Immunogenicity, Safety, and Protective Efficacy of Mucosal Vaccines Against Respiratory Infectious Diseases: A Systematic Review and Meta-Analysis
Abstract
1. Introduction
2. Methods
2.1. Study Design
2.2. Search Strategy and Selection Criteria
2.3. Development of Meta-Analysis
2.4. Statistical Analysis
3. Results
4. Characteristics of the Included Studies
5. The Immunogenicity of Mucosal Vaccines
6. The Safety of Mucosal Vaccines
7. The Vaccine Effectiveness of Mucosal Vaccines
8. Risk of Bias
9. Sensitivity Analyses and Publication Bias
10. Discussion
11. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Study | Country | Study Design | No. of Research Centers | Infectious Disease | Administration | Vaccines | Comparison | Population Characteristics | Sample Size | Safety | Immunogenicity | Protective Efficacy |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Li et al. (2023) [23] | China | A multicenter, open-label phase 3 trial. | Multicenter | COVID-19 | Inhalation | Ad5-nCoV | Inactivated vaccine | Men: 5738 Women: 4529 Median age: 53 years (18–92) | Safety cohort Aerosolized Ad5-nCoV: 10,059 Immunology sub-cohort Aerosolized Ad5-nCoV: 212 Inactivated vaccine: 208 | √ | √ | √ |
Li et al. (2022) [24] | China | A randomized, open label, single-center, controlled trial. | Single-center | COVID-19 | Inhalation | Ad5nCoV | CoronaVac | Chinese adult: ≥18 y | Low-dose group: 140 High-dose group: 140 CoronaVac group: 140 | √ | √ | N.A. |
Wang et al. (2023) [25] | China | A prospective cohort, open-label study. | Multicenter | COVID-19 | Inhalation | BBIBP-CorV+ Convidecia or BBIBP-CorV+ aerosolized Convidecia | CoronaVac+ aerosolized Convidecia | Age: 19–59 y Mean age: 37.5 y (SD 10.3 years) | BBIBP-CorV+ Convidecia: 101 BBIBP-CorV+ aerosolized Convidecia: 12 CoronaVac + aerosolized Convidecia: 23 | N.A. | √ | N.A. |
Sun et al. (2024) [34] | China | An open-label, single-center, investigator-initiated trial. | Single-center | COVID-19 | Intranasal spray | NB2155 | N.A. | Age: 18–59 y | I: 128 | √ | √ | N.A. |
Wu et al. (2021) [26] | China | A single-center, open-label, randomized phase 1 trial. | Single-center | COVID-19 | Inhalation | Ad5-nCoV | N.A. | Age: ≥18 y | HDmu group: 26 LDmu group: 26 MIX group: 26 1Dim group: 26 2Dim group: 26 | √ | √ | N.A. |
Dodaran et al. (2023) [35] | Iran | A single-center, randomized, double-blind controlled, dose-finding trial. | Single-center | COVID-19 | Intranasal spray | Spike Protein COVID-19 vaccine (RCP) | Placebo | Healthy men and non-pregnant women age: 18–55 y | Placebo: 30 Vac.5: 30 Vac.10: 30 Vac.20: 30 | √ | √ | N.A. |
Zhang et al. (2023) [27] | China | A non-randomized, open-label and parallel controlled phase 4 trial. | Multicenter | COVID-19 | Inhalation | Ad5-nCoV or ZF2001, CoronaVac | N.A. | Healthy people: 19–25 y | Ad5-nCoV-IM: 229 Ad5-nCoV-IH: 223 ZF2001: 219 CoronaVac: 233 | √ | √ | N.A. |
Madhavan et al. (2022) [36] | UK | An open-label phase 1 clinical trial. | Single-center | COVID-19 | Intranasal spray | IN ChAdOx1 nCoV-19 | N.A. | Healthy people: 18–53 y | Group 1 5 × 109vp ChAdOx1nCOV-19IN: 6 Group 2 5 × 1010vp ChAdOx1nCOV-19IN: 12 Group 3 2 × 1010vp ChAdOx1nCOV-19IN: 12 Group 4 Previous ChAdOx1nCoV-19IM: 6 Group 5 Previous BNT162b2IM: 6 | √ | √ | N.A. |
Mi et al. (2024) [37] | China | A prospective cohort study. | Single-center | COVID-19 | Intranasal spray | dNS1-RBD | N.A. | Healthy people: ≥18 y | I: 536 C: 811 | N.A. | N.A. | √ |
Huang et al. (2023) [28] | China | A randomized, open-label, parallel-controlled, non-inferiority study. | Multicenter | COVID-19 | Inhalation | Ad5-nCoV or BBIBP-CorV or CoronaVac | N.A. | Children: 6–12 y Adolescents: 13–17 y | Children AAd5: 110 IMAd5: 35 Inactivated vaccine: 35 Adolescents AAd5: 110 IMAd5: 35 Inactivated vaccine: 35 | √ | √ | N.A. |
Tang et al. (2023) [29] | China | An open-label, parallel-controlled, phase 4, randomized trial. | Multicenter | COVID-19 | Inhalation | Ad5-nCoV or CoronaVac | N.A. | Healthy people: ≥18 y | Aerosolized Ad5-nCoV: 117 Intramuscular Ad5-nCoV: 120 CoronaVac: 119 | √ | √ | N.A. |
Singh et al. (2023) [38] | India | A randomized, open-label, multicenter trial. | Multicenter | COVID-19 | Intranasal spray | iNCOVACC or Covaxin | N.A. | Healthy men and non-pregnant women age: ≥18 y | BBV154: 2989 Covaxin: 161 | √ | √ | N.A. |
Zhong et al. (2022) [30] | China | A randomized, open-label, single-center trial. | Single-center | COVID-19 | Intranasal spray | Ad5-nCoV or CoronaVac | N.A. | Group A median age: 41.62 y (41.62 ± 9.10). Group B median age: 40.90 y (40.90 ± 9.77). Group C median age: 42.12 y (42.12 ±8.56). | Group A low I-I-Ad5: 50 Group B high I-I-Ad5: 50 Group C I-I-I: 50 | N.A. | √ | N.A. |
Jin et al. (2023) [31] | China | A randomized, open-label, single-center trial. | Single-center | COVID-19 | Inhalation | Ad5-nCoV or CoronaVac | N.A. | Healthy people: ≥18 y | Low-dose group: 140 High-dose group: 139 CoronaVac group: 140 | √ | √ | N.A. |
Wang et al. (2023) [25] | China | A prospective cohort study. | Multicenter | COVID-19 | Inhalation | Convidecia Air | N.A. | Group A: 18–59 y Group B: ≥60 y Average age of infected individuals: 46.1 ± 15.5 y Average age of uninfected individuals: 46.3 ± 15.5 y | FAS-7d N: 13,600 FAS-14d N: 6576 | √ | N.A. | √ |
Xu et al. (2023) [33] | China | A randomized, double blinded, parallel controlled trial. | Single-center | COVID-19 | Inhalation | Ad5-nCoVO-IH or Ad5-nCoV/O-IH or Ad5-nCoV-IH | N.A. | Healthy people: ≥18 y | Ad5-nCoVO IH group: 150 Ad5-nCoV/O-IH group: 151 Ad5-nCoV IH group: 150 | √ | √ | N.A. |
Zhang et al. (2023) [39] | China | A phase 1, randomized, double-blinded, placebo-controlled, dose escalation study. | Single-center | COVID-19 | Intranasal spray | DelNS1-nCoV-RBD LAIV | Placebo | Healthy people: 18–55 y | High-dose: 12 Low-dose: 11 Placebo: 6 | √ | √ | N.A. |
Zhu et al. (2022) [40] | China | A single-center, double-blind, randomized, placebo-controlled study. | Single-center | COVID-19 | Intranasal spray | dNS1-RBD | Placebo | Healthy people: ≥18 y | Phase 1 trial I: 51 C: 12 Phase 2 trial I: 485 C: 239 Phase 2 extension trial (subgroup) I: 148 C: 149 | √ | √ | N.A. |
Zhu et al. (2023) [41] | China | A multicenter, randomized, double-blind, placebo-controlled, case-driven, and adaptive design phase 3 trial. | Multicenter | COVID-19 | Intranasal spray | dNS1-RBD | Placebo | Healthy men and non-pregnant women age: ≥18 y | Participants without a COVID-19 vaccination history I: 6910 C: 6904 Participants with a COVID-19 vaccination history I: 8586 C: 8590 | √ | N.A. | √ |
Ambrose et al. (2013) [42] | USA | A randomized, placebo-controlled study. | Multicenter | Influenza | Intranasal spray | LAIV | Placebo | Healthy people: 18–64 y | SA-LAIV: 2026 HCP-LAIV: 805 Placebo: 1420 | √ | √ | N.A. |
Pan et al. (2020) [43] | China | A multicenter, randomized controlled, double-blind phase 2 trial. | Multicenter | Influenza | Intranasal spray | LTh(αK) | Trivalent inactivated influenza virus antigens without adjuvant. | Healthy people: 20–70 y | Group 1 22.5 μg HA + 30 μg LTh(αK) adjuvant doses: 141 Group 2 22.5 μg HA + 45 μg LTh(αK) adjuvant doses: 139 Group 3 22.5 μg HA: 72 | √ | √ | N.A. |
Halperin et al. (2005) [44] | Canada | A randomized, placebo-controlled, dose-escalating clinical phase 1 trial. | Multicenter | Influenza | Intranasal spray | Inactivated trivalent influenza virus vaccine | Placebo | Healthy people: 18–50 y | N: 61 | √ | √ | N.A. |
Kiseleva et al. (2020) [45] | Russia | A randomized, double-blind, placebo-controlled study. | Multicenter | Influenza | Intranasal spray | H7N9 LAIV | Placebo | Healthy men and non-pregnant women age: 18–49 y | I: 30 C: 8 | √ | √ | N.A. |
Forrest et al. (2011) [46] | South Africa | A prospective, randomized, open-label, multicenter trial. | Multicenter | Influenza | Intranasal spray | LAIV or TIV | N.A. | Healthy people: ≥60 y | LAIV: 1508 TIV: 1501 | √ | √ | N.A. |
Manenti et al. (2017) [47] | Norway | A randomized, double-blind study. | Single-center | Influenza | Intranasal spray | IIV3 or LAIV3 | N.A. | Group A: <5 y Group B: 10–17 y Group C: ≥18 y Group D: ≥18 y | Group A Children <5: 15 Group B Children 10–17 y: 14 Group C LAIV3 vaccinated adults: 15 Group D IIV3 vaccinated adults: 15 | N.A. | √ | N.A. |
Nichol et al. (1999) [48] | USA | A randomized, double-blind, placebo-controlled trial. | Multicenter | Influenza | Intranasal spray | LAIV | Placebo | Healthy people: 18–64 y | I: 3041 C: 1520 | N.A. | √ | √ |
Mallory et al. (2010) [49] | USA | Two randomized, double-blind, placebo-controlled studies. | Multicenter | Influenza | Intranasal spray | H1N1 LAIV | Placebo | Children group: 2–17 y Adults group: 18–49 y | Children (2–17 y) I: 261 C: 65 Adults (18–49 y) I: 240 C: 60 | √ | √ | N.A. |
Block et al. (2007) [50] | USA | A prospective, phase 3, randomized, double-blind, multicenter trial. | Multicenter | Influenza | Intranasal spray | CAIV-T or frozen LAIV | N.A. | Healthy people: 5–49 y | Two-dose group (ages 5 to 8 y) CAIV-T: 186 LAIV: 190 One-dose group (ages 9 to 49 y) CAIV-T: 285 LAIV: 281 | √ | √ | N.A. |
Gruber et al. (1993) [51] | USA | A randomized, double-blind study. | Single-center | Influenza | Nose drop or Inhalation | Bivalent cold-adapted(ca) influenza A vaccine | N.A. | Healthy people: ≥18 y | ND: 97 LPA: 98 | √ | √ | N.A. |
Hammitt et al. (2009) [52] | USA | An open-label, 2-arm study. | Multicenter | Influenza | Intranasal spray | TIV or CAIV | N.A. | Healthy people: 18–45 y | CAIV: 10 TIV: 5 | N.A. | √ | N.A. |
Tong et al. (2024) [53] | USA | A randomized, double-blind study. | Multicenter | Influenza | Intranasal spray | IIV/Fluzone | LAIV/FluMist | LAIV/FluMist Median (range) age: 26 (18–49). IIV/Fluzone Median (range) age: 28 (20–51) | IIV/Fluzone: 63 LAIV/FluMist: 94 | N.A. | √ | N.A. |
Krishnan et al. (2021) [54] | India | A 2-year, triple (participant–observer–analyst)-blind, community-based vaccine trial. | Multicenter | Influenza | Intranasal spray | LAIV or IIV or IPV | Placebo | Healthy children: 2–10 y | LAIV: 1015 IIV: 1010 placebo: 507 IPV: 509 | √ | N.A. | √ |
Ai et al. (2025) [55] | China | A randomized, double-blind, placebo-controlled trial. | Multicenter | Influenza | Intranasal spray | LAIV | Placebo | Healthy children and adolescents: 3–17 y | I: 1500 C: 1500 | √ | √ | N.A. |
Phonrat et al. (2013) [56] | Thais | A randomized, double blind, placebo-controlled study. | Multicenter | Influenza | Intranasal spray | H1N1 LAIV candidate strain | Placebo | Healthy people: 12–75 y | I: 271 C: 92 | √ | √ | N.A. |
Williams et al. (2023) [57] | USA | A randomized controlled clinical trial. | Multicenter | Influenza | Intranasal spray | ccIIV4 | LAIV4 | Healthy children and adolescents: 4–21 y | ccIIV4: 112 LAIV4: 118 | √ | √ | N.A. |
Nakayama et al. (2024) [58] | Japan | A randomized, double-blind, phase 3 study. | Multicenter | Influenza | Intranasal spray | MEDI3250 | Placebo | Healthy children and adolescents: 2–18 y | I: 608 C: 302 | √ | N.A. | √ |
Pitisuttithum et al. (2017) [59] | Thais | A randomized, double-blind, placebo-controlled study. | Single-center | Influenza | Intranasal spray | LAIV H5N2 and H5N1 booster vaccine | Placebo | Healthy people: 18–49 y | Part 1 I: 101 C: 51 Part 2 I: 40 C: 20 | √ | √ | N.A. |
Rudenko et al. (2014) [60] | Russia | A randomized, double-blind, and placebo-controlled phase 1 study. | Single-center | Influenza | Intranasal spray | H7N3 LAIV | Placebo | Healthy people: 18–49 y | I: 30 C: 10 | √ | √ | N.A. |
Rudenko et al. (2015) [61] | Russia | A randomized, double-blind, placebo-controlled study. | Single-center | Influenza | Intranasal spray | A/H5N2 LAIV | Placebo | Healthy people: 18–49 y | I: 30 C: 10 | √ | √ | N.A. |
Rudenko et al. (2016) [62] | Russia | A phase 1, double-blind, randomized, placebo-controlled trial. | Single-center | Influenza | Intranasal spray | H7N9 live attenuated influenza vaccine (LAIV) | Placebo | Healthy adult men and non-pregnant women: 18–49 y. | I: 30 C: 10 | √ | √ | N.A. |
Eiden et al. (2024) [63] | USA | A randomized, double-blind, double-dummy phase 1b trial. | Multicenter | Influenza | Intranasal spray | H3N2M2SR vaccine plus placebo or H3N2 M2SR vaccine plus Fluzone HD or Fluzone HD plus placebo | Placebo | Healthy people: 65–85 y | H3N2M2SR plus placebo: 89 H3N2 M2SR plus Fluzone HD: 94 Fluzone HD plus placebo: 92 Placebo: 30 | √ | √ | N.A. |
Speroni et al. (2005) [64] | USA | An overarching survey. | Single-center | Influenza | Intranasal spray | Fluzone or FluMist | Unvaccinated | The population drawn from hospital employees, volunteers, physicians and students | Fluzone: 201 FluMist: 63 unvaccinated: 77 | √ | N.A. | N.A. |
Tasker et al. (2021) [65] | USA | A phase 2 randomized, double-blind, placebo-controlled, single ascending-dose study. | Single-center | Influenza | Intranasal spray | NasoVAX | Placebo | Healthy people: 18–49 y | I: 45 C: 15 | √ | √ | N.A. |
Treanor et al. (1999) [66] | USA | A randomized double-blind, placebo-controlled trial. | Multicenter | influenza | Intranasal spray | CAIV-T or TIV | Placebo | Healthy people: 18–45 y | CAIV-T: 36 TIV: 33 Placebo: 34 | √ | √ | √ |
Li et al. (2022) [67] | China | A randomized, double-blind, placebo-controlled study. | Single-center | Influenza | Intranasal spray | LAIV | Placebo | Group A: Healthy people ≥18 y Group B: Healthy people: 3–17 y | Group A I: 30 C: 10 Group B I: 30 C: 10 | √ | N.A. | N.A. |
Voorthuizen et al. (1981) [68] | The Netherlands | A double-blind placebo-controlled study. | N.A. | Influenza | Intranasal spray | Live influenza A vaccine | Placebo | Healthy people: 19–28 y (mean age 22.5 y) | I: 14 C: 14 | √ | √ | N.A. |
Vesikari et al. (2015) [69] | Finland | A randomized, double-blind, placebo-controlled study. | Multicenter | Influenza | Intranasal spray | CAIV-T | Placebo | Healthy infants: 6–24 w Gestational age: ≥37 w Birth weight: ≥2500 g | 6-to < 16-wk Cohort group I: 31 C: 28 16-to < 24-wk Cohort group I: 30 C: 31 | √ | N.A. | N.A. |
Plas et al. (2024) [70] | The Netherlands | A first-in-human, randomized, double-blind, controlled, dose-escalation study. | Single-center | Influenza | Intranasal spray | FluGEM | Unadjuvanted TIV only | Part 1: Healthy people: 18–49 y Part 2: Healthy people: ≥65 y | Age 18–49 Control group: 15 1.25 mgFluGEM: 15 2.5 mgFluGEM: 15 5.0 mgFluGEM: 15 Age ≥ 65 y Control group: 15 1.25 mg FluGEM: 15 | √ | √ | N.A. |
Wang et al. (2009) [71] | USA | A statistical analysis of the national defense medical testing system. | Single-center | Influenza | N.A. | LAIV or TIV | Unvaccinated | Healthy people: 17–49 y (Army: 16–43 y; Air Force: 16–28 y; Marine Corps: 16–30 y; Navy: 16–36 y). | N.A. | N.A. | N.A. | √ |
Rigamonti et al. (2024) [72] | Italy | A retrospective observational cohort study. | Single-center | Influenza | N.A. | LAIV-4 or IIV | N.A. | Healthy children: 2–14 y enrolled in the Pedianet database. | N.A. | N.A. | N.A. | √ |
Gasparini et al. (2021) [73] | Italy | An observational study. | Multicenter | Influenza | Intranasal spray | Fluenz Tetr | N.A. | Healthy children and adolescents: 2–17 y Preschoolers: 2–5 y School-age: 6–10 y Adolescents: 11–17 y | Preschoolers: 1924 School-age: 1179 Adolescents: 116 | √ | N.A. | N.A. |
Green et al. (2019) [74] | UK | An open-label, dose escalation, phase 1 clinical trial. | Multicenter | RSV | Intranasal spray | MVA-RSV or PanAd3-RSV | Unvaccinated | Healthy people: 18–50 y | I: 24 C: 6 | √ | √ | N.A. |
Verdijk et al. (2020) [75] | The Netherlands | A double-blinded, randomized, placebo-controlled, parallel-group, single-dose study. | Single-center | RSV | Intranasal spray | RSVΔG | Placebo | Healthy people: 18–50 y | I: 36 C: 12 | √ | √ | N.A. |
Cunningham et al. (2022) [76] | USA | A randomized, double-blind, placebo-controlled study. | Multicenter | RSV | Intranasal spray | RSV/ΔNS2/Δ1313/I1314L or RSV/276 | Placebo | Median age: 12.5 y Interquartile range: 8.0–15.0 y | RSV/ΔNS2/Δ1313/I1314L: 25 RSV/276: 25 Placebo: 12 | √ | √ | N.A. |
Karron et al. (2023) [77] | USA | A randomized, double-blind, placebo-controlled study. | Single-center | RSV | Nose drops | RSV/6120/ΔNS2/1030s | Placebo | RSV-seropositive children: 12–59 m RSV-seronegative children: 6–24 m | RSV-seropositive children I: 10 C: 5 RSV-seronegative infants I: 20 C: 10 | √ | √ | N.A. |
Spearman et al. (2023) [78] | USA | A phase 1 clinical trial. | Multicenter | RSV | Intranasal spray | PIV5-RSV | N.A. | Group 1: Healthy people: 33–59 y Group 2: Healthy people: 61–75 y | Group 1 Planned participant ages 18 to 59 years: 15 Group 2 Planned participant ages 60 to 75 years: 15 | √ | √ | N.A. |
Creech et al. (2022) [84] | USA | A phase 2a, single-center, randomized, partially blind, placebo-controlled clinical trial. | Multicenter | Pertussis | Intranasal spray | BPZE1 | Placebo | Healthy adult men and non-pregnant women: 18–49 y. | 107 CFU BPZE1 via VaxINator device: 15 109 CFU BPZE1 via VaxINator device: 15 Placebo via VaxINator device: 15 109 CFU BPZE1 via a needleless tuberculin syringe: 5 | √ | √ | N.A. |
Thorstensson et al. (2014) [85] | Sweden | A double-blind, placebo-controlled, dose-escalating study. | Single center | Pertussis | Intranasal spray | BPZE1 | N.A. | Healthy people: 19–31 y | Group 1 I: 12 C: 4 Group 2 I: 12 C: 4 Group 3 I: 12 C: 4 | √ | √ | N.A. |
Jahnmatz et al. (2020) [86] | Sweden | A phase 1b, double-blind, randomized, placebo-controlled, dose-escalation study. | Single center | Pertussis | Intranasal spray | BPZE1 | N.A. | Healthy people: 18–32 y | Group 1 I: 12 C: 4 Group 2 I: 12 C: 4 Group 3 I: 12 C: 4 | √ | √ | N.A. |
Keech et al. (2023) [87] | USA | A randomized, double-blind phase 2b study. | Multicenter | Pertussis | Intranasal spray | BPZE1 or Tdap | N.A. | Healthy people: 18–50 y | BPZE1–BPZE1: 92 BPZE1–placebo: 92 Tdap–BPZE1: 46 Tdap–placebo: 50 | √ | √ | √ |
Audran et al. (2024) [79] | Swiss | A randomized, double-blind, controlled phase 1 study. | Single-center | Tuberculosis | Inhalation | ChAdOx1-85A and saline placebo | ChAdOx1-85A | Healthy people: 18–55 y | 1 × 109 Group: 3 5 × 109 Group: 3 1 × 1010 Group: 3 Aerosol group: 10 Intramuscular group: 10 Naïve aerosol group: 10 | √ | √ | N.A. |
Thomas et al. (2019) [80] | UK | A phase 1 randomized, blinded clinical trial. | Multicenter | Tuberculosis | Inhalation | MVA85A | N.A. | Healthy people: 21–42 y | Group 1 aerosol (D0)-intradermal (D28): 12 Group 2 intradermal (D0)-aerosol (D28): 12 Group 3 intradermal (DO)-intradermal (D28): 12 | √ | √ | N.A. |
Jeyanathan et al. (2022) [81] | Canada | An open-label phase I trial. | Single-center | Tuberculosis | Inhalation | AdHu5Ag85A | N.A. | Healthy people: 18–55 y | LD group: 11 HD group: 11 IM group: 9 | √ | √ | N.A. |
Satti et al. (2024) [82] | UK | A controlled human infection trial consisting of a dose escalation trial followed by a single-blind, randomized, controlled, phase 1 trial. | Multicenter | Tuberculosis | Inhalation | BCG | N.A. | Healthy people: 18–50 y | Group 1 Aerosol BCG, dose escalation: 6 Aerosol BCG: 4 Intradermal BCG: 3 Group 2 Aerosol BCG, dose escalation: 9 Aerosol BCG: 12 Intradermal BCG: 12 | √ | √ | N.A. |
Satti et al. (2014) [83] | UK | A phase 1, double-blind, randomized controlled trial. | Multicenter | Tuberculosis | Inhalation | MVA85A | N.A. | Healthy people: 18–50 y | Group A aerosol MVA85A: 12 Group B intradermal MVA85A: 12 | √ | √ | N.A. |
Study | Study Design | Mucosal Vaccines | Compared Groups | Immunogenicity Results |
---|---|---|---|---|
Satti et al. (2014) [83] | Phase I, double-blind, RCT | MVA85A (modified vaccinia ankara vector tuberculosis vaccine) | Intradermal vaccination | MVA85A elicited Ag85A-specific CD4 T cells in bronchoalveolar (BAL) lavage fluid in both the inhaled and intradermal vaccination groups, with a more significant response noted in the inhaled group. |
Thomas et al. (2019) [80] | Phase I, RCT | MVA85A (modified vaccinia ankara vector tuberculosis vaccine) | Intradermal vaccination | MVA85A delivered through intradermal injection solely induced the synthesis of serum Ag85A antibodies, while inhaled MVA85A provoked considerably elevated levels of Ag85A-specific CD4+ and CD8+ T-cell cytokines in the pulmonary mucosa compared to intradermal immunization. |
Audran et al. (2024) [79] | Phase I, RCT, double-blind | ChAdOx1-85A (chimpanzee adenovirus vector tuberculosis vaccines) | Intramuscular vaccination | Inhaled ChAdOx1-85A induced robust lung mucosal and systemic Ag85A-specific T-cell responses compared to intramuscular ChAdOx1-85A vaccination. |
Jeyanathan et al. (2022) [81] | Phase I, open-labeled | AdHu5Ag85A (human adenovirus Type 5 vector tuberculosis vaccine) | Intramuscular vaccination | Inhaled AdHu5Ag85A remarkably induced airway tissue–resident memory CD4+ and CD8+ T cells of polyfunctionality and Ag85A-specific T cell responses in blood. |
Experimental Groups | Control Groups | Symptom | Number of Studies Included | Risk Ratio (95% CI) | Weight% | I2 | p-Value |
---|---|---|---|---|---|---|---|
Mucosal COVID-19 vaccines | Intramuscular COVID-19 vaccines | Fever | 4 | 2.24 (1.08, 4.64) | 100 | 0.00% | 0.929 |
Mucosal COVID-19 vaccines | Intramuscular COVID-19 vaccines | Myalgia | 4 | 1.12 (0.34, 3.72) | 100 | 0.00% | 0.582 |
Mucosal COVID-19 vaccines | Intramuscular COVID-19 vaccines | Cough | 3 | 2.86 (0.82, 10.03) | 100 | 1.00% | 0.364 |
Mucosal COVID-19 vaccines | Intramuscular COVID-19 vaccines | Sore throat | 3 | 3.93 (1.08, 14.27) | 100 | 0.00% | 0.531 |
Mucosal COVID-19 vaccines | Intramuscular COVID-19 vaccines | Headache | 4 | 2.35 (1.13, 4.87) | 94.95 | 0.00% | 0.860 |
Mucosal COVID-19 vaccines | Placebo | Headache | 1 | 0.30 (0.01, 7.09) | 5.05 | 0.00% | <0.001 |
Mucosal COVID-19 vaccines | Overall | Headache | 5 | 2.12 (1.04, 4.31) | 100 | 0.00% | 0.681 |
Mucosal COVID-19 vaccines | Intramuscular COVID-19 vaccines | Rhinorrhea | 3 | 4.56 (1.00, 20.68) | 100 | 0.00% | 0.875 |
Mucosal influenza vaccines | Placebo | Fever | 8 | 1.00 (0.89, 1.12) | 61.84 | 13.50% | 0.325 |
Mucosal influenza vaccines | Intramuscular influenza vaccines | Fever | 4 | 0.87 (0.79, 0.95) | 38.16 | 0.00% | 0.741 |
Mucosal influenza vaccines | Overall | Fever | 12 | 0.95 (0.86, 1.04) | 100 | 19.80% | 0.249 |
Mucosal influenza vaccines | Placebo | Myalgia | 4 | 2.32 (1.24, 4.34) | 23.92 | 0.00% | 0.969 |
Mucosal influenza vaccines | Intramuscular influenza vaccines | Myalgia | 2 | 1.02 (0.87, 1.21) | 76.08 | 0.00% | 0.663 |
Mucosal influenza vaccines | Overall | Myalgia | 6 | 1.28 (0.91, 1.79) | 100 | 24.40% | 0.251 |
Mucosal influenza vaccines | Placebo | Cough | 6 | 0.74 (0.61, 0.89) | 54.96 | 0.00% | 0.7 |
Mucosal influenza vaccines | Intramuscular influenza vaccines | Cough | 2 | 2.27 (0.80, 6.41) | 45.04 | 85.70% | 0.008 |
Mucosal influenza vaccines | Overall | Cough | 8 | 1.06 (0.63, 1.78) | 100 | 82.10% | <0.001 |
Mucosal influenza vaccines | Placebo | Sore throat | 5 | 1.01 (0.84, 1.20) | 60.71 | 0.00% | 0.999 |
Mucosal influenza vaccines | Intramuscular influenza vaccines | Sore throat | 2 | 1.75 (1.06, 2.87) | 39.29 | 47.50% | 0.167 |
Mucosal influenza vaccines | Overall | Sore throat | 7 | 1.24 (0.96, 1.59) | 100 | 52.10% | 0.051 |
Mucosal influenza vaccines | Placebo | Headache | 6 | 1.05 (0.81, 1.38) | 49.86 | 36.30% | 0.164 |
Mucosal influenza vaccines | Intramuscular influenza vaccines | Headache | 3 | 1.09 (0.77, 1.55) | 50.14 | 83.50% | 0.002 |
Mucosal influenza vaccines | Overall | Headache | 9 | 1.06 (0.87, 1.29) | 100 | 60.00% | 0.010 |
Mucosal influenza vaccines | Placebo | Nasal congestion | 6 | 1.20 (1.02, 1.42) | 51.16 | 0.00% | 0.849 |
Mucosal influenza vaccines | Intramuscular influenza vaccines | Nasal congestion | 2 | 2.78 (0.79, 9.77) | 48.84 | 94.20% | <0.001 |
Mucosal influenza vaccines | Overall | Nasal congestion | 8 | 1.66 (1.17, 2.34) | 100 | 73.70% | <0.001 |
Mucosal influenza vaccines | Placebo | Rhinorrhea | 6 | 1.11 (0.98, 1.25) | 80.7 | 0.00% | 0.535 |
Mucosal influenza vaccines | Intramuscular influenza vaccines | Rhinorrhea | 1 | 4.79 (2.44, 9.38) | 19.3 | 0.00% | <0.001 |
Mucosal influenza vaccines | Overall | Rhinorrhea | 7 | 1.26 (0.68, 2.32) | 100 | 72.30% | 0.001 |
Mucosal RSV vaccines | Placebo | Fever | 5 | 1.40 (0.56, 3.47) | 100 | 0.00% | 0.845 |
Mucosal RSV vaccines | Placebo | Cough | 5 | 1.86 (0.89, 3.89) | 100 | 0.00% | 0.751 |
Mucosal RSV vaccines | Placebo | Rhinorrhea | 2 | 1.79 (1.00, 3.20) | 100 | 0.00% | 0.381 |
Mucosal tuberculosis vaccines | Injectable tuberculosis vaccines | Fever | 2 | 1.63 (0.08, 32.05) | 100 | 49.90% | 0.158 |
Mucosal tuberculosis vaccines | Injectable tuberculosis vaccines | Myalgia | 3 | 0.75 (0.15, 3.85) | 100 | 47.30% | 0.15 |
Mucosal tuberculosis vaccines | Injectable tuberculosis vaccines | Sore throat | 2 | 1.01 (0.46, 2.22) | 100 | 0.00% | 0.532 |
Mucosal tuberculosis vaccines | Injectable tuberculosis vaccines | Headache | 3 | 1.10 (0.69, 1.75) | 100 | 0.00% | 0.485 |
Mucosal pertussis vaccines | Placebo | Cough | 2 | 0.75 (0.16, 3.64) | 100 | 0.00% | 0.55 |
Mucosal pertussis vaccines | Placebo | Headache | 2 | 1.17 (0.64, 2.15) | 100 | 0.00% | 0.631 |
Mucosal pertussis vaccines | Placebo | Nasal congestion | 2 | 2.30 (0.37, 14.38) | 100 | 0.00% | 0.837 |
Mucosal pertussis vaccines | Placebo | Rhinorrhea | 2 | 1.31 (0.59, 2.92) | 100 | 0.00% | 0.742 |
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Chen, J.; Lin, W.; Yang, C.; Lin, W.; Cheng, X.; He, H.; Li, X.; Yu, J. Immunogenicity, Safety, and Protective Efficacy of Mucosal Vaccines Against Respiratory Infectious Diseases: A Systematic Review and Meta-Analysis. Vaccines 2025, 13, 825. https://doi.org/10.3390/vaccines13080825
Chen J, Lin W, Yang C, Lin W, Cheng X, He H, Li X, Yu J. Immunogenicity, Safety, and Protective Efficacy of Mucosal Vaccines Against Respiratory Infectious Diseases: A Systematic Review and Meta-Analysis. Vaccines. 2025; 13(8):825. https://doi.org/10.3390/vaccines13080825
Chicago/Turabian StyleChen, Jiaqi, Weitong Lin, Chaokai Yang, Wenqi Lin, Xinghui Cheng, Haoyuan He, Xinhua Li, and Jingyou Yu. 2025. "Immunogenicity, Safety, and Protective Efficacy of Mucosal Vaccines Against Respiratory Infectious Diseases: A Systematic Review and Meta-Analysis" Vaccines 13, no. 8: 825. https://doi.org/10.3390/vaccines13080825
APA StyleChen, J., Lin, W., Yang, C., Lin, W., Cheng, X., He, H., Li, X., & Yu, J. (2025). Immunogenicity, Safety, and Protective Efficacy of Mucosal Vaccines Against Respiratory Infectious Diseases: A Systematic Review and Meta-Analysis. Vaccines, 13(8), 825. https://doi.org/10.3390/vaccines13080825