Viral vector vaccine

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (DNA), which can be transcribed by the recipient's host cells as mRNA coding for a desired protein (or: antigen) to elicit an immune response.[1] As of April 2021, six viral vector vaccines have been authorized for use in humans[2] in at least one country: four COVID-19 vaccines and two Ebola vaccines.

Technology

COVID-19 Vaccine Vial Prop
COVID-19 vaccine vial prop

Viral vector vaccines use a modified version of one virus as a vector to deliver to a cell a nucleic acid coding for a antigen for another infectious agent. Viral vector vaccines do not cause infection with either the virus used as the vector, or the source of the antigen.[3] The genetic material it delivers does not integrate into a person's genome.[4]

Viral vector vaccines enable antigen expression within cells and induce a robust cytotoxic T cell response, unlike subunit vaccines which only confer humoral immunity.[5][6] Most viral vectors are designed to be incapable of replication because the necessary genes are removed.[7] In order to be widely accepted and approved for medical use,the development of viral vector require a high biological safety level. Consequently, non or low pathogenic viruses are often selected. In most cases, viruses are genetically engineered to be replication-defective.[8] Despite the fact that replication-deficient viral vectors are generally safer than replication-competent viral vectors, they may require a higher dose or a prime-boost regimen to induce sufficient immunity.[9] Replicating vectors imitates natural infection, which stimulates the release of cytokines and co-stimulatory molecules that produce a strong adjuvant effect. When a replication-deficient viral vector does not elicit the most appropriate responses, the incorporation of an adjuvant may be required to boost the immune response against the encoded antigen.[10] Viral vector-based vaccines require assessment of efficacy and safety, including immunogenicity,genetic stability, ability to evade pre-existing immunity, replication deficiency or attenuation, and genotoxicity[5] Compared to the other vaccine platforms, viral vector vaccines are more stable, requiring less strigent storage and handling conditions. Example is Ad26.COV2.S,an adenoviral based vector vaccine.[11]

Advantages

The advantages of Viral vector vaccine include high efficiency gene transduction, specific delivery of genes to target cells and ability to induce potent humoral and cellular immune responses.[8] The immunogenicity is further enhanced through intrinsic vector motifs that stimulate the innate immunity pathways[12][13][14],thus, the use of expensive and mostly reactive adjuvants can be omitted.Viral vectors can use the host-cell protein-processing pathways that lead to antigen presentation via major histocompatibility complex class I and consequent cytotoxic T-cell stimulation[15] In addition, viral vectors can be produced in high quantities at relatively low costs, which allows the use of these systems in low-income countries.[16]

Viral vectors

The first viral vector created from the SV40 virus by genetic engineering was introduced in 1972.[17][18] Subsequently, other viruses, including adenoviruses, poxviruses, herpesviruses, vesicular stomatitis virus, cytomegalovirus and lentiviruses, have been designed into vaccine vectors capable of inducing a robust immune responses.[5] Vaccinia virus and adenovirus are the most commonly used viral vectors.[19]

Adenovirus

Adenovirus vectors have the advantage of high transduction efficiency, transgene expression, and broad viral tropism, and can infect both dividing and non-dividing cells. A disadvantage is that many people have pre-existing immunity to adenoviruses due to previous exposure.[5][20][21][22]The seroprevalence against Ad5 in the US population is as high as 40%–45%.[23] Most Adenovirus vectors are replication-defective because of the deletion of the E1A and E1B viral gene region. Currently,overcoming the effects of adenovirus- specific neutralizing antibodies is being greatly explored by vaccinologists.[24] Such studies include numerous strategies, such as designing alternative Adenovirus serotypes, diversifying routes of immunization and using prime-boost procedures.[20][25] Human adenovirus serotype 5 is often used because it can be easily produced in high titers.[7]

As of April 2021, four adenovirus vector vaccines for COVID-19 have been authorized in at least one country:

Zabdeno, the first dose of the Zabdeno/Mvabea Ebola vaccine, is derived from human adenovirus serotype 26 expressing the glycoprotein of the Ebola virus Mayinga variant.[36] Both doses are non-replicating vectors and carry the genetic code of several Ebola virus proteins.[37]

Vesicular stomatitis virus

Vesicular stomatitis virus was introduced as a vaccine vector in the late 1990s.[38] rVSV-ZEBOV vaccine, known as Ervebo was approved as a prophylactic vaccine for medical use by the FDA IN 2019.[1] The rVSV-ZEBOV vaccine is an Ebola vaccine.[39][1] It is a recombinant, replication-competent vaccine[40] consisting of vesicular stomatitis virus (VSV) genetically engineered[41] so that the gene for the natural VSV envelope glycoprotein is replaced with that from the Kikwit 1995 Zaire strain Ebola virus.[42][43][44] In most VSV vaccine vectors,attenuation provides safety against its virulence.[45]

Pox virus

Vaccinia virus, which is a member of pox virus family, is a large, complex and enveloped virus. Due to its large size, the viral genome capacity for foreign gene insertion is high. Modified vaccinia Ankara (MVA) is a highly attenuated strain derived from the vaccinia strain Ankara.[8] Mvabea, the second dose of the Zabdeno/Mvabea Ebola vaccine, is a modified vaccinia Ankara vector, a type of poxvirus.[36] Both doses are non-replicating vectors and carry the genetic code of several Ebola virus proteins.[37]

Other viruses that have been investigated as vaccine vectors include adeno-associated virus, retrovirus (including lentivirus), cytomegalovirus, Sendai virus, and avulavirus,[7][46] as well as influenza virus and measles virus.[4]

History

Since the development of vaccinia virus as a vaccine vector in 1984, the incorporation of many viruses in vaccination strategies has been studied.[47] Human clinical trials were conducted for viral vector vaccines against several infectious diseases including Zika virus, influenza viruses, respiratory syncytial virus, HIV, and malaria, before the vaccines targeting SARS-CoV-2, which causes COVID-19.[1][4]

Two Ebola vaccines using viral vector technology were used in Ebola outbreaks in West Africa (2013–2016) and in the Democratic Republic of the Congo (2018–2020).[4] The rVSV-ZEBOV vaccine was approved for medical use in the European Union in November 2019,[48] and in the United States in December 2019.[49][50] Zabdeno/Mvabea was approved for medical use in the European Union in July 2020.[37][51][52]

Routes of administration

The commonly used route for vaccine administration is through intramuscular injection.[18] The introduction of alternate routes for immunization of viral vector vaccines can induce mucosal immunology at site of administration thereby limiting respiratory or gastrointestinal infections.[53][54] Also studies are being made on how these diverse routes can be used to overcome the effects of specific neutralizing antibodies limiting the use of these vaccines.[20] These routes include intranasal,[55][56] oral, intradermal and aerosol vaccination[57][58]

References

  1. 1 2 3 4 Sasso E, D'Alise AM, Zambrano N, Scarselli E, Folgori A, Nicosia A (August 2020). "New viral vectors for infectious diseases and cancer". Seminars in Immunology. 50: 101430. doi:10.1016/j.smim.2020.101430. PMID 33262065. S2CID 227251541.
  2. ↑ Wang F, Qin Z, Lu H, He S, Luo J, Jin C, Song X (July 2019). "Clinical translation of gene medicine". The Journal of Gene Medicine. 21 (7): e3108. doi:10.1002/jgm.3108. PMID 31246328. S2CID 195695440.
  3. ↑ Deng, Shaofeng; Liang, Hui; Chen, Pin; Li, Yuwan; Li, Zhaoyao; Fan, Shuangqi; Wu, Keke; Li, Xiaowen; Chen, Wenxian; Qin, Yuwei; Yi, Lin; Chen, Jinding (2022-07-18). "Viral Vector Vaccine Development and Application during the COVID-19 Pandemic". Microorganisms. 10 (7): 1450. doi:10.3390/microorganisms10071450. ISSN 2076-2607. PMC 9317404. PMID 35889169.
  4. 1 2 3 4 "Understanding and Explaining Viral Vector COVID-19 Vaccines". U.S. Centers for Disease Control and Prevention. 25 February 2021. Archived from the original on 2 February 2021. Retrieved 2 April 2021.
  5. 1 2 3 4 Ura T, Okuda K, Shimada M (July 2014). "Developments in Viral Vector-Based Vaccines". Vaccines. 2 (3): 624–641. doi:10.3390/vaccines2030624. PMC 4494222. PMID 26344749.
  6. ↑ Li JX, Hou LH, Meng FY, Wu SP, Hu YM, Liang Q, et al. (March 2017). "Immunity duration of a recombinant adenovirus type-5 vector-based Ebola vaccine and a homologous prime-boost immunisation in healthy adults in China: final report of a randomised, double-blind, placebo-controlled, phase 1 trial". The Lancet. Global Health. 5 (3): e324–e334. doi:10.1016/S2214-109X(16)30367-9. PMID 28017642.
  7. 1 2 3 Ura T, Okuda K, Shimada M (July 2014). "Developments in Viral Vector-Based Vaccines". Vaccines. 2 (3): 624–641. doi:10.3390/vaccines2030624. PMC 4494222. PMID 26344749.
  8. 1 2 3 Ura, Takehiro; Okuda, Kenji; Shimada, Masaru (2014-07-29). "Developments in Viral Vector-Based Vaccines". Vaccines. 2 (3): 624–641. doi:10.3390/vaccines2030624. ISSN 2076-393X. PMC 4494222. PMID 26344749.
  9. ↑ Travieso, Tatianna; Li, Jenny; Mahesh, Sneha; Mello, Juliana Da Fonzeca Redenze E.; Blasi, Maria (2022-07-04). "The use of viral vectors in vaccine development". NPJ Vaccines. 7 (1): 75. doi:10.1038/s41541-022-00503-y. ISSN 2059-0105. PMC 9253346. PMID 35787629.
  10. ↑ Robert-Guroff, Marjorie (December 2007). "Replicating and non-replicating viral vectors for vaccine development". Current Opinion in Biotechnology. 18 (6): 546–556. doi:10.1016/j.copbio.2007.10.010. PMC 2245896. PMID 18063357.
  11. ↑ Sadoff, Jerald; Gray, Glenda; Vandebosch, An; Cárdenas, Vicky; Shukarev, Georgi; Grinsztejn, Beatriz; Goepfert, Paul A.; Truyers, Carla; Fennema, Hein; Spiessens, Bart; Offergeld, Kim; Scheper, Gert; Taylor, Kimberly L.; Robb, Merlin L.; Treanor, John (2021-06-10). "Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19". New England Journal of Medicine. 384 (23): 2187–2201. doi:10.1056/NEJMoa2101544. ISSN 0028-4793. PMC 8220996. PMID 33882225.
  12. ↑ Dempsey, Alan; Bowie, Andrew G. (May 2015). "Innate immune recognition of DNA: A recent history". Virology. 479–480: 146–152. doi:10.1016/j.virol.2015.03.013. PMC 4424081. PMID 25816762.
  13. ↑ Kell, Alison M.; Gale, Michael (May 2015). "RIG-I in RNA virus recognition". Virology. 479–480: 110–121. doi:10.1016/j.virol.2015.02.017. PMC 4424084. PMID 25749629.
  14. ↑ Akira, Shizuo; Uematsu, Satoshi; Takeuchi, Osamu (February 2006). "Pathogen Recognition and Innate Immunity". Cell. 124 (4): 783–801. doi:10.1016/j.cell.2006.02.015. PMID 16497588. S2CID 14357403. Archived from the original on 2023-02-02. Retrieved 2023-01-22.
  15. ↑ Liu, Margaret A. (October 2010). "Immunologic Basis of Vaccine Vectors". Immunity. 33 (4): 504–515. doi:10.1016/j.immuni.2010.10.004. PMID 21029961. Archived from the original on 2023-02-02. Retrieved 2023-01-22.
  16. ↑ Schrauf, Sabrina; Tschismarov, Roland; Tauber, Erich; Ramsauer, Katrin (2020). "Current Efforts in the Development of Vaccines for the Prevention of Zika and Chikungunya Virus Infections". Frontiers in Immunology. 11: 592. doi:10.3389/fimmu.2020.00592. ISSN 1664-3224. PMC 7179680. PMID 32373111.  This article incorporates text from this source, which is available under the CC BY 4.0 license.
  17. ↑ Jackson DA, Symons RH, Berg P (October 1972). "Biochemical method for inserting new genetic information into DNA of Simian Virus 40: circular SV40 DNA molecules containing lambda phage genes and the galactose operon of Escherichia coli". Proceedings of the National Academy of Sciences of the United States of America. 69 (10): 2904–2909. doi:10.1073/pnas.69.10.2904. PMC 389671. PMID 4342968.
  18. 1 2 Travieso T, Li J, Mahesh S, Mello JD, Blasi M (July 2022). "The use of viral vectors in vaccine development". NPJ Vaccines. 7 (1): 75. doi:10.1038/s41541-022-00503-y. PMC 9253346. PMID 35787629.
  19. ↑ Mackett M, Smith GL, Moss B (December 1982). "Vaccinia virus: a selectable eukaryotic cloning and expression vector". Proceedings of the National Academy of Sciences of the United States of America. 79 (23): 7415–7419. doi:10.1073/pnas.79.23.7415. PMC 347350. PMID 6296831.
  20. 1 2 3 Fausther-Bovendo H, Kobinger GP (2014-10-03). "Pre-existing immunity against Ad vectors: humoral, cellular, and innate response, what's important?". Human Vaccines & Immunotherapeutics. 10 (10): 2875–2884. doi:10.4161/hv.29594. PMC 5443060. PMID 25483662.
  21. ↑ Barouch DH, Kik SV, Weverling GJ, Dilan R, King SL, Maxfield LF, et al. (July 2011). "International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations". Vaccine. 29 (32): 5203–5209. doi:10.1016/j.vaccine.2011.05.025. PMC 3138857. PMID 21619905.
  22. ↑ Pinschewer, D. D. (2017-08-08). "Virally vectored vaccine delivery: medical needs, mechanisms, advantages and challenges". Swiss Medical Weekly. 147 (3132): w14465. doi:10.4414/smw.2017.14465. ISSN 1424-7860. PMID 28804866. Archived from the original on 2023-01-05. Retrieved 2023-01-22.
  23. ↑ Pichla-Gollon, Susan L.; Lin, Shih-Wen; Hensley, Scott E.; Lasaro, Marcio O.; Herkenhoff-Haut, Larissa; Drinker, Mark; Tatsis, Nia; Gao, Guang-Ping; Wilson, James M.; Ertl, Hildegund C. J.; Bergelson, Jeffrey M. (June 2009). "Effect of Preexisting Immunity on an Adenovirus Vaccine Vector: In Vitro Neutralization Assays Fail To Predict Inhibition by Antiviral Antibody In Vivo". Journal of Virology. 83 (11): 5567–5573. doi:10.1128/JVI.00405-09. ISSN 0022-538X. PMC 2681979. PMID 19279092.
  24. ↑ Tatsis N, Ertl HC (October 2004). "Adenoviruses as vaccine vectors". Molecular Therapy. 10 (4): 616–629. doi:10.1016/j.ymthe.2004.07.013. PMC 7106330. PMID 15451446.
  25. ↑ "149. Nasal Delivery of Adenovirus-Based Vaccine Bypasses Pre-Existing Immunity to the Vaccine Carrier and Improves the Quality of the Immune Response". Molecular Therapy. 15: S58. May 2007. doi:10.1016/s1525-0016(16)44355-8. ISSN 1525-0016. Archived from the original on 2023-02-02. Retrieved 2023-01-22.
  26. ↑ Clinical trial number NCT04400838 for "Investigating a Vaccine Against COVID-19" at ClinicalTrials.gov
  27. ↑ "A Phase 2/3 study to determine the efficacy, safety and immunogenicity of the candidate Coronavirus Disease (COVID-19) vaccine ChAdOx1 nCoV-19". EU Clinical Trials Register. European Union. 21 April 2020. EudraCT 2020-001228-32. Archived from the original on 5 October 2020. Retrieved 3 August 2020.
  28. ↑ Chauhan, Anil; Agarwal, Amit; Jaiswal, Nishant; Singh, Meenu (November 2020). "ChAdOx1 nCoV-19 vaccine for SARS-CoV-2". The Lancet. 396 (10261): 1485–1486. doi:10.1016/S0140-6736(20)32271-6. PMC 7832915. PMID 33160563.
  29. ↑ Corum J, Carl Z (8 January 2021). "How Gamaleya's Vaccine Works". The New York Times. Archived from the original on 20 April 2021. Retrieved 27 January 2021.
  30. ↑ Clinical trial number NCT04436471 for "An Open Study of the Safety, Tolerability and Immunogenicity of the Drug 'Gam-COVID-Vac' Vaccine Against COVID-19" at ClinicalTrials.gov
  31. ↑ Clinical trial number NCT04436276 for "A Study of Ad26.COV2.S in Adults" at ClinicalTrials.gov
  32. ↑ Clinical trial number NCT04505722 for "A Study of Ad26.COV2.S for the Prevention of SARS-CoV-2-Mediated COVID-19 in Adult Participants" at ClinicalTrials.gov
  33. ↑ FDA Briefing Document Janssen Ad26.COV2.S Vaccine for the Prevention of COVID-19 (PDF) (Report). U.S. Food and Drug Administration (FDA). Archived from the original on 2021-04-29. Retrieved 2023-01-22.
  34. ↑ Zhu FC, Guan XH, Li YH, Huang JY, Jiang T, Hou LH, et al. (August 2020). "Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial". Lancet. 396 (10249): 479–488. doi:10.1016/S0140-6736(20)31605-6. PMC 7836858. PMID 32702299.
  35. ↑ Clinical trial number NCT04566770 for "Phase IIb Clinical Trial of A COVID-19 Vaccine Named Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector)" at ClinicalTrials.gov
  36. 1 2 Clinical trial number NCT02313077 for "A Safety and Immunogenicity Study of Heterologous Prime-Boost Ebola Vaccine Regimens in Healthy Participants" at ClinicalTrials.gov
  37. 1 2 3 "Johnson & Johnson Announces European Commission Approval for Janssen's Preventive Ebola Vaccine" (Press release). Johnson & Johnson. 1 July 2020. Archived from the original on 22 May 2022. Retrieved 16 July 2020.
  38. ↑ Roberts A, Kretzschmar E, Perkins AS, Forman J, Price R, Buonocore L, et al. (June 1998). "Vaccination with a recombinant vesicular stomatitis virus expressing an influenza virus hemagglutinin provides complete protection from influenza virus challenge". Journal of Virology. 72 (6): 4704–4711. doi:10.1128/JVI.72.6.4704-4711.1998. PMC 109996. PMID 9573234.
  39. ↑ Woolsey C, Geisbert TW (December 2021). Dutch RE (ed.). "Current state of Ebola virus vaccines: A snapshot". PLOS Pathogens. 17 (12): e1010078. doi:10.1371/journal.ppat.1010078. PMC 8659338. PMID 34882741.
  40. ↑ Marzi A, Ebihara H, Callison J, Groseth A, Williams KJ, Geisbert TW, Feldmann H (November 2011). "Vesicular stomatitis virus-based Ebola vaccines with improved cross-protective efficacy". The Journal of Infectious Diseases. 204 Suppl 3 (Suppl 3): S1066–S1074. doi:10.1093/infdis/jir348. PMC 3203393. PMID 21987743.
  41. ↑ "Ervebo (Ebola Zaire Vaccine, Live) Suspension for intramuscular injection" (PDF). Merck Sharp & Dohme. Archived from the original on 2020-03-29. Retrieved 2023-01-22.
  42. ↑ Martínez-Romero C, García-Sastre A (November 2015). "Against the clock towards new Ebola virus therapies". Virus Research. 209: 4–10. doi:10.1016/j.virusres.2015.05.025. PMID 26057711.
  43. ↑ Choi WY, Hong KJ, Hong JE, Lee WJ (January 2015). "Progress of vaccine and drug development for Ebola preparedness". Clinical and Experimental Vaccine Research. 4 (1): 11–16. doi:10.7774/cevr.2015.4.1.11. PMC 4313103. PMID 25648233.
  44. ↑ Regules JA, Beigel JH, Paolino KM, Voell J, Castellano AR, Hu Z, et al. (January 2017). "A Recombinant Vesicular Stomatitis Virus Ebola Vaccine". The New England Journal of Medicine. 376 (4): 330–341. doi:10.1056/NEJMoa1414216. PMC 5408576. PMID 25830322.
  45. ↑ Humphreys, Ian R.; Sebastian, Sarah (January 2018). "Novel viral vectors in infectious diseases". Immunology. 153 (1): 1–9. doi:10.1111/imm.12829. PMC 5721250. PMID 28869761.
  46. ↑ Zimmer C (2021-04-05). "Researchers Are Hatching a Low-Cost Coronavirus Vaccine". The New York Times. Archived from the original on 2021-04-28. Retrieved 2023-01-22.
  47. ↑ Humphreys IR, Sebastian S (January 2018). "Novel viral vectors in infectious diseases". Immunology. 153 (1): 1–9. doi:10.1111/imm.12829. PMC 5721250. PMID 28869761.
  48. ↑ "Ervebo EPAR". European Medicines Agency (EMA). 12 December 2019. Archived from the original on 29 March 2020. Retrieved 1 July 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  49. ↑ "First FDA-approved vaccine for the prevention of Ebola virus disease, marking a critical milestone in public health preparedness and response". U.S. Food and Drug Administration (FDA). 19 December 2019. Archived from the original on 20 December 2019. Retrieved 19 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  50. ↑ "Ervebo". U.S. Food and Drug Administration (FDA). 19 December 2019. Archived from the original on 14 February 2021. Retrieved 1 July 2020.
  51. ↑ "Zabdeno EPAR". European Medicines Agency (EMA). 26 May 2020. Archived from the original on 23 July 2020. Retrieved 23 July 2020.
  52. ↑ "Mvabea EPAR". European Medicines Agency (EMA). 26 May 2020. Archived from the original on 23 July 2020. Retrieved 23 July 2020.
  53. ↑ Hassan AO, Shrihari S, Gorman MJ, Ying B, Yuan D, Raju S, et al. (July 2021). "An intranasal vaccine durably protects against SARS-CoV-2 variants in mice". Cell Reports. 36 (4): 109452. doi:10.1016/j.celrep.2021.109452. PMC 8270739. PMID 34289385.
  54. ↑ Xu F, Wu S, Yi L, Peng S, Wang F, Si W, et al. (December 2022). "Safety, mucosal and systemic immunopotency of an aerosolized adenovirus-vectored vaccine against SARS-CoV-2 in rhesus macaques". Emerging Microbes & Infections. 11 (1): 438–441. doi:10.1080/22221751.2022.2030199. PMC 8803102. PMID 35094672.
  55. ↑ Chavda, Vivek P.; Vora, Lalitkumar K.; Pandya, Anjali K.; Patravale, Vandana B. (November 2021). "Intranasal vaccines for SARS-CoV-2: From challenges to potential in COVID-19 management". Drug Discovery Today. 26 (11): 2619–2636. doi:10.1016/j.drudis.2021.07.021. PMC 8319039. PMID 34332100.
  56. ↑ Rauch, Susanne; Jasny, Edith; Schmidt, Kim E.; Petsch, Benjamin (2018-09-19). "New Vaccine Technologies to Combat Outbreak Situations". Frontiers in Immunology. 9: 1963. doi:10.3389/fimmu.2018.01963. ISSN 1664-3224. PMC 6156540. PMID 30283434.
  57. ↑ de Gruijl, Tanja D.; Ophorst, Olga J. A. E.; Goudsmit, Jaap; Verhaagh, Sandra; Lougheed, Sinéad M.; Radosevic, Katarina; Havenga, Menzo J. E.; Scheper, Rik J. (2006-08-15). "Intradermal Delivery of Adenoviral Type-35 Vectors Leads to High Efficiency Transduction of Mature, CD8+ T Cell-Stimulating Skin-Emigrated Dendritic Cells". The Journal of Immunology. 177 (4): 2208–2215. doi:10.4049/jimmunol.177.4.2208. ISSN 0022-1767. PMID 16887980. S2CID 25279434. Archived from the original on 2023-02-02. Retrieved 2023-01-22.
  58. ↑ Liebowitz D, Gottlieb K, Kolhatkar NS, Garg SJ, Asher JM, Nazareno J, et al. (April 2020). "Efficacy, immunogenicity, and safety of an oral influenza vaccine: a placebo-controlled and active-controlled phase 2 human challenge study". The Lancet. Infectious Diseases. 20 (4): 435–444. doi:10.1016/S1473-3099(19)30584-5. PMID 31978354. S2CID 210892802.

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