Viral vector-based vaccines
Viral vector-based vaccines are vaccines that can deliver specific antigen gene to target cells based on the infection ability of viruses, produce antigens via the nutrition substances in host cells, and then provoke immune responses with the newly synthesized antigens. Compared with the traditional vaccines, viral vector vaccines have a great number of advantages: ①highly efficient in gene transduction; ② mediate specific gene delivery to target cells; ③induce of both humoral and cell-mediated immune responses; ④ better efficacy and safety;⑤ just need low administration dose; ⑥ easy to be applied into large-scale manufacturing; ⑦ possessing widespread potential target diseases, ranging from infectious diseases to cancers. As well, some drawbacks also have been discovered: ① several kinds of vectors mediate gene integration into host genome, which may lead to cancer; ② some hosts may be exposed to antigens prior to the vaccine administration, which may result in the production of neutralizing antibodies (pre-existing immunity) and thus reduce the vaccine efficacy .
To date, numerous kinds of viral vectors have been introduced to produce vaccines, such as adeno-associated virus (AAV) vectors (Fig. 2A), adenoviral vectors (Fig. 2B) and lentiviral vectors (Fig. 2C) . Different kinds of viral vectors have their advantages and drawbacks, which are summarized in Table 1.
|Genome||ss RNA||ds DNA||ss DNA|
|Time to peak expression||72h||36h-72h||Cell: 7 days;
Animals: 2 weeks
|Sustainable time||Stable expression||Transient expression||> 6 months|
|Cell Type||Most Dividing/Non-Dividing Cells||Most Dividing/Non-Dividing Cells||Most Dividing/Non-Dividing Cells|
|Titer||10^8 TU/ml||10^11 PFU/ml||10^12 vg/ml|
|Animal experiment||Low efficiency||Lowest efficiency||Most suitable|
1) AAV vector-based vaccines
Adeno-associated virus (AAV) is a small single strand DNA virus, member of human parvovirus [3, 4], approximately 25nm in diameter and encapsidates a single-stranded DNA genome of 4.7 kilobases (Fig. 3A). The genome consists of two large open reading frames (ORFs) flanked by 145bp inverted terminal repeats (ITR), which are the only cis-acting elements required for AAV genome replication and AAV packaging. The left ORF encodes four replication proteins, Rep40, Rep52, Rep68, and Rep78, in charge of site-specific integration, as well as regulation of AAV capsid formation initiation within the AAV genome, while the right ORF encodes the viral structural proteins, VP1, VP2, and VP3, which interact together to assemble into icosahedral virion shells comprising 60 subunits each (Fig. 3B).
AAV transduces cells through several stages: ① viral binding to cell surface receptor/coreceptor, ② endocytosis of the virus, ③ intracellular trafficking of the virus through the endosomal compartment, ④ endosomal escape of the virus, ⑤ intracellular trafficking of the virus to the nucleus and nuclear import, ⑥ virion uncoating, ⑦ viral genome conversion from a single-stranded to a double-stranded genome capable of expressing an encoded gene [5-7]. Since AAV has no ability to encode polymerases, AAV is dependent upon cellular polymerase activity to replicate its own genome . The presence of a helper virus such as adenovirus is indispensable for wild-type AAV to facilitate gene expression and replication (Fig. 4A). Without helper virus, expression of Rep68/Rep78 would be restricted owing to Ying Yang 1 (YY1) repression of the P5 promoter, leading to inhibition of AAV genome replication and gene expression, and initiation of AAV chromosome integration (Fig. 4B) . AAV establishes latency by undergoing specifically integration into a genome site, termed as the adeno-associated virus integration site 1 (AAVS1), a 4kb region on chromosome 19 (q13.4).
During the entry of AAV into host cells, AAV virions may uncoat and release their genomes into the endosome, and be recognized by toll like receptor 9 (TLR9) of plasmacytoid dendritic cell (pDC) to provoke innate immune response and produce Interferon (IFN) α/β . This process is dependent on MyD88 signaling, but not the form of transgene or capsid serotype . Besides TLR9, TLR2 dependent cytokine expression was also observed in Kupffer cells . Moreover, some AAV virions are degraded and processed into peptides within proteasomes, and then presented by MHC I of antigen presenting cells (APCs), such as conventional dendritic cells (cDCs), which can be targeted by capsid-specific CD8+ T cells to lyse virally infected cells . In addition to IFNα/β, CD40-CD40L co-stimulation by CD4+ T helper cells, is required for cross-priming of CD8+ T cells against AAV capsid . CD4+ T helper cells is also indispensable to generate memory responses and stimulate B cells to produce antibody against AAV capsid, which is dependent on MyD88 signaling .
Over the past decades, numerous AAV serotypes have been identified with variable tropism. To date, 12 AAV serotypes and over 100 AAV variants have been isolated from adenovirus stocks or from human/nonhuman primate tissues. Among them, AAV2, AAV3, AAV5, AAV6 were discovered in human cells, while AAV1, AAV4, AAV7, AAV8, AAV9, AAV10 (AAVrh10), AAV11, AAV12 in nonhuman primate samples . Different serotypes have different tissue tropism, which are summarized in Table 2.
|AAV Serotype||Tissue tropism|
Though wild-type AAV is not associated with human disease, it is naturally defective and requiring helper adenovirus or herpes simplex virus (HSV) coinfection for AAV replication, so recombinant AAV (rAAV) has been developed for gene therapy or vaccines by replacing the viral genome with gene of interest (GOI) to reduce the risk. Traditionally, rAAV vectors used in clinical trials were prepared with a plasmid containing the therapeutic gene flanked by AAV-inverted terminal repeats (ITRs), co-transfected with AAV packaging plasmid pAAV-RC (AAV replication and AAV capsid) and pHelper (AAV helper plasmid) (Fig. 6). The adenovirus helper factors, such as E1A, E1B, E2A, E4 ORF6 and VA RNAs, would be provided by the third helper plasmid. Due to the deletion of Rep and Cap coding regions between the ITRs, rAAV vectors cannot integrate into the genome of host cells, just persist in an episomal form, which significantly reduced their tumorigenicity.
To date, more than 244 clinical trials have been carried out using AAV vectors for gene delivery , and promising gene therapy outcomes have been achieved from Phase 1, Phase 2 and Phase 3 trials for a great number of diseases, including lipoprotein lipase deficiency (LPLD) , spinal muscular atrophy (SMA) , retinal dystrophy [20, 21], cystic fibrosis [22, 23], Duchenne Muscular Dystrophy , Hemophilia , congestive heart failure , Parkinson’s disease  and Rheumatoid Arthritis [28, 29].
But, as a viral vector used for vaccine production, AAV only induces mild immune responses, which is not enough for vaccine to provoke the immune system in host. Several animal studies show that AAV vector-based vaccines can be used to defense HIV-1 [30-32], influenza , and papillomavirus  and have great potentials in clinical applications. However, AAV vector-based vaccines are rarely applied in clinical trials. Some of the examples are listed in the following Table 3. There are two reasons: ① AAV vectors only cause mild humoral and cellular immunity; ② infectious vaccines transduce a large population of people ranging from children and adolescents, and more safety risks need to be considered. Therefore, compared to the gene therapy with AAV vectors, there is a long way for the clinical applications of AAV vector-based vaccines.
|Disease||Vaccine component||Status||Clinical trials|
|Stage IV gastric cancer||AAV-DC-CTL||Phase I||NCT01637805|
|Stage IV gastric cancer||AAV-DC-CTL||Phase I||NCT02496273|
AAV viral vector has been developed into a very attractive candidate for gene delivery due to various advantages: ① superior biosafety rating of recombinant AAV after removing most AAV genome elements; ② stable physical properties; ③ broad range of infectivity, AAV has the ability to infect both dividing and quiescent cells in vivo; ④ mediate long term and stable gene expression.
However, there are also some drawbacks for AAV to be used as vaccine vector: ① limited cloning capacity (less than 4.7kb) of the vector, which restricts its use in gene delivery of large genes ; ② only inducing mild immunity, restraining the vaccine development; ③ pre-existing immunity and neutralizing antibodies (NAB) against AAV vectors may attenuate the effect of AAV-based gene therapy or vaccines .
To improve the efficacy of AAV vector for vaccine development, several strategies are adopted: ① assemble and recombine proteins between different viruses, which can produce hybrid rAAVs, such as transcapsidation, which is a process involving the packaging of the ITR from one AAV serotype into the capsid of another serotype, which may determine the tissue tropism of hybrids. ② Recombine, redesign, or introduce random mutations into the capsid protein of AAV by different methods to artificially increase the variance of AAV serotypes, and then screen the appropriate AAV serotypes, including rational design AAV capsid , AAV directed evolution , point mutation , peptide display , and DNA shuffling . ③ In combination with other kinds of vaccines.
GeneMedi holds the expertise at AAV production, you can find more information and protocols about AAV on this website: https://www.genemedi.com/i/aav-packaging.
1.Ura T, Okuda K, Shimada M. Developments in Viral Vector-Based Vaccines. Vaccines (Basel). 2014;2:624-641.
2.Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune Responses to Viral Gene Therapy Vectors. Mol Ther. 2020;28:709-722.
3.Atchison RW, Casto BC, Hammon WM. Adenovirus-Associated Defective Virus Particles. Science. 1965;149:754-756.
4.Hoggan MD, Blacklow NR, Rowe WP. Studies of small DNA viruses found in various adenovirus preparations: physical, biological, and immunological characteristics. Proceedings of the National Academy of Sciences of the United States of
5.Bartlett JS, Wilcher R, Samulski RJ. Infectious entry pathway of adeno-associated virus and adeno-associated virus vectors. Journal of virology. 2000;74:2777-2785.
6.Ding W, Zhang L, Yan Z, Engelhardt JF. Intracellular trafficking of adeno-associated viral vectors. Gene therapy. 2005;12:873-880.
7.Srivastava A. Adeno-associated virus-mediated gene transfer. Journal of cellular biochemistry. 2008;105:17-24.
8.Berns KI. Parvovirus replication. Microbiological reviews. 1990;54:316-329.
9.Pereira DJ, McCarty DM, Muzyczka N. The adeno-associated virus (AAV) Rep protein acts as both a repressor and an activator to regulate AAV transcription during a productive infection. Journal of virology. 1997;71:1079-1088.
10.Zhu J, Huang X, Yang Y. The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice. J Clin Invest. 2009;119:2388-2398.
11.Hosel M, Broxtermann M, Janicki H, Esser K, Arzberger S, Hartmann P, et al. Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors. Hepatology. 2012;55:287-297.
12.Pien GC, Basner-Tschakarjan E, Hui DJ, Mentlik AN, Finn JD, Hasbrouck NC, et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J Clin Invest. 2009;119:1688-1
13.Shirley JL, Keeler GD, Sherman A, Zolotukhin I, Markusic DM, Hoffman BE, et al. Type I IFN Sensing by cDCs and CD4(+) T Cell Help Are Both Requisite for Cross-Priming of AAV Capsid-Specific CD8(+) T Cells. Mol Ther. 2020;28:758-770.
14.Sudres M, Cire S, Vasseur V, Brault L, Da Rocha S, Boisgerault F, et al. MyD88 signaling in B cells regulates the production of Th1-dependent antibodies to AAV. Mol Ther. 2012;20:1571-1581.
15.Rabinowitz J, Chan YK, Samulski RJ. Adeno-associated Virus (AAV) versus Immune Response. Viruses. 2019;11.
16.Weitzman MD, Linden RM. Adeno-associated virus biology. Methods in molecular biology. 2011;807:1-23.
17.Vectors used in gene therapy clinical trials. The Journal of Gene Medicine Online Library. [Online] Updated Nov 2017.
18.Kassner U, Hollstein T, Grenkowitz T, Wuhle-Demuth M, Salewsky B, Demuth I, et al. Gene Therapy in Lipoprotein Lipase Deficiency: Case Report on the First Patient Treated with Alipogene Tiparvovec Under Daily Practice Conditions. Hum
19.Passini MA, Bu J, Richards AM, Treleaven CM, Sullivan JA, O’Riordan CR, et al. Translational fidelity of intrathecal delivery of self-complementary AAV9-survival motor neuron 1 for spinal muscular atrophy. Human gene therapy. 2014;25
20.Stieger K, Lorenz B. [Specific gene therapy for hereditary retinal dystrophies – an update]. Klinische Monatsblatter fur Augenheilkunde. 2014;231:210-215.
21.Trapani I, Colella P, Sommella A, Iodice C, Cesi G, de Simone S, et al. Effective delivery of large genes to the retina by dual AAV vectors. EMBO molecular medicine. 2014;6:194-211.
22.Doi K, Takeuchi Y. Gene therapy using retrovirus vectors: vector development and biosafety at clinical trials. Uirusu. 2015;65:27-36.
23.Duncan GA, Kim N, Colon-Cortes Y, Rodriguez J, Mazur M, Birket SE, et al. An Adeno-Associated Viral Vector Capable of Penetrating the Mucus Barrier to Inhaled Gene Therapy. Molecular therapy. Methods & clinical development. 2018;9:29
24.Bowles DE, McPhee SW, Li C, Gray SJ, Samulski JJ, Camp AS, et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Molecular therapy : the journal of the American Society of Gene Therap
25.Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. The New England journal of medicine. 2011;365:2357-2365.
26.Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reti
27.LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, et al. AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. The Lancet. Neurology. 2011;10:309-319.
28.Aalbers CJ, Bevaart L, Loiler S, de Cortie K, Wright JF, Mingozzi F, et al. Preclinical Potency and Biodistribution Studies of an AAV 5 Vector Expressing Human Interferon-beta (ART-I02) for Local Treatment of Patients with Rheumatoid
29.Bevaart L, Aalbers CJ, Vierboom MP, Broekstra N, Kondova I, Breedveld E, et al. Safety, Biodistribution, and Efficacy of an AAV-5 Vector Encoding Human Interferon-Beta (ART-I02) Delivered via Intra-Articular Injection in Rhesus Monke
30.Xin KQ, Urabe M, Yang J, Nomiyama K, Mizukami H, Hamajima K, et al. A novel recombinant adeno-associated virus vaccine induces a long-term humoral immune response to human immunodeficiency virus. Hum Gene Ther. 2001;12:1047-1061.
31.Xin KQ, Ooki T, Mizukami H, Hamajima K, Okudela K, Hashimoto K, et al. Oral administration of recombinant adeno-associated virus elicits human immunodeficiency virus-specific immune responses. Hum Gene Ther. 2002;13:1571-1581.
32.Xin KQ, Mizukami H, Urabe M, Toda Y, Shinoda K, Yoshida A, et al. Induction of robust immune responses against human immunodeficiency virus is supported by the inherent tropism of adeno-associated virus type 5 for dendritic cells. J
33.Lin J, Calcedo R, Vandenberghe LH, Bell P, Somanathan S, Wilson JM. A new genetic vaccine platform based on an adeno-associated virus isolated from a rhesus macaque. J Virol. 2009;83:12738-12750.
34.Nieto K, Stahl-Hennig C, Leuchs B, Muller M, Gissmann L, Kleinschmidt JA. Intranasal vaccination with AAV5 and 9 vectors against human papillomavirus type 16 in rhesus macaques. Hum Gene Ther. 2012;23:733-741.
35.Grieger JC, Samulski RJ. Packaging capacity of adeno-associated virus serotypes: impact of larger genomes on infectivity and postentry steps. Journal of virology. 2005;79:9933-9944.
36.Fitzpatrick Z, Leborgne C, Barbon E, Masat E, Ronzitti G, van Wittenberghe L, et al. Influence of Pre-existing Anti-capsid Neutralizing and Binding Antibodies on AAV Vector Transduction. Mol Ther Methods Clin Dev. 2018;9:119-129.
37.Kotterman MA, Schaffer DV. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet. 2014;15:445-451.
38.Grimm D, Zolotukhin S. E Pluribus Unum: 50 Years of Research, Millions of Viruses, and One Goal–Tailored Acceleration of AAV Evolution. Mol Ther. 2015;23:1819-1831.
39.Maheshri N, Koerber JT, Kaspar BK, Schaffer DV. Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nature biotechnology. 2006;24:198-204.
40.Khabou H, Desrosiers M, Winckler C, Fouquet S, Auregan G, Bemelmans AP, et al. Insight into the mechanisms of enhanced retinal transduction by the engineered AAV2 capsid variant -7m8. Biotechnology and bioengineering. 2016;113:2712-2
41.Kienle E, Senis E, Borner K, Niopek D, Wiedtke E, Grosse S, et al. Engineering and evolution of synthetic adeno-associated virus (AAV) gene therapy vectors via DNA family shuffling. Journal of visualized experiments : JoVE. 2012.
42.Rowe WP, Huebner RJ, Gilmore LK, Parrott RH, Ward TG. Isolation of a cytopathogenic agent from human adenoids undergoing spontaneous degeneration in tissue culture. Proceedings of the Society for Experimental Biology and Medicine. So
43.Wong CM, McFall ER, Burns JK, Parks RJ. The role of chromatin in adenoviral vector function. Viruses. 2013;5:1500-1515.
44.Ranki T, Hemminki A. Serotype chimeric human adenoviruses for cancer gene therapy. Viruses. 2010;2:2196-2212.
45.Ison MG, Hayden RT. Adenovirus. Microbiology spectrum. 2016;4.
46.Vorburger SA, Hunt KK. Adenoviral gene therapy. The oncologist. 2002;7:46-59.
47.Seiler MP, Cerullo V, Lee B. Immune response to helper dependent adenoviral mediated liver gene therapy: challenges and prospects. Curr Gene Ther. 2007;7:297-305.
48.Othman M, Labelle A, Mazzetti I, Elbatarny HS, Lillicrap D. Adenovirus-induced thrombocytopenia: the role of von Willebrand factor and P-selectin in mediating accelerated platelet clearance. Blood. 2007;109:2832-2839.
49.Atasheva S, Shayakhmetov DM. Adenovirus sensing by the immune system. Curr Opin Virol. 2016;21:109-113.
50.Doronin K, Flatt JW, Di Paolo NC, Khare R, Kalyuzhniy O, Acchione M, et al. Coagulation factor X activates innate immunity to human species C adenovirus. Science. 2012;338:795-798.
51.Tam JC, Bidgood SR, McEwan WA, James LC. Intracellular sensing of complement C3 activates cell autonomous immunity. Science. 2014;345:1256070.
52.Parker AL, Waddington SN, Nicol CG, Shayakhmetov DM, Buckley SM, Denby L, et al. Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes. Blood. 2006;108:2554-2561.
53.Shayakhmetov DM, Gaggar A, Ni S, Li ZY, Lieber A. Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. J Virol. 2005;79:7478-7491.
54.Allen RJ, Byrnes AP. Interaction of adenovirus with antibodies, complement, and coagulation factors. FEBS Lett. 2019;593:3449-3460.
55.Cotter MJ, Zaiss AK, Muruve DA. Neutrophils interact with adenovirus vectors via Fc receptors and complement receptor 1. J Virol. 2005;79:14622-14631.
56.McEwan WA, Tam JC, Watkinson RE, Bidgood SR, Mallery DL, James LC. Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat Immunol. 2013;14:327-336.
57.Fletcher AJ, James LC. Coordinated Neutralization and Immune Activation by the Cytosolic Antibody Receptor TRIM21. J Virol. 2016;90:4856-4859.
58.Khare R, Hillestad ML, Xu Z, Byrnes AP, Barry MA. Circulating antibodies and macrophages as modulators of adenovirus pharmacology. J Virol. 2013;87:3678-3686.
59.Bottermann M, Foss S, van Tienen LM, Vaysburd M, Cruickshank J, O’Connell K, et al. TRIM21 mediates antibody inhibition of adenovirus-based gene delivery and vaccination. Proc Natl Acad Sci U S A. 2018;115:10440-10445.
60.Di Paolo NC, Baldwin LK, Irons EE, Papayannopoulou T, Tomlinson S, Shayakhmetov DM. IL-1alpha and complement cooperate in triggering local neutrophilic inflammation in response to adenovirus and eliminating virus-containing cells. PL
61.Di Paolo NC, Miao EA, Iwakura Y, Murali-Krishna K, Aderem A, Flavell RA, et al. Virus binding to a plasma membrane receptor triggers interleukin-1 alpha-mediated proinflammatory macrophage response in vivo. Immunity. 2009;31:110-121.
62.Muruve DA, Petrilli V, Zaiss AK, White LR, Clark SA, Ross PJ, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008;452:103-107.
63.Suzuki M, Bertin TK, Rogers GL, Cela RG, Zolotukhin I, Palmer DJ, et al. Differential type I interferon-dependent transgene silencing of helper-dependent adenoviral vs. adeno-associated viral vectors in vivo. Mol Ther. 2013;21:796-80
64.Anghelina D, Lam E, Falck-Pedersen E. Diminished Innate Antiviral Response to Adenovirus Vectors in cGAS/STING-Deficient Mice Minimally Impacts Adaptive Immunity. J Virol. 2016;90:5915-5927.
65.Wang L, Wen M, Cao X. Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses. Science. 2019;365.
66.Avgousti DC, Herrmann C, Kulej K, Pancholi NJ, Sekulic N, Petrescu J, et al. A core viral protein binds host nucleosomes to sequester immune danger signals. Nature. 2016;535:173-177.
67.Fields PA, Kowalczyk DW, Arruda VR, Armstrong E, McCleland ML, Hagstrom JN, et al. Role of vector in activation of T cell subsets in immune responses against the secreted transgene product factor IX. Mol Ther. 2000;1:225-235.
68.Amalfitano A, Parks RJ. Separating fact from fiction: assessing the potential of modified adenovirus vectors for use in human gene therapy. Current gene therapy. 2002;2:111-133.
69.Appaiahgari MB, Vrati S. Adenoviruses as gene/vaccine delivery vectors: promises and pitfalls. Expert Opin Biol Ther. 2015;15:337-351.
70.Sweeney K, Hallden G. Oncolytic adenovirus-mediated therapy for prostate cancer. Oncolytic virotherapy. 2016;5:45-57.
71.Castro JE, Melo-Cardenas J, Urquiza M, Barajas-Gamboa JS, Pakbaz RS, Kipps TJ. Gene immunotherapy of chronic lymphocytic leukemia: a phase I study of intranodally injected adenovirus expressing a chimeric CD154 molecule. Cancer resea
72.Predina JD, Keating J, Venegas O, Nims S, Singhal S. Neoadjuvant intratumoral immuno-gene therapy for non-small cell lung cancer. Discovery medicine. 2016;21:275-281.
73.Schiza A, Wenthe J, Mangsbo S, Eriksson E, Nilsson A, Totterman TH, et al. Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients. Journal of
74.Garcia-Carbonero R, Salazar R, Duran I, Osman-Garcia I, Paz-Ares L, Bozada JM, et al. Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection. Journal for i
75.Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, et al. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N Engl J Med. 2013;369:2083-2092.
76.Kibuuka H, Kimutai R, Maboko L, Sawe F, Schunk MS, Kroidl A, et al. A phase 1/2 study of a multiclade HIV-1 DNA plasmid prime and recombinant adenovirus serotype 5 boost vaccine in HIV-Uninfected East Africans (RV 172). J Infect Dis.
77.Gurwith M, Lock M, Taylor EM, Ishioka G, Alexander J, Mayall T, et al. Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1
78.Smaill F, Jeyanathan M, Smieja M, Medina MF, Thanthrige-Don N, Zganiacz A, et al. A human type 5 adenovirus-based tuberculosis vaccine induces robust T cell responses in humans despite preexisting anti-adenovirus immunity. Sci Transl
79.Diaz CM, Chiappori A, Aurisicchio L, Bagchi A, Clark J, Dubey S, et al. Phase 1 studies of the safety and immunogenicity of electroporated HER2/CEA DNA vaccine followed by adenoviral boost immunization in patients with solid tumors.
80.Kallel H, Kamen AA. Large-scale adenovirus and poxvirus-vectored vaccine manufacturing to enable clinical trials. Biotechnol J. 2015;10:741-747.
81.Perreau M, Pantaleo G, Kremer EJ. Activation of a dendritic cell-T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells. J Exp Med. 2008;205:2717-2725.
82.Sekaly RP. The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? J Exp Med. 2008;205:7-12.
83.Fausther-Bovendo H, Kobinger GP. Pre-existing immunity against Ad vectors: humoral, cellular, and innate response, what’s important? Hum Vaccin Immunother. 2014;10:2875-2884.
84.Yang Y, Nunes FA, Berencsi K, Furth EE, Gonczol E, Wilson JM. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A. 1994;91:4407-4411.
85.Xin KQ, Jounai N, Someya K, Honma K, Mizuguchi H, Naganawa S, et al. Prime-boost vaccination with plasmid DNA and a chimeric adenovirus type 5 vector with type 35 fiber induces protective immunity against HIV. Gene Ther. 2005;12:1769
86.Gao GP, Yang Y, Wilson JM. Biology of adenovirus vectors with E1 and E4 deletions for liver-directed gene therapy. J Virol. 1996;70:8934-8943.
87.Okada N, Iiyama S, Okada Y, Mizuguchi H, Hayakawa T, Nakagawa S, et al. Immunological properties and vaccine efficacy of murine dendritic cells simultaneously expressing melanoma-associated antigen and interleukin-12. Cancer Gene The
88.Salgado CD, Kilby JM. Retroviruses and other latent viruses: the deadliest of pathogens are not necessarily the best candidates for bioterrorism. Journal of the South Carolina Medical Association. 2009;105:104-106.
89.Jacome A, Navarro S, Rio P, Yanez RM, Gonzalez-Murillo A, Lozano ML, et al. Lentiviral-mediated genetic correction of hematopoietic and mesenchymal progenitor cells from Fanconi anemia patients. Molecular therapy : the journal of the
90.Yasutsugu Suzuki and Youichi Suzuki (July 20th 2011). Gene Regulatable Lentiviral Vector System, Viral Gene Therapy Ke Xu, IntechOpen, DOI: 10.5772/18155.
91.Borsotti C, Borroni E, Follenzi A. Lentiviral vector interactions with the host cell. Curr Opin Virol. 2016;21:102-108.
92.Rossetti M, Gregori S, Hauben E, Brown BD, Sergi LS, Naldini L, et al. HIV-1-derived lentiviral vectors directly activate plasmacytoid dendritic cells, which in turn induce the maturation of myeloid dendritic cells. Hum Gene Ther. 20
93.Wang CX, Torbett BE. Role of the mammalian target of rapamycin pathway in lentiviral vector transduction of hematopoietic stem cells. Curr Opin Hematol. 2015;22:302-308.
94.Merlin S, Cannizzo ES, Borroni E, Bruscaggin V, Schinco P, Tulalamba W, et al. A Novel Platform for Immune Tolerance Induction in Hemophilia A Mice. Mol Ther. 2017;25:1815-1830.
95.Merlin S, Follenzi A. Transcriptional Targeting and MicroRNA Regulation of Lentiviral Vectors. Mol Ther Methods Clin Dev. 2019;12:223-232.
96.Milone MC, O’Doherty U. Clinical use of lentiviral vectors. Leukemia. 2018;32:1529-1541.
97.Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467:318-322.
98.Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009;326:818-823.
99.Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341:1233158.
100.Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D, Baldoli C, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016;388:476-487.
101.Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341:1233151.
102.Palmowski MJ, Lopes L, Ikeda Y, Salio M, Cerundolo V, Collins MK. Intravenous injection of a lentiviral vector encoding NY-ESO-1 induces an effective CTL response. J Immunol. 2004;172:1582-1587.
103.Lopes L, Dewannieux M, Gileadi U, Bailey R, Ikeda Y, Whittaker C, et al. Immunization with a lentivector that targets tumor antigen expression to dendritic cells induces potent CD8+ and CD4+ T-cell responses. J Virol. 2008;82:86-95.
104.Bobisse S, Rondina M, Merlo A, Tisato V, Mandruzzato S, Amendola M, et al. Reprogramming T lymphocytes for melanoma adoptive immunotherapy by T-cell receptor gene transfer with lentiviral vectors. Cancer Res. 2009;69:9385-9394.
105.Iglesias MC, Mollier K, Beignon AS, Souque P, Adotevi O, Lemonnier F, et al. Lentiviral vectors encoding HIV-1 polyepitopes induce broad CTL responses in vivo. Mol Ther. 2007;15:1203-1210.
106.Dai B, Yang L, Yang H, Hu B, Baltimore D, Wang P. HIV-1 Gag-specific immunity induced by a lentivector-based vaccine directed to dendritic cells. Proc Natl Acad Sci U S A. 2009;106:20382-20387.
107.Lemiale F, Asefa B, Ye D, Chen C, Korokhov N, Humeau L. An HIV-based lentiviral vector as HIV vaccine candidate: Immunogenic characterization. Vaccine. 2010;28:1952-1961.
108.Sinn PL, Hickey MA, Staber PD, Dylla DE, Jeffers SA, Davidson BL, et al. Lentivirus vectors pseudotyped with filoviral envelope glycoproteins transduce airway epithelia from the apical surface independently of folate receptor alpha. J Virol. 2003;77:5902-5910.
109.Pistello M, Bonci F, Zabogli E, Conti F, Freer G, Maggi F, et al. Env-expressing autologous T lymphocytes induce neutralizing antibody and afford marked protection against feline immunodeficiency virus. J Virol. 2010;84:3845-3856.
110.Chiuppesi F, Vannucci L, De Luca A, Lai M, Matteoli B, Freer G, et al. A lentiviral vector-based, herpes simplex virus 1 (HSV-1) glycoprotein B vaccine affords cross-protection against HSV-1 and HSV-2 genital infections. J Virol. 2012;86:6563-6574.
111.Norton TD, Zhen A, Tada T, Kim J, Kitchen S, Landau NR. Lentiviral Vector-Based Dendritic Cell Vaccine Suppresses HIV Replication in Humanized Mice. Mol Ther. 2019;27:960-973.
112.Wee EG, Ondondo B, Berglund P, Archer J, McMichael AJ, Baltimore D, et al. HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells. Mol Ther. 2017;25:494-503.
113.Pinschewer DD. Virally vectored vaccine delivery: medical needs, mechanisms, advantages and challenges. Swiss Med Wkly. 2017;147:w14465.
114.Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990;247:1465-1468.
115.Tagawa ST, Lee P, Snively J, Boswell W, Ounpraseuth S, Lee S, et al. Phase I study of intranodal delivery of a plasmid DNA vaccine for patients with Stage IV melanoma. Cancer. 2003;98:144-154.
116.Ulmer JB, Donnelly JJ, Parker SE, Rhodes GH, Felgner PL, Dwarki VJ, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science. 1993;259:1745-1749.
117.Fynan EF, Webster RG, Fuller DH, Haynes JR, Santoro JC, Robinson HL. DNA vaccines: protective immunizations by parenteral, mucosal, and gene-gun inoculations. Proc Natl Acad Sci U S A. 1993;90:11478-11482.
118.Suschak JJ, Williams JA, Schmaljohn CS. Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity. Hum Vaccin Immunother. 2017;13:2837-2848.
119.Hobernik D, Bros M. DNA Vaccines-How Far From Clinical Use? Int J Mol Sci. 2018;19.
120.Cui Z. DNA vaccine. Adv Genet. 2005;54:257-289.
121.Colluru VT, Johnson LE, Olson BM, McNeel DG. Preclinical and clinical development of DNA vaccines for prostate cancer. Urol Oncol. 2016;34:193-204.
122.Boyle JS, Silva A, Brady JL, Lew AM. DNA immunization: induction of higher avidity antibody and effect of route on T cell cytotoxicity. Proc Natl Acad Sci U S A. 1997;94:14626-14631.
123.Weber R, Bossart W, Cone R, Luethy R, Moelling K. Phase I clinical trial with HIV-1 gp160 plasmid vaccine in HIV-1-infected asymptomatic subjects. Eur J Clin Microbiol Infect Dis. 2001;20:800-803.
124.Fidler S, Stohr W, Pace M, Dorrell L, Lever A, Pett S, et al. Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial. Lancet. 2020;395:888-898.
125.Spearman P, Mulligan M, Anderson EJ, Shane AL, Stephens K, Gibson T, et al. A phase 1, randomized, controlled dose-escalation study of EP-1300 polyepitope DNA vaccine against Plasmodium falciparum malaria administered via electroporation. Vaccine. 2016;34:5571-5578.
126.Klencke B, Matijevic M, Urban RG, Lathey JL, Hedley ML, Berry M, et al. Encapsulated plasmid DNA treatment for human papillomavirus 16-associated anal dysplasia: a Phase I study of ZYC101. Clin Cancer Res. 2002;8:1028-1037.
127.Timmerman JM, Singh G, Hermanson G, Hobart P, Czerwinski DK, Taidi B, et al. Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma. Cancer Res. 2002;62:5845-5852.
128.Norell H, Poschke I, Charo J, Wei WZ, Erskine C, Piechocki MP, et al. Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial. J Transl Med. 2010;8:53.
129.Staff C, Mozaffari F, Haller BK, Wahren B, Liljefors M. A Phase I safety study of plasmid DNA immunization targeting carcinoembryonic antigen in colorectal cancer patients. Vaccine. 2011;29:6817-6822.
130.Conry RM, Curiel DT, Strong TV, Moore SE, Allen KO, Barlow DL, et al. Safety and immunogenicity of a DNA vaccine encoding carcinoembryonic antigen and hepatitis B surface antigen in colorectal carcinoma patients. Clin Cancer Res. 2002;8:2782-2787.
131.Ginsberg BA, Gallardo HF, Rasalan TS, Adamow M, Mu Z, Tandon S, et al. Immunologic response to xenogeneic gp100 DNA in melanoma patients: comparison of particle-mediated epidermal delivery with intramuscular injection. Clin Cancer Res. 2010;16:4057-4065.
132.Yuan J, Ku GY, Gallardo HF, Orlandi F, Manukian G, Rasalan TS, et al. Safety and immunogenicity of a human and mouse gp100 DNA vaccine in a phase I trial of patients with melanoma. Cancer Immun. 2009;9:5.
133.Wolchok JD, Yuan J, Houghton AN, Gallardo HF, Rasalan TS, Wang J, et al. Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma. Mol Ther. 2007;15:2044-2050.
134.Triozzi PL, Aldrich W, Allen KO, Carlisle RR, LoBuglio AF, Conry RM. Phase I study of a plasmid DNA vaccine encoding MART-1 in patients with resected melanoma at risk for relapse. J Immunother. 2005;28:382-388.
135.Weber J, Boswell W, Smith J, Hersh E, Snively J, Diaz M, et al. Phase 1 trial of intranodal injection of a Melan-A/MART-1 DNA plasmid vaccine in patients with stage IV melanoma. J Immunother. 2008;31:215-223.
136.Dangoor A, Lorigan P, Keilholz U, Schadendorf D, Harris A, Ottensmeier C, et al. Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine. Cancer Immunol Immunother. 2010;59:863-873.
137.Cassaday RD, Sondel PM, King DM, Macklin MD, Gan J, Warner TF, et al. A phase I study of immunization using particle-mediated epidermal delivery of genes for gp100 and GM-CSF into uninvolved skin of melanoma patients. Clin Cancer Res. 2007;13:540-549.
138.Nabel GJ, Gordon D, Bishop DK, Nickoloff BJ, Yang ZY, Aruga A, et al. Immune response in human melanoma after transfer of an allogeneic class I major histocompatibility complex gene with DNA-liposome complexes. Proc Natl Acad Sci U S A. 1996;93:15388-15393.
139.Nemunaitis J, Meyers T, Senzer N, Cunningham C, West H, Vallieres E, et al. Phase I Trial of sequential administration of recombinant DNA and adenovirus expressing L523S protein in early stage non-small-cell lung cancer. Mol Ther. 2006;13:1185-1191.
140.Hovav AH, Panas MW, Rahman S, Sircar P, Gillard G, Cayabyab MJ, et al. Duration of antigen expression in vivo following DNA immunization modifies the magnitude, contraction, and secondary responses of CD8+ T lymphocytes. J Immunol. 2007;179:6725-6733.
141.Pollard C, De Koker S, Saelens X, Vanham G, Grooten J. Challenges and advances towards the rational design of mRNA vaccines. Trends Mol Med. 2013;19:705-713.
142.Iavarone C, O’Hagan D T, Yu D, Delahaye NF, Ulmer JB. Mechanism of action of mRNA-based vaccines. Expert Rev Vaccines. 2017;16:871-881.
143.De Beuckelaer A, Grooten J, De Koker S. Type I Interferons Modulate CD8(+) T Cell Immunity to mRNA Vaccines. Trends Mol Med. 2017;23:216-226.
144.Cruz CC, Suthar MS, Montgomery SA, Shabman R, Simmons J, Johnston RE, et al. Modulation of type I IFN induction by a virulence determinant within the alphavirus nsP1 protein. Virology. 2010;399:1-10.
145.Maruggi G, Shaw CA, Otten GR, Mason PW, Beard CW. Engineered alphavirus replicon vaccines based on known attenuated viral mutants show limited effects on immunogenicity. Virology. 2013;447:254-264.
146.Kramps T, Elbers K. Introduction to RNA Vaccines. Methods Mol Biol. 2017;1499:1-11.
147.Bedoui S, Whitney PG, Waithman J, Eidsmo L, Wakim L, Caminschi I, et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol. 2009;10:488-495.
148.Scheel B, Aulwurm S, Probst J, Stitz L, Hoerr I, Rammensee HG, et al. Therapeutic anti-tumor immunity triggered by injections of immunostimulating single-stranded RNA. Eur J Immunol. 2006;36:2807-2816.
149.Seregin SS, Appledorn DM, McBride AJ, Schuldt NJ, Aldhamen YA, Voss T, et al. Transient pretreatment with glucocorticoid ablates innate toxicity of systemically delivered adenoviral vectors without reducing efficacy. Mol Ther. 2009;17:685-696.
150.Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature. 2016;534:396-401.
151.Sebastian M, Papachristofilou A, Weiss C, Fruh M, Cathomas R, Hilbe W, et al. Phase Ib study evaluating a self-adjuvanted mRNA cancer vaccine (RNActive(R)) combined with local radiation as consolidation and maintenance treatment for patients with stage IV non-small cell lung cancer. BMC Cancer. 2014;14:748.
152.Weide B, Pascolo S, Scheel B, Derhovanessian E, Pflugfelder A, Eigentler TK, et al. Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients. J Immunother. 2009;32:498-507.
153.Weide B, Carralot JP, Reese A, Scheel B, Eigentler TK, Hoerr I, et al. Results of the first phase I/II clinical vaccination trial with direct injection of mRNA. J Immunother. 2008;31:180-188.
154.Rittig SM, Haentschel M, Weimer KJ, Heine A, Muller MR, Brugger W, et al. Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients. Mol Ther. 2011;19:990-999.
155.Rittig SM, Haentschel M, Weimer KJ, Heine A, Muller MR, Brugger W, et al. Long-term survival correlates with immunological responses in renal cell carcinoma patients treated with mRNA-based immunotherapy. Oncoimmunology. 2016;5:e1108511.
156.Alberer M, Gnad-Vogt U, Hong HS, Mehr KT, Backert L, Finak G, et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet. 2017;390:1511-1520.
157.Bahl K, Senn JJ, Yuzhakov O, Bulychev A, Brito LA, Hassett KJ, et al. Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses. Mol Ther. 2017;25:1316-1327.
158.Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395:514-523.
159.Rothe C, Schunk M, Sothmann P, Bretzel G, Froeschl G, Wallrauch C, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med. 2020;382:970-971.
160.Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA. 2020.
161.Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020.
162.Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020.
163.Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367:1260-1263.
164.Pan RY, Chung WH, Chu MT, Chen SJ, Chen HC, Zheng L, et al. Recent Development and Clinical Application of Cancer Vaccine: Targeting Neoantigens. J Immunol Res. 2018;2018:4325874.
165.Ghanem G, Fabrice J. Tyrosinase related protein 1 (TYRP1/gp75) in human cutaneous melanoma. Mol Oncol. 2011;5:150-155.
166.di Pietro A, Tosti G, Ferrucci PF, Testori A. Oncophage: step to the future for vaccine therapy in melanoma. Expert Opin Biol Ther. 2008;8:1973-1984.
167.Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res. 2011;17:3520-3526.
168.Schmitz-Winnenthal FH, Hohmann N, Niethammer AG, Friedrich T, Lubenau H, Springer M, et al. Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial. Oncoimmunology. 2015;4:e1001217.
169.Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:59-68.
170.Butts C, Murray RN, Smith CJ, Ellis PM, Jasas K, Maksymiuk A, et al. A multicenter open-label study to assess the safety of a new formulation of BLP25 liposome vaccine in patients with unresectable stage III non-small-cell lung cancer. Clin Lung Cancer. 2010;11:391-395.
171.Eton O, Ross MI, East MJ, Mansfield PF, Papadopoulos N, Ellerhorst JA, et al. Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma. J Transl Med. 2010;8:9.
172.Schirrmacher V. Clinical trials of antitumor vaccination with an autologous tumor cell vaccine modified by virus infection: improvement of patient survival based on improved antitumor immune memory. Cancer Immunol Immunother. 2005;54:587-598.
173.Schreiber S, Kampgen E, Wagner E, Pirkhammer D, Trcka J, Korschan H, et al. Immunotherapy of metastatic malignant melanoma by a vaccine consisting of autologous interleukin 2-transfected cancer cells: outcome of a phase I study. Hum Gene Ther. 1999;10:983-993.
174.Rosenberg SA, Zhai Y, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, et al. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J Natl Cancer Inst. 1998;90:1894-1900.
175.Kusumoto M, Umeda S, Ikubo A, Aoki Y, Tawfik O, Oben R, et al. Phase 1 clinical trial of irradiated autologous melanoma cells adenovirally transduced with human GM-CSF gene. Cancer Immunol Immunother. 2001;50:373-381.
176.Butterfield LH, Comin-Anduix B, Vujanovic L, Lee Y, Dissette VB, Yang JQ, et al. Adenovirus MART-1-engineered autologous dendritic cell vaccine for metastatic melanoma. J Immunother. 2008;31:294-309.
177.Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, et al. Intravesical rAd-IFNalpha/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. J Clin Oncol. 2017;35:3410-3416.
178.Navai N, Benedict WF, Zhang G, Abraham A, Ainslie N, Shah JB, et al. Phase 1b Trial to Evaluate Tissue Response to a Second Dose of Intravesical Recombinant Adenoviral Interferon alpha2b Formulated in Syn3 for Failures of Bacillus Calmette-Guerin (BCG) Therapy in Nonmuscle Invasive Bladder Cancer. Ann Surg Oncol. 2016;23:4110-4114.
179.Dinney CP, Fisher MB, Navai N, O’Donnell MA, Cutler D, Abraham A, et al. Phase I trial of intravesical recombinant adenovirus mediated interferon-alpha2b formulated in Syn3 for Bacillus Calmette-Guerin failures in nonmuscle invasive bladder cancer. J Urol. 2013;190:850-856.
180.Morse MA, Chaudhry A, Gabitzsch ES, Hobeika AC, Osada T, Clay TM, et al. Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients. Cancer Immunol Immunother. 2013;62:1293-1301.
181.Butterfield LH, Economou JS, Gamblin TC, Geller DA. Alpha fetoprotein DNA prime and adenovirus boost immunization of two hepatocellular cancer patients. J Transl Med. 2014;12:86.
182.Gavazza A, Lubas G, Fridman A, Peruzzi D, Impellizeri JA, Luberto L, et al. Safety and efficacy of a genetic vaccine targeting telomerase plus chemotherapy for the therapy of canine B-cell lymphoma. Hum Gene Ther. 2013;24:728-738.
183.Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J, Bumbaca S, et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature. 2014;515:572-576.
184.Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015;348:803-808.