Advances and challenges in intranasal vaccines development for respiratory infectious diseases
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摘要: 呼吸道传染性疾病由于传播途径难以被有效阻断，易发生大范围流行，而鼻腔免疫被认为是极有潜力的疫苗接种途径。与传统的疫苗不同，鼻腔疫苗可同时诱导呼吸道局部和全身性系统免疫，具有在抵御呼吸道传染性疾病的第一线预防病原体感染和阻断传播的特点。目前已有安全有效的鼻喷流感疫苗获批上市。自COVID-19流行以来，多条技术路线的新型冠状病毒疫苗(简称新冠疫苗)采用了鼻腔免疫方式。本文拟综述目前已上市或进入临床试验阶段的呼吸道传染性疾病鼻腔疫苗研究进展，并讨论鼻腔疫苗的独特优势和面临的挑战。Abstract: The great challenge to prevent transmission makes widespread of respiratory infectious diseases easily occur. Intranasal immunization is considered to be a promising route of vaccination to prevent it. Different from parenteral vaccines, intranasal vaccines can induce mucosal immune in respiratory tracts in addition to systemic immune, which provide the first line of defense against respiratory pathogen infection and further prevent transmission. Safe and effective intranasal spray flu vaccines have been licensed. Since the outbreak of COVID-19, intranasal administration has been applied in different vaccine platforms. This article has reviewed the progress of intranasal vaccines for respiratory infectious diseases that have been licensed or are under evaluation in the clinical trials, meanwhile discusses its unique advantages and challenges faced.
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Key words:
- Intranasal vaccine /
- Respiratory infectious diseases /
- COVID-19 /
- SARS-CoV-2 /
- Vaccine /
- Mucosal immunity
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表 1 截至2022年6月25日呼吸道传染性疾病鼻腔疫苗研究进展
Table 1. Progress in intranasal vaccine development for respiratory infectious diseases as of June 25, 2022
适应症 疫苗名称 疫苗类型 抗原成分 研发单位 研究阶段 代表性文献 流感 Ultravac® 减毒活疫苗 血凝素、神经氨酸酶 俄罗斯实验医学研究所 已上市 [6] [19-20] Nasovac-S® 减毒活疫苗 血凝素、神经氨酸酶 印度血清研究所 已上市 [49] 雾感® 减毒活疫苗 血凝素、神经氨酸酶 长春百克生物 已上市 - FluMist® 减毒活疫苗 血凝素、神经氨酸酶 Medlmmune 已上市 [8] [11] [13] NasoVAX Ad5型腺病毒载体疫苗 血凝素 Altimmune Phase Ⅱa(NCT03232567)Phase Ⅱb(NCT03760549) [15] GamFluVac Ad5型腺病毒载体疫苗 血凝素 Gamaleya研究所 Phase Ⅱ(NCT04034290) - COVID-19 SPRAY 08-Gam-COVID-Vac-2021 Ad5/Ad26型腺病毒载体疫苗 刺突蛋白 Gamaleya研究所 已上市 [22] DelNS1-2019-nCoV-RBD-OPT1 减毒H1N1流感病毒载体疫苗 受体结合域亚单位 厦门大学/香港大学/北京万泰生物 Phase Ⅲ(ChiCTR2100051391) [24] AZD1222 Y25型黑猩猩腺病毒载体疫苗 刺突蛋白 牛津大学 Phase Ⅰ(NCT04816019) [28] BBV154 Ad36型黑猩猩腺载体疫苗 刺突蛋白 华盛顿大学/Bharat生物 Phase Ⅰ(NCT04751682) [29] MV-014-212 减毒呼吸道合胞病毒载体疫苗 刺突蛋白 Meissa疫苗 Phase Ⅰ(NCT04798001) [30-31] AVX/COVID-12-HEXAPRO 减毒新城疫病毒载体疫苗 刺突蛋白 Avi-Mex Phase Ⅰ(NCT04871737) [50] CVXGA1-001 5型副流感病毒载体疫苗 刺突蛋白 CyanVac LLC Phase Ⅰ(NCT04954287) [51] COVI-VAC 减毒活疫苗 减毒病毒颗粒 Codagenix生物/印度血清研究所 Phase Ⅲ(ISRCTN15779782) [34] Mambisa(CIGB-669) 重组蛋白亚单位疫苗 受体结合域亚单位 古巴遗传工程和生物技术中心 Phase Ⅰ/Ⅱ(RPCE000000345) - 百日咳 BPZE1 减毒活疫苗 减毒病毒颗粒 法国国家健康与医学研究院 Phase Ⅱ(NCT03541499) [39] GamLPV 减毒活疫苗 减毒病毒颗粒 Gamaleya研究所 Phase Ⅱ(NCT03137927) - 结核 TB/FLU-01L 减毒H1N1流感病毒载体疫苗 ESAT-6 俄罗斯流感研究所 Phase Ⅰ(NCT03017378) [40] 
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表 2 截至2022年6月25日已上市鼻喷流感疫苗的保护效力
Table 2. Efficacy of licensed intranasal spray influenza vaccines as of June 25, 2022
鼻喷流感疫苗 上市时间 适用人群 使用国家 与三价灭活流感疫苗(TIV)的保护效力/效果(95% CI)对比 Ultravac® 1987年 3岁及以上 俄罗斯 1.7~10岁：30.0% (21.7%~37.4%) vs. 24.2% (14.9%~32.5%); 11~14岁：51.9% (45.1%~57.9%) vs. 29.6% (20.7%~37.5%)[6]; 2.9~12岁：47% vs 56%[19]; 3.41~95岁：51% (17%~79%) vs. 50% (26%~80%)[20] FluMist® 2003年 2~49岁 美国、欧盟、日本、加拿大等 1.2~8岁：71% (58%~78%) vs. 71% (50%~83%); 9~49岁：42% (-28%~74%) vs. 52% (37%~64%)[11]; 2.2~17岁：45% vs. 48%[13]; 3.18~45岁：85% vs. 71%[8] Nasovac-S® 2014年 2岁及以上 印度 雾感® 2020年 3~17岁 中国
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[1] Hellfritzsch M, Scherliess R. Mucosal vaccination via the respiratory tract[J]. Pharmaceutics, 2019, 11(8): 375. DOI: 10.3390/pharmaceutics11080375. [2] Czerkinsky C, Holmgren J. Topical immunization strategies[J]. Mucosal Immunol, 2010, 3(6): 545-555. DOI: 10.1038/mi.2010.55. [3] Kraehenbuhl JP, Neutra MR. Mucosal V: where do we stand?[J]. Curr Top Med Chem, 2013, 13(20): 2609-2628. DOI: 10.2174/15680266113136660186. [4] Krammer F. SARS-CoV-2 vaccines in development[J]. Nature, 2020, 586(7830): 516-527. DOI: 10.1038/s41586-020-2798-3. [5] Lobaina Mato. Nasal route for vaccine and drug delivery: features and current opportunities[J]. Int J Pharm, 2019, 572: 118813. DOI: 10.1016/j.ijpharm.2019.11-8813. [6] Rudenko L, Van DBH, Kiseleva I, et al. Live attenuated pandemic influenza vaccine: clinical studies on A/17/California/2009/38 (H1N1) and licensing of the Russian-developed technology to WHO for pandemic influenza preparedness in developing countries[J]. Vaccine, 2011, 29 Suppl 1: A40-A44. DOI: 10.1016/j.va-ccine.2011.04.122. [7] Biodiem. LAIV[EB/OL]. (2021-10-23)[2022-04-14]. https://www.biodiem.com/l-aiv/ .[8] Treanor JJ, Kotloff K, Betts RF, et al. Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses[J]. Vaccine, 1999, 18(9-10): 899-906. DOI: 10.1016/s0264-410x(99)00334-5. [9] Ohmit SE, Thompson MG, Petrie JG, et al. Influenza vaccine effectiveness in the 2011-2012 season: protection against each circulating virus and the effect of prior vaccination on estimates[J]. Clin Infect Dis, 2014, 58(3): 319-327. DOI: 10.1093-/cid/cit736. [10] Mclean HQ, Thompson MG, Sundaram ME, et al. Influenza vaccine effectiveness in the United States during 2012-2013: variable protection by age and virus type[J]. J Infect Dis, 2015, 211(10): 1529-1540. DOI: 10.1093/infdis/jiu647. [11] Treanor JJ, Talbot HK, Ohmit SE, et al. Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains[J]. Clin Infect Dis, 2012, 55(7): 951-959. DOI: 10.1093/cid/cis574. [12] Gaglani M, Pruszynski J, Murthy K, et al. Influenza vaccine effectiveness against 2009 pandemic influenza A(H1N1) virus differed by vaccine type during 2013-2014 in the United States[J]. J Infect Dis, 2016, 213(10): 1546-1556. DOI: 10.1093/infdis/jiv577. [13] Gill MA, Schlaudecker EP. Perspectives from the society for pediatric research: decreased effectiveness of the live attenuated influenza vaccine[J]. Pediatr Res, 2018, 83(1-1): 31-40. DOI: 10.1038/pr.2017.239. [14] FDA. Information Regarding FluMist Quadrivalent Vaccine[EB/OL]. (2018-01-26)[2022-04-14]. https://www.fda.gov/vaccines-blood-biologics/vaccines/fda informat-ion-regarding-flumist-quadrivalent-vaccine .[15] Tasker S, Wight O'Rourke A, Suyundikov A, et al. Safety and immunogenicity of a novel intranasal influenza vaccine (NasoVAX): a phase 2 randomized, controlled trial[J]. Vaccines (Basel), 2021, 9(3): 224. DOI: 10.3390/vaccines9030224. [16] Skowronski DM, Janjua NZ, De Serres G, et al. Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses[J]. PLoS One, 2014, 9(3): e92153. DOI: 10.13-71/journal.pone.0092153. [17] Bicho D, Queiroz JA, Tomaz CT. Influenza plasmid DNA vaccines: progress and prospects[J]. Curr Gene Ther, 2015, 15(6): 541-549. DOI: 10.2174/15665232156-66150929111048. [18] Kremer EJ, Perricaudet M. Adenovirus and adeno-associated virus mediated gene transfer[J]. Br Med Bull, 1995, 51(1): 31-44. DOI: 10.1093/oxfordjournals.bmb.a-072951. [19] Khan AS, Polezhaev F, Vasiljeva R, et al. Comparison of US inactivated split-virus and Russian live attenuated, cold-adapted trivalent influenza vaccines in russian schoolchildren[J]. J Infect Dis, 1996, 173(2): 453-456. DOI: 10.1093/infdi-s/173.2.453. [20] Rudenko LG, Arden NH, Grigorieva E, et al. Immunogenicity and efficacy of Russian live attenuated and US inactivated influenza vaccines used alone and in combination in nursing home residents[J]. Vaccine, 2000, 19(2): 308-318. DOI: 10.1016/S0264-410X(00)00153-5. [21] WHO. COVID-19 vaccine tracker and landscape[EB/OL]. (2022-01-11)[2022-04-14]. https://www.who.int/teams/blueprint/covid-19/covid-19-vaccine-tracker-and-landscape .[22] Russia: State Register of Medicinal Product. Gam-COVID-Vac Combined vector vaccine for the prevention of coronavirus infection caused by the SARS-CoV-2 virus[EB/OL]. (2022-03-29)[2022-04-14]. https://grls.rosminzdrav.ru/Grls_Vie-w_v2.a-spx?routingGuid=c9b0af9a-2d86-4ad1-8c53-9a0087b6c270&= .[23] Wang P, Zheng M, Lau SY, et al. Generation of DelNS1 influenza viruses: a strategy for optimizing live attenuated influenza vaccines[J]. mBio, 2019, 10(5): e02180-19. DOI: 10.1128/mBio.02180-19. [24] Chen J, Wang P, Yuan L, et al. A live attenuated influenza virus-vectored intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2 infection[J]. Sci Bull (Beijing), 2022, 67(13): 1372-1387. DOI: 10.1016/j.scib.2022.05.018. [25] Pilankatta R, Chawla T, Khanna N, et al. The prevalence of antibodies to adenovirus serotype 5 in an adult Indian population and implications for adenovirus vector vaccines[J]. J Med Virol, 2010, 82(3): 407-414. DOI: 10.1002/jmv.21721. [26] Barouch DH, Kik SV, Weverling GJ, et al. International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations[J]. Vaccine, 2011, 29(32): 5203-5209. DOI: 10.1016/j.vaccine.2011.05.025. [27] Zaiss AK, Machado HB, Herschman HR. The influence of innate and pre-existing immunity on adenovirus therapy[J]. J Cell Biochem, 2009, 108(4): 778-790. DOI: 10.1002/jcb.22328. [28] Van Doremalen N, Purushotham JW, Schulz JE, et al. Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces shedding of SARS-CoV-2 D614G in rhesus macaques[J]. Sci Transl Med, 2021, 13(607): eabh0755. DOI: 10.1126/scitranslmed.abh0755. [29] Hassan AO, Kafai NM, Dmitriev IP, et al. A single-dose intranasal chAd vaccine protects upper and lower respiratory tracts against SARS-CoV-2[J]. Cell, 2020, 183(1): 169-184. DOI: 10.1016/j.cell.2020.08.026. [30] Stobart CC, Rostad CA, Ke ZL, et al. A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation[J]. Nat Commun, 2016, 7: 13916. DOI: 10.1038/ncomms13916. [31] Tioni MF, Jordan R, Pena AS, et al. One mucosal administration of a live attenuated recombinant COVID-19 vaccine protects nonhuman primates from SARS-CoV-2[J]. NPJ Vaccines, 2022, 7(1): 85. DOI: 10.1038/s41541-022-00509-6. [32] Peacock TP, Goldhill DH, Zhou J, et al. The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets[J]. Nat Microbiol, 2021, 6(7): 899-909. DOI: 10.1038/s41564-021-00908-w. [33] Johnson BA, Xie XP, Bailey AL, et al. Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis[J]. Nature, 2021, 591(7849): 293-299. DOI: 10.1038/s41586-021-03237-4. [34] Wang Y, Yang C, Song YT, et al. Scalable live-attenuated SARS-CoV-2 vaccine candidate demonstrates preclinical safety and efficacy[J]. Proc Natl Acad Sci USA, 2021, 118(29): e2102775118. DOI: 10.1073/pnas.2102775118. [35] Moradi Vahdat M, Hemmati F, Ghorbani A, et al. Hepatitis B core-based virus-like particles: A platform for vaccine development in plants[J]. Biotechnol Rep (Amst), 2021, 29: e00605. DOI: 10.1016/j.btre.2021.e00605. [36] Billaud JN, Peterson D, Schodel F, et al. Comparative antigenicity and immunogenicity of hepadnavirus core proteins[J]. J Virol, 2005, 79(21): 13641-13655. DOI: 10.1128/JVI.79.21.13641-13655.2005. [37] Center for Genetic E. Biotechnology I H. MAMBISA Study[EB/OL]. (2020-11-26)[2022-04-14]. https://rpcec.sld.cu/en/trials/RPCEC00000345-En .[38] Center for Genetic E. Biotechnology. CIGB-Mambisa/Abdala in convalescents[EB/OL]. (2021-09-08)[2022-04-14]. https://rpcec.sld.cu/en/trials/RPCEC000003-82-En .[39] Thorstensson R, Trollfors B, Al-Tawil N, et al. A phase I clinical study of a live attenuated Bordetella pertussis vaccine--BPZE1; a single centre, double-blind, placebo-controlled, dose-escalating study of BPZE1 given intranasally to healthy adult male volunteers[J]. PLoS One, 2014, 9(1): e83449. DOI: 10.1371/journal.po-ne.0083449. [40] Soundarya JSV, Ranganathan UD, Tripathy SP. Current trends in tuberculosis vaccine[J]. Med J Armed Forces India, 2019, 75(1): 18-24. DOI: 10.1016/j.mjafi.2018.12.013. [41] Piedra PA. Safety of the trivalent, cold-adapted influenza vaccine (CAIV-T) in children[J]. Semin Pediatr Infect Dis, 2002, 13(2): 90-96. DOI: 10.1053/spid.2002.122995. [42] Kendal AP. Cold-adapted live attenuated influenza vaccines developed in Russia: can they contribute to meeting the needs for influenza control in other countries?[J]. Eur J Epidemiol, 1997, 13(5): 591-609. DOI: 10.1023/a:1007327505862. [43] Ainai A, Ichinohe T, Tamura SZ, et al. Zymosan enhances the mucosal adjuvant activity of poly(I: C) in a nasal influenza vaccine[J]. J Med Virol, 2010, 82(3): 476-484. DOI: 10.1002/jmv.21694. [44] Tamura SI, Ainai A, Suzuki T, et al. Intranasal Inactivated Influenza Vaccines: a Reasonable Approach to Improve the Efficacy of Influenza Vaccine?[J]. Jpn J Infect Dis, 2016, 69(3): 165-179. DOI: 10.7883/yoken.JJID.2015.560. [45] Vesikari T, Karvonen A, Korhonen T, et al. A randomized, double-blind study of the safety, transmissibility and phenotypic and genotypic stability of cold-adapted influenza virus vaccine[J]. Pediatr Infect Dis J, 2006, 25(7): 590-595. DOI: 10.1097/01.inf.0000220229.51531.47. [46] Block SL, Yogev R, Hayden FG, et al. Shedding and immunogenicity of live attenuated influenza vaccine virus in subjects 5-49 years of age[J]. Vaccine, 2008, 26(38): 4940-4946. DOI: 10.1016/j.vaccine.2008.07.013. [47] Izurieta HS, Haber P, Wise RP, et al. Adverse events reported following live, cold-adapted, intranasal influenza vaccine[J]. JAMA, 2005, 294(21): 2720-2725. DOI: 10.1001/jama.294.21.2720. [48] Earle KA, Ambrosino DM, Fiore-Gartland A, et al. Evidence for antibody as a protective correlate for COVID-19 vaccines[J]. Vaccine, 2021, 39(32): 4423-4428. DOI: 10.1016/j.vaccine.2021.05.063. [49] Nigwekar PV, Kumar A, Padbidri VV, et al. Safety of Russian-Backbone Trivalent, Live Attenuated Seasonal Influenza Vaccine in Healthy Subjects: Open-Label, Non-randomized Phase 4 Study[J]. Drug Safety, 2018, 41(2): 171-177. DOI: 10.1007/s-40264-017-0605-3. [50] Sun WN, Leist SR, Mccroskery S, et al. Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as a live virus vaccine candidate[J]. EBioMedicine, 2020, 62: 103132. DOI: 10.1101/2020.07.26.221861. [51] An D, Li K, Rowe DK, et al. Protection of K18-hACE2 mice and ferrets against SARS-CoV-2 challenge by a single-dose mucosal immunization with a parainfluenza virus 5-based COVID-19 vaccine[J]. Sci Adv, 2021, 7(27): eabi5246. DOI: 10.1126/sciadv.abi5246. -
