
==== Front
J Clin Immunol
J Clin Immunol
Journal of Clinical Immunology
0271-9142
1573-2592
Springer US New York

38578389
1613
10.1007/s10875-023-01613-5
Original Article
COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report
http://orcid.org/0000-0002-7438-5471
McDonnell John mcdonnj@ccf.org
mcdonnell.jack@gmail.com

1
Cousins Kimberley 2
Younger M. Elizabeth M. 130
Lane Adam 34
Abolhassani Hassan 56
Abraham Roshini S. 78
Al-Tamemi Salem 9
Aldave-Becerra Juan Carlos 10
Al-Faris Eman Hesham 11
Alfaro-Murillo Alberto 12
AlKhater Suzan A. 1314
Alsaati Nouf 15
Doss Alexa Michelle Altman 16
Anderson Melissa 17
Angarola Ernestina 18
Ariue Barbara 19
Arnold Danielle E. 20
Assa’ad Amal H. 21
Aytekin Caner 22
Bank Meaghan 23
Bergerson Jenna R. E. 24
Bleesing Jack 34
Boesing John 25
Bouso Carolina 26
Brodszki Nicholas 27
Cabanillas Diana 28
Cady Carol 29
Callahan Meghan A. 30
Caorsi Roberta 31
Carbone Javier 32
Carrabba Maria 33
Castagnoli Riccardo 3435
Catanzaro Jason R. 36
Chan Samantha 37
Chandra Sharat 34
Chapdelaine Hugo 38
Chavoshzadeh Zahra 39
Chong Hey Jin 40
Connors Lori 41
Consonni Filippo 42
Correa-Jimenez Oscar 43
Cunningham-Rundles Charlotte 2
D’Astous-Gauthier Katherine 44
Delmonte Ottavia Maria 24
Demirdag Yesim Yilmaz 45
Deshpande Deepti R. 46
Diaz-Cabrera Natalie M. 47
Dimitriades Victoria R. 48
El-Owaidy Rasha 49
ElGhazali Gehad 50
Al-Hammadi Suleiman 51
Fabio Giovanna 33
Faure Astrid Schellnast 52
Feng Jin 53
Fernandez James M. 54
Fill Lauren 55
Franco Guacira R. 56
Frenck Robert W. 457
Fuleihan Ramsay L. 58
Giardino Giuliana 59
Galant-Swafford Jessica 60
Gambineri Eleonora 4261
Garabedian Elizabeth K. 62
Geerlinks Ashley V. 63
Goudouris Ekaterini 64
Grecco Octavio 56
Pan-Hammarström Qiang 5
Khani Hedieh Haji Khodaverdi 39
Hammarström Lennart 5
Hartog Nicholas L. 65
Heimall Jennifer 66
Hernandez-Molina Gabriela 67
Horner Caroline C. 68
Hostoffer Robert W. 55
Hristova Nataliya 69
Hsiao Kuang-Chih 707172
Ivankovich-Escoto Gabriela 73
Jaber Faris 53
Jalil Maaz 74
Jamee Mahnaz 75
Jean Tiffany 45
Jeong Stephanie 53
Jhaveri Devi 76
Jordan Michael B. 3477
Joshi Avni Y. 78
Kalkat Amanpreet 55
Kanarek Henry J. 79
Kellner Erinn S. 80
Khojah Amer 81
Khoury Ruby 34
Kokron Cristina M. 56
Kumar Ashish 34
Lecerf Kelsey 82
Lehman Heather K. 83
Leiding Jennifer W. 84
Lesmana Harry 85
Lim Xin Rong 86
Lopes Joao Pedro 87
López Ana Laura 88
Tarquini Lucia 89
Lundgren Ingrid S. 90
Magnusson Julieann 91
Marinho Ana Karolina B. B. 56
Marseglia Gian Luigi 34
Martone Giulia M. 83
Mechtler Annamaria G. 92
Mendonca Leonardo 5693
Milner Joshua D. 94
Mustillo Peter J. 95
Naderi Asal Gharib 96
Naviglio Samuele 97
Nell Jeremy 98
Niebur Hana B. 99
Notarangelo Luigi 24
Oleastro Matias 26
Ortega-López María Claudia 100
Patel Neil R. 101
Petrovic Gordana 102
Pignata Claudio 103
Porras Oscar 104
Prince Benjamin T. 95
Puck Jennifer M. 105
Qamar Nashmia 106
Rabusin Marco 97
Raje Nikita 17
Regairaz Lorena 107
Risma Kimberly A. 108
Ristagno Elizabeth H. 109
Routes John 110
Roxo-Junior Persio 111
Salemi Negin 112
Scalchunes Christopher 113
Schuval Susan J. 114
Seneviratne Suranjith L. 115
Shankar Ashwin 55
Sherkat Roya 112
Shin Junghee Jenny 116
Siddiqi Abeer 117
Signa Sara 31
Sobh Ali 118
Lima Fabiana Mascarenhas Souza 56
Stenehjem Kristen K. 101
Tam Jonathan S. 119
Tang Monica 120
Barros Myrthes Toledo 56
Verbsky James 110
Vergadi Eleni 121
Voelker Dayne H. 122
Volpi Stefano 12331
Wall Luke A. 124
Wang Christine 125
Williams Kelli W. 126
Wu Eveline Y. 127
Wu Shan Shan 128129
Zhou Jessie J. 131
Cook Alexandria 110
Sullivan Kathleen E. 15
Marsh Rebecca 34
1 grid.239578.2 0000 0001 0675 4725 Pediatric Allergy and Immunology, Cleveland Clinic Children’s Hospital, 9500 Euclid Ave/R3, Cleveland, OH 44195 USA
2 https://ror.org/04a9tmd77 grid.59734.3c 0000 0001 0670 2351 Clinical Immunology, Departments of Medicine and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY USA
3 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
4 https://ror.org/01e3m7079 grid.24827.3b 0000 0001 2179 9593 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
5 https://ror.org/056d84691 grid.4714.6 0000 0004 1937 0626 Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
6 grid.411705.6 0000 0001 0166 0922 Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
7 https://ror.org/003rfsp33 grid.240344.5 0000 0004 0392 3476 Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, USA
8 grid.261331.4 0000 0001 2285 7943 Dept of Pathology, The Ohio State Univ Wexner College of Medicine, Columbus, USA
9 https://ror.org/049xx5c95 grid.412855.f 0000 0004 0442 8821 Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman
10 Allergy and Clinical Immunology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru
11 https://ror.org/01m1gv240 grid.415280.a 0000 0004 0402 3867 Department of Internal Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
12 Department of Internal Medicine and Clinical Immunology, Hospital San Juan de Dios, San José, Costa Rica
13 https://ror.org/038cy8j79 grid.411975.f 0000 0004 0607 035X Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
14 grid.412131.4 0000 0004 0607 7113 King Fahd Hospital of University, Al-Khobar, Saudi Arabia
15 https://ror.org/01z7r7q48 grid.239552.a 0000 0001 0680 8770 Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA USA
16 https://ror.org/00qw1qw03 grid.416775.6 0000 0000 9953 7617 Division of Pediatric Allergy, Immunology, and Pulmonary Medicine, St. Louis Children’s Hospital, St. Louis, MO USA
17 grid.266756.6 0000 0001 2179 926X Division of Allergy Immunology Pulmonary and Sleep Medicine, Department of Pediatrics, Children’s Mercy Kansas City, University of Missouri-Kansas City, Kansas City, MO USA
18 Immunology and Histocompatibility Unit, Hospital C. G. Durand, Buenos Aires, Argentina
19 Department of Pediatrics, Division of Allergy and Immunology, Loma Linda Children’s Hospital, Loma Linda, CA USA
20 grid.48336.3a 0000 0004 1936 8075 Immune Deficiency-Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD USA
21 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA
22 grid.414136.5 Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children’s Health and Diseases Training and Research Hospital, Ankara, Turkey
23 grid.279863.1 0000 0000 8954 1233 Department of Internal Medicine, Louisiana State University Health Sciences Center, New Orleans, USA
24 grid.419681.3 0000 0001 2164 9667 Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Rockville, MD USA
25 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
26 grid.414531.6 0000 0001 0695 6255 Immunology Department, Hospital Nacional de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
27 https://ror.org/012a77v79 grid.4514.4 0000 0001 0930 2361 Department of Pediatric Immunology, Children’s Hospital, Lund University Hospital, Lund, Sweden
28 Immunology Unit-Hospital Sor María Ludovica, La Plata, Argentina
29 https://ror.org/0028g5429 grid.414657.5 0000 0004 0448 5762 Community Medical Center, Missoula, MT USA
30 https://ror.org/04679fh62 grid.419183.6 0000 0000 9158 3109 Lake Erie College of Osteopathic Medicine, Elmira, USA
31 grid.419504.d 0000 0004 1760 0109 Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
32 https://ror.org/0111es613 grid.410526.4 0000 0001 0277 7938 Immunology Department, Hospital General Universitario Gregorio Maranon, Madrid, Spain
33 https://ror.org/016zn0y21 grid.414818.0 0000 0004 1757 8749 Department of Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
34 https://ror.org/00s6t1f81 grid.8982.b 0000 0004 1762 5736 Pediatric Unit, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
35 https://ror.org/05w1q1c88 grid.419425.f 0000 0004 1760 3027 Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
36 https://ror.org/03v76x132 grid.47100.32 0000 0004 1936 8710 Section of Pulmonology, Allergy, Immunology and Sleep Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, CT USA
37 https://ror.org/005bvs909 grid.416153.4 0000 0004 0624 1200 Department of Clinical Immunology & Allergy, Royal Melbourne Hospital, Melbourne, VIC Australia
38 grid.511547.3 0000 0001 2106 1695 Clinical Immunology, Montreal Clinical Research Institute, Université de Montréal, Montreal, Canada
39 https://ror.org/034m2b326 grid.411600.2 Immunology and Allergy Department, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
40 grid.21925.3d 0000 0004 1936 9000 Division of Allergy and Immunology, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
41 https://ror.org/01e6qks80 grid.55602.34 0000 0004 1936 8200 Department of Medicine, Dalhousie University, Halifax, NS Canada
42 grid.413181.e 0000 0004 1757 8562 Centre of Excellence, Division of Pediatric Oncology and Hematology, Meyer Children’s Hospital IRCCS, Florence, Italy
43 https://ror.org/059yx9a68 grid.10689.36 0000 0004 9129 0751 Pediatric Pulmonology and Immunology Research Group, Universidad Nacional de Colombia, Bogotá, Colombia
44 grid.86715.3d 0000 0000 9064 6198 Department of Pediatric Clinical Immunology and Allergy, University of Sherbrooke, Sherbrooke, QC Canada
45 grid.266093.8 0000 0001 0668 7243 Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, CA USA
46 https://ror.org/01esghr10 grid.239585.0 0000 0001 2285 2675 Department of Pediatrics, Columbia University Medical Center, New York, NY USA
47 https://ror.org/032db5x82 grid.170693.a 0000 0001 2353 285X Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL USA
48 https://ror.org/05rrcem69 grid.27860.3b 0000 0004 1936 9684 Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, University of California Davis Health, Sacramento, CA USA
49 https://ror.org/00cb9w016 grid.7269.a 0000 0004 0621 1570 Pediatric Allergy, Immunology and Rheumatology Unit, Children’s Hospital, Ain Shams University, Cairo, Egypt
50 grid.43519.3a 0000 0001 2193 6666 Abu Dhabi and College of Medicine and Health Sciences, Sheikh Khalifa Medical City, Union71 - Purehealth, United Arab Emirates University, Al Ain, United Arab Emirates
51 https://ror.org/01xfzxq83 grid.510259.a 0000 0004 5950 6858 College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
52 Hospital Sor María Ludovica, La Plata, Argentina
53 https://ror.org/04a9tmd77 grid.59734.3c 0000 0001 0670 2351 Clinical Immunology, Department of Medicine at Icahn School of Medicine at Mount Sinai, New York, NY USA
54 grid.239578.2 0000 0001 0675 4725 Department of Allergy & Clinical Immunology, Cleveland Clinic Foundation, Cleveland, OH USA
55 grid.241104.2 0000 0004 0452 4020 University Hospitals, Cleveland Medical Centers, Cleveland, OH USA
56 https://ror.org/036rp1748 grid.11899.38 0000 0004 1937 0722 Division of Clinical Immunology and Allergy, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
57 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Division of Infectious Disease, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
58 https://ror.org/01esghr10 grid.239585.0 0000 0001 2285 2675 Division of Pediatric Allergy, Immunology and Rheumatology, Columbia University Medical Center, New York, NY USA
59 grid.4691.a 0000 0001 0790 385X Pediatric Section, Department of Translational Medical Science, Federico II University, Naples, Italy
60 https://ror.org/016z2bp30 grid.240341.0 0000 0004 0396 0728 Division of Allergy & Clinical Immunology, National Jewish Health, Denver, CO USA
61 https://ror.org/04jr1s763 grid.8404.8 0000 0004 1757 2304 Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
62 grid.280128.1 0000 0001 2233 9230 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA
63 https://ror.org/02grkyz14 grid.39381.30 0000 0004 1936 8884 Pediatric Hematology and Oncology, Children’s Hospital, Western University, London, ON Canada
64 https://ror.org/03490as77 grid.8536.8 0000 0001 2294 473X Division of Allergy and Clinical Immunology – IPPMG, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil
65 grid.17088.36 0000 0001 2150 1785 Helen DeVos Children’s Hospital Division of Allergy and Immunology, Michigan State University College of Human Medicine, East Lansing, MI USA
66 grid.239552.a 0000 0001 0680 8770 Division of Allergy and Immunology, Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA 19104 USA
67 https://ror.org/00xgvev73 grid.416850.e 0000 0001 0698 4037 Immunology and Rheumatology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
68 grid.4367.6 0000 0001 2355 7002 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO USA
69 grid.107984.3 Department of Clinical Immunology and Stem Cell Bank, University Hospital Álexandrovska, Sofia, Bulgaria
70 Starship Child Health, Auckland, New Zealand
71 https://ror.org/03b94tp07 grid.9654.e 0000 0004 0372 3343 Department of Paediatrics: Child and Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
72 Clinical Immunogenomics Research Consortium Australasia, Sydney, Australia
73 grid.440331.1 0000 0004 0570 8251 Department of Pediatrics, Caja Costarricense de Seguro Social, Hospital Nacional de Niños, San José, Costa Rica
74 https://ror.org/0244gtc77 grid.428147.c Advanced ENT & Allergy, Medford, NJ USA
75 https://ror.org/034m2b326 grid.411600.2 Pediatric Nephrology Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
76 https://ror.org/0130jk839 grid.241104.2 0000 0004 0452 4020 Allergy Immunology Associates Inc., Allergy Immunology Fellowship Associate Program Director University Hospitals of Cleveland Medical Center, Cleveland, USA
77 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
78 https://ror.org/02qp3tb03 grid.66875.3a 0000 0004 0459 167X Mayo Clinic Children’s Center, Pediatric and Adult Allergy and Immunology, Mayo Clinic, Rochester, MN USA
79 Kanarek Allergy Asthma Immunology, Overland Park, KS USA
80 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH USA
81 https://ror.org/01xjqrm90 grid.412832.e 0000 0000 9137 6644 Department of Pediatrics, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
82 https://ror.org/003rfsp33 grid.240344.5 0000 0004 0392 3476 Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children’s Hospital and The Ohio State University College of Medicine, Columbus, OH USA
83 https://ror.org/01y64my43 grid.273335.3 0000 0004 1936 9887 Department of Pediatrics, University of Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY USA
84 https://ror.org/00za53h95 grid.21107.35 0000 0001 2171 9311 Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD USA
85 https://ror.org/02x4b0932 grid.254293.b 0000 0004 0435 0569 Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, OH USA
86 https://ror.org/032d59j24 grid.240988.f 0000 0001 0298 8161 Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore, 308433 Singapore
87 grid.67105.35 0000 0001 2164 3847 UH Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, OH USA
88 Unidad de Inmunología E Histocompatibilidad, Hospital Dr. Carlos G. Durand, Buenos Aires, Argentina
89 grid.7010.6 0000 0001 1017 3210 Section of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region, 60020 Ancona, Italy
90 https://ror.org/02m0cd826 grid.428896.9 Pediatric Infectious Diseases, St. Luke’s Children’s Hospital, Boise, ID USA
91 grid.430922.e 0000 0004 5902 9238 USIDNET, Towson, MD USA
92 https://ror.org/01y64my43 grid.273335.3 0000 0004 1936 9887 University of Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY USA
93 grid.517844.b 0000 0004 0509 8924 Center for Rare and Immunological Diseases, Hospital 9 de Julho - Rede DASA, São Paulo, Brazil
94 https://ror.org/01esghr10 grid.239585.0 0000 0001 2285 2675 Department of Pediatrics, Columbia University Irving Medical Center, New York, NY USA
95 https://ror.org/003rfsp33 grid.240344.5 0000 0004 0392 3476 Division of Allergy and Immunology, Department of Pediatrics, Nationwide Children’s Hospital and The Ohio State University Wexner College of Medicine, Columbus, OH USA
96 grid.42505.36 0000 0001 2156 6853 Allergy & Immunology, Keck School of Medicine of USC, Los Angeles, CA USA
97 grid.418712.9 0000 0004 1760 7415 Pediatric Hematology-Oncology, Institute for Maternal and Child Health IRCCS “Burlo Garofolo,”, Trieste, Italy
98 grid.1006.7 0000 0001 0462 7212 Department of Infection and Tropical Medicine, Newcastle Upon Tyne Hospitals National Health Service (NHS) Foundation Trust and Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
99 grid.414033.1 Department of Pediatrics, University of Nebraska Medical Center, Children’s Hospital and Medical Center, Omaha, NE USA
100 https://ror.org/05at6sw30 grid.488465.3 Division of Pediatrics, Allergy and Clinical Immunology, Hospital Infantil Universitario de San José, Bogotá, Colombia
101 https://ror.org/03wa2q724 grid.239560.b 0000 0004 0482 1586 Department of Pediatrics, Children’s National Hospital, Washington, D.C. USA
102 Department of Clinical Immunology and Allergology, Institute of Mother and Child Health, Belgrade, Serbia
103 grid.4691.a 0000 0001 0790 385X Pediatrics, Department of Translational Medical Sciences, Federico II University, Naples, Italy
104 https://ror.org/04skaq459 grid.440331.1 0000 0004 0570 8251 Pediatric Immunology and Rheumatology Department, Hospital Nacional de Niños “Dr. Carlos Sáenz Herrera,”, San José, Costa Rica
105 grid.266102.1 0000 0001 2297 6811 Division of Allergy and Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco School of Medicine and UCSF Benioff Children’s Hospital, San Francisco, CA USA
106 grid.413808.6 0000 0004 0388 2248 Division of Allergy and Immunology, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL USA
107 Chief of Immunology Unit, Children’s Hospital “Sor María Ludovica, Buenos Aires, Argentina
108 https://ror.org/01hcyya48 grid.239573.9 0000 0000 9025 8099 Division of Allergy Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
109 https://ror.org/02qp3tb03 grid.66875.3a 0000 0004 0459 167X Division of Pediatric Infectious Diseases, Mayo Clinic, Rochester, MN USA
110 https://ror.org/00qqv6244 grid.30760.32 0000 0001 2111 8460 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI USA
111 https://ror.org/036rp1748 grid.11899.38 0000 0004 1937 0722 Division of Immunology and Allergy, Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
112 https://ror.org/04waqzz56 grid.411036.1 0000 0001 1498 685X Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
113 https://ror.org/05qz4r376 grid.434854.a 0000 0004 5902 4250 Immune Deficiency Foundation, 7550 Teague Road, Hanover, MD 21076 USA
114 https://ror.org/056rkh971 grid.459972.4 Division of Allergy and Immunology, Stony Brook Children’s Hospital, Stony Brook, NY USA
115 https://ror.org/03d5h2g68 grid.461188.2 Department of Clinical Immunology, Nawaloka Hospitals, Colombo, Sri Lanka
116 https://ror.org/03v76x132 grid.47100.32 0000 0004 1936 8710 Section of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT USA
117 Houston ENT and Allergy, Houston, TX USA
118 https://ror.org/01k8vtd75 grid.10251.37 0000 0001 0342 6662 Department of Pediatrics, Faculty of Medicine, Mansoura University Children’s Hospital, Mansoura University, Mansoura, Egypt
119 https://ror.org/00412ts95 grid.239546.f 0000 0001 2153 6013 Children’s Hospital Los Angeles, Los Angeles, CA USA
120 https://ror.org/043mz5j54 grid.266102.1 0000 0001 2297 6811 Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California San Francisco, San Francisco, USA
121 https://ror.org/00dr28g20 grid.8127.c 0000 0004 0576 3437 Department of Paediatrics, Medical School, University of Crete, Rethymno, Greece
122 grid.4367.6 0000 0001 2355 7002 Division of Allergy and Immunology, Department of Medicine, Washington University School of Medicine, St. Louis, MO USA
123 https://ror.org/0107c5v14 grid.5606.5 0000 0001 2151 3065 Dipartimento Di NeuroscienzeRiabilitazioneOftalmologiaGenetica e Scienze Materno Infantili, University of Genoa, 16132 Genoa, Italy
124 https://ror.org/02etexs15 grid.413979.1 0000 0004 0438 4435 Section of Allergy Immunology, Department of Pediatrics, Louisiana State University Health and Children’s Hospital New Orleans, New Orleans, LA USA
125 Section of Rheumatology, Department of Pediatrics, Children’s Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO USA
126 https://ror.org/012jban78 grid.259828.c 0000 0001 2189 3475 Division of Pediatric Pulmonology, Allergy and Immunology, Department of Pediatrics, Medical University of South Carolina, Charleston, SC USA
127 https://ror.org/0130frc33 grid.10698.36 0000 0001 2248 3208 Division of Pediatric Allergy and Immunology, Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, NC USA
128 grid.443867.a 0000 0000 9149 4843 University Hospitals Cleveland Medical Center, Cleveland, OH USA
129 Allergy and Immunology Associates Inc., Mayfield Heights, OH USA
130 grid.21107.35 0000 0001 2171 9311 Johns Hopkins University School of Medicine, Baltimore, MD USA
131 https://ror.org/005bvs909 grid.416153.4 0000 0004 0624 1200 Department of Clinical Immunology & Allergy, The Royal Melbourne Hospital, Melbourne, Australia
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Background

The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI.

Objective

To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI.

Methods

We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022.

Results

Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission.

Conclusion

Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.

Keywords

Immunodeficiency
Immunization
Viruses: respiratory diseases
Outcomes
http://dx.doi.org/10.13039/100015691 Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases R24AI171055 issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2024
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pmcIntroduction

Coronaviruses are medium-sized, enveloped, positive-stranded RNA viruses named for their crown-like appearance under the electron microscope [1]. Viruses in this family played an important role in human health long before the COVID-19 pandemic, responsible for both nonspecific upper respiratory tract infections and specific viral syndromes like severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). In 2019, cases of coronavirus-induced pneumonia clustered in the Hubei Province of China. This started out as a local outbreak in Wuhan but soon spread internationally, developing into a global pandemic. The implicated virus was designated SARS-CoV-2, and the disease that virus caused was named COVID-19.

Clinically, COVID-19 infections can range from asymptomatic to life threatening. Several factors place infected patients at higher risk for poor outcomes, including increasing age, obesity, and chronic disease [2, 3]. Among the many chronic diseases that may lead to more severe infection are inborn errors of immunity (IEI), a collection of diseases which lead to immunodeficiency and immune dysregulation. The earliest survey of 94 patients with IEI observed 10% mortality and found that risk factors for severe disease in the general public also affected outcomes in patients with IEI [4]. A recently published review of the literature supports that mortality among most IEI diagnosis subgroups ranges from 4 to 16% [5]. One large collection reported that the case fatality rate could be as high as 100 times the general population among patients 0–19 years of age. Patients with disrupted type I interferon (IFN) immunity in particular have worse outcomes [6–9].

The first COVID-19 vaccines became available in 2020, and since their introduction, vaccines have proven to be critically important to decreasing both SARS-CoV-2 spread and COVID-19 disease severity. There have been obvious concerns regarding how well vaccines work in patients with IEI. Few studies have been performed, and the highly varied nature of the more than 450 IEI disorders make generalization across disorders impossible. IEI patients can have lower rates of seroconversion compared to healthy controls, though responses tend to improve with additional (third dose) vaccine administrations or when given in the setting of previous COVID-19 infection [5, 10–13]. In addition to antibody responses to COVID-19 vaccination, T-cell responses have proven to be important [14, 15]. Pham and colleagues found that most patients with IEI were able to mount at least a T-cell response to vaccination, even if their humoral immune response to vaccination was lackluster [16]. These findings suggested the importance of COVID-19 vaccination even in patients with severe humoral immune defects, as these patients may benefit from adaptive cellular immune responses even in the absence of a functioning humoral immune system.

Regardless of laboratory-observed vaccination responses, an important consideration for both IEI patients and practicing immunologists is the real-world effectiveness of vaccination against SARS-CoV-2. A previous large healthcare claims study of vaccinated patients found that most infections after vaccination resulting in hospitalization and/or death occurred in patients with primary and secondary immunodeficiencies, but no data were presented regarding just primary IEI patients [17]. A small single-center study of COVID-19 outcomes in 113 IEI patients who predominantly had CVID, hypogammaglobulinemia, and agammaglobulinemia observed that COVID-19-related hospitalization occurred in 40% of unvaccinated patients versus 4% in vaccinated patients, suggesting a dramatic protective effect of vaccination [18].

Overall, COVID-19 vaccines have proven safe in the general population, although mild local and systemic reactions are common such as pain, lymphadenopathy, headache, and fever. Although severe events are possible, including myocarditis, pericarditis, anaphylaxis, and thromboembolic events, these serious adverse events are rare [19, 20]. Little is known about the safety of COVID-19 vaccines in patients with IEI. For example, patients with autoinflammatory IEIs may fear that vaccination could precipitate a disease flare, requiring increased immunosuppression or hospitalization. Indeed, the rarity of many IEI conditions and the relative recency of COVID-19 disease has made it difficult for professional organizations, the normal adjudicators of such questions, to be able to determine if there are unique or increased risks for these patients. In fact, the 2021 consensus statement from the European Alliance of Associations for Rheumatology and the American College of Rheumatology on diagnosis and management of type 1 interferonopathies expresses agnosticism, stating “whether vaccines against COVID-19 have the potential to provoke a disease flare is unknown” and “there are currently no data to back specific recommendations” [21].

In this study, we investigated the real-world safety and effectiveness of vaccination in IEI patients. Our findings demonstrate that COVID-19 vaccination is safe and effective in a large, phenotypically diverse, and multinational IEI registry including more than 1000 patients.

Materials and Methods

This study was performed as a collaboration between Cincinnati Children’s Hospital, the US Immunodeficiency Network (USIDNET), the Clinical Immunology Society, and additional physicians who contributed patient data. We created a COVID-19-specific registry database as part of the USIDNET for the collection of IEI patient data related to SARS-CoV-2 infection and/or SARS-CoV-2 vaccination. This REDCap database was used to house de-identified clinical patient data submitted by immunologists worldwide. The study was approved as exempt research by the Cincinnati Children’s Hospital institutional review board (IRB ID: 2021–0406). Members of the Clinical Immunology Society (CIS) were invited by email to contribute patient data via entry into the registry database. The database opened for entries on January 1, 2022, and closed on August 19, 2022.

Patients of any age with IEI and COVID-19/SARS-CoV-2 infection, COVID-19 vaccination, or both were eligible for inclusion. Diagnoses were linked to International Union of Immunological Societies (IUIS) subcategories by phenotypic or molecular defect as entered by the clinician [22]. All types of COVID-19/SARS-CoV-2 infections and complications were eligible for inclusion—asymptomatic, acute, long COVID, and multisystem inflammatory syndrome in children or adults (MIS-C/MIS-A). In addition to basic demographics and information on the nature of the subject’s IEI and relevant medical comorbidities, data were collected on hospitalization, requirement of ICU care, and patient survival. For patients who had COVID-19 vaccination, data were collected on vaccine side effects, need for escalation of IEI treatment in relation to vaccination, and healthcare utilization.

Primary outcomes of interest were (1) adverse vaccine effects and (2) real-world vaccine effectiveness in preventing hospitalization, ICU admission, and death. Adverse vaccine effects were determined by analyzing reported need for medical care in association with vaccination (emergency, outpatient, and inpatient environments), evaluating for significant changes to patients’ immunology medication regimen, examining for development of vaccine-induced myocarditis and anaphylaxis, and reviewing reported adverse effects beyond expected pain and fever for up to 3 days. Real-world vaccine effectiveness was assessed by comparison of reported hospital admission, ICU admission, and death in patients with at least one vaccine dose versus those without. Consideration of the timing of a COVID-19 infection in relation to vaccination was built into the analysis. For example, subjects who had a COVID-19 infection prior to vaccination were analyzed differently from subjects with first infection after vaccination.

We report descriptive statistics for the study population, including medians for continuous variables and counts and percentages for categorical variables. Categorical variables were compared using the Pearson chi-square test. Logistic regression analysis for outcomes of non-ICU hospitalization, ICU hospitalization, and death against vaccination status was performed both unadjusted and adjusted for potential confounding factors. Confounders considered in the adjusted models were age, obesity, kidney disease, lung disease, immunosuppressive medication use in the previous 3 months, neuromuscular disease, tracheostomy status, heart disease, sickle cell disease, and diabetes. Confounders that occurred infrequently in the data set (< 20 times each in the entire cohort)—namely, neuromuscular disease, tracheostomy, heart disease, diabetes, and sickle cell disease—were grouped together into a composite risk factor binary variable. For all these confounders, we assumed nonresponse on the survey instrument to be equivalent to a “no” answer, as not all fields were required for submission of a patient entry. All analysis was performed using Stata 17.0 (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC).

Results

Patients

A total of 1245 subjects were entered in the registry (Table 1). Of these, 806 (64.7%) had received at least one vaccine against COVID-19. The type of vaccine received was reported for 80.7% of vaccinated patients: the majority of patients received mRNA-based vaccines (84.0%) followed by viral vector (10.9%) and protein subunit vaccines (5.1%). Seven-hundred twenty-five received two or more vaccinations. Males were slightly predominant (53%), and patients were mostly Caucasian (70.1%) and from the USA (63.5%). Demographic characteristics were generally similar between the unvaccinated and vaccinated groups. Major exceptions were age (vaccinated patients tended to be older) and country of the treating medical center (higher percentage of vaccinated patients in US centers). The burden of comorbidities including lung disease, obesity, diabetes, and other conditions was similar between the groups, although the proportion of patients with history of bone marrow transplant (n = 96) was higher in the vaccinated group (8.9% compared to 5.5%). Table 1 Demographic characteristics of subjects in the USIDNET registry

	Overall	 ≥ 1 vaccine	No vaccine	
Demographics	1245	806 (64.7)	439 (35.3)	
Sex	
  Female	585 (47.0)	379 (47.0)	206 (46.9)	
  Male	660 (53.0)	427 (53.0)	233 (53.1)	
Race/ethnicity*	
  White	873 (70.1)	567 (70.3)	306 (69.7)	
  Black	57 (4.6)	34 (4.2)	23 (5.2)	
  Native American	3 (0.2)	3 (0.4)	0 (0.0)	
  Asian	31 (2.5)	19 (2.4)	12 (2.7)	
  Hawaiian	5 (0.4)	3 (0.4)	2 (0.5)	
  Other	91 (7.3)	52 (6.4)	39 (8.9)	
  Not Reported	185 (14.9)	128 (15.9)	57 (13.0)	
Age at entry (years) median (p25–p75) (min–max)*	22 (14–43) (0–80)	28 (17–48) (4–80)	15 (8–26) (0–80)	
Evaluating center	
  US-based*	791 (63.5)	529 (65.6)	262 (59.7)	
Comorbidities	
  Lung disease^	440 (35.3)	290 (36.0)	150 (34.2)	
  Obesity^	154 (12.4)	107 (13.3)	47 (10.7)	
  Neuromuscular disease^	3 (0.4)	3 (0.4)	0 (0)	
  Tracheostomy^	6 (0.5)	3 (0.4)	3 (0.7)	
  Heart disease^	16 (1.3)	11 (1.4)	5 (1.1)	
  Sickle cell disease^	1 (0.1)	1 (0.1)	0 (0)	
  Diabetes^	10 (0.8)	7 (0.9)	3 (0.7)	
  Renal disease^	67 (5.4)	44 (5.5)	23 (5.2)	
Immunosuppressive medications (past 3 months)^^	238 (19.1)	165 (20.5)	73 (16.6)	
Bone marrow transplant history^	96 (7.7)	72 (8.9)	24 (5.5)	
Data are presented as no. (%) unless otherwise indicated

*variable had missing data

^includes assumed variables—if entry was left blank assumed response was “no”

^^immunosuppressive medication as determined by physician entering data for patient

A wide variety of IEI phenotypes and molecular diagnoses were represented in the cohort (Fig. 1). Most patients (n = 793, 63.7%) had antibody defects, predominantly CVID, hypogammaglobulinemia, and agammaglobulinemia. Combined immune deficiencies, syndrome-associated and otherwise, together made up the second largest category (n = 163, 13.1%). Disorders of immune dysregulation, including primary immune regulatory disorders and genetic disorders associated with hemophagocytic lymphohistiocytosis (HLH) or Epstein-Barr virus (EBV) susceptibility, were also well represented (n = 106, 8.5%). Forty-six patients had autoinflammatory disorders. There were 27 patients with chronic granulomatous disease (CGD) and 16 patients with other disorders of phagocyte function or number. Remaining categories are shown in Fig. 1. Note that 33 patients did not have enough information recorded to be categorized into a specific grouping. The breakdown of molecular diagnoses is given in Table 2 and included close to 150 different genetic diagnoses. The genetic disorders in the registry with 10 or more patients reported included pathogenic changes in ADA, CD40L, ATM, WAS, BTK, TNFRSF13B, CTLA4, XIAP, and 22q11 deletion.Fig. 1 Patient diagnoses in USIDNET registry, categorized by International Union of Immunologic Societies (IUIS) schema. General IUIS categories further subclassified based on phenotype or genetic defect. Abbreviations: SCID, severe combined immune deficiency; CID, combined immune deficiency; A-T, ataxia-telangiectasia; WAS, Wiskott-Aldrich syndrome; CHARGE, coloboma/heart defects/atresia choanae/growth retardation/genital abnormalities/ear abnormalities; NEMO, nuclear factor-kappa B essential modulator deficiency; CVID, common variable immune deficiency; hypogamma, hypogammaglobulinemia; agamma, agammaglobulinemia; Comp. Def., complement deficiency; SAD, specific antibody deficiency; Subclass Def., IgG subclass deficiency; IgA Def., IgA deficiency; HLH/EBV Susc., hemophagocytic lymphohistiocytosis and EBV susceptibility; ALPS, autoimmune lymphoproliferative syndrome; IPEX, immune dysregulation/polyendocrinopathy/enteropathy/X-linked syndrome; VEO-IBD, very early onset inflammatory bowel disease; CGD, chronic granulomatous disease; MSMD, Mendelian susceptibility to mycobacterial disease; Cong. Neut., congenital neutropenia; Marrow Fail., bone marrow failure; Viral Predisp., predisposition to severe viral infection

Table 2 Molecular defects of subjects in the USIDNET COVID-19 registry as entered and categorized by registering clinicians

Category	Defect	N (%)	Category	Defect	N (%)	Category	Defect	N (%)	Category	Defect	N (%)	
SCID	ADA	12 (40.0)	(Antibody	NFKB1	8 (1.0)	Immune	nr	38 (35.9)	Autoinflammatory	NLRP3	6 (13.0)	
	nr	5 (16.7)	Def. Cont)	NFKB2	7 (0.9)	Dysregulation	CTLA4	16 (15.1)		ADA2	5 (10.9)	
	RAG1	3 (10.0)		STAT3 GOF	4 (0.5)		XIAP	11 (10.4)		MEFV	4 (8.7)	
	IL7R	2 (6.7)		47 + 21	3 (0.4)		FOXP3	5 (4.7)		MVK	4 (8.7)	
	LIG4	2 (6.7)		CTLA4	3 (0.4)		AIRE—AR	4 (3.8)		IL1RN	3 (6.5)	
	DCLRE1C	1 (3.3)		IGLL1	3 (0.4)		SH2D1A	4 (3.8)		PSTPIP1	3 (6.5)	
	IL2RA	1 (3.3)		Kabuki	3 (0.4)		STAT3 GOF	4 (3.8)		nr	3 (6.5)	
	IL2RG	1 (3.3)		NOD2	3 (0.4)		STXBP2	3 (2.8)		CARD14	2 (4.4)	
	JAK3	1 (3.3)		16p11	2 (0.3)		TNFRSF6	3 (2.8)		CDC42	2 (4.4)	
	NHEJ1	1 (3.3)		DUOX2	2 (0.3)		UNC13D	3 (2.8)		TMEM173	2 (4.4)	
	RAG2	1 (3.3)		IKBKB	2 (0.3)		FAS	2 (1.9)		ATP6AP1	1 (2.2)	
CID	nr	20 (40.0)		IKZF1	2 (0.3)		LRBA	2 (1.9)		COPA	1 (2.2)	
	CD40L	12 (24.0)		IRF2BP2	2 (0.3)		AIRE—AD	1 (0.9)		NFKB1	1 (2.2)	
	AICDA	6 (12.0)		LRBA	2 (0.3)		ELF4	1 (0.9)		IFIH1	1 (2.2)	
	RAG1	2 (4.0)		PIK3R1—AD	2 (0.3)		IPEX	1 (0.9)		S124F	1 (2.2)	
	CARD11	1 (2.0)		TCF3	2 (0.3)		LYST	1 (0.9)		NLRC4	1 (2.2)	
	CARMIL2	1 (2.0)		47 XXY	1 (0.1)		MAGT1	1 (0.9)		PEPD	1 (2.2)	
	CD70	1 (2.0)		ADA2	1 (0.1)		PRKCD	1 (0.9)		RELA	1 (2.2)	
	IL2RA	1 (2.0)		ATM	1 (0.1)		RAB27A	1 (0.9)		TNFAIP3	1 (2.2)	
	PGM3	1 (2.0)		BLNK	1 (0.1)		SLC7A7	1 (0.9)		TNFRSF1A	1 (2.2)	
	PIK3R1	1 (2.0)		C1QA	1 (0.1)		STX11	1 (0.9)		TNFSF13	1 (2.2)	
	RMRP	1 (2.0)		CARD11	1 (0.1)		TNFAIP3	1 (0.9)		TRNT1	1 (2.2)	
	SASH3	1 (2.0)		CD21	1 (0.1)		TPP2	1 (0.9)	Complement	nr	8 (61.5)	
	STK4	1 (2.0)		CD40	1 (0.1)	Phagocyte	nr	21 (48.8)	 Deficiency	C1S	1 (7.7)	
	TNFRSF13B	1 (2.0)		CXCR4	1 (0.1)	 Defects	GATA2	7 (16.3)		C2	1 (7.7)	
Syndromic	22q11	40 (35.4)		DNASE2	1 (0.1)		CYBB	6 (14.0)		C4A + C4B	1 (7.7)	
CID	ATM	16 (14.2)		DNMT3B	1 (0.1)		NCF1	4 (9.3)		C5	1 (7.7)	
	WAS	14 (12.4)		DOCK2	1 (0.1)		CYBA	1 (2.3)		CFI	1 (7.7)	
	STAT3 LOF	13 (11.5)		ERCC2	1 (0.1)		FCGR3A	1 (2.3)	Unknown (n = 33)			
	CHD7	7 (6.2)		FANCA	1 (0.1)		HAX1	1 (2.3)				
	IKBKG (NEMO)	7 (6.2)		GATA2	1 (0.1)		JAGN1	1 (2.3)	nr not reported			
	nr	5 (4.4)		HYOU1	1 (0.1)		NCF4	1 (2.3)				
	KMT2D	4 (3.5)		IGHM	1 (0.1)	Innate Immune	IL17RA	3 (20.0)				
	TBX1	2 (1.8)		IRF7	1 (0.1)	 Defects	STAT1 GOF	3 (20.0)				
	FOXI3	1 (0.9)		LIG4	1 (0.1)		IL12RB1	2 (13.3)				
	KMT2A	1 (0.9)		NCKAPIL	1 (0.1)		MYD88	2 (13.3)				
	NFKBIA	1 (0.9)		PIK3CG	1 (0.1)		IFNAR1	1 (6.7)				
	RMRP	1 (0.9)		PIK3R1—AR	1 (0.1)		IFNGR1—AD	1 (6.7)				
	SKIV2L	1 (0.9)		PLCG2	1 (0.1)		IFNGR1—AR	1 (6.7)				
Antibody	nr	633 (79.8)		POLG	1 (0.1)		TLR3	1 (6.7)				
Deficiencies	BTK	56 (7.1)		TCIRG1	1 (0.1)		nr	1 (6.7)				
	TNFRSF13B	17 (2.1)		TRNT1	1 (0.1)	Bone Marrow	DKC1	1 (33.3)				
	PIK3CD	9 (1.1)		TOP2B	1 (0.1)	Failure	SAMD9	1 (33.3)				
				WDR19	1 (0.1)		nr	1 (33.3)				

Vaccine Complications

Adverse events reported after vaccination are listed in Table 3. Of the 806 patients who received at least one vaccine, only 17 were reported to seek medical care in the outpatient clinic (n = 9) or emergency room (n = 8) for a vaccine-related complication. One patient was hospitalized in association with the COVID-19 vaccine. This patient had a diagnosis of hyper-IgM syndrome and a history of recurrent cytopenias and developed an exacerbation of pre-existing autoimmune hemolytic anemia after his first COVID-19 mRNA vaccine. Table 3 Vaccine safety in the IEI cohort (n = 806)

Emergency room visit	8 (1.0)	Significant treatment changes	10 (1.2)	
Outpatient clinic visit	9 (1.1)	Increased immunosuppression	4 (0.5)	
  IPEX patient with worsening eczema, required topical corticosteroids and dupilumab		
Hospitalization	1 (0.1)	  STAT1 GOF patient developed severe aphthous ulcers, required baricitinib		
  Specific antibody deficiency patient with asthma exacerbation, required prednisone		
Adverse effects/frequency (some patients with > 1)	25 (3.1)	  XIAP patient took previously prescribed oral steroids for possible disease flare		
	Fatigue	8		Increased infections/requirement for antimicrobial treatment	3 (0.4)	
	Myalgia	5		  CVID patient developed herpetic infections, required antiviral treatment		
	Arthralgia	3		  MSMD patient developed Salmonella bacteremia and lymphadenitis		
	Headache	3		  CVID patient started on antibiotic prophylaxis, unclear indication		
	Chest pain	2				
	Congestion	2		Other	3 (0.4)	
	Diarrhea	2		  Hereditary angioedema patient had increased disease flares requiring increased C1 INH		
	Palpitations	2		  CVID patient developed cholelithiasis requiring surgery, 4 months after vaccine		
				  Hyper IgM patient had exacerbation of pre-existing autoimmune hemolytic anemia		
	Abdominal pain	1				
	Confusion	1		Anaphylaxis	0 (0)	
	Costochondritis	1				
	Cough	1		Myocarditis	0 (0)	
	Diabetes	1				
	Fever (> 3 days)	1		MIS-C/MIS-A	1 (0.1)	
	Flushing	1				
	Headache	1				
	Lethargy	1				
	Lymph node pain	1				
	Malaise	1				
	Nausea	1				
	Rash	1				
	Serum sickness	1				
	Sore throat	1				
	Unspecified	1				

Twenty-five patients were reported as having adverse effects secondary to the vaccines, with several having more than one listed complaint. Common issues included fatigue (8 patients), myalgia (5 patients), arthralgia (3 patients), and headache (3 patients). Most adverse effects were mild and self-limited, although one patient, a teenage girl with CVID, developed a serum sickness-like reaction after mRNA vaccination which required an outpatient physician visit and treatment with oral antihistamines. Seven patients required either increased immunosuppression or a change in antibiotic regimen after vaccination as detailed in Table 3. It is not clear what role vaccination may have played in many of these events, and some (e.g., onset of diabetes, gallstones) seem likely unrelated. There were no cases of anaphylaxis or vaccine-related myocarditis. MIS-C/MIS-A was reported to occur in one patient following vaccination. This patient had his second COVID vaccination, followed by a mild COVID-19 infection 6 days later. He then developed MIS-C approximately 6 weeks after the infection and required ICU care. His unusual presentation led to a genetic workup, and ultimately, this patient was diagnosed with familial HLH due to pathogenic variants in STXBP2.

COVID-19/SARS-CoV-2 Infection

Sixty-six percent (n = 823) of the patients in the USIDNET cohort experienced SARS-CoV-2 infections (Table 4). Of these, the majority (89.2%) were acute/symptomatic. MIS-C/MIS-A was reported in 7/823 patients (0.8%); these patients’ ages ranged from 2 to 24 years (median 11 years). The underlying IEI diagnoses in patients with MIS-C/MIS-A were X-linked agammaglobulinemia (n = 2), hyper-IgM syndrome (n = 2), interferonopathy (n = 1), inherited bone marrow failure (n = 1), and APECED (n = 1). Long COVID was reported in 13/823 patients (1.6%). One-hundred and fifty-one patients (18.4% of those infected) received monoclonal antibodies to prevent or treat COVID-19, and 41 (5.0% of those infected) received convalescent plasma. One-hundred and fifty-six IEI patients infected with SARS-CoV-2 required hospitalization (19.0% of those infected), 47 required ICU care (5.7%), and 28 died (3.4%) (Fig. 2). Characteristics of the 28 patients who died are given in Table 5. Most deceased patients had multiple comorbidities. The cause(s) of death for most adult patients included COVID-19, pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), or multiorgan failure. Sepsis was more commonly reported as an additional or only cause of death in pediatric patients, with Escherichia coli and Stenotrophomonas maltophilia identified in 2 patients. Table 4 SARS-CoV-2 infection outcomes in the IEI cohort and effect of vaccination. Data are presented as column totals/percentages for outcomes of infection and hospitalization, ICU admission, and death among those infected

IEI patients with ≥ 1 SARS-CoV-2 infection		N = 823	p	
  Asymptomatic	64 (7.8%)			
  Acute	734 (89.2%)			
  MIS-C/MIS-A	7 (0.8%)			
  Long	13 (1.6%)			
  Other	5 (0.6%)			
Required hospitalization for COVID-19/SARS-CoV-2 infection		N = 156 (19.0%)	p < 0.001	
  History of ≥ 1 vaccine prior to hospitalization	20 (12.8%)			
  No vaccination prior to hospitalization	132 (84.6%)			
  Vaccinated but unknown timing relative to hospitalization	4 (2.6%)			
Required ICU stay for COVID-19/SARS-CoV-2 infection		N = 47 (5.7%)	p < 0.001	
  History of ≥ 1 vaccine prior to ICU	6 (12.8%)			
  No vaccination prior to ICU	41 (87.2%)			
  Vaccinated but unknown timing relative to ICU stay	0 (0%)			
Died in association with COVID-19/SARS-CoV-2 infection		N = 28 (3.4%)	p < 0.001	
  History of ≥ 1 vaccine prior to death	5 (17.9%)			
  No vaccination prior to death	23 (82.1%)			
  Vaccinated but unknown timing relative to death	0 (0%)			

Fig. 2 Hospitalization, ICU admission, and death among the USIDNET registry cohort. Categorization was adapted from International Union of Immunological Societies (IUIS) phenotypic classification. Age quartile (years) is based on patient age at time of COVID-19 infection. Three infected patients lacked data on age. COVID-19 risk factors included history of lung disease, immunosuppressive medication use in the 3 months preceding infection, obesity, and renal disease. Additionally, a measure of “other risk factors” was determined, representing a composite of uncommonly observed risk factors in the cohort—neuromuscular disease, tracheostomy, heart disease, sickle cell disease, and diabetes. Any patient with at least one of these uncommonly observed risk factors was counted for this measure. Vaccination was determined as receipt of at least one COVID-19 vaccine prior to SARS-CoV-2 infection. Sixty-six patients lacked adequate information on timing of vaccination relative to infection and were not included

Table 5 Characteristics of deceased patients

Age	Diagnosis	Comorbidities and other conditions	Vaccination status	Reported c ause of death	Δ^	
85	CVID	GLILD, CLL, ITP	Vaccinated	Acute hypoxic respiratory failure due to COVID pneumonia, septic shock	9	
76	CVID	Obesity, chronic kidney disease, diabetes mellitus, coronary artery disease, GLILD	Unvaccinated	ARDS secondary to COVID-19	11	
75	IgG subclass deficiency	Diabetes mellitus, AIHA	Unvaccinated	COVID pneumonia, ARDS, multiorgan failure	21	
74	CVID	Asthma, obesity, atrophic gastritis, hypertension	Unvaccinated	COVID-19	6	
74	CVID	Asthma, dysphagia, granulomatosis	Unvaccinated	Respiratory failure	10	
74	CVID	Obesity, pulmonary granuloma	Vaccinated	COVID-19 pneumonia	14	
54	CVID	ITP, bronchiectasis	Unvaccinated	Respiratory failure	21	
50	CVID	Bronchiectasis, diarrhea, cirrhosis, portal hypertension	Vaccinated	Pneumonia, respiratory failure	9	
49	CVID	Bronchiectasis	Vaccinated	Multiorgan failure	88	
41	CVID	ITP, bronchiectasis, GLILD, lymphoproliferative disorder, portal HTN, lymphoma with secondary HLH	Unvaccinated	COVID-19 respiratory failure	12	
39	Hypogammaglobulinemia	Kidney transplant, T-cell leukemia/lymphoma, Hodgkin lymphoma	Unvaccinated	Multiorgan failure, shock	35	
28	Kabuki	Interstitial lung disease	Unvaccinated	Respiratory failure	26	
28	Unspecified agammaglobulinemia	None	Vaccinated	Unknown	31	
28	XLA	Bronchiectasis	Unvaccinated	ARDS due to COVID-19, bacterial pneumonia, sepsis	9	
26	XLA	None	Unvaccinated	Respiratory failure	Unknown	
18	KMT2A	Asthma, chronic respiratory failure on BiPAP, epilepsy, dysphagia	Unvaccinated	Respiratory failure	3	
18	HLH (transplanted)	Encephalitis, hemolytic anemia, TMA	Unvaccinated	Pneumonia, COVID-19	50	
15	APECED	Hypoparathyroidism, Addison disease, vitiligo, thyroiditis, asplenia, hypocalcemia	Unvaccinated	Pneumonia, pulmonary failure, nosocomial fungal sepsis	39	
14	LRBA deficiency	Inflammatory bowel disease, AIHA, ITP, EBV, CMV colitis, arthritis, obliterative bronchiolitis, asthma	Unvaccinated	E. coli sepsis	Unknown	
12	CVID	Malnutrition, bronchiectasis, TTP, diarrhea	Unvaccinated	Respiratory failure	36	
12	STK4	Meningitis, cellulitis, ITP, AIHA, lymphadenopathy, seizures	Unvaccinated	Respiratory failure, cardiac failure	10	
9	TPP2 deficiency	Ataxia, chronic idiopathic thrombocytopenic purpura	Unvaccinated	Respiratory failure, DIC	10	
7	HLH (not transplanted)	None	Unvaccinated	HLH	87	
3	Combined immune deficiency	Childhood bullous pemphigoid, candidiasis, failure to thrive	Unvaccinated	Sepsis	37	
3	Unspecified autoinflammatory disorder	Psoriasis with arthropathy	Unvaccinated	Sepsis, ARDS	17	
3*	IFNAR1 mutation	Chronic sinusitis, thrush, mucormycosis	Unvaccinated	Respiratory failure, left ventricular dysfunction/arrhythmias	51	
1	NEMO (transplanted)	Norovirus enteritis, adenoviral gastroenteritis	Unvaccinated	Stenotrophomonas sepsis	76	
 < 1	SCID (not transplanted)	None	Unvaccinated	Sepsis, COVID-19 pneumonia	59	
All vaccinated subjects had vaccine prior to acute infection; ages listed in years

*subject developed MIS-C in addition to acute COVID-19

^Δ = diagnosis date—death date, given in days

Hospitalization, ICU admission, and death rates varied by IUIS diagnosis group (Fig. 2). The highest rates were observed in patients with innate immune defects with hospitalization observed in 44%, ICU admission observed in 22%, and death observed in 11% of these patients. Patients with combined immune deficiencies, immune dysregulation, and autoinflammatory disorders also had higher rates of hospitalization, ICU admission, and death (Fig. 2). Lower rates were observed in patients with antibody deficiencies, and the lowest rates were observed in patients with phagocyte deficiencies and complement deficiencies, with no ICU admissions or deaths observed in those two patient groups. Rates of hospitalization, ICU admission, and death were higher in patients with comorbidities and in patients in the oldest age quartile (Fig. 2).

Effect of Vaccination on COVID-19 Outcomes

Of 806 patients who received one or more vaccinations against SARS-CoV-2, 216 patients received vaccination prior to COVID-19/SARS-CoV-2 infection, 541 were vaccinated after infection, and timing of vaccination was not clear in the remaining patients. Patients who received vaccination after SARS-CoV-2 infection were counted in the unvaccinated group for analyses, and subjects with uncertain timing of vaccination relative to infection were excluded.

Rates of hospitalization, ICU admission, and death were all proportionately lower in the patients who received one or more vaccinations prior to COVID-19/SARS-CoV-2 infection (Fig. 2, Table 4). Twenty of 216 (9.3%) IEI patients who received one or more vaccinations prior to COVID-19 were hospitalized, compared with 132/541 (24.4%) who had not received at least one vaccine (p < 0.001). Six of 216 (2.8%) vaccinated patients were admitted to the ICU, compared with 41 of 541 (7.6%) unvaccinated patients (p = 0.013). Five of 216 (2.3%) vaccinated patients died, and 23 of 541 (4.3%) unvaccinated patients died (p = 0.202).

In unadjusted logistic regression analysis (Table 6), not having at least one COVID-19 vaccine prior to first COVID-19/SARS-CoV-2 infection significantly increased the odds of non-ICU admission by a factor of 3.16 (95% CI (1.92–5.22), p < 0.001) and the odds of ICU admission by a factor of 2.87 (95% CI (1.20–6.86), p = 0.018). Although the odds of death were also increased in the unvaccinated group, this difference was not statistically significant. Table 6 Logistic regression analysis for COVID-19-related hospitalization, ICU admission, and death

	Unadjusted analysis		
	Odds ratio	95% CI	p value	
Outcome: hospitalization (n = 757)*	
  Variable				
    No COVID-19 vaccine	3.16	1.92–5.22	 < 0.001	
Outcome: ICU admission (n = 757)*				
  Variable				
    No COVID-19 vaccine	2.87	1.20–6.86	0.018	
Outcome: death (n = 757)*				
  Variable				
    No COVID-19 vaccine	1.87	0.70–4.99	0.209	
	Adjusted analysis		
	Point estimate	95% CI	p value	
Outcome: hospitalization (n = 748)^	
  Variable				
    No COVID-19 vaccine	3.84	2.28–6.49	 < 0.001	
    Composite risk factors	1.08	0.34–3.46	0.901	
    Obesity	1.26	0.72–2.21	0.421	
    Renal	1.40	0.61–3.19	0.426	
    Immunosuppressive meds	1.37	0.85–2.20	0.196	
    Lung disease	1.55	1.06–2.25	0.023	
    Age	1.01	1.00–1.02	0.005	
Outcome: ICU admission (n = 748)^	
  Variable				
    No COVID-19 vaccine	3.61	1.48–8.79	0.005	
    Composite risk factors	0.94	0.12–7.45	0.956	
    Obesity	0.30	0.07–1.28	0.103	
    Renal	0.76	0.17–3.41	0.719	
    Immunosuppressive meds	2.26	1.13–4.50	0.021	
    Lung disease	1.43	0.77–2.63	0.256	
    Age	1.02	1.00–1.03	0.011	
Outcome: death (n = 748)^	
  Variable				
    No COVID-19 vaccine	2.30	0.85–6.28	0.103	
    Composite risk factors	1.63	0.20–13.09	0.645	
    Obesity	0.87	0.25–3.00	0.827	
    Renal	0.58	0.07–4.53	0.602	
    Immunosuppressive medications	2.69	1.17–6.19	0.020	
    Lung disease	1.59	0.73–3.45	0.239	
    Age	1.02	1.00–1.04	0.048	
*Eight hundred twenty-three patients had a SARS-CoV-2 infection at least once. Of these, 66 patients were vaccinated but lacked information on timing of vaccine relative to COVID-19 illness and were thus excluded from unadjusted analysis

^Eight hundred twenty-three patients had a SARS-CoV-2 infection at least once. Of these, 66 patients were known to be vaccinated but lacked information on timing of vaccination relative to COVID-19 illness, and an additional 9 were missing data on age. These were excluded from adjusted analysis

Similarly, we performed regression analysis for the same outcomes, but adjusting for the potential confounders age, obesity, renal disease, immunosuppressive medication use, lung disease, and other composite risk factors (Table 6). Not having at least one COVID-19 vaccine prior to first COVID-19 infection significantly increased the odds of non-ICU admission (OR 3.84, 95% CI (2.28–6.49), p < 0.001) and ICU admission (OR 3.61, 95% CI (1.48–8.79), p = 0.005). While odds of death were increased in the nonvaccinated group (OR 2.30, 95% CI (0.85–6.28)), this difference was not statistically significant (p = 0.103. There was also a small but significant effect on the odds of hospitalization, ICU admission, and death for each increase in year of age (Table 6). Lung disease significantly impacted risk of hospitalization, and immunosuppressive medication use significantly impacted risk of ICU admission and death.

Discussion

This is the largest registry report of COVID-19 vaccination and/or infection in IEI patients (n = 1245) to date. The disease burden in this multinational cohort of patients was diverse, with representation of even very rare diseases in each IUIS category.

Our study demonstrates that SARS-CoV-2 infections were most commonly mild in this phenotypically diverse patient population. Over 95% of patients can be expected to survive COVID-19. However, a significant proportion of infected IEI patients required hospitalization (19%) and ICU care (5.7%), and a minority did succumb (3.4%). The observed COVID-19 death rate in this large IEI registry cohort, which is largely US based, is higher than the US COVID-19 death rate in general (1.1%) and approaches that seen in medically underserved Ecuador (3.6%) [23]. Similar to previous studies, we observed that patients with innate immune defects, combined immunodeficiencies, disorders of immune dysregulation, and autoinflammatory disorders appear to have higher rates of severe complications of COVID-19 compared to patients with antibody deficiencies, phagocyte disorders, and complement deficiencies [4, 5, 24]. However, previous reports have included higher complication and death estimates in the IEI population than observed in our registry cohort. A recent systematic review on COVID-19 in patients with primary immunodeficiency found a case fatality rate of 9% and hospitalization rate of 49% [24]. These differences may be due to the different populations of the patients, with US patients representing a minority of patients in the review versus 63.5% of our USIDNET registry cohort. Abolhassani and colleagues performed a review of the COVID-19/IEI literature and found severe COVID-19 presentations in 21.5% of IEI patients and COVID-19-related mortality in 8.3% [7]. Of note, however, many of these cases of SARS-CoV-2 infection occurred prior to the widespread availability of vaccinations, and the Abolhassani cohort included more innate immune deficiencies which have been linked to more severe outcomes. A study based in the UK by Shields and colleagues found even higher rates of hospitalization (53.3%) and case fatality (39.2%), although this cohort included patients with secondary immune deficiencies in addition to IEI patients [25]. In contrast, an Italian IEI/COVID-19 study by Milito and colleagues reported a comparable infection mortality rate (3.8%) to that observed in our cohort [26] as did the Cousins study (3%) although the latter found a much larger difference in odds of hospitalization [18]. As before, the heterogeneity in these estimates is likely secondary to various confounding effects—temporal factors such as predominant SARS-CoV-2 variant at different times and increasing access to vaccination over time, cohort-level factors including diagnosis breakdown, and varying inclusion–exclusion criteria.

Vaccination in the IEI population was noted in our study to be quite effective in preventing COVID-19 general hospitalization and ICU admission, with > 3.5 times increased odds ratios for these outcomes in the unvaccinated group compared to those with at least one vaccine dose in adjusted regression analyses. Notably, the odds of death were not significantly decreased in the COVID-19 vaccinated group—a fact that is likely attributable to the generally low numbers of deaths in the cohort (28 patients), and even lower number of vaccinated deaths (5 patients), affecting statistical power.

Adverse effects of vaccination were generally mild and occurred in < 3.5% of vaccinated patients, further supporting the use of COVID-19 vaccination in patients with IEI. For the few vaccinated patients who required escalation of care after vaccination, it is not clear whether or how the vaccination event itself may have contributed to this. Importantly, there were no cases of anaphylaxis or vaccine-induced myocarditis in the cohort, though this does not rule out the occurrence. Myocarditis has been reported following a third mRNA vaccination in a 17-year-old male with CVID, for instance, and anaphylaxis would certainly be expected to occur in a minority of patients [27].

Limitations of the study include several inherent in registry-based observational research. These include recall bias on the part of clinicians filling out the survey, as well as ascertainment bias in terms of cases included. Additionally, respondents entered surveys at one point in time and were unable to update their entries later. Thus, information on repeat COVID-19 infections/outcomes and repeat COVID-19 vaccinations/outcomes was not captured. To facilitate analysis, subjects with more than one COVID-19 vaccine were pooled with those receiving only one, although it is reasonable to suppose that the degree of protection was different between these groups. Finally, the study design precluded evaluating for differences in rates of SARS-CoV-2 infection in vaccinated and unvaccinated patients. However, the apparent impact of vaccination on improving COVID-19 outcomes and the generally observed safety are important observations that may encourage hesitant IEI patients (up to 42%) to receive vaccination [28].

In summary, our study of a largely US-based registry cohort demonstrates that SARS-CoV-2 infections are mild in most patients with IEI but can be severe, and the percentages of serious COVID-19 outcomes (hospitalization, ICU care, or death) in this medically vulnerable group remain substantial. Vaccination appears safe and effective in decreasing serious outcomes among patients with diverse IEI.

Acknowledgements

The authors wish to thank Claudia Terrazas Saavedra for her contributions to the project.

Author Contribution

JMD and KC collected and analyzed data. JMD performed statistical analyses and wrote the manuscript. AL supervised statistical analyses. JB and RM designed the database. JMD and RM created figures. RM and KS designed the project and edited the manuscript. RA, DA, CC-R, JMF, RF, AG, AJ, JL, LN, JP, NR, KS, JT, KW, and RF made substantial contributions to the conception and design of the project as well as editing of the manuscript. All remaining authors contributed patient cases, commented on previous versions of the manuscript, and read and approved the final manuscript.

Funding

This study was funded by a grant from the National Institutes of Health National Institute of Allergy and Infectious Diseases, R24AI171055.

Data Availability

Researchers interested in access to the data may contact John McDonnell at mcdonnj@ccf.org.

Declarations

Ethics Approval

The study was approved as exempt research by the Cincinnati Children’s Hospital institutional review board (IRB ID: 2021–0406).

Consent to Participate

Not applicable

Consent for Publication

Not applicable

Conflict of Interest

Deepti Deshpande is employed by Regeneron Pharmaceuticals, spouse employed by Arch Oncology. Elizabeth Ristagno owns stock in Moderna and Pfizer. Kathleen Sullivan is a consultant for the Immune Deficiency Foundation. Rebecca Marsh is an employee of Pharming Healthcare, Inc. Nikita Raje is a speaker and on the medical advisory board for Enzyvant, a consultant for Pfizer, and a speaker for Pharming.

John McDonnell and Kimberley Cousins contributed equally as first authors.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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