key: cord-0276951-bc6nxteb
authors: Di Fusco, M.; Lin, J.; Vaghela, S.; Lingohr-Smith, M.; Nguyen, J. L.; Scassellati Sforzolini, T.; Judy, J.; Cane, A.; Moran, M. M.
title: COVID-19 vaccine effectiveness among immunocompromised populations: a targeted literature review of real-world studies
date: 2021-12-31
journal: nan
DOI: 10.1101/2021.12.29.21268511
sha: 191fe2caa69f49f525d00a9c21d2f703cbd3e0de
doc_id: 276951
cord_uid: bc6nxteb

Introduction: From July through October of 2021, several countries issued recommendations for increased COVID-19 vaccine protection for individuals with one or more immunocompromised (IC) conditions. It is critically important to understand the vaccine effectiveness (VE) of COVID-19 vaccines among IC populations as recommendations are updated over time in response to the evolving COVID-19 pandemic. Areas covered: A targeted literature review was conducted to identify real-world studies that assessed COVID-19 VE in IC populations between December 2020 and September 2021. A total of 10 studies from four countries were identified and summarized in this review. Expert opinion/commentary: VE of the widely available COVID-19 vaccines, including BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), and ChAdOx1 nCoV-19 (Oxford/AstraZeneca), ranged from 64%-90% against SARS-CoV-2 infection, 73%-84% against symptomatic illness, 70%-100% against severe illness, and 63%-100% against COVID-19-related hospitalization among the fully vaccinated IC populations included in the studies. COVID-19 VE for most outcomes in the IC populations included in these studies was lower than in the general populations. These findings provide preliminary evidence that the IC population requires greater protective measures to prevent COVID-19 infection and associated illness, hence should be prioritized while implementing recommendations of additional COVID-19 vaccine doses.

As of September 30, 2021, approximately 45% of the worldwide population had received at least one dose of a coronavirus disease 2019 (COVID-19) vaccine [1] . Scientific evidence gained from real-world studies conducted in multiple countries is increasingly showing that widely available COVID-19 vaccines, including BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), and ChAdOx1 nCoV-19 (Oxford/AstraZeneca), are effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, symptomatic COVID-19 illness, and COVID-19-related hospitalization and death [2, 3] . Such findings from real-world studies are generally consistent with the efficacy results of the randomized clinical trials (RCTs) of these vaccines [4] [5] [6] [7] . Vaccine efficacy in clinical trials and vaccine effectiveness (VE) measured in real-world studies both calculate the risk of disease among vaccinated and unvaccinated individuals and the percentage reduction in risk of disease among vaccinated individuals relative to unvaccinated individuals; VE equates to the reduction in disease occurrence for those who are vaccinated (i.e., a VE of 85% = an 85% reduction in disease occurrence among the vaccinated) [8] .

From July through October of 2021, several countries across the world issued recommendations for increased COVID-19 vaccine protection for individuals with one or more immunocompromised (IC) conditions; many of these recommendations also included other subpopulations (e.g., elderly) [9] . IC individuals are generally defined as those with suppressed immunity resulting from health conditions (e.g., organ transplant, malignancy, rheumatological condition, human immunodeficiency virus [HIV] infection, etc.) and/or with active usage of immunosuppressive medications [10] . These recommendations were informed by real-world studies of IC populations, who were largely excluded from the RCTs of the COVID-19 vaccines COVID-19-related hospitalization, VE for the IC populations tended to be lower than that observed in the general population [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] .

As new COVID-19 vaccine recommendations are implemented and updated over time in response to the evolving COVID-19 pandemic, it is necessary to rapidly and more comprehensively understand the effectiveness of COVID-19 vaccines in IC populations. From a policy perspective, such information could provide decision makers with the data to help to fill vaccine coverage gaps and instill greater protective measures towards the IC population, measures such as additional dose/booster prioritization. This objective has become even more critical given the continuing risk of emergence of more transmissible variants (i.e., Omicron).

Towards, this objective, in this review, we have summarized the findings of real-world studies that have assessed COVID-19 VE in IC populations.

The research question and study eligibility criteria were developed based on the Population, Intervention, Comparator, Outcomes (PICO) framework [28] . The research question was, what is the reported COVID-19 VE in IC populations? IC populations were defined according to the definitions used in the individual studies. The interventions assessed were any of the widely available COVID-19 vaccines in the world. The outcomes explored included COVID-19 VE against SARS-CoV-2 infection, symptomatic COVID-19 illness, severe COVID-19 illness, and COVID-19-related hospitalization/death. We targeted real-world observational studies, either cross-sectional or longitudinal in design, conducted in any country that assessed these outcomes and reported calculated VE estimates. Studies that evaluated vaccine efficacy in the context of a clinical trial or immunogenicity were not included in this review.

The best practice in systematic literature reviews is to prioritize searches and to include studies that are peer reviewed and published [29] . Given that the interventions (i.e, COVID-19 vaccines), in the scope of this review were recently introduced, and that there has been a high influx of COVID-19 research being posted on pre-print servers, we included both peer-reviewed . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 31, 2021. ; https://doi.org/10.1101/2021.12.29.21268511 doi: medRxiv preprint and non-peer-reviewed preprint studies. While this approach strengthens the comprehensiveness of this review, the author team recognizes the potential limitations in the reproducibility of the review and the quality of the collected evidence base.

Based on the above, a targeted search was performed using PubMed and the preprint servers, medRxiv and Khub, to identify real-world studies that assessed COVID-19 VE in IC populations between December 2020 and September 30, 2021 (inclusive). The following list of terms was generated and searched across all study fields: "COVID-19", "SARS-CoV-2", "vaccine effectiveness", and "immunocompromised". To maximize the scope of the search, no search terms were included for interventions or outcomes. All studies found written in the English language, without restrictions of countries, but with reported COVID-19 VE against SARS-CoV-2 infection, symptomatic COVID-19 illness, severe COVID-19 illness, and/or COVID-19-related hospitalization/death were examined for inclusion. Titles, abstracts, and full study contents publicly available were screened by one independent reviewer (MLS). Since there was only one reviewer, random selection and inter-rater reliability scores (e.g., kappa) were not determined. 7 US study, by Polinski et al. [ 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint in both studies, patients also had maintenance immunosuppressive medication usage. In the other six studies [17, 18, 19, 21, 22, 23, 24] , IC populations were defined according to various IC conditions; only two IC conditions, organ transplant and immunosuppressive medication usage, were common across the six studies. Other IC conditions common across multiple studies included HIV infection in five studies, active cancer in four, immunodeficiencies in four, rheumatoid arthritis/other related inflammatory conditions in three; chronic kidney disease (CKD) was included in only one study. In these six studies, some patient groups with other IC diseases that were not specifically defined may have been captured among those grouped with immunosuppressive medication usage.

The sample sizes of the IC populations were reported in eight studies and are summarized in Table 3 . Sample sizes included 16,315 (22% of overall study population) in Young-Xu et al. [17] , 254 (21% of overall study population) in Tenforde et al. [18] , 652 (21% of overall study population) in Tenforde et al. [19] [10] . In this study, the IC represented 6.8% (N=26,720) of the overall vaccinated population and 6.9% (N=105,100) of the overall unvaccinated population; mean age of matched vaccinated and unvaccinated IC groups was 59 years, 60% were female, ethnicity/race was not reported, and approximately 41% resided in the South US region [21] .

Chemaitelly et al.

[27] conducted their study specifically in kidney transplant recipients who were on maintenance immunosuppressive medication; the study population (N=782) was in Qatar; median age of the vaccinated cohort was 52 years and 70% were male; the median age of the unvaccinated cohort was 49 years and 63% were male [27] . The incidence of breakthrough infections was 2.58% in those who were vaccinated compared to 4.74% among those who were unvaccinated (follow-up: 120 days after 14 days after 2 nd dose) [27]. Table 4 reports the details of the study outcome measures related to COVID-19 VE (i.e., outcome measures, controls, VE follow-up duration, VE calculations, and analysis methods), while Table 5 presents the reported VE estimates, including 95% confidence intervals (95% CI), against SARS-CoV-2 infection, symptomatic COVID-19 illness, severe COVID-19 illness, and COVID-19-related hospitalization across the studies included in this review. Figure 1 graphically presents COVID-19 VE in IC populations relative to overall study populations from those studies with such available data.

Seven studies (Young-Xu et al. [17] infection, which was 64% (95% CI: 57%-70%) in the IC population and 79% in both the overall (95% CI: 77%-80%) and non-IC (95% CI: 78%-81%) populations. ChAdOx1 nCoV-19 VE against symptomatic COVID-19 illness, which was 75% (95% CI: 19%-92%) among the IC population, 78% (95% CI:70%-84%) among the overall population 16-64 years of age, and 76% (95% CI: 59%-86.5%) among the overall population ≥65 years of age. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 31, 2021. ; https://doi.org/10.1101/2021.12.29.21268511 doi: medRxiv preprint to 85% (95% CI: 36%-96.5%) and 84% (95% CI: 31%-96%) at ≥42 days and ≥56 days, respectively.

Four studies assessed VE against COVID-19-related hospitalization in IC populations; three Tenforde et al. [18] , mRNA VE against COVID-19-related hospitalization was 63% (95% CI: 21%-83%) in the IC population, 87% (95% CI: 81%-91%) in the overall study population, and 91% (95% CI: 86%-95%) in the non-IC population. The second CDC study by Tenforde et al. [19] , which included nearly three times more hospitalized patients, had similar findings, with mRNA VE against COVID-19 related hospitalization reported at 63% (95% CI: 44%-76%) in the IC population, 86% (95% CI: 82%-88%) in the overall study population, and 90% (95% CI: 87%-92%) in the non-IC population over the full surveillance period (March-July 2021).

Although overall VE in the IC population was lower than that in the non-IC population, it was sustained over the two study periods (March-May: 2-12 weeks and June-July: 13-24 weeks post full vaccination), which was consistent to the sustained VE observed in the overall population [19] . Dagan in the IC population compared to 81% (95% CI: 79%-84%) in the overall study population and 83% (95% CI: 80%-85%) in the non-IC population [21].

This targeted literature review of 10 real-world studies conducted in four different countries gives an early view of COVID-19 VE in IC populations. Among the fully vaccinated IC populations included in the studies, VE of widely available COVID-19 vaccines ranged from 64% to 90% against SARS-CoV-2 infection, 73% to 84% against symptomatic COVID-19

illness, 70% to 100% against severe COVID-19 illness, and 63% to 100% against COVID-19-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 31, 2021. ; https://doi.org/10.1101/2021.12.29.21268511 doi: medRxiv preprint related hospitalization. COVID-19 VE for most outcomes in the IC populations included in these studies was lower than in the general populations, in which VE ranged from 79% to 95% against SARS-CoV-2 infection, from 76% to 96% against symptomatic COVID-19 illness, and from 81% to 92% against COVID-19-related hospitalization. Important to consider when interpreting the reported VE estimates for the IC populations are the accompanying confidence intervals, ranges of which were wider than those reported among the general populations across studies; such findings are related to the smaller sample sizes of the IC populations, but also stress the population. This test-negative designed study utilized data from the VISION network, a CDC collaboration with seven US healthcare systems and research centers, including 187 hospitals in nine US states; it included over 89,000 COVID-19-associated hospitalizations of IC and immunocompetent adults [34] . The IC population in this study was defined as individuals with a diagnosis of solid malignancy, hematologic malignancy, rheumatologic or other inflammatory disorders, other intrinsic immune conditions or immunodeficiencies, or organ or stem cell transplants; immunosuppressive medication usage was not included in this study since the data were not available [34] . Embi et al. [34] reported a COVID-19 mRNA VE against COVID-19associated hospitalization of 77% (95% CI: 74%-80%) among 10,564 fully vaccinated IC individuals during January 17 through September 5, 2021, [34] and a VE of 90% (95% CI: 89%-91%) among those considered immunocompetent [34] . Additionally, Embi et al. [34] assessed COVID-19 mRNA VE before and during Delta variant predominance in the US; they consistently found a lower VE against COVID-19-associated hospitalization among the IC compared to the immunocompetent before (76%; 95% CI: 69%-81% versus 91%; 95% CI: 90%-93%) and during Delta variant predominance (79%; 95% CI: 74%-83% versus 90%; 95% CI: 89%-91%). COVID-19 mRNA VE in the IC population relative to the immunocompetent population did not significantly differ by age group (18-64 years of age and aged ≥65 years) or mRNA vaccine type, nor by time periods of assessment [34] .

In the four studies reviewed herein that estimated VE against COVID-19-related hospitalization, VE ranged from 63% to 100% in the IC populations and 81% to 92% in the general populations [18, 19, 21, 22, 23] . Only Tenforde et al. [19] included a time period in which the Delta variant emerged as predominant; similar to the above findings of Embi et al. [34] , during emerging Delta variant predominance (June-July 2021), COVID-19 mRNA VE against COVID-19-associated hospitalization did not significantly change among the IC or the overall study population from the earlier study period of March-May 2021. Embi et al. [34] also performed subgroup analyses among the IC population, in which mRNA VE against COVID-19-related hospitalization was estimated between January 17 and September 5, 2021 in organ or stem cell transplant recipients at 59% (95% CI: 38%-73%), in those with solid malignancy at 79% (95% CI: 73%-84%), in those with hematologic malignancy at 74% (95% CI: 62%-83%), in those with intrinsic immune conditions or primary immunodeficiencies at 73% (95% CI: 66%-80%), and in those with . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint [36] , reported incidence rates of symptomatic COVID-19 illness in solid organ transplant recipients (N=2,151) and not a calculated VE; in those who were vaccinated the incidence rate was 0.065 per 1000/person days (95% CI: 0.024-0.17) and in those who were unvaccinated or partially vaccinated, the incidence rate was 0.34 per 1000/person days (95% CI: 0.26-0.44).

In a US real-world study of nearly 1.2 million people fully vaccinated with the BNT162b2 mRNA vaccine, over 212,000 (18%) individuals were designated as having an IC condition [37] .

This study utilized the broadest IC case algorithm of real-world studies to date, wherein 12 mutually exclusive IC conditions were identified (e.g., symptomatic HIV, solid/hematologic malignancy, organ transplant, rheumatologic/inflammatory condition, primary immunodeficiency, chronic kidney disease, usage of immunosuppressive/antimetabolite medication) [37] . Although this study did not directly measure VE, it reported the number of COVID-19 vaccine breakthrough infections following a second BNT162b2 dose between December 10, 2020 and July 8 th , 2021 [37] . The total number of breakthrough infections was low . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint

The copyright holder for this this version posted December 31, 2021. ; https://doi.org/10.1101/2021.12.29.21268511 doi: medRxiv preprint (N=978; 0.08%) but nearly 40% of cases occurred among the IC population, which only accounted for approximately 18% of the overall study population [37] . The calculated incidence rate of COVID-19 vaccine breakthrough infections was 2.6 times higher among the IC population than in the non-IC population (0.89 vs. 0.34 per 100 person-years) [37] . Moreover, approximately 60% (N=74 of 124) of the breakthrough infections that resulted in hospitalization and 100% (N=2 of 2) of those that resulted in inpatient death, occurred in the IC population [37] .

In this study, subgroup analyses of the 12 IC condition groups were also conducted; organ transplant recipients excluding bone marrow transplant had the highest incidence rate of breakthrough infections (3.66 per 100 person-years) [37] . Additionally, compared to the incidence rate among the overall IC population in this study, incidence rates of breakthrough infections were higher in those who had >1 IC condition, those with usage of antimetabolites, those with a primary immunodeficiency, those with a hematologic malignancy, and those with kidney disease [37] . The findings of this study underscore the need to standardize the definition of IC across research studies evaluating COVID-19 VE and to also conduct studies of specific IC patient groups, so that a risk stratification can be established across the overall IC population.

At the time this review was written, only 10 real-world studies, four of which were preprints without peer-review, were available that assessed COVID-19 VE in IC populations. Although our approach of including preprints for this targeted literature review strengthens the comprehensiveness of this review, we acknowledge the potential limitations in the reproducibility of this review and the quality of the collected evidence base. Moreover, of the 10 included studies, study designs, follow-up periods after full vaccination, IC definitions and IC populations, methods of computing VE, and adjustment for confounders significantly varied across these real-world studies. Hence, a comparison of study findings or a meta-analysis estimating the pooled VE for outcomes of interest was considered unfeasible. As discussed earlier, the most notable inconsistency across the studies summarized in this review, was the substantial variability in the definitions of IC populations. In this context, the COVID-19 VE estimates across these studies should be interpreted cautiously.

Additionally, the reviewed studies had limited follow-up after vaccination ranging from 7 days to 6.5 months. Four studies by Tenforde et al. [ [19] reported, albeit in a figure only, mRNA VE in the IC during March to May (Alpha variant predominance) and June to July (Delta variant emerging as predominant) 2021. The study period in Tenforde et al. [19] went through July 2021, which covered only the early period of Delta variant predominance in the US (approximately the first six weeks), and a Delta-specific VE was not reported [19] . As mentioned earlier, Embi et al. [34] did not observe a significant change in COVID-19 mRNA VE against COVID-19-associated hospitalization among IC or immunocompetent individuals during Delta variant predominance compared with an earlier time period. Altogether, the studies summarized in this review covered up to eight months after COVID-19 vaccines became available. Thus, waning COVID-19 vaccine protection remains relatively undescribed, particularly among the IC, and further followup studies are needed to better understand not only waning vaccine protection but also the impact of increased vaccine protection with an additional dose. Only a few studies performed subgroup analyses by IC condition groups or severity of IC conditions. The included studies were also from only four countries including the US, Israel, England, and Qatar. Therefore, study findings may not be generalizable to IC population in other countries, especially in countries where particular IC conditions are endemic to the region. While this review provides an early view of COVID-19 VE in IC populations, mostly as an aggregate group, further study is warranted.

As the COVID-19 pandemic continues across the world and if in the future, COVID-19 becomes endemic to societies, it may be of clinical utility to more consistently and precisely define IC populations across research studies evaluating COVID-19 VE. A consensus on defining IC condition groups will provide more useful evidence for policymakers and healthcare providers in the decision-making process when recommending and updating vaccination protocols and treating patients at high-risk for COVID-19. Across the studies included in this review, only two IC conditions, organ transplant and immunosuppressive medication usage, were common in the definitions of IC populations. Only a few studies included in this review focused on particular IC conditions and only one study included CKD as an IC condition. A consensus on the list of immunosuppressive medications to designate individuals as IC also needs to be developed.

Moreover, it may be useful to stratify overall IC populations into low-, medium-, and high-risk . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this this version posted December 31, 2021. ; https://doi.org/10.1101/2021.12.29.21268511 doi: medRxiv preprint patient groups for COVID-19 illness. This may also involve the identification of IC groups with comorbidities known to increase the risk for severe COVID-19 (e.g., older age, type 2 diabetes, obesity) [38, 39] and their risk stratification. Furthermore, individuals with IC conditions that are endemic to certain countries and regions that heighten the risk for COVID-19 illness may also need to be identified so that the necessary preventive and protective measures can be put in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. • In this review, we have summarized the findings of real-world studies that have assessed COVID-19 VE in IC populations.

• Among the fully vaccinated IC populations included in the reviewed studies, VE of widely available COVID-19 vaccines ranged from 64% to 90% against SARS-CoV-2 infection, 73%

to 84% against symptomatic COVID-19 illness, 70% to 100% against severe COVID-19 illness, and 63% to 100% against COVID-19-related hospitalization.

• VE for most outcomes in the IC populations included in these studies was lower than in the general populations, in which VE ranged from 79% to 95% against SARS-CoV-2 infection, from 76% to 96% against symptomatic COVID-19 illness, and from 81% to 92% against COVID-19-related hospitalization.

• Our summarized findings provide preliminary evidence that individuals who are IC require greater protective measures to prevent COVID-19 infection and associated illness; hence, should be prioritized while implementing recommendations of additional COVID-19 vaccine doses.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. reported that as of July 28, 2021, Delta was at low incidence in Qatar. however, only two such events occurred in the unvaccinated IC group and none in the vaccinated group.

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Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the aHR: Adjusted hazard ratio; CI: Confidence interval; COVID-19: Coronavirus disease 2019; IBD: Inflammatory bowel disease; IC: Immunocompromised; mRNA: messenger ribonucleic acid; OR: Odds ratio; NR: Not reported; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; yrs: Years; VE: Vaccine effectiveness CI: Confidence interval; COVID-19: Coronavirus disease

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