe COVID-19 can cause a substantial delay of oncological treatment in these patients, thereby worsening their longer-term prognosis [41].

Whilst at the end of 2021 there was very little available clinical evidence relating to the effectiveness of COVID-19 vaccines in patients with cancer, the picture has changed significantly in 2022 with the publication of numerous systematic reviews/meta-analyses (Table 2) [42–52]. Based on reviews of the early clinical evidence, seroconversion rates post-vaccination were generally higher in patients with solid tumors compared with hematological malignancies [53–56]. Indeed, impaired/delayed humoral antibody responses and diminished T-cell responses have been reported in cancer patients, most notably in those with hematological malignancies [53–56]. However, a lack of standardization of the methodologies used, the heterogeneity of the populations studied, the changing landscape of the infecting SARS-CoV-2 strains involved, and the range of different vaccine schedules employed, somewhat confuse the overall picture.

Table 2. Summary of systematic reviews published in 2022 investigating immune responses to COVID-19 vaccination in patients with cancer.

Ref	Number of studies and patients	Vaccination	Results			Patients responding poorly to COVID-19 vaccination (low seropositivity) and conclusions
Cavanna et al. 2021 [42]	6 studies; 621 cancer pts and 256 controls	Pfizer/BioNTech, Moderna, and Janssen/J&J. Complete.	There was no reduced rate of seroconversion for vaccinated pts with solid tumors compared with controls (RR 0.95 [95%CI, 0.90–1.00]). However, for pts with HMs, the difference was significant (RR 0.62 [95%CI, 0.41–0.92] P = 0.02)			The authors concluded that this systematic review demonstrates generally high immunogenicity from COVID-19 vaccines in pts with cancer, with better results for solid tumors than HMs, and with a good safety profile.
Becerril-Gaitan et al. 2022 [43]	35 studies; 8332 cancer pts and 1555 controls	Pfizer/BioNTech, Moderna, Astra Zeneca and CoronaVac. Complete and incomplete.	Overall, 73% [95%CI, 64–81] of pts with cancer developed anti-S IgG above the threshold level after complete immunization. Pts with HMs had a significantly lower seroconversion rate than those with solid tumors after complete immunization (65% vs 94%; P < 0.0001). Compared with controls, cancer pts were less likely to attain seroconversion after incomplete (RR 0.45 [95%CI, 0.35–0.58]) and complete (RR 0.69 [95%CI, 0.56–0.84]) immunization. Pts with cancer had a higher likelihood of having a documented SARS-CoV-2 infection after partial (RR 3.21 [95%CI, 0.35–29.04]) and complete (RR 2.04 [95%CI, 0.38–11.10]) immunization.			Cancer pts have a lower immunological response compared with controls. Even after completing the immunization scheme, pts with HMs and solid tumors had inferior seroconversion rates vs. controls. Despite this, SARS-CoV-2 infection was documented in only a small % of immunized cancer pts. Growing evidence show that pts with HM are less likely to develop robust anti-S IgG after COVID-19 vaccination owing to immunosuppression induced by disease-related lineage defects and its treatments. Furthermore, a markedly reduced response to COVID-19 immunization could be expected in pts receiving therapeutic agents that interfere with humoral and cellular response. Studies focusing on strategies to enhance the immune response among cancer pts are urgently needed, as well as those evaluating the effectiveness, feasibility and optimal timing for this population to receive a booster dose after completing the COVID-19 vaccination schedule.
Corti et al. 2022 [44]	36 studies; 9260 cancer pts	Pfizer/BioNTech, Moderna, Astra Zeneca, Janssen/J&J and CoronaVac. Complete and incomplete.	After 2 doses of the COVID-19 vaccine the seroconversion rate ranged widely, from 7.3–100%: 7.3% to 88.8%, for HM pts and from 47.5% to 100% for pts with solid tumors. Seroconversion data were collected at non-uniform time points after the second dose, across all the studies (median: 3 w range, 1–16 w).			In cancer pts, vaccination against COVID-19 appears safe and immunogenic. Yet the seroconversion rate remains lower, lagged or both compared to the general population. Pts with HMs, especially those receiving B-cell-depleting agents in the past 12 m, are the most at risk of poor seroconversion.
Guven et al. 2022 [45]	27 studies; 3276 cancer pts and 1862 controls	Pfizer/BioNTech, Moderna, and Astra Zeneca. Complete and incomplete.	Cancer pts had lower seroconversion rates (37.3%) than controls (74.1%) (RD −0.44 [95%CI, −0.52 to −0.35] p < 0.001) one vaccine dose. After 2 doses, the seroconversion rates were 99.6% in controls and 78.3% in cancer pts (RD −0.19 [95%CI, −0.28 to −0.10] p < 0.001). The difference in seroconversion rates was more pronounced pts with HMs (72.6%) (RD −0.25 [95%CI, −0.27 to −0.22] p < 0.001) than pts with solid tumors (91.6%) (RD −0.09 [95%CI: −0.13 to −0.04] p < 0.003) and patients in remission (RD −0.10 [95%CI, −0.14 to −0.06] p < 0.001).			Vaccination against SARS-CoV-2 is vital for pts with cancer. However, T-cell immunity is severely impaired in most cancer pts which could reduce the immune responses to vaccines. While cancer pts had significant seroconversion rates with a 2-dose vaccination schedule, the rates were much lower than that for controls, and was significantly lower in pts with hematological malignancies and pts actively treated (e.g. pts treated with anti-B cell antibodies targeting CD20 or CD38 antigens). Given the life-saving nature of anti-cancer treatments, further research focusing on these pts is urgently needed.
Sakuraba et al. 2022 [46]	16 observational studies; 1453 pts with cancer	Pfizer/BioNTech, Moderna, Astra Zeneca, and Janssen/J&J.	Serologic responses after 1–2 doses of COVID-19 vaccine were 54.2% [95%CI, 41.0–66.9) and 87.7% [95%CI, 82.5–91.5], respectively. Pts with HMs had lower response rates after the second dose of vaccine compared to pts with solid tumors (63.7% vs. 94.9%), which was attributable to the low response rates associated with specific malignancies (e.g. CLL and lymphoma) and therapies (anti-CD20, kinase inhibitors). A lower proportion of pts with cancer achieved a serologic response compared to controls after 1 and 2 doses of vaccine (OR 0.073 [95%CI, 0.026–0.20] and 0.10 [95%CI, 0.039–0.26], respectively).			Pts with CLL and lymphoma, which are mainly of B-cell origin, had lower serologic response rates compared to MM, AML/CML and MPM pts and therapies such as CAR-T therapy, anti-CD20 therapy, and kinase inhibitors were associated with lower rates. In contrast, most solid tumors had serologic response rates in the 80–95% range after 2 doses of vaccine, and therapies mostly used for these conditions such as chemotherapy, immune checkpoint inhibitors, and hormonal therapy had higher response rates. Cancer pts should receive 2 doses of vaccines without delay and continue to follow safety measures including mask-wearing after vaccination. Further studies assessing optimal prophylactic strategy in cancer pts are clearly warranted.
Javadinia et al, 2022 [47]	28 studies; 4789 pts with cancer	Pfizer/BioNTech, Moderna, Janssen/J&J, and Sinopharm. Complete.	2 weeks after the second dose of vaccine the seroconversion rate was 81% [95%CI 75%–86%]. The rate was markedly higher for pts with solid tumors (88% [95%CI 81%–92%]) compared with pts with HMs (70% [95%CI 60%–79%].			Overall, vaccination against COVID-19 in cancer pts was beneficial; however, factors such as type of malignancy and anticancer therapy, and pt demographics (e.g. age) may be associated with reduced protection in some patients. The authors suggest that to improve the efficiency of vaccination, particularly in pts with HMs or those receiving immunosuppressive anticancer therapy such as anti-CD20 or anti-CD38 therapies, alternative approaches may be required. These pts may benefit from passive immunization using anti-COVID-19 antibodies.
Yang et al. 2022 [48]	20 studies; 5499 pts with cancer	Pfizer/BioNTech, Moderna and CoronaVac	Risk Factor Chemotherapy Anti-CD20 in last 12 m Metastases Gender Age Immunotherapy	Cancer type Solid tumor HM Solid tumor All All Solid tumor	OR [95%CI] 2.79 [1.84–4.23] 2.72 [1.28–5.78] 1.61 [1.04–2.49] 1.34 [1.13–1.58] 1.29 [1.11–1.50] 1.10 [0.62–1.98]	In cancer pts, factors most associated with poor seroconversion included chemotherapy in pts with solid tumors, anti-CD20 therapy in pts with HMs and older age across all pt groups. Prediction of poor seroconversion in order to plan better prevention strategies is important in the frail population of pts with cancer. The results proposed that enhanced vaccination strategies would be beneficial for the special patients such as older male patients and those receiving chemotherapy, and carefully managed prevention should be emphasized even after a complete course of vaccination.
Tang et al. 2022 [49]	39 studies; 11,075 pts with cancer (4278 pts with solid tumors and 6637 HM pts).	Pfizer/BioNTech, Moderna, Astra Zeneca, Janssen/J&J and CoronaVac. Complete and incomplete.	Humoral response was significantly decreased in pts receiving anticancer therapy (OR 2.55 [95% CI, 2.04–3.18]) compared with pts not on active treatment. Seroconversion rates were significantly lower with chemotherapy (OR 3.04 [95%CI, 2.28–4.05]), targeted therapy (OR 4.72 [95% CI, 3.18–7.01]) and steroid usage (OR 2.19 [95%CI, [1.57–3.07]). Subgroup analyses showed that anti‐CD20 therapy (OR 11.28 [95%CI, 6.40–19.90]), B‐cell lymphoma 2 inhibitors (OR 5.76 [95% CI: 3.64–9.10]), and Bruton tyrosine kinase inhibitors (OR 6.86 [95%CI, 4.23–11.15]) were significantly correlated with inferior humoral responses to vaccination.			Cancer pts undergoing treatment are at a higher risk of suboptimal humoral response after both partial and complete vaccination against COVID‐19. This was specifically in those receiving chemotherapy, targeted therapy, or steroids, compared to patients not being actively treated at the time of vaccination. The period without active treatment seems to be an optimal time window for patients with cancer to be immunized, and an adapted vaccination strategy, such as a third dose, heterologous vaccine regimens, and temporary adjustment of anticancer therapy, may be required. In addition, the effect of postvaccination cellular responses and long‐term efficacy of vaccination require detailed study and updates for this vulnerable population.
Martins-Branco et al. 2022 [50]	89 studies; 30,183 pts with cancer	Pfizer/BioNTech, Moderna, Astra Zeneca, Janssen/J&J and inactivated SARS-CoV-2 vaccine.	The overall seropositive rate 1-month after complete anti-SARS-CoV-2 vaccination was 80% [95%CI, 72–86%] in the whole group; 60% [95% CI, 53–67%] in pts with HM versus 94% [95%CI, 88–97%] in pts with solid tumors. HM pts had significantly lower seropositive rates (OR 0.35 [95%CI, 0.18–0.69]; P = 0.002). The overall humoral response was 49% [95%CI, 42–56%] after incomplete vaccination, and 79% [95%CI, 70–86%] 2 months after complete vaccination. These responses were lower in HM pts at these time points. The overall cellular response rate at any time after vaccination was 61% [95%CI, 44–76%].			This meta-analysis provides evidence of humoral and adaptive immune responses against SARS-CoV-2 in cancer pts. Humoral responses lasted for at least 2 months after vaccination, even in HM pts who have lower humoral responses initially (within the first month) despite similar adaptive immune responses.
Yin et al. 2022 [51]	34 studies; 30 studies in meta-analysis; 11,245 subjects: 5031 with solid tumors and 6130 controls)	Pfizer/BioNTech (30 studies), Moderna (15 studies), Astra Zeneca, Janssen/J&J and CoronaVac.	After the first vaccine dose, the pooled RR of seroconversion in pts with solid cancer vs healthy controls was 0.54 [95%CI, 0.38–0.78] and after the second dose it was 0.87 [0.86–0.88]. There was no significant difference in the pooled RR of seroconversion rate between pts with solid cancer and healthy controls after a third vaccine dose (RR 0.76 [95%CI 0.50–1.14]).			This meta-analysis demonstrated that, compared with healthy controls, COVID-19 vaccines produce favorable immunogenicity and efficacy in pts with solid cancer. A second dose was associated with improved seroconversion, although it remained slightly lower in pts with solid cancer compared with controls. Additional strategies, such as the administration of a third (booster) vaccination with mRNA COVID-19 vaccines, might improve seroprotection for these patients.
Al Hajji et al. 2022 [52]	15 studies; 1205 pts with cancer	Pts vaccinated with a third booster dose of Pfizer/BioNTech, Moderna or Janssen/J&J	Booster vaccine responses differed greatly between pts with solid tumors compared to HMs. Studies directly comparing these pt groups found that booster vaccination induced a higher response in pts with solid cancer compared to HMs. In 1 study it was found that 88% pts with solid cancers responded after the second dose of vaccine vs. 100% after the booster dose. In HM pts, 50% responded after the second dose and 50% responded after the booster dose. This was in comparison to healthy controls who all responded to both second and booster doses.			Cancer pts, particularly those with HMs, have an increased risk of adverse outcomes from COVID-19 compared to the general population. Pts with HM have poorer seroconversion rates which is exacerbated by B-cell-depleting therapy. All studies reported a significant improvement in vaccine efficacy in pts with solid and hematological cancer following a third booster dose. This includes pts who did not have a humoral immune response after receiving 2 doses of vaccine. This highlights the need for further research into the role of boosters for patients with cancer, as well as in other high-risk groups vulnerable to severe disease.

Abbreviations: BCL2 inhibitors, B-cell lymphoma 2 inhibitors; BTK inhibitors, Bruton tyrosine kinase inhibitors; CAR T-cell therapy, chimeric antigen receptor T-cell therapy; CI, confidence interval; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CRC, colorectal cancer HL, Hodgkin lymphoma; HM, hematological malignancies; HSCT, hematopoietic stem-cell transplantation; J&J, Johnson & Johnson; LM, lymphoid malignancies; MM, multiple myeloma; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms; NHL, non-Hodgkin lymphoma; OR, odds ratio; PC, plasma cell; pts, patients; RD, risk-difference; RR, risk-ratio; WM, Waldenstrom macroglobulinemia.

In a review investigating seropositivity in patients with diverse health disorders following two doses of COVID-19 vaccination, rates of more than 80% were generally reported for the majority of patients with solid tumors (Box 1) [57]. After two doses of vaccine, seropositivity rates were 90.5% [95%CI, 87.3–93.4] in patients with solid tumors and 67.0% [95%CI, 55.4–77.0] for hematological malignancies. In cancers reporting low rates of seropositivity (e.g. sarcoma, esophageal/gastric cancer, and neurological cancer), very small numbers of patients were involved (<6) and further research is needed [57].

Table

Seropositivity	Solid-tumor type (seropositivity)
0.900–1.000	Head & neck (0.909); bladder (0.923); GI (0.929); prostate (0.933); gynecological (0.951); and hepatobiliary, melanoma, neurological, sarcoma, and testicular (all 1.000)
0.800 – <0.900	Gynecological and head & neck (0.800); GI (0.804); lung (0.806); pancreatic (0.818); kidney (0.824); breast (0.829); lung (0.860); colorectal (0.882); and gynecological and non-small cell lung cancer (both 0.889)
0.500 – <0.800	Sarcoma (0.500); esophageal/gastric (0.600); neurological (0.667); breast (0.731 after 14 days and 0.763 after 180 days)
Overall	After 1 dose of vaccine seropositivity was: 27.1% [95%CI, 14.1–41.6] After 2 doses of vaccine seropositivity was: 90.5% [95%CI, 87.3–93.4]

Box 1. Rates of seropositivity after two doses of COVID-19 vaccination (Pfizer-BioNTech, CoronaVac, AstraZeneca, Moderna and Sputnik V vaccines) in different studies involving patients with solid tumors [57].

In systematic reviews of COVID-19 vaccination in patients with ‘cancer’, immunological responses were consistently in the order, control patients (~99%) ≥ solid tumors (88–95%) > hematological malignancies (60–73%) (Table 2) [42–52] and Table 3 [38,58,59,60–63]. Risk factors for a poor immunological response to COVID-19 vaccination included cancer in general and more definitively hematological malignancies, anticancer treatments interfering with humoral and cellular responses [43], chemotherapy in patients with solid tumors [48], anti-B cell antibodies targeting CD20 or CD39 [44–48], and CAR T-cell therapy [46]. While cancer patients have been clearly shown to mount a lower and/or delayed immunological response to the SARS-CoV-2 virus, most authors reported only a small number of COVID-19 cases in immunized patients, highlighting the benefits of vaccination. However, Becerril-Gaitan and colleagues noted that patients with cancer were more likely to develop COVID-19 after partial (RR 3.21 [95%CI, 0.35–29.04]) and complete (RR 2.04 [95%CI, 0.38–11.10]) immunization [43]. Data are also now becoming available for booster (third) COVID-19 vaccinations in patients who remained seronegative after the standard vaccination regimen. Mai and colleagues demonstrated a substantial seroconversion rate in patients with hematological malignancies receiving a booster dose of the COVID-19 vaccine, but this rate was about half that of patients with solid tumors (44% vs. 80%) [63; Table 3]. Of note, patients with lung cancer or gastrointestinal cancer were more likely to produce a meaningful increase in antibody titers (16.8 and 25.4 times greater, respectively; both P ≤ 0.05) compared with patients with hematological malignancies. In a short report, Fendler and colleagues noted that a third dose of vaccine (Pfizer or AstraZeneca) boosted the antibody response against variants of concern (Delta or Beta) in approximately 90% of patients with solid tumors and 50% of patients with hematological malignancies who were non-responders after two doses of the vaccine [64]. Al Haji and colleagues also investigated the effectiveness of booster doses of COVID-19 vaccines in a systematic review of 15 studies involving 1205 cancer patients [52]. All studies reported a significant improvement in vaccine efficacy in patients with solid and hematological cancers following a third booster dose. This included patients who did not have a humoral immune response after receiving two doses of vaccine. However, studies directly comparing responses in different cancers found that booster vaccinations were more efficacious in patients with solid tumors compared to those with hematological malignancies (Table 2). Indeed, patients with hematological malignancies had poorer seroconversion rates, which were exacerbated by B-cell-depleting therapy. Population studies in cancer patients also highlighted the benefits of a third dose of COVID-19 vaccine. However, the effectiveness was heterogeneous and lower than in the general population. The authors advocate combining vaccine boosters to prevent severe disease with pharmacological interventions to prevent transmission and improve viral clearance [65,66].

Table 3. Summary of systematic reviews published in 2022 investigating immune responses to COVID-19 vaccination in patients with hematological malignancies.

Ref	Number of studies and patients	Vaccination	Results	Patients responding poorly to COVID-19 vaccination (low seropositivity) and conclusions
Gong et al. 2022 [58]	57 studies; 7393 pts with HM	COVID-19 vaccines; Pfizer/Biontech, Moderna, AstraZeneca and Janssen	Serological response (SR) varied according to HM subtype with better responses seen in myeloid malignancies: 83% [95%CI 77%–89%] for AL; 81% [95%CI 72%–89%] for MPN; and 63% [95%CI 47%–78%] for MDS.Pts with history of HSCT had good SR of 79% [95%CI 75–82], irrespective of whether they were allogeneic (78%) or autologous (88%).	Lower SRs were observed for: CLL: 44% (95%CI 35%–53%) Lymphoid malignancies: 52% (95%CI 44%–61%) PC dyscrasias: 72%, (95%CI 64%–79%) Pts with a history of CAR T‐cell therapy had poor SR of 33% (95%CI 18–49) as did pts receiving BTK inhibitors [38% (95%CI 23–53) . Further studies are needed to determine whether immunologic response can be improved with booster vaccine doses, as well as with anti‐COVID‐19 mAbs and convalescent serum. This is especially important in HM pts unable to mount an adequate immunologic response to vaccination.
Teh et al. 2022 [59]	44 studies; 7000 pts with HM	Pts received ≥1 dose of COVID-19 vaccine (any type)	After a single dose of COVID-19 vaccine, pooled seropositivity rates in pts with HM were 51% in single-arm studies and 37% in comparator studies. After 2 doses of vaccine, pooled seropositivity rates were 62% in single-arm studies and 66% in comparator studies. Versus controls, pts with HM were less likely to achieve seropositivity with ORs of 0.04 (95%CI, 0.02–0.08; P < .01) after 2 doses and 0.10 (95%CI, 0.04–0.29; P < .01) after a single dose) of COVID-19 vaccine. Of the different HMs, pooled seropositivity rates after 2 doses of vaccine were highest in pts with acute leukemia, MDS, or MPNs (~90%) and the lowest at 51% in pts with CLL. Pts with CLL respond poorly to vaccination.	OR for achieving seropositivity vs. healthy controls: CLL: after 2 doses 0.01 (95%CI, 0.01–0.03) and after 1 dose 0.03 (95%CI, 0.00–0.80) Lymphoma: after 2 doses 0.02 (95%CI, 0.00–0.02) and after 1 dose 0.01 (95%CI, 0.00–1.24) MPN and CML: after 2 doses 0.07 (95%CI, 0.00–1.55) and after 1 dose 0.13 (95%CI, 0.01–1.71) Myeloma: after 2 doses 0.09 (95%CI, 0.03–0.29) and after 1 dose 0.23 (95%CI, 0.05–0.99) Pts on active therapy (vs. no active therapy): after 2 doses of vaccine 0.21 (95%CI, 0.06–0.67) Pts on CD-20 mAb therapy within 12 m (vs. after 12 m): after 2 doses 0.08 (95%CI, 0.01–0.59) New approaches to treating high-risk patients with HM who are poor responders to vaccination are urgently required.
Piechotta et al. 2022 [38]	57 studies; 7393 pts with HM	One dose for the Janssen vaccine and 2 doses for 4 others (Pfizer /Biontech), Moderna, AstraZeneca, and Sinopharm)	Event/Response rates: SARS-CoV-2 infection: 0–11.9% Symptomatic COVID-19: 0–2.7% COVID-19 hospitalization: 0–2.8% COVID-19 mortality: 0–0.5% Antibody response: 38.1–99.1% T-cell response: 26.5–79.3% AEs (any grade): 0 − 50.9% Serious AEs: 0–7.5%	Seroconversion rates ranged from 38.1–99.1% and were lowest in pts with CLL. Pts with lymphoma showed very diverse responses. HM pts had impaired humoral and cellular immune response to COVID-19 vaccination. Pts with B-cell depleting or -directed treatment (e.g. MS or SLE) had lower seroconversion rates vs. those receiving chemotherapy or other targeted treatments. New treatment approaches to avert severe infection are urgently needed for this vulnerable pt population that responds poorly to current COVID-19 vaccine regimens.
Rinaldi et al. 2022 [60]	15 studies; 2055 pts with HM and 1105 healthy controls	COVID-19 mRNA vaccines; Pfizer/Biontech, Moderna, and AstraZeneca	All cohorts with HM had lower rates of seroconversion after 2 doses of vaccination compared to healthy controls. The pooled seroconversion rates were 61.8% for the HM vs. 97.2% for healthy controls. Meta-analysis of all included studies showed that after 2 doses of COVID-19 vaccine, only 60% of patients with HM seroconverted compared to healthy controls (RR = 0.60; 95%CI, 0.50–0.71; P < 0.0001)	RR for achieving seropositivity vs. healthy controls: NHL: 0.50 (95%CI, 0.35–0.71) P < 0.0001 CLL: 0.56 (95%CI, 0.46–0.69) P = 0.002 AL: 0.72 (95%CI, 0.32–1.60) P = 0.27 MM: 0.74 (95%CI, 0.61–0.90) P < 00001 WM: 0.50 (95%CI 0.35–0.71) P = 0.0001 MPN: 0.84 (95%CI 0.76–0.94) P = 0.002 Policy makers must develop better protection strategies against COVID-19 for patients with HM.
Noori et al. 2022 [61]	82 studies; 13,804 pts with HM	Pfizer/Biontech alone (n = 33); Pfizer/Biontech and Moderna (24); Pfizer/Biontech and AstraZeneca (13); Pfizer/Biontech, Moderna and AstraZeneca (6); Pfizer/Biontech, Moderna and J&J (5) and Sinopharm (1)	After first and second COVID-19 vaccine doses seropositivity was achieved by 30.0% [95%CI, 11.9–52.0] and 62.3% [95%CI, 56.0–68.5] of HM pts, respectively. HM pts were less likely to develop an antibody response compared to pts with solid tumors (RR 0.73 [95%CI, 0.67–0.79] and healthy subjects (RR 0.62 [95%CI, 0.54–0.71]) following 2 doses of vaccine.	RR for achieving seropositivity vs. healthy controls after 2 doses: CLL: 0.51 (95%CI, 0.42–0.62) I^2 = 76.6% NHL: 0.54 (95%CI, 0.43–0.67) I^2 = 82.1% LM: 0.66 (95%CI, 0.62–0.71) I^2 = 87.7% MDS: 0.77 (95%CI, 0.50–1.18) I^2 = 89.8% PC disorders: 0.79 (95%CI, 0.75–0.83) I^2 = 60.4% Antibody response after 2 doses of vaccine according to treatment: BTK inhibitors: 26.8% (95%CI, 16.9–37.8) I^2 = 76.1% CAR T-cell therapy: 28.4% (95%CI, 12.4–47.0) I^2 = 62.7% Anti-CD20: 31.2% (95%CI, 24.7–38.1) I^2 = 79.7% BCL2 inhibitors: 33.3% (95%CI, 19.9–47.9) I^2 = 41.2% Lower antibody responses to the COVID-19 vaccine occurred in HM pts generally, and there was wide range of rates in different disease subgroups and with different treatments (see above). This highlights the need for alternative approaches to improve immunity including the use of booster doses.
Gagelmann et al. 2022 [62]	49 studies; 11,086 pts with HM	Full COVID-19 vaccination: 2 doses of mRNA vaccines or 1 dose of vector-based vaccine	39 studies reported antibody responses after full vaccination (mostly 2 doses of mRNA vaccines). Significant between-group differences were recorded for HMs vs. solid tumors, and healthy controls. Antibody responses were 64% (95%CI: 59–69) for HM, 96% [95%CI, 0.92–0.97] for pts with solid tumors and 98% [95%CI, 96–99], for healthy controls (P < 0.001). There were marked differences between different types of HM. The pooled antibody response rate for allogeneic and autologous HSCT was 82% and 83%, respectively.	Pooled antibody responses were: CLL: 50% (95%CI: 43–57; I^2 = 84%) Aggressive NHL: 58% (95%CI: 44–70; I^2 = 84%) Indolent NHL: 61% (95%CI: 48–72; I^2 = 85%) MM: 76% (95%CI: 67–83; I^2 = 92%) MPN: 83% (95%CI: 69–91; I^2 = 85%) HL: 91% (95%CI: 82–96; I^2 = 12%) Low pooled response was identified for active treatment (35%), and particularly for: Anti-CD20 therapy ≤1 year (15%); BTK inhibitors (23%); venetoclax (26%); ruxolitinib (42%); and CAR T-cell therapy (42%). This large meta-analysis of pts with HM demonstrated a significantly reduced response to the COVID-19 vaccine. These findings highlight the need for improved treatment options for pts with HM, including the added value that booster vaccinations may provide.
Mai et al. 2022 [63]	22 studies; 931 cancer pts (849 HM, 82 with solid tumors)	Pfizer/BioNTech, Moderna, and Janssen/J&J. Cancer pts who received a booster dose of any approved COVID-19 vaccine having completed an initial regimen of vaccination	Pts with HM not responding to treatment had a lower seroconversion rate (44% [95%CI, 36–53%]) than pts with solid tumors (80% [95%CI, 69–87%]). The odds of having a meaningful rise in antibody titers was significantly associated with increased duration between the second and third dose of the COVID-19 vaccine (OR 1.02 [95%CI, 1.00–1.03]; P ≤ 0.05), pt age (OR 0.960 [95%CI, 0.934–0.987]; P ≤ 0.05) and cancer type. Using HM pts as a reference the odds of achieving a meaningful increase in antibody titers was increased in pts with lung cancer (OR 16.8 [95%CI, 2.95–318]; P ≤ 0.05), GI cancer pts (OR 25.4 [95%CI, 5.26–492], P ≤ 0.05) and in pts with other solid tumors (OR 6.4 [95%CI, 2.60–18.1]; P ≤ 0.05).	Pts with HMs have been shown to have much poorer seroconversion rates after the standard 2-dose COVID-19 vaccine regimen. In the current meta-analysis, it was shown that giving a booster vaccine resulted in increased seroconversion in pts with HM who did not seroconvert after 2 COVID-19 immunizations. However, the seroconversion rate was about half that of pts with solid tumors (44% vs. 80%). Pts treated with lymphodepleting or plasma cell-depleting therapies have been shown to produce a lesser immune response to COVID-19 and, of note, anti-CD20 therapy, has been shown to deplete peripheral B cells for at least 4 months after vaccination. Pts undergoing such treatments are extremely unlikely to mount an adequate response to COVID-19 vaccination.

Abbreviations: BCL2 inhibitors, B-cell lymphoma 2 inhibitors; BTK inhibitors, Bruton tyrosine kinase inhibitors; CAR T-cell therapy, chimeric antigen receptor T-cell therapy; CI, confidence interval; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; HL, Hodgkin lymphoma; HM, hematological malignancies; HSCT, hematopoietic stem-cell transplantation; LM, lymphoid malignancies; MM, multiple myeloma; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms; NHL, non-Hodgkin lymphoma; OR, odds ratio; PC, plasma cell; pts, patients; RR, risk-ratio; WM, Waldenstrom macroglobulinemia.

4.3.1. Patients with hematological malignancies

As noted above, patients with hematological malignancies infected with SARS-CoV-2 have been reported to have a higher risk of COVID-19-related complications including severe/critical disease and a worse prognosis (including death), and this has been attributed to, at least in part, complex immunodeficiency caused by the disease and/or treatment [37,38]. An analysis of the OpenSAFELY health analytics platform, involving 17,278,392 primary care records for adult NHS patients in England prior to the availability of vaccines, highlighted an increased risk of COVID-19-related deaths (within the last year) in patients with hematological malignancies with Hazard Ratios (95%CI) adjusted for age and sex of 3.02 (95%CI, 2.24–4.08) [if diagnosed <1 year ago] and 2.56 (95%CI, 2.14–3.06) [if diagnosed between 1 and 4.9 years ago] [19].

Systematic reviews in patients with hematological malignancies published in 2022 are summarized in Table 3 [38,58,59,60–63]. Noori and colleagues (2022) reported significantly reduced rates of seroprotection following one and two doses of the COVID-19 vaccine compared with healthy subjects (risk ratios 0.36 and 0.62, respectively) [61]. Thus, after two doses of COVID-19 vaccines, pooled seroresponse (SR) rates were approximately 60% across the overall population of patients with hematological malignancies, but the rates were significantly lower (30–51%) after only one dose of vaccine [59,60,61]. In comparative studies, patients with hematological malignancies had a much lower antibody response compared with patients with solid tumors, those undergoing hematopoietic stem cell transplantation (HSCT), and healthy subjects [60–62]. Gagelmann and colleagues reported a response rate of 64% (95%CI, 59–69) for patients with hematological malignancies, versus 82% (95%CI, 77–87) for allogenic HSCT patients, 96% (95%CI, 92–97) for patients with solid tumors, and 98% (95%CI, 96–99) for healthy subjects [62]. The need for alternative treatment approaches to improve immunologic responses in patients with hematological malignancies is highlighted in the systematic reviews in Table 3. As noted by Gong et al. [58] these might include improved booster vaccines/doses, anti-COVID-19 monoclonal antibodies, and convalescent serum.

4.3.2. Immune responses in different hematological malignancies

Hematological malignancies comprise a heterogeneous group of disorders in terms of pathophysiology, and they are associated with variable levels of immune dysfunction, which can be further exacerbated by the specific therapies used in their treatment [67]. This is highlighted in the findings from the systematic reviews summarized in Table 3. In the largest meta-analysis to date, comparing the two major subtypes of hematological malignancies, pooled SR data demonstrated a lower seropositivity rate for lymphoid vs. myeloid cancers after complete vaccination (62.3% [95%CI, 57.7–66.9] vs. 83.6% [95%CI, 76.3–89.9] [61]. Across all of the reviews, chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) had the poorest COVID-19 vaccine antibody responses, and this is reflected in the lowest risk ratios for seroconversion at around 0.5 [60; Figure 1].

Figure 1. Risk Ratio for seroconversion after 2 doses of COVID-19 mRNA vaccines according to hematological malignancy versus healthy controls [60].

4.3.3. Immune responses in relation to hematological malignancy status and treatment

A number of authors undertook subgroup analyses to ascertain the relationship between the humoral response to COVID-19 vaccination and the current status of the patient’s malignancy and its treatment. Pooled antibody responses to COVID-19 vaccination were reported to be higher in patients whose disease was in remission vs. those with stable or progressive disease (72 vs. 48%; P = 0.014), in individuals who had previously had COVID-19 (87 vs. 66%; P = 0.005), and in patients not being actively treated (76 vs. 35%; P < 0.001) [62].

All systematic reviews/meta-analyses summarized in Table 3 consistently reported that serologic responses to COVID-19 vaccination were abrogated by cancer treatment, and Noori et al. calculated an RR of 0.58 [95%CI, 0.47–0.73]. In this large analysis of patients with hematological malignancies, the lowest rates of pooled antibody responses after two doses of the COVID-19 vaccine in relation to their anticancer treatment are shown in Box 2 [61].

Table

Anticancer treatment	Pooled antibody response rate [95%CI]
BTK inhibitors	26.8% [24.7–38.1]
CAR T-cell	28.4% [12.4–47.0]
Anti-CD20	31.2% [24.7–38.1]
BCL2 inhibitors	33.3% [19.9–47.9]
Ruxolitinib	66.3% [52.8–78.7]
Anti-CD38	69.7% [58.3–80.1]

Abbreviations: BCL2 inhibitors, B-cell lymphoma 2 inhibitors; BTK inhibitors, Bruton tyrosine kinase inhibitors; CAR T-cell therapy, chimeric antigen receptor T-cell therapy

Regarding targeted anti-CD20 therapy, lower seropositivity rates were observed in patients who were vaccinated within 12 months of anti-CD20 therapy compared with those vaccinated ≥12 months after completion of their anticancer treatment (15–19% vs. 59–61%, respectively [59,62]. Other targeted anticancer treatments associated with particularly poor antibody response rates to COVID-19 vaccination include Bruton tyrosine kinase inhibitors (BTK; 26.8%), chimeric antigen receptor T-cell therapy (CAR T-cell; 28.4%), and B-cell lymphoma 2 inhibitors (BCL2; 33.3%) [61; Box 2].

Box 2. Pooled antibody response after two doses of the COVID-19 vaccine in subgroups of patients with hematological malignancies according to their anticancer treatment [61]

Based on the above findings, the conclusions from these large systematic reviews were consistent and include the following:

• Patients with hematological malignancies receiving COVID-19 vaccination mount a lower antibody response compared to healthy subjects and those with solid tumors

• The weakest antibody responses were demonstrated in patients with CLL and NHL

• Anticancer treatments such as BTK inhibitors, CAR T-cell therapy, anti-CD20 therapy, and other B-cell depleting modalities are also associated with weak antibody responses

• Additional studies are needed to ascertain whether booster immunization strategies with COVID-19 vaccines will improve the situation

• Failing this, new approaches for treating these high-risk patients will be required including prophylaxis with pre-exposure monoclonal antibodies.

4.4. Patients undergoing solid organ transplantation

In the analysis of the large OpenSAFELY health analytics platform study, organ transplantation was associated with one of the highest risk levels for death with a Hazard Ratio [95%CI]) adjusted for age and sex of 6.00 [4.73–7.61]) [19]. An and colleagues also reported worse clinical outcomes (mortality, morbidity, and severity) in a meta-analysis of 47 studies, which included solid organ transplant recipients (kidney, liver, heart, lung, or multi-organ). Mortality was 17.4%, which is about 8 times more than that reported in the general population [68]. In contrast, a systematic review/meta-analysis of 31 studies and 590,375 patients (5759 solid organ transplant recipients) with confirmed COVID-19 found no increased risk of mortality in organ transplant patients compared with controls when appropriate adjustments were made for demographic and clinical features at baseline [69]. In a meta-analysis of mortality risk factors in kidney transplant patients with COVID-19 (13 studies, 4440 patients), non-survivors were significantly older, had co-morbidities such as pneumonia, dyspnea, diabetes, cardiovascular, active cancer, and acute kidney injury, and were deceased donor kidney recipients [70].

Publications assessing the effectiveness of COVID-19 vaccines in solid organ transplant recipients have increased significantly in 2022, including numerous systematic reviews/meta-analyses (Table 4) [71–81]. The systematic reviews/meta-analyses summarized in Table 4 consistently reported a weaker immune response in patients undergoing solid organ transplantation and a number of risk factors were identified such as:

• Older age (>65 years) was reported to be associated with lower seroconversion rates in almost all studies

• Concomitant treatments including not only immunosuppressive regimens (mostly mycophenolate mofetil but also corticosteroids, calcineurin inhibitors and belatacept; and multiple regimens); recent rituximab or antithymocyte globulin exposure

• Receipt of an organ from a deceased donor

• Patients with concomitant underlying disorders such as diabetes and reduced renal function

• In one study, the BNT162b2 vaccine (Pfizer) was less effective than the mRNA-1273 (Moderna) vaccine [74]

• A number of studies compared antibody responses to COVID-19 by type of organ transplantation and reported and order (best response > to lesser response) of liver > heart > kidney > kidney-pancreas > lung [76,78,81]

• Finally, a number of studies highlighted the benefits of extra doses of COVID-19 vaccine, including multiple booster doses [e.g. 72].

Table 4. Summary of systematic reviews published in 2022 investigating immune responses to COVID-19 vaccination in patients undergoing solid organ transplantation.

Ref	Number of studies and patients	Vaccination	Results	Patients responding poorly to COVID-19 vaccination (low seropositivity) and conclusions
Akyol et al. 2022 [71]	Of 18 prospective studies investigating RRT, 8 KTs (823 pts and 129 healthy controls)	Pfizer/BioNTech and Moderna	The seroconversion rate in KT pts ranged from 2.5–37.5% with an overall rate of 27.2%. In 5 studies that also included a control group, the seroconversion rate for KT pts was 19.7% vs. 100% for controls. However, the total number of controls was low (n = 129), and they were generally younger (up to 13 y) than transplant pts.	In KT pts, a lower seroconversion rate was associated with older age, and with immunosuppressive regimens (mostly MMF, but also with CS, calcineurin inhibitors and belatacept). Seroconversion rates following vaccination in KT pts are suboptimal and this is an unmet clinical need. Future studies should address how to optimize treatment in order to improve the pt’s response, including assessing the impact of a third dose of vaccine, as well as studying the best way to assess clinically relevant immunological responses (e.g. are pts with low antibody titers, but preserved cellular responses protected from clinically significant disease?).
Manothummetha et al. 2022 [72]	83 studies in systematic review and 29 in meta-analysis. SOT included heart, lung, liver, kidney, pancreas and combinations	mRNA vaccines: 1 dose (18 studies) 2 doses (54 studies) 3 doses (11 studies) 4 doses (2 studies)	In SOT recipients (n = 11,713), the weighted mean (range) of total positive humoral response for antispike antibodies after mRNA COVID-19 vaccination was 10.4% (0–37.9%) for 1 dose, 44.9% (0–79.1%) for 2 doses, and 63.1% (49.1–69.1%) for 3 doses. In 2 studies, 50% of pts with no or minimal antibody response after 3 doses mounted an antibody response after a fourth dose of mRNA COVID-19 vaccine.	Factors associated with a poor antibody response (mean [SE] age difference between responders and non-responders) included: older age, 3.94 [1.1] years; deceased donor status (pOR, 0.66 [95%CI, 0.53–0.83]; I^2 = 0%), antimetabolite use (pOR, 0.21 [95%CI, 0.14–0.29]; I^2 = 70%), recent rituximab exposure (pOR, 0.21 [95%CI, 0.07–0.61]; I^2 = 0%), and recent antithymocyte globulin exposure (OR, 0.32 [95%CI, 0.15–0.71]; I^2 = 0%). The authors concluded that more efforts are needed to modulate risk factors associated with reduced humoral responses and to study mAb prophylaxis among recipients of SOT who are at high risk of diminished humoral response.
Shoar et al. 2022 [73]	12 studies; 563 heart transplant recipients	Pfizer/BioNTech, Moderna, AstraZeneca, and Janssen/J&J	90% had received Pfizer/ BioNTech or Moderna vaccines. Immune response was measured after the second dose of an mRNA vaccine in 464 pts (82.4%) and after the third dose of an mRNA vaccine in 96 pts (17.1%). Regardless of the laboratory test, immune response (humoral or cellular) a positive response was variably observed in 0% to 100% of the HTX pts.	Based on an appraisal of included studies, a weaker immune response was observed in pts >65 y, males, a short time interval between second dose of the SARS-CoV-2 vaccine and the time of measuring the immune response, vaccination within the first year after HTX, antimetabolite immunosuppressant therapy, and a weaker cellular immune response. The authors concluded that cellular and humoral immunity seem to mount in parallel after vaccination against SARS-CoV-2, with a strong cellular response paving the way for a stronger humoral immunity.
Verleye et al. 2022 [74]	8 studies; 1877 SOT pts (kidney, n = 1070; liver, 290; lung, 247; heart, 231; pancreas, 5; multiorgan, 26; and unknown, 8)	2 doses of BNT162b2 (Pfizer/BioNTech) vs. mRNA-1273 (Moderna)	The meta-analysis revealed lower seroconversion rates in SOT recipients vaccinated with two doses of BNT162b2 vaccine (44.3%[95%CI, 34.1–54.7]) as compared with patients vaccinated with two doses of the mRNA-1273 vaccine (58.4% [95%CI, 47.2–69.2]). The relative seroconversion rate was 0.795 [95%CI, 0.732–0.864].	The seroconversion rate appeared to be higher after immunization with the mRNA-1273 vaccine vs. the BNT162b2 vaccine in SOT recipients. Future studies should assess whether these differences are confirmed after a third-dose, and whether they are associated with better protection against severe disease, hospitalization and/or mortality. This will help to determine which is the preferred vaccine in SOT recipients. In addition, it is preferable to vaccinate KT pts transplantation, as the overall efficacy of SARSCoV-2 vaccines is better during dialysis than after KT.
Zong et al. 2022 [75]	29 studies; kidney (predominant), liver, pulmonary, heart, and other	2 doses of SARS-CoV-2 vaccine	Old age, diabetes mellitus, MPA/MMF, high-dose CS, and triple immunosuppression therapy are important risk factors for negative antibody response in SOT recipients receiving 2 doses of a SARS-CoV-2 vaccine. BNT162b2, antimetabolites, belatacept, and tacrolimus may be associated with weak antibody responses in SOT recipients. In contrast, the factor “living donors” showed opposite results. The administration of low-dose CS and mTOR inhibitor did not increase the risk of negative humoral response in SOT recipients receiving a 2-dose SARS-CoV-2 vaccine.	In general, during the COVID-19 pandemic, MMF/MPA, high-dose CS, and triple immunosuppression therapy should be limited. For the population with risk factors, such as diabetes mellitus, old age, and low eGFR, the SARS-CoV-2 vaccination should be enhanced and more attention should be paid to COVID-19 prevention. Compared with BNT162b2, the mRNA-1273 vaccine appears to be a better choice for SOT recipients.
Li et al. 2022 [76]	96 studies; 10,923 transplant pts (both SOT and allo-HSCT) and 2326 healthy controls	Pfizer/BioNTech, Moderna, AstraZeneca, and CoronaVac	85 studies with antibody response data for transplant recipients after 2 doses of a COVID-19 vaccine were included in the analysis. Of these, 37 studies included data for healthy controls. The pooled seroconversion rate was 49% [95%CI, 44%-55%) in transplant recipients, which was markedly lower than that for controls (99% [95%CI, 99%-99%]). Classification by organ types showed that lung transplant recipients had the lowest rate of seroconversion (29% [95%CI, 21%-36%]), followed by kidney (37% [95%CI, 30%-43%]) and heart (37% [95%CI, 23%-51%]); liver transplant recipients had the highest seroconversion rate (65% [95%CI, 58%-72%]).	Transplant pts (both SOT and allo-HSCT), compared with healthy controls, had much lower humoral responses to COVID-19 vaccines. A booster (third) dose improved the responsiveness, but it still remained suboptimal. The use of immunosuppressive regimens was the most prominent risk factor associated with reduced seroconversion but, interestingly, the response varied markedly between the different immunosuppressants. Furthermore, patients with advanced age, short time from transplantation, or comorbidities are also at higher risk of negative response.
Ge et al. 2022 [77]	27 studies; including 2506 allo-HSCT recipients, 286 auto-HSCT recipients, 107 CAR T-cell recipients and 683 healthy controls	Pfizer/BioNTech, Moderna, AstraZeneca, and Janssen/J&J	Pooled seropositivity rates in HSCT and CAR T-cell recipients were 0.624 [95%CI, 0.506–0.729] for 1 dose, 0.745 [95%CI, 0.712–0.776] for 2 doses. The rates were significantly lower than those in controls (~100%). In subgroup analyses, CAR T-cell recipients had lower seroconversion rates (1 dose: 0.204 [95%CI, 0.094–0.386]; 2 doses: 0.277 [95%CI, 0.190–0.386]) than HSCT pts (1 dose: 0.779 [95%CI, 0.666–0.862]; 2 doses: 0.793 [0.762–0.821]). The rates were comparable between auto- and allo-HSCT recipients. Other factors related to seropositivity were time interval between therapy and vaccination, use of immunosuppressive drugs and immune cell counts.	This meta-analysis noted an impaired humoral response to COVID-19 vaccination in HSCT recipients, and a lower response in CAR T-cell recipients. Improved seropositivity rates may be achieved if the interval between therapy and vaccination exceeds 6 months. Regularly repeated COVID-19 vaccinations at appropriate time intervals may therefore be beneficial in these patients. Further studies assessing response to a fourth dose as well as alternative vaccine protocols are warranted.
Meshram et al. 2022 [78]	112 studies (57 kidney, 11 liver, 4 lung, 3 heart and 37 mixed); 15,391 SOT pts and 2844 controls	Pfizer/BioNTech, Moderna, AstraZeneca and inactivated whole virus vaccine	A low humoral response (ES: 0.44 [0.40–0.48]) was noted in overall and in control studies (OR: −4.46 [−8.10 to −2.35]) in SOT pts. The humoral response was highest in liver (ES: 0.67 [0.61–0.74]) followed by heart (ES: 0.45 [0.32–0.59]), kidney (ES: 0.40 [0.36–0.45]), kidney-pancreas (ES: 0.33 [0.13–0.53]), and lung (0.27 [0.17–0.37]) transplants. The meta-analysis for standard and booster dose (ES: 0.43 [0.39–0.47] vs. 0.51 [0.43–0.54]) showed a marginal increase of 18% efficacy. SOT with prior infection had higher response (ES: 0.94 [0.92–0.96] vs. ES: 0.40 [0.39–0.41]; p-value < .01). The seroresponse with mRNA-12723 vaccination was highest 0.52 (0.40–0.64). MPA (OR: 1.42 [1.21–1.63]) and belatacept (OR: 1.89 [1.3–2.49]) had the highest risk for nonresponse. SOT also had a decreased cellular response in overall and control studies.	Pts with SOT had an immunogenicity rate of about 40%, for both humoral and cellular response. The increase in immune response following a booster dose was important, and additional doses may also be needed for SOT pts. Immunosuppression with MPA and belatacept has a significant impact on vaccine response. Immunizing SOT with higher efficacy vaccines, higher doses and possibly heterologous booster doses are possibly important procedures that can further increase the response. Additional investigations and treatment strategies for SOT pts may be required in future.
Sakaruba et al. 2022 [79]	44 observational studies (22 kidney, 7 heart and/or lung, 1 liver and 14 mixed); 6158 SOT recipients	Mostly Pfizer/BioNTech and Moderna	After a 1 and 2 doses of vaccine, serologic response rates were 8.6% [95%CI, 6.8–11.0] and 34.2% [95%CI, 30.1–38.7], respectively. Compared to controls, response rates were lower after 1 and 2 doses of vaccine (OR 0.0049 [95%CI, 0.0021–0.012] and 0.0057 [95%CI, 0.0030–0.011], respectively). A third dose improved the rate to 65.6% [95%CI, 60.4–70.2], but in a subset of pts who had not achieved a response after 2 doses, it remained low at 35.7% [95%CI, 21.2–53.3].	In summary, only a small proportion of SOT recipients achieved serologic response to the COVID-19 mRNA vaccine, and that even the third dose had an insufficient response. These results suggest the urgent need for improved prophylaxis strategies including the use of mAb-based immune prophylaxis as a substitute or as a complement to vaccines in this vulnerable pt population and that they need to continue following safety measures.
Ma et al. 2022 [80]	Of 27 studies investigating RRT, 13 (n = 1888) involved KT	99% received mRNA platform vaccines (Pfizer/BioNTech or Moderna)	Only 26% of KT pts (n = 1888) developed anti-SARS-CoV-2 antibodies [95%CI, 14.9-, 37.4]. Compared with healthy individuals, kidney transplant pts were 80% less likely to be seropositive for anti-SARS-CoV-2 [95%CI, −62 to −99; p < 0.001]. For every 1% increase in the use of MMF there was a 0.92% decrease in the number pf pts developing anti-SARS-CoV-2 antibodies [95%CI, −1.68 to −0.17; p = 0.021].	KT pts had significantly lower titers and seropositivity rates for anti-SARS-CoV-2 antibodies after 2 doses of COVID19 vaccine compared to both dialysis pts and the general population. Indeed, only 26% developed antibodies after 2 doses of COVID-19 vaccine, while the rest remained seronegative despite completion of immunization. COVID-19 vaccine produces a significantly reduced antibody response in pts undergoing RRT, especially among transplant pts, and is generally well tolerated. The results support an additional dose of COVID-19 vaccine in transplant recipients and the need for novel strategies to enhance immunogenicity in these susceptible patients.
Luo et al. 2022 [81]	19 observational studies; 4191 participants (1700 LT recipients, 1624 with CLD, and 867 healthy controls)	Pfizer/BioNTech, Moderna, AstraZeneca, Janssen/J&J, CoronaVac, and Sinopharm	The pooled detectable humoral immune responses after 2 doses of COVID-19 vaccination in LT recipients and CLD pts were 66% [95%CI, 57%–74%] and 95% [95%CI, 88%–99%], respectively. After 2 doses of vaccination, the humoral immune response rate was lower in LT recipients had a lower humoral immune response rate after two doses of vaccination than healthy controls (RR 0.68 [95%CI, 0.59–0.77]; p< 0.01). In contrast, the rate was similar in CLD patients vs. healthy controls (RR 0.96 [95%CI, 0.90–1.02]; p = 0.14).	COVID-19 vaccination produced a poor humoral immune response in LT recipients. In contrast a strong humoral response was demonstrated in CLD. The findings support the administration of a third dose of vaccine to LT recipients. With both the appearance of novel variants of the virus and waning antibody responses, further studies assessing the immunogenicity and effectiveness of different vaccines and treatment approaches are warranted.

Abbreviations: allo-HSCT, allogenic hematopoietic stem cell transplant; BCL2 inhibitors, B-cell lymphoma 2 inhibitors; BTK inhibitors, Bruton tyrosine kinase inhibitors; CAR T-cell therapy, chimeric antigen receptor T-cell therapy; CI, confidence interval; CLD, chronic liver disease; CS, corticosteroids; eGFR, estimated glomerular filtration rate; ES, effect size; HTX, heart transplant; J&J, Johnson & Johnson; KT, kidney transplant; LT, liver transplant; MPA/MMF, mycophenolic acid/mycophenolate mofetil; mTOR, mammalian target of rapamycin; OR, odds ratio; pOR, pooled odds ratio; PC, plasma cell; pts, patients; RD, risk-difference; RR, risk-ratio; RRT, renal replacement therapy; SOT, solid organ transplant.

4.5. Patients with chronic kidney disease

From the outset of the COVID-19 pandemic, persons with chronic kidney disease were reported to have a higher rate of complications, including more severe morbidity and deaths, than the general population [19,82–84]. Furthermore, large multicenter and population-based studies highlighted a mortality rate of between 20 and 30% in patients receiving dialysis for kidney failure, and a 4-fold increased mortality rate in dialysis versus non-dialysis patients with kidney disease [19,85–87]. In an umbrella review (incorporating 103 reviews), patients with chronic kidney disease/kidney transplantation were at increased risk of developing COVID-19, and these patients had a notably higher incidence of acute kidney injury associated with advanced age, male gender, coronary artery disease, diabetes, and hypertension as risk factors [88]. Separately, in a systematic review involving 13 studies and 18,822 patients with chronic kidney disease and COVID-19, individuals with diabetes had an increased mortality rate compared with non-diabetic patients (RR 1.41 [95%CI, 1.15–1.72; P < 0.001]) [89]. In 3160 patients with kidney failure (dialysis or renal transplant recipients) and COVID-19, there was an increased risk of mortality associated with obesity [90].

Systematic reviews evaluating the effectiveness of COVID-19 vaccination in patients with chronic kidney disease and undergoing dialysis, are summarized in Table 5 [71,80,91–94]. Key findings include:

• Seroconversion rates were markedly lower in patients undergoing dialysis for chronic kidney disease receiving one dose of COVID-19 vaccination, but the response improved significantly with a second dose of vaccine.

• Of the various forms of renal replacement therapy, kidney transplant patients had the worst response to COVID-19 vaccination

• Risk factors for lower seroconversion rates following COVID-19 vaccination included older age, current immunosuppressive therapy or chemotherapy, lower serum albumin levels, lower white blood cell/lymphocyte counts, length of time on dialysis, and concomitant diabetes.

Table 5. Summary of systematic reviews published in 2022 investigating immune responses to COVID-19 vaccination in patients with renal insufficiency on dialysis.

Ref	Number of studies and patients	Vaccination	Results	Patients responding poorly to COVID-19 vaccination (low seropositivity) and conclusions
Akyol et al. 2022 [71]	Of 18 prospective studies investigating RRT, 14 involved dialysis pts (1279 pts and 450 healthy controls)	Pfizer/BioNTech and Moderna	Seroconversion rates in HD pts ranged from 72.8–96.4% and in HD+PD pts from 70.5–90%. The overall seroconversion rate was 88.5% of HD and 88.0% of HD+PD pts studied. In 8 studies that also included a control group, the seroconversion rate for dialysis patients ranged from 70.5–96.4% (85.0% overall) and in controls it was 100%. However, control pts were generally younger (up to 23 y) than HD pts.	In dialysis pts, older age, current immunosuppressive therapy or chemotherapy, lower serum albumin, lower white blood cell or lymphocyte counts, lower hemoglobin and lower dialysis vintage were identified as indicators of a lower antibody response or non-response. Seroconversion rates following vaccination in dialysis pts are suboptimal and this is an unmet clinical need. Future studies should address how to optimize treatment in order to improve the pt’s response, including assessing the impact of a third dose of vaccine, as well as studying the best way to assess clinically relevant immunological responses (e.g. are pts with low antibody titers, but preserved cellular responses protected from clinically significant disease?).
Chen et al. 2021 [91]	32 studies; 4917 participants with end-stage renal disease	Pfizer/BioNTech, Moderna, AstraZeneca, and Janssen/J&J	HD was the predominant RRT. The overall immunogenicity rate in patients receiving dialysis was 86% [95%CI, 81%-89%] with no difference between HD and PD. Immunogenicity rates after the first dose (RR 0.61 [95%CI, 0.47–0.79]) and second dose (RR 0.88 [95%CI, 0.82–0.93]) were significantly lower in the dialysis groups than in the control group, but the difference was less apparent after 2 doses of vaccine. A higher prevalence of diabetes was significantly correlated with a lower immune response rate (regression coefficient, −0.06 [95%CI, −0.10 to −0.02; P = .004].	These findings showed that the immunogenicity rate among patients receiving dialysis was 41% after the first dose and 89% after the second dose. Diabetes appeared to be a risk factor for nonresponse in the dialysis population.
Mehta et al. 2022 [92]	8 studies; 1826 pts on long-term HD.	Pfizer/BioNTech and Moderna,	Across the 8 studies the humoral response seroconversion rate was between 81 and 97% after 2 doses of the COVID‐19 vaccines. The T‐cell response was 67% and 100% in 2 studies.	A single dose did not effectively improve the humoral immune response in most studies involving HD pts. However, 2 doses did improve the seroconversion rate. More research is needed to see if HD pts can mount an effective T‐cell response.
Ma et al. 2022 [80]	Of 27 studies investigating RRT, 16 (n = 2175) involved pts on HD and 6 (n = 121) involved pts on PD	99% received mRNA platform vaccines (Pfizer/BioNTech or Moderna)	Chronic HD pts (n = 2175) attained a seropositivity rate of 84.3% [95%CI, 79.1–89.4]. Compared to healthy controls, HD pts were 18% less likely to achieve seropositivity [95%CI, −9 to −27%; p < 0.001]. PD pts attained a seropositivity rate of 92.4% [95%CI, 88.3–96.6]. Compared to healthy controls, PD patients were 11% less likely to become seropositive [95%CI, −1 to −21; p = 0.39].	Compared with healthy controls, kidney transplant pts, and HD and PD patients were 80%, 18% and 11% less likely to develop antibodies after vaccination. Thus, COVID-19 vaccine produces a significantly reduced antibody response in pts undergoing RRT, especially those receiving a transplantation. The results support an additional dose of COVID-19 vaccine in transplant recipients and the need for novel strategies to enhance immunogenicity in these susceptible patients.
Peiyao et al. 2022 [93]	38 studies involving 5628 participants (pts requiring RRT and healthy controls)	Pfizer/BioNTech, Moderna, AstraZeneca, and Covaxin	The overall immunogenicity of dialysis pts was 87% [95%CI, 84–89]. The vaccine response rate was 85.1 in HD pts and 97.4% in healthy controls. The serological positivity rate was 82.9% in infection-naive individuals and 98.4% in pts with previous infection. The standard mean difference of antibody titers in dialysis patients with or without previous COVID-19 infection was 1.14 [95%CI, 0.68–1.61].	Vaccination helped dialysis patients achieve effective humoral immunity, with an overall immune efficiency of 87%. Subgroup analysis showed that the immunosuppression rate was an influential factor affecting the immunogenicity rate.
Falahi et al. 2022 [94]	39 studies involving 806 HD pts and 336 controls receiving 1 dose, and 6314 HD pts and 927 controls 2 doses of COVID-19 vaccines	COVID-19 mRNA vaccines	After the first dose of mRNA vaccines, the seroconversion rate was 36% [95%CI, 0.24–0.47] and 68% [95%CI, 0.45–0.91] in HD pts and controls, respectively. The seroconversion rate after the second dose of mRNA vaccines was 86% [95%CI, 0.81–0.91] and 100% [95%CI, 1.00–1.00] in HD patients and controls, respectively.	Different mRNA‐based vaccines induced comparable seroconversion rates in HD pts and healthy controls. Although the immune response of HD pts to a second dose of COVID-19 vaccine is very promising, the seroconversion rate of dialysis patients is lower than controls. As a result, closer attention should be applied to this population to periodically assess the antibody levels of HD pts at short intervals and renew their vaccination when necessary.

Abbreviations: CI, confidence interval; CS, corticosteroids; eGFR, estimated glomerular filtration rate; ES, effect size; HD, hemodialysis; HTX, heart transplant; J&J, Johnson & Johnson; MPA/MMF, mycophenolic acid/mycophenolate mofetil; mTOR, mammalian target of rapamycin; OR, odds ratio; pOR, pooled odds ratio; PC, plasma cell; PD, peritoneal dialysis; pts, patients; RD, risk-difference; RR, risk-ratio; RRT, renal replacement therapy; SOT, solid organ transplant.

The poorer response in kidney transplant recipients has been noted in studies that investigated renal replacement therapy in general [71,80,84]. The need to optimize treatment schedules in patients with chronic kidney disease, including the value of booster doses of the COVID-19 vaccine, is an important priority. Indeed, El Karoui & De Vriese noted that progressive waning of immunity and emergence of SARS-CoV-2 variants with a high potential of immune escape highlight the need for booster vaccinations in dialysis patients. Persistent poor vaccine responders are potential candidates for primary prophylaxis with neutralizing monoclonal antibodies [95].

5. Risk factors for COVID-19 vaccine failure

COVID-19 vaccines have proven highly effective in producing high levels of short-term protection against the SARS-CoV-2 virus, reducing the risk of severe infections, hospital admissions and death [96–98]. However, there is evidence that the protective effects of current vaccines against symptomatic disease decreases over time and this has led to the introduction of COVID-19 vaccine booster programs [98]. It was previously reported that COVID-19 vaccine effectiveness against the Delta variant peaked in the early weeks after the second dose and decreased to 47.3% [95%CI, 45–49.6] and 69.7% [95%CI, 68.7–70.5] by ≥20 weeks for ChAdOx1-S (AstraZeneca) and BNT162b (Pfizer/BioNTech) vaccines, respectively. The vaccine remained effective against severe disease outcomes for up to 20 weeks in most groups, although there was greater waning in older adults and those with underlying medical conditions [99]. Vaccine effectiveness of a booster dose was very similar (≥90%) independent of the vaccine used in the primary course, and there was no clear evidence of waning against severe disease up to 10 weeks after the booster. Limited waning was seen 10 or more weeks after the booster. This study provides real-world evidence of substantially increased protection from booster vaccination against mild and severe disease irrespective of the primary course [99].

Primary vaccination with two doses of BNT162b2 (Pfizer/BioNTech), ChAdOx1 nCoV-19 (AstraZeneca), or mRNA-1273 (Moderna) vaccines provided limited protection against COVID-19 caused by the Omicron variant of SARS-CoV-2. A BNT162b2 or mRNA-1273 booster after either the ChAdOx1 nCoV-19 or BNT162b2 primary course increased protection, but the protection waned over time [100]. Significant waning of vaccine effectiveness against symptomatic COVID-19 has been reported and was highest in older adults and in clinical risk groups (patients with chronic diseases, who were immunocompromised or had severe respiratory disease) [101].

Breakthrough infections in persons vaccinated against COVID-19 have been a reality since 2021 and have continued to increase with the predominance of Omicron variants [101]. Vo and colleagues undertook a nationwide retrospective cohort study in US Veterans Affairs Hospitals to identify key risk factors for severe breakthrough of SARS-CoV-2 infections in 110,760 fully vaccinated individuals. The most strongly associated risk factors for severe disease are shown in Box 3 [102].

Box 3. The main demographic, clinical, or vaccination-related risk factors (odds ratios all >2.0) associated with COVID-19 breakthrough despite being fully vaccinated [102].

Table

Characteristic	Adjusted Odds Ratio [95%CI]
Age ≥80 years	16.58 [13.49–20.37]
Age 75–79 years	8.72 [7.10–10.70]
Age 70–74 years	6.63 [5.42–8.11]
Age 65–69 years	4.82 [3.93–5.92]
Age 60–64 years	3.24 [2.64–3.99]
Comorbid multiple sclerosis/transverse myelitis	2.86 [2.17–3.78]
Leukocyte inhibitory^a	2.80 [2.39–3.28]
Chemotherapy^a	2.71 [2.27–3.24]
Glucocorticoids^a	2.34 [2.18–2.50]
Age 55–59 years	2.24 [1.80–2.78]
Lymphocyte depleting^a	2.07 [1.57–2.72]
Comorbid Alzheimer disease and related disorders	2.01 [1.83–2.20]

Characteristics with Odds Ratios between 1.50 and 1.99 included: mobility impairment (OR< 1.92), leukemias and lymphomas (1.87), heart failure (1.74), schizophrenia and other psychotic disorders (1.71), cytokine-blocking therapy^a (1.66), COPD and bronchiectasis (1.65), age 50–54 years (1.60), chronic kidney disease (1.59), ≥12 months since fully vaccinated.

^aImmunosuppressive therapy before breakthrough

Findings from our literature search identified the following risk factors for a poor immunological response to COVID-19 vaccination:

• All immunocompromised persons who have not been fully vaccinated, and in some instances who have not received at least one booster dose as well

• Older age (>65 years) was reported to be associated with lower seroconversion rates in almost all studies

• Patients with PI, especially with X-linked agammaglobulinemia (who produce few or no antibodies following vaccination)

• Cancer patients in general, and more definitively, those with hematological malignancies (the weakest antibody responses were demonstrated in patients with CLL and NHL)

• Anticancer treatments interfering with humoral and cellular responses (e.g. anti-CD20 therapy and other B-cell depleting modalities)

• Solid organ transplant recipients having the lowest responses to vaccination by type of organ transplantation were in the order (worst response > to best response) lung > kidney-pancreas > kidney > heart > liver; also, patients receiving an organ from a deceased donor

• Solid organ transplant recipients on concomitant treatments such as immunosuppressive regimens (not only mycophenolate mofetil, but also corticosteroids, calcineurin inhibitors, and belatacept; and multiple regimens), recent rituximab or antithymocyte globulin exposure, and CAR T-cell recipients

• Patients with concomitant underlying disorders such as diabetes and reduced kidney function

• In one study, the BNT162b2 vaccine (Pfizer) was less effective than the mRNA-1273 (Moderna) vaccine [74]

• Chronic kidney disease risk factors for lower seroconversion rates following COVID-19 vaccination included older age, current immunosuppressive therapy, or chemotherapy, lower serum albumin levels, lower white blood cell/lymphocyte counts, length of time on dialysis and concomitant diabetes.

Excess bodyweight/obesity has been speculated to be a risk factor for vaccine failure, but large studies have shown that the protection provided by COVID-19 vaccines against severe disease outcomes was high across all BMI categories when comparing vaccinated versus unvaccinated persons [103,104]. Patients with immune-mediated diseases such as rheumatoid arthritis and inflammatory bowel disease need special mention since the two conditions can be very similar in terms of pathogenesis (excessive release of inflammatory cytokines to B cell activation and excessive macrophage activation, which can lead to damage to various organs) [105]. In some cases, patients with autoimmune/autoinflammatory diseases (e.g. systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis, among others) are more susceptible to SARS-CoV-2 infection, either because of the active autoimmune diseases per se or because of the medications used to treat them [105,106]. Despite blunted immunogenicity observed with some agents, vaccination is generally beneficial in patients with immune-mediated diseases. The greatest reduction in vaccine response has been observed in patients taking B cell-depleting agents, followed by TNF inhibitors, and the CTLA-4 fusion protein abatacept [106]. The importance of COVID-19 vaccination is clearly highlighted in a number of systematic reviews in patients with rheumatic diseases [107,108], inflammatory bowel disease [109,110], and immune-mediated diseases in general [111].

6. Treatment options for patients poorly responsive to COVID-19 vaccination

The pharmacological management of COVID-19 has continued to evolve since SARS-CoV-2 emerged in late 2019, driven in part by global efforts to accelerate vaccine, anti-viral, and monoclonal antibody development [112]. While vaccination has clearly benefitted a large proportion of the world’s population with almost 70% receiving at least one dose of the COVID-19 vaccine [113], there are many individuals who remain unvaccinated, have not completed a primary series plus booster, or who mounted a weak immune response to vaccination (especially immunocompromised persons). These patients are at a higher risk of severe disease and will likely require additional therapeutic support [17,114]. There is therefore an unmet need for alternative approaches.

A variety of medicines have been recommended for the prevention or treatment of COVID-19 in at-risk patients [115]. Broadly speaking, these include antiviral drugs, monoclonal antibodies, convalescent plasma, immunomodulatory agents, and others (e.g. anticoagulants). It is important to note that this field of medical treatment is evolving rapidly with new therapies being made available and others being discontinued. A full review of therapeutic approaches is outside the scope of this review, and we provide an overview for the reader to provide context. For a fuller review see Zhang et al. 2023 [116].

Antiviral agents mainly include polymerase inhibitors (e.g. remdesivir), protease inhibitors (e.g. ritonavir and nirmatrelvir), inhibitors of nucleoside and nucleotide reverse transcriptase (e.g. molnupiravir) entry and uncoating inhibitors (e.g. amantadine and enfuvirtide), and others [116,117]. Antivirals are generally considered most effective when prescribed early in the course of the disease to reduce the risk of severe disease [118].

Host-related therapies are typically immunomodulatory therapies such as corticosteroids, Janus kinase inhibitors (e.g. baricitinib and tofacitinib), and antibody therapies (e.g. anakinra and tocilizumab), which are prescribed following the onset of severe illness to reduce harmful inflammation [116,117].

Monoclonal antibodies have demonstrated efficacy as both pre-/post-exposure prophylaxis and treatment for COVID-19 [119–125]. Antibodies have high specificity, although mutations in the targeted regions (usually of the spike protein) can prevent binding, resulting in viral evasion and resistance [119]. Because of the high frequency of non-susceptible Omicron variants currently circulating in the US, casirivimab/imdevimab, sotrovimab, and bamlanivimab/etesevimab are no longer currently authorized [126–128], whereas tixagevimab/cilgavimab has received Emergency Use Authorization for pre-exposure immunoprophylaxis from the FDA [129].

In Europe, a number of agents have received authorization for use against COVID-19 from the EMA including the monoclonal antibodies tixagevimab/cilgavimab, sotrovimab, casirivimab/imdevimab, and regdanvimab; the antiviral drug ritonavir/nirmatrelvir and remdesivir (molnupiravir is currently under review); and the immune modulators anakinra and tocilizumab [130,131]. This is a dynamic area as new variants emerge, and for the latest information of availability and usage, the reader is referred to the applicable FDA [126] and EMA [130] websites.

A subset of people develop chronic/persistent symptoms after an acute episode of COVID-19, and such symptoms can last for weeks and up to many months. These post-acute sequelae of COVID-19 are often referred to as ‘Long COVID’ [132–134]. Multivariate regression analysis showed that long COVID was more common in females and individuals presenting with at least one co-morbidity [132]. While the response to COVID-19 vaccines has been variable in patients with Long COVID, there is mounting evidence that they are protective, even against breakthrough infections [133,134]. However, evidence against Omicron strains of the virus is limited and different therapeutic options may be required long term to optimally manage patients at risk of developing Long COVID [132–135]. The individualized nature of long COVID supports the need for different therapeutic approaches. Furthermore, improved diagnostic procedures to identify patients at-risk, possibly including genomic biomarkers, could support a more effective and predictive personalized approach to patient management.

7. Limitations

As noted in a recent Cochrane review, there has been an explosion in COVID-19-related research to an extent that it is highly challenging for a clinician to keep up-to-date with the published literature [67]. Practically, we decided to limit our search to the most recent 12 months and solely to systematic reviews/meta-analyses (clinical best evidence). Furthermore, we focused our searches and discussions on patient groups known to be associated with a compromised immune status or receiving immunosuppressant therapy (primary and secondary immunodeficiencies (e.g. HIV), cancer (especially hematological malignancies), chronic kidney disease, and solid organ transplant recipients). This scoping review approach offers a high-level view of the dynamic changes occurring with COVID-19 vaccines in the management of immunocompromised patients at risk from SARS-CoV-2 infection. Our primary focus was to identify any subgroups of patients that had a reduced response to COVID-19 vaccination and who may therefore be candidates for alternative treatment approaches better suited to their needs. However, it should be noted that a limitation of our review is that we did not assess the methodological quality of the included systematic reviews.

This review has a number of other notable limitations related to dynamic changes that are characteristic of the COVID-19 pandemic, and these result in significant heterogeneity across studies. Factors that were generally poorly reported and could lead to bias included the virus strains involved (the changing pattern of ‘variants of concern’ potentially influencing vaccine effectiveness); details of vaccines/dosages (including effects of booster doses) and timing of results relative to the time of administration; the majority of data relate to the use of mRNA vaccines and are markedly less for viral vector vaccines and inactivated whole virus vaccines; the data derive almost exclusively from observational studies (which is typical for infection prevention literature); and there was a lack of consistency with respect to serological testing to quantify antibody responses. Consequently, despite the fact that this review represents data from a very large number of patients, the findings should be viewed with caution given the considerable heterogeneity in the identified studies.

8. Conclusions

Our analysis of 12-month data from late 2021 takes an aerial view of the rapidly expanding literature related to vaccination in immunocompromised persons at risk from COVID-19. The goal was to identify factors relating to a suboptimal response to vaccination and provide evidence of which patients may benefit from preexposure prophylaxis. Findings from our literature review identified a number of risk factors for a poor immunological response to COVID-19 vaccination with key ones being non-fully vaccinated immunocompromised persons, older age (especially >75 years), patients with hematological malignancies, patients receiving treatments interfering with humoral and cellular responses (e.g. anti-CD20 therapy and other B-cell depleting modalities), some solid organ transplant recipients, and those receiving immunosuppressive therapy.

Development of models to estimate the probability of a patient progressing to severe disease and to guide treatment and prophylaxis planning will be a step forward to meet the unmet need for many patients not adequately protected from the SARS-CoV-2 virus at the present time. This will require more detailed reporting of virus ‘variants of concern,’ full details of vaccines/dosages (including effects of booster doses), and timing of results relative to the time of administration.

9. Expert opinion

The emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic have led to an unprecedented research effort related to zoonotic infections in general and coronavirus infections in particular. The response of the global community, including the pharmaceutical industry, particularly in regard to disease management initiatives has been impressive after the catastrophic early phases of the pandemic. From protective measures, such as social distancing, mask wearing, and hand sanitization, to vaccine development and newer antiviral approaches including monoclonal antibodies (e.g. tixagevimab/cilgavimab, casirivimab/imdevimab and sotrovimab), we have come a long way in a relatively short time. However, it is important to note that the journey is clearly still ongoing. While the Omicron variant has led to a milder form of the disease, the morbidity and mortality associated with COVID-19 remains too high, and optimization of treatment for all—including poorer communities, vulnerable patients such as immunocompromised individuals and those not benefiting from current vaccines—needs to be prioritized. Beyond this, we have no idea what future variants of SARS-CoV-2 will look like in terms of pathogenicity and virulence. Efforts to maintain the currency of vaccination programs based on variants of interest as well personalization of pharmacological approaches (including immunotherapy) need to be ongoing.

The findings of this review of systematic reviews in immunocompromised populations provide further knowledge about COVID-19 vaccination status and effectiveness in an at-risk/vulnerable group of patients. By necessity, it takes a broad view of the dynamic changes that are occurring during the pandemic, when many variables such as virus strains, vaccine types, and vaccination status are all changing and impact our view of the disease. The administration of booster doses of COVID-19 vaccines has helped maintain vaccine effectiveness against different outcomes, such as infection, symptomatic disease, and hospitalization in the short term, but there is emerging evidence of a waning level of protection against Omicron strains on COVID-19.

The COVID-19 pandemic is both complex and unpredictable, and development of effective vaccines and alternative treatments is a key strategy to manage the disease. In terms of vaccine research, a number of developments are being investigated such as:

• variant-specific COVID-19 vaccines and a number of companies are developing Omicron-specific vaccines

• development of a multi-antigenic vaccine that has antigens of different variants to increase the breadth of the immune response

• a ‘prime-boost strategy’ in which a priming response is initiated with an effective mRNA vaccine and boosted with a different vaccine such as an intranasal product—this again is intended to produce a broad immunological response with higher protection against infection and transmission. There is a long list of intranasal vaccines under development

• development of bivalent vaccines to produce a potent, more durable, and broader immune responses is also being investigated. One such approach involves a modified, bivalent booster vaccine containing equal amounts of messenger RNAs (mRNAs) encoding the ancestral SARS-CoV-2 and beta variant spike proteins. This bivalent vaccine elicited superior and more durable neutralizing antibody responses against the Beta, Delta, and Omicron variants as compared with mRNA-1273 alone

• Another potential development is a bivalent vaccine against SARS-CoV-2 and influenza viruses, but this is still in the early phases of development.

COVID-19 has changed the world as we know it, and the pandemic has caused immense economic and healthcare disruption. The societal consequences have been enormous, but the global response to manage the disease, especially via vaccine development programmes and the introduction of new treatment modalities, has been impressive. However, the disease burden from SARS-CoV-2 infection is a concern as the number of new cases worldwide continues to be high. While COVID-19 vaccination is helping to reduce the number of deaths and serious cases of the disease, for the time being, there is little evidence that levels of immunity in the community are sufficient to consider the pandemic to be over. This is possibly driven by the emergence of new viral variants, which remains a major concern given the possibility of a more virulent mutation of SARS-CoV-2 evolving. This is already causing problems for some treatment choices, with the emergence of sub-variants such as SARS-CoV-2 Omicron BA.2 in the US. This strain has resulted in the FDA recommending that sotrovimab is no longer used and also restricting the use of bamlanivimab/etesevimab and casirivimab/imdevimab to patients likely to have been infected with or exposed to variants that are susceptible to these treatments.

Now, more than ever, we need to maintain our focus on providing the best clinical protection against the SARS-CoV-2 virus. This could include optimization of vaccine strategies (type of vaccine and dosage schedules) and provision of alternative immunotherapeutic approaches for immunocompromised individuals who do not respond adequately to COVID-19 vaccination.

Declaration of interest

V Shetty and N Azmi are employees of AstraZeneca. S Clissold is a professional scientific writer (ContentEdNet, Singapore). 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

A reviewer of this manuscript has disclosed that they have provided consultancies for epidemiological research and data analyses for Moderna, Pfizer, GSK, Seqirus, and Astra Zeneca. Peer reviewers of this manuscript have received an honorarium for their review work.

Authors’ contributions

All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, which was developed in line with Good Publishing Practice-3 guidelines. All authors contributed to the review’s conception and search strategy, focus, and interpretation, drafting, and/or revision of the manuscript and have given their approval for this version of the manuscript to be submitted for publication.

Additional information

Funding

This manuscript was funded by AstraZeneca, Singapore.