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Vaccination for the Prevention of Infection among Immunocompromised Patients: A Concise Review of Recent Systematic Reviews

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.


Introduction
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.

Materials and Methods
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.

Systematic Reviews of COVID-19 Vaccines
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.

Overview of Results
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].

Limitations of the Current Study
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.

Future Directions
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].

Conclusions
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.