Safety and Seroconversion of Immunotherapies against SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis of Clinical Trials
Abstract
:1. Introduction
2. Results
2.1. Systematic Review of Clinical Trials
2.1.1. Cross-Protective Vaccines Realizing Heterologous Immunity
2.1.2. Inactivated and Subunit Vaccines Allowing for Active Immunity
2.1.3. Convalescent Plasma or Immunoglobulin Transfer Providing Passive Immunity
2.1.4. Immunotherapy
2.2. Meta-Analysis of Trial Reports
3. Discussion
4. Challenges and Perspectives
5. Conclusions
6. Materials and Methods
Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Strategy | Treatment | Total % | Total # | # of Clinical Trial Phases | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
N/A | 1 | 1&2 | 2 | 2 & 3 | 3 | 4 | ||||||
Heterologous immunity | Mycobacterium vaccine | 8.0 | 6.5 | 32 | 26 | 0 | 0 | 0 | 1 | 0 | 19 | 6 |
MMR vaccine | 0.5 | 2 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | |||
Polio vaccine | 0.8 | 3 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | |||
Zoster Vaccine | 0.3 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | |||
Active immunity | Protein | 62.4 | 12.3 | 249 | 49 | 0 | 19 | 11 | 10 | 3 | 5 | 1 g |
RNA | 17.0 | 68 | 15 a,b | 8 | 11 | 13 c,d | 5 e | 10 | 6 h | |||
DNA | 3.3 | 13 | 0 | 4 | 7 | 0 | 2 | 0 | 0 | |||
Viral vector | 17.5 | 70 | 5 a | 23 | 17 | 6 c,d | 3 e | 13 f | 3 g,h,i | |||
Bacterial vector | 0.3 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | |||
Inactivated | 10.5 | 42 | 5 a,b | 4 | 8 | 3 | 0 | 14 f | 8 i | |||
Virus-like particle | 1.3 | 5 | 0 | 3 | 1 | 0 | 1 | 0 | 0 | |||
Live attenuated | 0.3 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | |||
Passive immunity | Immunoglobulin | 14.8 | 4.5 | 59 | 18 | 0 | 3 | 4 | 3 | 2 | 5 | 1 |
Convalescent plasma | 10.3 | 41 | 8 | 4 | 1 | 19 | 3 | 6 | 0 | |||
Immunotherapy | Neutralized antibody/ inhibitor | 14.8 | 7.3 | 59 | 30 | 3 | 1 | 1 | 18 | 3 | 3 | 0 |
Cytokine | 3.5 | 14 | 0 | 2 | 1 | 10 | 0 | 1 | 0 | |||
Immune cell | 4.0 | 16 | 0 | 7 | 9 | 0 | 0 | 0 | 0 | |||
Total # of clinical trial phases | 389 | 33 | 81 | 71 | 81 | 21 | 78 | 24 | ||||
Total % of clinical trial phases | 100.0 | 8.5 | 20.8 | 18.3 | 20.8 | 5.4 | 20.1 | 6.2 |
Strategy | Treatment | Total # | # of Participants in Clinical Trial Phases | |||||||
---|---|---|---|---|---|---|---|---|---|---|
N/A | 1 | 1&2 | 2 | 2 & 3 | 3 | 4 | ||||
Heterologous immunity | Mycobacterium vaccine | 48,601 | 41,066 | 0 | 0 | 0 | 1000 | 0 | 29,202 | 10,864 |
MMR vaccine | 260 | 0 | 0 | 0 | 0 | 260 | 0 | |||
Polio vaccine | 7025 | 0 | 0 | 0 | 0 | 0 | 3600 | 3425 | ||
Zoster Vaccine | 250 | 0 | 250 | 0 | 0 | 0 | 0 | 0 | ||
Active immunity | Protein | 878,370 | 172,672 | 0 | 1616 | 6600 | 18,016 | 29,320 | 117,000 | 120 g |
RNA | 162,052 | 9502 a,b | 981 | 13,961 | 6708 c,d | 54,550 e | 65,500 | 10,850 h | ||
DNA | 8481 | 0 | 298 | 1105 | 0 | 7078 | 0 | 0 | ||
Viral vector | 271,524 | 3770 a | 2688 | 9025 | 3691 c,d | 17,930 e | 224,000 f | 10,420 g,h,i | ||
Bacterial vector | 84 | 0 | 84 | 0 | 0 | 0 | 0 | 0 | ||
Inactivated/LVP | 263,949 | 2461 a,b | 570 | 5300 | 1750 | 30,612 | 175,790 f | 47,466 i | ||
Live attenuated | 48 | 0 | 48 | 0 | 0 | 0 | 0 | 0 | ||
Passive immunity | Immunoglobulin | 16,620 | 2756 | 0 | 74 | 239 | 226 | 390 | 1787 | 40 |
Convalescent plasma | 13,864 | 6424 | 150 | 15 | 2527 | 688 | 4060 | 0 | ||
Immunotherapy | Neutralized antibody/ inhibitor | 6988 | 3547 | 204 | 50 | 18 | 2409 | 320 | 546 | 0 |
Cytokine | 2329 | 0 | 82 | 80 | 1129 | 0 | 1038 | 0 | ||
Immune cell | 1112 | 0 | 280 | 832 | 0 | 0 | 0 | 0 | ||
Total participants in clinical trial phases | 929,359 | 22,761 | 7171 | 37,175 | 34,816 | 136,888 | 618,783 | 72,765 |
Type | Authors (Journal & Year) | NCT Number | Phase | Participants | Vaccination Procedures | Outcome Measures on Safety and Immunogenicity | Storage |
---|---|---|---|---|---|---|---|
Protein | Keech et al. (N Engl J Med 2020) [18] | 04368988 | 1 | 131 | Intramuscular injections of NVX-CoV2373 (5, 25 μg) at day 0 or/and 21 | Local, systemic, and unsolicited AEs; anti-S antibody; SARS-CoV-2-neutralizing antibody | 2–8 °C |
Richmond et al. (Lancet 2021) [19] | 04405908 | 1 | 151 | Intramuscular injections of SCB-2019 (3, 9, or 30 μg) at days 0 and 21 | Local and systemic AEs; anti-SCB-2019 antibody; SARS-CoV-2-neutralizing antibody | 2–8 °C | |
Yang et al. (Lancet Infect Dis 2021) [20] | 04445194 & 04466085 | 1 & 2 | 950 | Intramuscular injections of ZF2001 at day 0, 30, 60 for phase 1 trial, and at day 0, 30 or day 0, 30, 60 for phase 2 trial | Local, systemic, and unsolicited AEs; anti-RBD antibody; SARS-CoV-2-neutralizing antibody | 2–8 °C | |
Chappell (Lancet Infect Dis 2021) [21] | 04495933 | 1 | 120 | Intramuscular injections of S-clamp vaccine (5, 15, or 45 μg) at days 0 and 28 | Local, systemic, and unsolicited AEs; Anti-clamp antibody; SARS-CoV-2-neutralizing antibody | 2–8 °C | |
Goepfert et al. (Lancet Infect Dis 2021) [22] | 04537208 | 1 & 2 | 441 | Intramuscular injections of CoV2 preS dTM (1.3 or 2.6 μg) at day 1 for one dose or day 1 and 28 for two doses | Local, systemic, and unsolicited AEs; SARS-CoV-2-neutralizing antibody | 2–8 °C | |
RNA | Anderson et al. (N Engl J Med 2020) [23] | 04283461 | 1 | 40 | Intramuscular injections of mRNA-1273 (25 or 100 μg) at days 1 and 29 | Local and systemic AEs; anti-S-2P antibody; anti-RBD antibody; SARS-CoV-2 neutralizing antibody | −20 °C or 2–8 °C |
Chu et al. (Vaccine 2021) [24] | 04405076 | 2 | 600 | Intramuscular injections of mRNA-1273 (50 or 100 μg) at days 1 and 29 | Local and systemic AEs; Anti-S antibody; SARS-CoV-2-neutralizing antibody | −20 °C or 2–8 °C | |
Jackson et al. (N Engl J Med 2020) [25] | 04283461 | 2 | 45 | Intramuscular injections of mRNA-1273 (25, 100, 250 μg) at days 1 and 29 | Local, systemic, and unsolicited AEs; anti-S-2P antibody; anti-RBD antibody; SARS-CoV-2-neutralizing antibody | −20 °C or 2–8 °C | |
Mulligan et al. (Nature 2020) [26] | 04368728 | 1 & 2 | 45 | Intramuscular injection of BNT162b1 (10, 30 μg) at day 0 and 21 or BNT162b1 (100 μg) at day0 | Local and systemic AEs; anti-RBD antibody; SARS-CoV-2-neutralizing antibody | −80 °C | |
Sahin et al. (Nature 2020) [27] | 04368728 | 1 & 2 | 60 | Intramuscular injections of BNT162b1 (1, 10, 30, 50 μg) at day 1 and 22 or BNT162b1 (60 μg) at day 1 | Local and systemic AEs; anti-RBD antibody; SARS-CoV-2-neutralizing antibody | −80 °C | |
Walsh et al. (N Engl J Med 2020) [28] | 04368728 | 1 & 2 | 195 | Intramuscular injections of BNT162b1 or BNT162b2 (10, 20, 30 μg) at day 0 and 21 | Local and systemic AEs; anti-S1 antibody; SARS-CoV-2-neutralizing antibody | −80 °C | |
DNA | Tebas et al. (EClinicalMedicine 2021) [29] | 04336410 | 1 | 40 | Intrdermal injections of INO-4800 (1, 2 mg) at weeks 0 and 4 | Local and systemic AEs; anti-S antibody; SARS-CoV-2-neutralizing antibody | 2–8 °C |
Viral vector | Zhu et al. (Lancet 2020a) [30] | 04313127 | 1 | 108 | Intramuscular injection of adenovirus type-5 vectored COVID-19 vaccine (5 × 1010, 1 × 1011, and 1.5 × 1011 viral particles) at day 0 | Local and systemic AEs; anti-RBD antibody; SARS-CoV-2 neutralizing antibody | N/A |
Folegatti et al. (Lancet 2020) [31] | 04324606 | 1 & 2 | 1077 | Intramuscular injections of AZD1222 (5 × 1010 viral particles) at days 0 and 28 | Local, systemic, and unsolicited AEs; anti-Spike antibody; SARS-CoV-2 neutralizing antibody | −80 °C or 2–8 K22 | |
Barrett et al. (Nat Med 2021) [32] | 04324606 | 1 & 2 | 52 | Intramuscular injections of AZD1222 (5 × 109 or 2.5 × 1010 viral particles) at days 0 and 28 | Local and systemic AEs; anti-S antibody; anti-RBD antibody; SARS-CoV-2-neutralizing antibody | −80 °C or 2–8 °C | |
Zhu et al. (Lancet 2020b) [33] | 04341389 | 2 | 508 | Intramuscular injection of adenovirus type-5 vectored COVID-19 vaccine (5 × 1010 or 1 × 1011 viral particles) at day 0 | Local, systemic, and unsolicited AEs; anti-RBD antibody; SARS-CoV-2-neutralizing antibody | N/A | |
Ramasamy et al. (Lancet 2021) [34] | 04400838 | 2 & 3 | 560 | Intramuscular injections of AZD1222 (2.2 × 1010 or 3.5–6.5 × 1010 viral particles) at days 0 and 28 | Local and systemic AEs; anti-S antibody; anti-RBD antibody; SARS-CoV-2-neutralizing antibody | −80 °C or 2–8 °C | |
Sadoff et al. (N Engl J Med 2021) [35] | 04436276 | 1 & 2 | 805 | Intramuscular injections of Ad26.COV2.S (5 × 1010 or 1 × 1011 viral particles) at day 1 or/and day 57 | Local, systemic, and severe unsolicited AEs; Anti-S antibody; SARS-CoV-2-neutralizing antibody | 2–8 °C | |
Stephenson et al. (JAMA 2021) [36] | 04436276 | 1 | 25 | Intramuscular injections of Ad26.COV2.S (5 × 1010 or 1 × 1011 viral particles) at day 1 or/and day 57 | Local, systemic, and unsolicited AEs; Anti-S antibody; Anti-RBD antibody SARS-CoV-2-neutralizing antibody | 2–8 °C | |
Logunov et al. (Lancet 2020) [37] | 04436471 & 04437875 | 1 & 2 | 76 | Intramuscular injections of rAd26-S and rAd5-S at day 0 for phase 1 trial, and at day 0 and 21 for phase 2 trial | Local and systemic AEs; anti-RBD antibody; SARS-CoV-2-neutralizing antibody | Frozen: −18 °C & lyophilized: 2–8 °C | |
Inactivated virus | Zhang et al. (Lancet Infect Dis 2021) [38] | 04352608 | 1 & 2 | 744 | Intramuscular injections of CoronaVac (3 or 6 μg) at day 0 and 14 or 28 for phase 1or phase 2 | Local, systemic, and unsolicited AEs; Anti-RBD antibody; SARS-CoV-2-neutralizing antibody | 2–8 °C |
Wu et al. (Lancet Infect Dis 2021) [39] | 04383574 | 1 & 2 | 422 | Intramuscular injections of inactivated CN02 strain at day 0 and 28 for phase 1 trial (3, 6 μg), and at day 0 for phase 2 trial (1.5, 3, 6 μg) | Local and systemic AEs; SARS-CoV-2 neutralizing antibody | 2–8 °C | |
Che et al. (Clin Infect Dis 2020) [40] | 04412538 | 2 | 750 | Injections of inactivated virus (100 EU or 150 EU viral antigen) at day 0 and boost at day 14 or 28 | Local, systemic, and unsolicited AEs; anti-SARS-CoV-2 antibody; SARS-CoV-2-neutralizing antibody | N/A | |
Pu et al. (Vaccine 2021) [41] | 04412538 | 1 | 192 | Intramuscular injections of inactivated virus with a D614G mutation in the S protein (50, 100, or 150 EU) at days 0 and 14 or 28. | Local, systemic, and unsolicited AEs; Anti-S antibody; SARS-CoV-2-neutralizing antibody | N/A | |
Ella et al. (Lancet Infect Dis 2021a) [42] | 04471519 | 1 | 375 | Intramuscular injections of BBV152 (3 or 6 μg) at days 0 and 14 | Local and systemic AEs; anti-S antibody; anti-RBD antibody; SARS-CoV-2 neutralizing antibody | 2–8 °C | |
Ella et al. (Lancet Infect Dis 2021b) [43] | 04471519 | 2 | 380 | Intramuscular injections of BBV152 (3 or 6 μg) at days 0 and 28 | Local and systemic AEs; anti-S antibody; anti-RBD antibody; SARS-CoV-2-neutralizing antibody | 2–8 °C | |
Virus-like particle | Ward et al. (Nat Med 2021) [44] | 04450004 | 1 | 180 | Intramuscular injections of CoVLP (3.75, 7.5, or 15 μg) at days 0 and 21 | Local, systemic, and unsolicited AEs; Anti-S antibody; SARS-CoV-2-neutralizing antibody | 2–8 °C |
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Ma, K.S.-K.; Lee, C.-C.; Liu, K.-J.; Wei, J.C.-C.; Lee, Y.-T.; Wang, L.-T. Safety and Seroconversion of Immunotherapies against SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis of Clinical Trials. Pathogens 2021, 10, 1537. https://doi.org/10.3390/pathogens10121537
Ma KS-K, Lee C-C, Liu K-J, Wei JC-C, Lee Y-T, Wang L-T. Safety and Seroconversion of Immunotherapies against SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis of Clinical Trials. Pathogens. 2021; 10(12):1537. https://doi.org/10.3390/pathogens10121537
Chicago/Turabian StyleMa, Kevin Sheng-Kai, Chien-Chang Lee, Ko-Jiunn Liu, James Cheng-Chung Wei, Yuan-Ti Lee, and Li-Tzu Wang. 2021. "Safety and Seroconversion of Immunotherapies against SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis of Clinical Trials" Pathogens 10, no. 12: 1537. https://doi.org/10.3390/pathogens10121537