Despite prioritization of immunocompromised individuals within COVID-19 vaccine protocols, this population remains vulnerable to adverse effects of SARS-CoV-2 infection, including high morbidity and mortality. |
Patients with various immunocompromising conditions exhibit diverse responses to SARS-CoV-2 infection, and available vaccines elicit lower immune responses, particularly in solid organ transplant recipients. |
Additional COVID-19 vaccine doses may enhance vaccine effectiveness and protect against emerging SARS-CoV-2 variants. |
Continued investigation of COVID-19 vaccine dosing and intervals, heterologous vaccination regimens, and breadth of coverage of emerging variants is needed to optimize vaccination recommendations to protect this vulnerable population. |
Introduction
Vaccine | Characteristics | Dosing | Reported populations |
---|---|---|---|
Encodes the full length of the SARS-CoV-2 spike, modified by two proline mutations locking it in a prefusion conformation | 2 doses at a 21-day interval Third dose ≥ 28 days after dose 2 in immunocompromised individuals or solid organ transplant recipients 5 years and older Booster dose ≥ 5 months after primary series in individuals 12 years and older (18 and older for heterologous booster; same interval and dose) | 5 years and older Healthy or with stable chronic medical conditions (e.g., HIV, HBV, HCV infection)a | |
LNP-encapsulated and expressing the prefusion-stabilized spike | 2 doses at a 1-month interval Third dose ≥ 1 month after dose 2 in immunocompromised individuals or solid organ transplant recipients Booster dose ≥ 5 months after primary series (same interval and dose for heterologous booster) | 18 years and older In a medically stable condition |
Methods
Outcomes in Specific Immunocompromised Conditions
Malignancy
COVID-19 Characteristics
Vaccination Response
Reference | Country | Population | Men, % | Median age, years | Therapeutic regimena | Vaccine | Timing of serology assessment | Immunoassays | Antibody response | Vaccine safety |
---|---|---|---|---|---|---|---|---|---|---|
Hematologic malignancies | ||||||||||
Agha et al. [43] | USA | Patients with various hematologic malignancies (n = 67); most commonly MM (43%) | 52 | 71 | Cancer-directed therapy within 3 months of treatment Observation: 57% Active treatment: 43% | BNT162b2 mRNA-1273 | PD2 (time period NR) | IgG-anti-spike protein levels | 54% (PD2) | NR |
Bird et al. [44] | UK | Patients with MM (n = 93) | 59 | 67 | On therapy: 71% Most common therapy Immunomodulatory drug: 47% PI: 19% Steroid: 45% Anti-CD38 mAb: 23% Other: 11% | BNT162b2 AZ1222 | ≥ 21 days PD1 | IgG-anti-spike protein levels | 56% (PD1) | NR |
Herishanu et al. [45] | Israel | Patients with CLL (n = 167) | 67 | 71 | Protocol of currently treated patients BTKi: 67% Venetoclax ± anti-CD20 mAb: 29% Other: 4% | BNT162b2 | 2–3 weeks PD2 | IgG-anti-spike protein levels | 40% (PD2) | Mild local reactions: 31% PD1; 34% PD2 (most commonly injection site pain) Mild systemic events: 13% PD1; 23% PD2 (most commonly weakness) No significant differences in AE rates between patients actively treated vs. not actively treated at time of vaccination |
Harrington et al. [46] | UK | Patients with myeloproliferative neoplasms (n = 21) | 33 | 58 | Peg-IFN: 19% Surveillance: 33% Hydroxycarbamide: 19% Ruxolitinib: 29% | BNT162b2 | 21 days PD1 | IgG-anti-spike protein levels Neutralizing antibodies Cell response | 86% (PD1) | Localized inflammation: 57% Systemic events: 48% |
Solid tumor malignancies | ||||||||||
Barrière et al. [47] | France | Patients with solid tumors (n = 122); HV (n = 29) | 53 | 69 | Chemotherapy ± targeted therapy: 86% | BNT162b2 | 3–4 weeks PD2 | IgG-anti-spike protein levels | 48% (PD1) 95% (PD2) | No SAE reported |
Palich et al. [48] | France | Patients with solid tumors (n = 110), which was most commonly breast (34%); HV (n = 25) | 40 | 66 | Chemotherapy: 35% Targeted therapy: 24% Immunotherapy: 16% Hormonal therapy: 15% Radiotherapy: 6% Surveillance: 16% | BNT162b2 | 4 weeks PD1 | IgG-anti-spike protein levels | 58% (PD1) | NR |
Chronic inflammatory diseases | ||||||||||
Geisen et al. [52] | Germany | Patients with CID (n = 26); HVs (n = 42) | 36 | 50.5 | Biological DMARD: 77% Conventional DMARD: 31% Corticosteroid: 27% | BNT162b2 mRNA-1273 | 7 days PD2 | IgG-anti-spike protein levels Neutralizing antibodies | 87% (PD2) | Although side effects were comparable in study groups, patients with CID had marginal propensity towards mild AEs vs. HVs |
Braun-Moscovici et al. [53] | Israel | Patients with CID (n = 264 vaccinated); most commonly RA (37%) | 24 | 57.6 | Biological DMARD: 67% Conventional DMARD: 61% Colchicine: 0.2% Nintedanib: 0.1% Corticosteroid: 35% | BNT162b2 | 4–6 weeks PD2 | IgG-anti-spike protein levels | 86% (PD2) | Local reactions: 58% Fatigue: 30% Myalgia: 12% Headache: 20% Low-grade fever: 3% |
Deepak et al. [54] | USA | Patients with CID (n = 133) compared with immunocompetent controls (n = 53); most commonly IBD (32%) and RA (29%) | 26 | 45.5b | Biologic therapy: 59% Conventional DMARD: 63% Prednisone: 13% Janus kinase inhibitors: 8% NSAID: 20% No immunosuppression: 7% | BNT162b2 mRNA-1273 | Within 20 days PD2 | IgG-anti-spike protein levels Neutralizing antibodies | 89% (PD2) | NR |
Boyarsky et al. [55] | USA | Patients with rheumatic and musculoskeletal diseases (n = 123); most commonly inflammatory arthritis (28%) | 5 | 50 | None: 28% Conventional DMARD: 19% Biologic DMARD: 14% Corticosteroid monotherapy: 3% Combination therapy: 37% | BNT162b2 mRNA-1273 | Median 22 days PD1 | IgG-anti-spike protein levels | 74% (PD1) | NR |
Wong et al. [56] | USA | IBD (n = 48) | 48 | 35.2 (mean) | Biologics: 85% Oral corticosteroid: 6% Non therapy: 10% | BNT162b2 mRNA-1273 | NR | IgG-anti-spike protein levels | 67% (PD1) 100% (PD2) | NR |
Hemodialysis | ||||||||||
Schrezenmeier et al. [61] | Germany | Dialysis patients with stage 5 CKD (vaccinated, n = 36; unvaccinated n = 18); controls (n = 44) | 69 | 74 | NR | BNT162b2 | 1–10 weeks PD2 | IgG-anti-spike protein levels Neutralizing antibodies Cell response | 56% (1 week PD2) 89% (3 week PD2) | NR |
Goupil et al. [62] | Canada | Hemodialysis patients (n = 154); controls (n = 40)b | 63 | 70–76 (mean) | Immunosuppressive medications: 16% | BNT162b2 | 4 weeks PD1 | IgG-anti-spike protein levels | 43% (PD1; without prior SARS-CoV-2 infection) 84% (PD1; with prior SARS-CoV-2 infection) | NR |
Simon et al. [63] | Austria | Hemodialysis patients (n = 81); controls (n = 80) | 55 | 67 (mean) | RAAS inhibitor: 43% Immunosuppressants: 11% Vitamin D: 75% EPO: 91% | BNT162b2 | 3 weeks PD2 | Neutralizing antibodies | 53% (PD2) | No grade 4 AEs Hemodialysis patients had significantly fewer local and systemic events compared with control group |
Grupper et al. [64] | Israel | Hemodialysis patients (n = 56); HV (n = 95) | 75 | 74 | NR | BNT162b2 | PD2 | IgG-anti-spike protein levels | 96% (PD2) | NR |
Solid organ transplant | ||||||||||
Boyarsky et al. [75] | USA | SOT (n = 436) | 39 | 55.9 | Tacrolimus: 83% Corticosteroids: 54% Mycophenolate: 66% Azathioprine: 9% Sirolimus: 4% Everolimus: 2% | BNT162b2 mRNA-1273 | 17–24 days PD1 | Anti-spike protein levels | 17% (PD1) | NR |
Sattler et al. [76] | Germany | Kidney transplant (n = 39); HV (n = 39)c | 72 | 57.4 (mean) | CS + TAC + MMF: 56% CS + CyA + MMF: 33% mTORi + MMF ± CS: 8% mTORi + CyA + MMF: 3% CMV seropositive pre-treatment: 67% | BNT162b2 | 7–22 days PD2 | IgG-anti-spike protein levels Neutralizing antibodies Cell response | 3% (PD2) | NR |
Itzhaki Ben Zadok et al. [77] | Israel | Heart transplant (n = 42) | 83 | 61 | Calcineurin inhibitor: 81% mTOR inhibitor: 57% Oral steroid: 69% Anti-metabolite: 55% | BNT162b2 | 14–19 days PD2 | IgG-anti-spike protein levels | 15% (PD1) 49% (PD2) | Injection site pain: 71% Fatigue: 14% Arthralgia: 12% Myalgia: 10% |
Basic-Jukic and Ivo [78] | Croatia | Kidney transplant (< 50 patients received vaccination at the time of the report) | NR | NR | NR | BNT162b2 | N/A | NR | NR | NR |
Rusk et al. [79] | USA | Case report of patient with bilateral lung transplant (n = 1) | 0 | 55 | Various post-transplant medications including prednisone, mycophenolate, tacrolimus, and alendronate | BNT162b2 | 16 days PD2 | IgG-anti-spike protein levels | 0% (PD2) | Mild injection site pain PD1 and PD2 |
Grupper et al. [80] | Israel | Kidney transplant (n = 136); HV (n = 25) | 82 | 58.6 (mean) | Calcineurin inhibitor backbone: 90% Prednisone: 89% MMF: 76% Combination regimen: 79% Prednisone + tacrolimus + MMF: 60% | BNT162b2 | 10–20 days PD2 | IgG-anti-spike protein levels | 38% (PD2) | Local pain: 52% Systemic symptoms: 19% |
Rozen-Zvi et al. [81] | Israel | Kidney transplant (n = 308) | 64 | 57.5 | Mycophenolic acid: 73% Tacrolimus: 93% Cyclosporine: 8% mTOR inhibitor: 8% Corticosteroid: 8% Rituximab: 2% Antithymocyte globulin: 5% | BNT162b2 | 4 weeks PD2 | IgG-anti-spike protein levels | 36% (PD2) | NR |
Narasimhan et al. [82] | USA | Lung transplant (n = 73) | 74 | 65 | Anti-metabolite: 99% | BNT162b2 mRNA-1273 | Up to ~ 50 days PD2 | IgG-anti-spike protein levels Cell response | 25% (PD2) | NR |
Peled et al. [83] | Israel | Heart transplant (n = 77) | 65 | 62 | Mycophenolic acid: 75% Everolimus: 26% Prednisone: 75% | BNT162b2 | 3 weeks PD2 | IgG-anti-spike protein levels Neutralizing antibodies | 18% (PD2) | Local reaction: 49–56% (most commonly pain) Systemic event: 37–49% (most commonly fatigue or headache) |
Rincon-Arevalo et al. [84] | Germany | Kidney transplant (n = 40); HV (n = 35)d | 70 | 62 | MMF: 98% Steroid: 93% Calcineurin inhibitor: 93% | BNT162b2 | 7 days PD2 | IgG-anti-spike protein levels Neutralizing antibodies Cell response | 2.5% (PD2) | NR |
HIV | ||||||||||
Levy et al. [94] | Israel | PLWH (n = 143); HV (n = 261) | 92 | 49.8 (mean) | ART: 100% | BNT162b2 | 2–3 weeks PD2 | IgG-anti-spike protein levels Neutralizing antibodies | 97% (PD2) | Local reaction: 26–41% (most commonly mild pain) Systemic event: 20–48% (most commonly fatigue and headache PD1 and fatigue and fever PD2) |
Chronic Inflammatory Diseases
COVID-19 Characteristics
Vaccination Response
Hemodialysis
COVID-19 Characteristics
Vaccination Response
Solid Organ Transplant Recipients
COVID-19 Characteristics
Vaccination Response
HIV
COVID-19 Characteristics
Vaccination Response
Additional COVID-19 Vaccine Doses for Immunocompromised Individuals
Country or region | Issuing body | Date of recommendation | Recommendation |
---|---|---|---|
Government of France | April 11, 2021 | Third dose 4 weeks PD2 in severely immunocompromised individuals | |
Government of France | January 28, 2022 | Administration of a fourth dose in severely immunocompromised individuals within 3 months of the third dose | |
Israel [100] | December 30, 2021 | Fourth dose in individuals who have undergone organ or stem cell transplants, with hematologic cancers, autoimmune diseases, and who are receiving specific immunosuppressive medications Those with breast, lung, or colon cancer do not qualify | |
Global [96] | WHO | October 26, 2021 | Additional dose recommended in moderately to severely immunocompromised individuals 1–3 months after the primary series. This recommendation applies to individuals with active cancer, solid organ and stem cell transplant recipients, individuals with immunodeficiency, HIV, and those receiving immunosuppressive therapies Homologous additional doses are recommended, but heterologous platforms may be considered because of vaccine supply and access |
USA [97] | CDC | February 17, 2022 | Individuals 5–11 years old who are moderately or severely immunocompromised should receive a primary series of three doses of BNT162b2, with the second dose given 3 weeks after the first dose and the third dose given ≥ 4 weeks after the second dose; a fourth dose is not recommended at this time Individuals 12 years and older (for BNT162b2) and 18 years and older (for mRNA-1273) who are moderately or severely immunocompromised should receive a third dose ≥ 4 weeks after receiving their second dose; a booster dose ≥ 3 months after the third dose is recommended; mRNA COVID-19 vaccines are preferred This recommendation extends to individuals receiving cancer treatment, who have received an organ transplant and are using immunosuppressive therapies, who received a stem cell transplant in the past 2 years or are taking immunosuppressive therapies, with moderate or severe primary immunodeficiency, with advanced or untreated HIV infection, or receiving active treatment with high-dose corticosteroids or other immunosuppressive therapies |
EU [101] | EMA | October 4, 2021 | An additional dose of BNT162b2 or mRNA-1273 may be given to individuals with severely weakened immune systems ≥ 28 days after the second dose |
MHRA | September 9, 2021 | One dose of BNT162b2 may be administered as a third dose ≥ 8 weeks after the second dose of an mRNA or adenovirus-vectored COVID-19 vaccine if the potential benefits are greater than any potential risks | |
UK Health Security Agency | February 11, 2022 | For those 12 years and older, a reinforcing dose 3 months after the third dose is recommended |
Discussion
Vaccine | Clinical trial identifier | Details | Status |
---|---|---|---|
BNT162b2 | NCT04952766 | Phase 4 study assessing humoral response against SARS-CoV-2 after vaccination in immunocompromised adults compared with healthy volunteers | Recruiting (estimated primary completion March 2022) |
BNT162b2 | NCT04895982 | Phase 2 study assessing a three-dose schedule in immunocompromised children and adults | Recruiting |
BNT162b2 | NCT04969601 | Phase 1/2 study assessing a two-dose schedule in children 1–15 years of age with acute leukemia and in their siblings (12–15 years of age) | Recruiting (estimated primary completion May 2022) |
BNT162b2 mRNA-1273 | NCT04805125 | Phase 3 study using Swiss cohorts of immunocompromised patients to assess the comparative effectiveness and safety of BNT162b2 and mRNA-1273 | Ongoing (estimated completion July 2022) |
BNT162b2 | NCT04844489 | Study to assess the humoral and cellular responses to vaccination against SARS-CoV-2 variants in immunocompromised individuals | Recruiting |
mRNA-1273 | NCT04847050 | Phase 2 study assessing the safety and immunogenicity of vaccination in adults with hematologic malignancies, various regimens of immunosuppression, and in participants with solid tumors on PD1/PDL1 inhibitor therapy | Recruiting (estimated primary completion June 2023) |