key: cord-0848595-5hfbt161
authors: See, Kay Choong
title: Vaccination for the Prevention of Infection among Immunocompromised Patients: A Concise Review of Recent Systematic Reviews
date: 2022-05-18
journal: Vaccines (Basel)
DOI: 10.3390/vaccines10050800
sha: 4b6bf6580ee01946c0d4c4e088f84de845c4226c
doc_id: 848595
cord_uid: 5hfbt161

Vaccination is crucial for avoiding infection-associated morbidity and mortality among immunocompromised patients. However, immunocompromised patients respond less well to vaccinations compared to healthy people, and little is known about the relative efficacy of various vaccines among different immunocompromised states. A total of 54 systematic reviews (22 COVID-19; 32 non-COVID-19) published within the last 5 years in Pubmed(®) were reviewed. They demonstrated similar patterns within three seroconversion response categories: good (about >60% when compared to healthy controls), intermediate (~40–60%), and poor (about <40%). Good vaccine responses would be expected for patients with chronic kidney disease, human immunodeficiency virus infection (normal CD4 counts), immune-mediated inflammatory diseases, post-splenectomy states, and solid tumors. Intermediate vaccine responses would be expected for patients with anti-cytotoxic T-lymphocyte antigen-4 therapy, hematologic cancer, and human immunodeficiency virus infection (low CD4 counts). Poor vaccine responses would be expected for patients with B-cell-depleting agents (e.g., anti-CD20 therapy), hematopoietic stem-cell transplant, solid organ transplant, and liver cirrhosis. For all vaccine response categories, vaccination should be timed when patients are least immunosuppressed. For the intermediate and poor vaccine response categories, high-dose vaccine, revaccination when patients are less immunosuppressed, checking for seroconversion, additional booster doses, and long-acting monoclonal antibodies may be considered, supplemented by shielding measures.

Immunocompromised patients have weakened immune systems due to chronic illness (e.g., chronic kidney failure) or therapies that depress immunity (e.g., chemotherapy for cancer, immunomodulation for immune-mediated diseases, and anti-rejection drugs for organ transplantation). Consequently, immunocompromised patients suffer increased susceptibility to sepsis. Sepsis, which is the combination of severe infection with a dysregulated response to infection and organ dysfunction [1] , is in turn associated with increased morbidity, mortality, and cost of care.

To improve the overall prognosis for immunocompromised patients, both downstream improvements of sepsis care and upstream prevention of infection are crucial. For the latter, vaccination against common pathogens is a key strategy which is recommended by major guidelines [2] . Common vaccine-preventable pathogens include those transmitted via the respiratory route (e.g., SARS-CoV-2, influenza, pneumococcus, and varicella-zoster virus) and those transmitted via other routes (e.g., viral hepatitis A and B, and yellow fever virus). Given the risk of proliferation of attenuated vaccine strains in immunocompromised patients [3] , live virus vaccines are contraindicated in patients with active immunosuppression and are only allowed after careful balancing of benefit versus risk [4] . Concerns about vaccine-related relapse of inflammatory rheumatic diseases and post-vaccination allograft rejection exist; however, in general, these appear uncommon [5] [6] [7] [8] , and vaccinations should not be withheld on the basis of these concerns [2] . However, just as immunocompromised patients have deficient immunity to defend against infection, such patients may also have deficient immune responses to vaccination, rendering the latter less effective than expected from studies among healthy controls. Substantial reductions in vaccine efficacy (measured within controlled study environments) or effectiveness (measured in real-world studies) using standard vaccination regimes would necessitate enhanced vaccination strategies or the addition of non-vaccine-based preventive methods (e.g., shielding measures).

Systematic reviews on vaccination for the prevention of infection in immunocompromised patients are ideal for aggregating the published literature on individual vaccines and individual immunocompromising conditions. Given that immunocompromised patients are a heterogeneous group with varying levels of immunosuppression, subgroups of immunocompromising conditions with varying vaccine responses may be identified. Knowledge of these patient subgroups may help stratify preventive measures, with more intensive measures being provided for patients with the poorest vaccine response. A review of systematic reviews was, therefore, conducted to elucidate broad immunocompromised patient subgroups. In doing so, this paper can serve as a source of information for readers interested in an overview of studies, as well as stimulate further research into host-dependent classification of vaccine effectiveness.

Using a validated systematic review filter [9] , a comprehensive search of Pubmed ® (pubmed.ncbi.nlm.nih.gov) was performed (Table 1) . To study contemporary and clinically relevant vaccines, the search was limited to papers published within 5 years of 13 April 2022. Studies were excluded if vaccination against infection was not studied, study outcome was not about vaccine efficacy/effectiveness, patients were not immunocompromised, or primary studies were not reviewed. Screening of titles and abstracts was conducted, and the following data fields were extracted from the full-text documents: vaccine type, number of adult and pediatric patients, number of studies, the reason for being immunocompromised, description of vaccine efficacy, and interventions to improve vaccine efficacy. A qualitative review of included studies was then performed to uncover a general understanding of the associations of various immunocompromising conditions with immune responses to vaccines, as well as construct vaccine seroconversion response categories. In addition, interventions to improve vaccine efficacy were reviewed to inform potential solutions for various vaccine seroconversion response categories.

Out of 979 studies extracted from Pubmed ® , 54 systematic reviews (22 COVID-19; 32 non-COVID-19) were included (Table 1) .

A total of 22 systematic reviews focused on COVID-19 vaccines ( Table 2 ). Most the COVID-19 vaccines were mRNA-based, while the remainder were viral vector-based and inactivated virus vaccines. Immunocompromised states studied included use of B-celldepleting anti-CD20 therapy, chronic kidney failure, immune-mediated inflammatory diseases, malignancy, and solid organ transplant recipients.

The COVID-19 vaccine systematic reviews predominantly used seroconversion as a marker for vaccine efficacy. In general, the studies showed that patients with chronic kidney failure on dialysis (not requiring organ transplantation) [10] [11] [12] , immune-mediated inflammatory diseases [13] [14] [15] [16] , and solid tumors [17] had seroconversion rates that were high and similar to healthy controls (seroconversion rates among patients ranged from about 83% to 97%). In contrast, patients with receipt of anti-CD20 therapy [18] and solid organ transplants [11, 19, 20] (thus requiring anti-rejection immunosuppression) had markedly low vaccine seroconversion rates (rates ranged from about 26% to 45% after two vaccine doses). Patients with hematologic cancers had intermediate seroconversion rates (rates ranged from about 54% to 65%) [21] [22] [23] [24] [25] [26] [27] [28] . An intervention that improved vaccine efficacy was the use of additional booster vaccine doses [20] . 

A total of 32 systematic reviews focused on non-COVID-19 vaccines (Table 3) . Several vaccines were studied, including inactivated hepatitis A vaccine [32] , recombinant hepatitis B vaccine [33] [34] [35] [36] [37] [38] , recombinant human papillomavirus vaccines [39, 40] , inactivated influenza vaccine [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] , live-attenuated measles vaccine (given post hematopoietic stemcell transplantation [52] and in children living with human immunodeficiency virus [53] ), pneumococcal conjugate and polysaccharide vaccines [46, 49, [54] [55] [56] , live-attenuated and recombinant subunit zoster vaccines [57, 58] , live-attenuated yellow fever vaccine [59] , and others [60] [61] [62] [63] . Immunocompromised states studied included use of B-cell-depleting anti-CD20 therapy, chronic kidney failure, human immunodeficiency virus infection, immunemediated inflammatory diseases, liver cirrhosis, malignancy, post-splenectomy status, and solid organ transplant recipients. [46] 785 adults (5) Inflammatory bowel disease

No decreased seropositivity with non-anti-TNF therapy and 72% decreased seropositivity with anti-TNF therapy, compared to non-immunosuppressed patients Not studied The non-COVID-19 vaccine systematic reviews predominantly used seroconversion as a marker for vaccine efficacy. In general, the studies showed that patients with immunemediated inflammatory diseases [33, 34, 38, 43, 46, 47, 49, 61] , human immunodeficiency virus infection [35, 37, 39, 40] , post-splenectomy status [55] , and solid tumors [48] had seroconversion rates that were high and similar to healthy controls (seroconversion rates among patients ranged from about 61% to 100%). In contrast, patients with receipt of anti-CD20 therapy [50] , solid organ transplants [32, 42] , and liver cirrhosis [36] had markedly low vaccine seroconversion rates (rates ranged from about 3% to 49%). Patients with hematologic cancers [58] had intermediate seroconversion rates (about 52%). Systematic reviews involving children [35, 39, 40, 42, 44, [52] [53] [54] [59] [60] [61] [62] [63] demonstrated findings consistent with those involving adults. An intervention that improved vaccine efficacy was the use of high-dose vaccines [35, 37, 42, 44, 45, 51] .

According to the humoral responses to vaccines of various immunocompromising conditions, the systematic reviews for COVID-19 and non-COVID-19 vaccines demonstrated similar patterns. Given the absence of any validated guidelines or recommendations for classification of vaccine seroconversion, three seroconversion response categories were arbitrarily constructed from the data: good (about >60% when compared to healthy controls), intermediate (~40-60%), and poor (about <40%) ( Table 4 ). Good vaccine responses would be expected for patients with chronic kidney disease, human immunodeficiency virus infection with normal CD4 counts, immune-mediated inflammatory diseases, post-splenectomy states, and solid tumors. Intermediate vaccine responses would be expected for patients with anti-cytotoxic T-lymphocyte antigen-4 therapy, hematologic cancer, and human immunodeficiency virus infection with low CD4 counts. Poor vaccine responses would be expected for patients with B-cell-depleting agents (e.g., anti-CD20 therapy), hematopoietic stem-cell transplant, solid organ transplant, and liver cirrhosis.

For all vaccine response categories, vaccination should be timed when patients are least immunosuppressed (e.g., before initiating immunosuppressive treatment) and when immunosuppressive disease states are optimally treated [64] . For the intermediate and poor vaccine response categories, methods to improve vaccine response include the use of highdose vaccine and revaccination when patients are less immunosuppressed. These vaccinebased methods should also be supplemented by non-vaccine methods such as shielding measures (e.g., face mask use, hand hygiene, and physical distancing for respiratory pathogens). For the poor vaccine response category, given possible vaccine nonresponse, seroconversion may be checked. If nonresponse is demonstrated, additional booster doses may be considered [11, 20, 65] . Alternatively, long-acting monoclonal antibodies for preexposure prophylaxis may be considered in patients at high risk of acquiring serious infection [66] . 

Firstly, this review only analyzed systematic reviews included in Pubmed ® , which would not encompass systematic reviews included in other databases such as Embase©. Nonetheless, the individual systematic reviews would have included papers from both Pubmed ® -listed and non-Pubmed ® -listed journals, and missing important data are, hence, unlikely. Secondly, this review was limited to the last 5 years of publication, which would exclude older systematic reviews covering other vaccines. However, this would avoid the inclusion of noncontemporary vaccines, which might affect the overall pattern of vaccine efficacy among immunocompromised patients. Thirdly, this review did not include a quality assessment of individual systematic reviews, as it was the intention to be as inclusive as possible. Nevertheless, the studies all showed fairly consistent results, and stratification by study quality would not have affected the overall interpretation of the current findings. Fourthly, given the heterogeneity of studies, statistical pooling of the results could not be performed, although the current results may serve as a source of information for readers interested in an overview of studies. Lastly, systematic reviews were not available for studying the interaction of immune-mediated diseases and many immunosuppressive medications or for studying combinations of immunocompromised states. Logically, the vaccine response is expected to worsen with greater doses or number of immunosuppressive medications and with coexisting immunocompromised states.

Although a substantial number of non-COVID-19 vaccine systematic reviews contained data from children [35, 39, 40, 42, 44, [52] [53] [54] [59] [60] [61] [62] [63] (13 out of 32), none of the COVID-19 vaccine systematic reviews included pediatric studies. Furthermore, none of the systematic reviews had long-term vaccine efficacy or effectiveness results, and none were performed for oral vaccines (e.g., oral rotavirus, oral cholera, oral polio, and oral typhoid). These important knowledge gaps could potentially be filled once more primary studies are available.

Vaccine development is often a long process involving multiple rounds of preclinical studies and clinical trials. Even for clinically successful vaccines, eventual vaccine efficacy would be dependent on both pathogen and host [67, 68] . From this study, according to the systematic reviews focusing on vaccines targeting a variety of pathogens, the type of immunosuppression in the host appears to play an important role. This review provides a broad overview of various vaccine studies, leading to the construction of three seroconversion response categories. Further studies, which include prediction of vaccination efficacy using baseline measures of circulating B cells [69] , could be performed to refine these categories and to highlight exceptions within these categories. These categories should also be validated against long-term serological protection and clinical effectiveness data. In addition, interventions to improve vaccine efficacy are limited and more studies are required to investigate novel methods such as heterologous prime-boost techniques [70] and long-acting preventive antibody therapy [66] .

In conclusion, this review of 54 systematic reviews demonstrated three vaccine seroconversion response categories among immunocompromised patients: good (about >60% when compared to healthy controls), intermediate (~40-60%), and poor (about <40%). For all vaccine response categories, vaccination should be timed when patients are least immunosuppressed. For the intermediate and poor vaccine response categories, high-dose vaccine, revaccination when patients are less immunosuppressed, checking for seroconversion, additional booster doses, and long-acting monoclonal antibodies may be considered, supplemented by shielding measures.

The third international consensus definitions for sepsis and septic shock (sepsis-3)

idsa clinical practice guideline for vaccination of the immunocompromised host

Varicella vaccination in a child with acute lymphoblastic leukaemia

Safety of live vaccines on immunosuppressive or immunomodulatory therapy-a retrospective study in three swiss travel clinics

Acute rejection after anti-SARS-CoV-2 mRNA vaccination in a patient who underwent a kidney transplant

Risk of solid organ transplant rejection following vaccination with seasonal trivalent inactivated influenza vaccines in england: A self-controlled case-series

Safety of the zoster vaccine recombinant adjuvanted in rheumatoid arthritis and other systemic rheumatic disease patients: A single center's experience with 400 patients

Association between inactivated influenza vaccine and primary care consultations for autoimmune rheumatic disease flares: A self-controlled case series study using data from the clinical practice research datalink

Translation and validation of pubmed and embase search filters for identification of systematic reviews, intervention studies, and observational studies in the field of first aid

Immunogenicity of SARS-CoV-2 mrna vaccine in dialysis and kidney transplant patients: A systematic review

Immunogenicity and safety of COVID-19 vaccines in patients receiving renal replacement therapy: A systematic review and meta-analysis

Humoral and cellular immune response to severe acute respiratory syndrome coronavirus-2 vaccination in haemodialysis and kidney transplant patients

Effectiveness and safety of SARS-CoV-2 vaccine in inflammatory bowel disease patients: A systematic review, meta-analysis and meta-regression

Effectiveness and durability of COVID-19 vaccination in 9447 patients with ibd: A systematic review and meta-analysis

Response to SARS-CoV-2 vaccination in immune mediated inflammatory diseases: Systematic review and meta-analysis

Serologic response to coronavirus disease 2019 (COVID-19) vaccination in patients with immune-mediated inflammatory diseases: A systematic review and meta-analysis

Serologic response following SARS-CoV2 vaccination in patients with cancer: A systematic review and meta-analysis

Humoral and cellular immune responses on SARS-CoV-2 vaccines in patients with anti-cd20 therapies: A systematic review and meta-analysis of 1342 patients

Efficacy and safety of third dose of the COVID-19 vaccine among solid organ transplant recipients: A systemic review and meta-analysis

Immunogenicity and risk factors associated with poor humoral immune response of SARS-CoV-2 vaccines in recipients of solid organ transplant: A systematic review and meta-analysis

Immunogenicity and risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after coronavirus disease 2019 (COVID-19) vaccination in patients with cancer: A systematic review and meta-analysis

COVID-19 vaccines in cancer patients. Seropositivity and safety. Systematic review and meta-analysis. Vaccines

Seroconversion rate after vaccination against COVID-19 in patients with cancer-a systematic review

Antibody response after vaccination against SARS-CoV-2 in adults with haematological malignancies: A systematic review and meta-analysis

Immunological and clinical efficacy of COVID-19 vaccines in immunocompromised populations: A systematic review

Impact of therapy in patients with hematologic malignancies on seroconversion rates after SARS-CoV-2 vaccination

Antibody responses to COVID-19 vaccination in cancer: A systematic review

Immunogenicity of COVID-19 vaccines in patients with hematologic malignancies: A systematic review and meta-analysis

Efficacy of COVID-19 vaccines in immunocompromised patients: Systematic review and meta-analysis

Short-term effectiveness of COVID-19 vaccines in immunocompromised patients: A systematic literature review and meta-analysis

Immunogenicity of COVID-19 mrna vaccines in immunocompromised patients: A systematic review and meta-analysis

Hepatitis a vaccine immunogenicity in patients using immunosuppressive drugs: A systematic review and meta-analysis

Immune response to hepatitis b vaccination among people with inflammatory bowel diseases: A systematic review and meta-analysis

Hepatitis-b vaccine response in inflammatory bowel disease patients: A systematic review and meta-analysis

Systematic review and meta-analysis of immune response of double dose of hepatitis b vaccination in hiv-infected patients

New immunization schedule effectiveness against hepatitis b in liver transplantation patients

Immune response to hepatitis b virus vaccine among people living with hiv: A meta-analysis

Meta-analysis: Hepatitis b vaccination in inflammatory bowel disease

A systematic review of immunogenicity, clinical efficacy and safety of human papillomavirus vaccines in people living with the human immunodeficiency virus

Efficacy and safety of human papillomavirus vaccination in hiv-infected patients: A systematic review and meta-analysis

Influenza vaccines in immunosuppressed adults with cancer

A systematic review of safety and immunogenicity of influenza vaccination strategies in solid organ transplant recipients

Is rheumatoid arthritis associated with reduced immunogenicity of the influenza vaccination? A systematic review and meta-analysis

Alternative-dose versus standard-dose trivalent influenza vaccines for immunocompromised patients: A meta-analysis of randomised control trials

Clinical efficacy and safety of high dose trivalent influenza vaccine in adults and immunosuppressed populations-A systematic review and meta-analysis

Immune response to influenza and pneumococcal vaccines in adults with inflammatory bowel disease: A systematic review and metaanalysis of 1429 patients

Immunogenicity of the influenza vaccine in multiple sclerosis patients: A systematic review and meta-analysis

Influenza vaccination in cancer patients receiving immune checkpoint inhibitors: A systematic review

A systematic review and metaanalysis of antirheumatic drugs and vaccine immunogenicity in rheumatoid arthritis

Vaccine response following anti-cd20 therapy: A systematic review and meta-analysis of 905 patients

Influenza vaccination for hiv-positive people: Systematic review and network meta-analysis

Safety and efficacy of early vaccination with live attenuated measles vaccine for hematopoietic stem cell transplant recipients and solid organ transplant recipients

Immunogenicity and safety of the measles vaccine in hiv-infected children: An updated systematic review

Immunogenicity, safety and tolerability of anti-pneumococcal vaccination in systemic lupus erythematosus patients: An evidence-informed and prisma compliant systematic review and meta-analysis

Efficacy, immunogenicity, and evidence for best-timing of pneumococcal vaccination in splenectomized adults: A systematic review

The effect of immunosuppressive agents on immunogenicity of pneumococcal vaccination: A systematic review and meta-analysis

Systematic review and meta-analysis of herpes zoster vaccine in patients with ckd

A systematic literature review of the recombinant subunit herpes zoster vaccine use in immunocompromised 18-49 year old patients

Immunogenicity and duration of protection after yellow fever vaccine in people living with human immunodeficiency virus: A systematic review

Vaccination among hiv-infected, hiv-exposed uninfected and hiv-uninfected children: A systematic review and meta-analysis of evidence related to vaccine efficacy and effectiveness

Immune response to vaccination in children and young people with inflammatory bowel disease: A systematic review and meta-analysis

Immunogenicity and safety of routine vaccines in children and adolescents with rheumatic diseases on immunosuppressive treatment-A systematic review

Immune response and safety of viral vaccines in children with autoimmune diseases on immune modulatory drug therapy

A practical approach for vaccinations including COVID-19 in autoimmune/autoinflammatory rheumatic diseases: A non-systematic review

Recommendations for vaccination in multiple myeloma: A consensus of the european myeloma network

Serum neutralization of SARS-CoV-2 omicron sublineages ba.1 and ba.2 in patients receiving monoclonal antibodies

Limited available evidence supports theoretical predictions of reduced vaccine efficacy at higher exposure dose

Host factors impact vaccine efficacy: Implications for seasonal and universal influenza vaccine programs

B-cell immunophenotyping to predict vaccination outcome in the immunocompromised-A systematic review

Optimize prime/boost vaccine strategies: Trained immunity as a new player in the game

Funding: This research received no external funding.

Data Availability Statement: Data supporting this review are available in the reference section.

The author declares no conflict of interest.