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{{short description|Biotechnology to deliver genetic material into a cell}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
[[File:How viral vector COVID-19 Vaccines Work (English).pdf|thumb|upright=1|alt=CDC poster explaining viral vector vaccines|A 2021 [[U.S. Centers for Disease Control and Prevention]] poster on the COVID-19 viral vector vaccines]]
'''Viral vectors''' are  modified [[viruses]] designed to [[gene delivery|deliver genetic material]] into [[cell (biology)|cells]]. This process can be performed inside an organism or in [[cell culture]]. Viral vectors have widespread applications in basic research, agriculture, and medicine.

Viruses have evolved specialized molecular mechanisms to transport their [[genomes]] into infected hosts, a process termed [[transduction (genetics)|transduction]]. This capability has been exploited for use as viral vectors, which may integrate their genetic cargo—the [[transgene]]—into the host genome, although non-integrative vectors are also commonly used. In addition to agriculture and laboratory research, viral vectors are widely applied in [[gene therapy]]: as of 2022, all approved gene therapies were viral vector-based. Further, compared to traditional [[vaccines]], the intracellular [[antigen]] expression enabled by [[viral vector vaccines]] offers more robust immune activation.

Many types of viruses have been developed into viral vector platforms, ranging from [[retroviruses]] to [[cytomegaloviruses]]. Different viral vector classes vary widely in strengths and limitations, suiting some to specific applications. For instance, relatively non-immunogenic and integrative vectors like [[lentiviral vectors]] are commonly employed for gene therapy. Chimeric viral vectors—such as hybrid vectors with qualities of both [[bacteriophages]] and eukaryotic viruses—have also been developed.

Viral vectors were first created in 1972 by [[Paul Berg]]. Further development was temporarily halted by a [[recombinant DNA]] research moratorium following the [[Asilomar Conference on Recombinant DNA|Asilomar Conference]] and stringent [[National Institutes of Health]] regulations. Once lifted, the 1980s saw both the first recombinant viral vector gene therapy and the first viral vector vaccine. Although the 1990s saw significant advances in viral vectors, clinical trials had a number of setbacks, culminating in [[Jesse Gelsinger]]'s death. However, in the 21st century, viral vectors experienced a resurgence and have been globally approved for the treatment of various diseases. They have been administered to billions of patients, notably during the [[COVID-19 pandemic]].

==Characteristics==
[[File:Hegasy Hep C Virus EN-01.jpg|thumb|alt=Structure of a virus|[[Virus#Structure|Structure]] of a virus, specifically the [[hepatitis C virus]]]]
[[Viruses]], [[infectious agents]] composed of a protein coat that encloses a [[genome]], are the most numerous biological entities on Earth.{{sfn|Pasin|Menzel|Daròs|2019|p=1010}}{{sfn|Labbé|Vessillier|Rafiq|2021|p=1}} As they cannot replicate independently, they must infect [[Cell (biology)|cells]] and hijack the [[Host (biology)|host]]'s replication machinery in order [[Viral replication|to produce copies of themselves]].{{sfn|Labbé|Vessillier|Rafiq|2021|p=1}} Viruses do this by inserting their genome—which can be [[DNA]] or [[RNA]], either [[Nucleic acid#Molecular composition and size|single-stranded or double-stranded]]—into the host.{{sfn|Kayser|Bienz|Eckert|Zinkernagel|2005|pp=377-378}} Some viruses may [[Viral transformation|integrate]] their genome directly into that of the host in the form of a [[provirus]].{{sfn|Barth|Aylward|2024|p=1}}

This ability to transfer foreign genetic material has been exploited by [[genetic engineers]] to create viral vectors, which can [[Transduction (genetics)|transduce]] the desired [[transgene]] into a target cell.{{sfn|Labbé|Vessillier|Rafiq|2021|p=1}} Viral vectors consists of three components:{{sfn|Bulcha|Wang|Ma|Tai|2021|pp=1-2}}{{sfn|Nomaguchi|Fujita|Miyazaki|Adachi|2012|p=1}}

#A [[Capsid|protein capsid]] and sometimes an [[Viral envelope|envelope]] that encapsidates the genetic payload. This determines the range of [[cell types]] that the vector infects, termed its [[Tissue tropism|tropism]].
#A genetic payload: the transgene that results in the desired effect when [[Gene expression|expressed]].
#A "[[Expression cassette|regulatory cassette]]" that controls transgene expression, whether integrated into a host [[chromosome]] or as an [[episome]]. The cassette comprises an [[Enhancer (genetics)|enhancer]], a [[Promoter (genetics)|promoter]], and auxiliary elements.

==Applications==
[[File:GFP Mice 01.jpg|thumb|upright=.9|alt=Genetically engineered mice glowing green|Mice transduced by a lentiviral vector fluoresce under UV-illumination{{sfn|Moen|Jevne|Wang|Kalland|2012|p=2}}]]
===Basic research===
Viral vectors are routinely used in a [[basic research]] setting and can introduce genes encoding, for instance, [[Complementary DNA|complementary DNA]], [[short hairpin RNA]], or [[CRISPR gene editing|CRISPR/Cas9 systems]] for gene editing.{{sfn|Lanigan|Kopera|Saunders|2020|pp=1,7}} Viral vectors are employed for cellular reprogramming, like [[induced pluripotent stem cells|inducing pluripotent stem cells]] or differentiating adult somatic cells into different cell types.{{sfn|Sakuma|Barry|Ikeda|2012|p=612}} Researchers also use viral vectors to create [[Genetically modified mouse|transgenic mice and rats]] for experiments.{{sfn|Lanigan|Kopera|Saunders|2020|p=1}} Viral vectors can be used for ''[[in vivo]]'' imaging via the introduction of a [[reporter gene]]. Further, transduction of stem cells can permit the tracing of cell lineage during [[Embryogenesis|development]].{{sfn|Sakuma|Barry|Ikeda|2012|p=612}}

===Gene therapy===
{{main|Gene therapy}}
[[File:Viral mediated delivery of genes to neurons 1.jpg|thumb|upright=2|Viral vector-based gene therapy]]
[[Gene therapy]] seeks to modulate or otherwise affect gene expression via the introduction of a therapeutic transgene. Gene therapy by viral vectors can be performed by ''in vivo'' delivery by directly administering the vector to the patient, or ''[[ex vivo]]'' by extracting cells from the patient, transducing them, and then reintroducing the modified cells into the patient.{{sfn|Bulcha|Wang|Ma|Tai|2021|p=1}} Viral vector gene therapies may also be used for plants, tentatively enhancing crop performance or promoting sustainable production.{{sfn|Pasin|Uranga|Charudattan|Kwon|2024|p=1}}

There are four broad categories of gene therapy: gene replacement, [[gene silencing]], gene addition, or gene editing.{{sfn|Bulcha|Wang|Ma|Tai|2021|p=1}}{{sfn|Li|Le|Zhang|Nian|2023|p=2}} Relative to other non-integrative gene therapy approaches, transgenes introduced by viral vectors offer multi-year long expression.{{sfn|Sasmita|2019|p=29}}

===Vaccines===
{{Main|Viral vector vaccine}}
[[File:201021 Llegada de la vacuna conytra COVID -19 S-putnik V (12) (51611494786).jpg|thumb|upright=1.3|left|alt=Shipments of the Russian-made Sputnik V COVID-19 vaccine, an adenoviral vector, are lined up in a storage facility in Guatemala, 2021|Shipments of the Russian-made [[Sputnik V COVID-19 vaccine]], an adenoviral vector, are seen in Guatemala in 2021.]]
For use as [[vaccine]] platforms, viral vectors can be engineered to carry a specific [[antigen]] associated with an infectious disease or a [[tumor antigen]].{{sfn|Wang|Liang|Wang|Li|2023|p=1}}{{sfn|Larocca|Schlom|2011|p=1}} Conventional vaccines are not suitable for protection against some pathogens due to unique immune evasion strategies and differences in pathogenesis.{{sfn|Elkashif|Alhashimi|Sayedahmed|Sambhara|2021|p=1}} Viral vector-based vaccines, for instance, could eventually offer immunity against [[HIV-1]] and [[malaria]].{{sfn|Ura|Okuda|Shimada|2014|p=625}} 

While traditional subunit vaccines elicit a humoral response,{{sfn|Ura|Okuda|Shimada|2014|p=624}} viral vectors allow for intracellular antigen expression that activates MHC pathways via both direct and crosspresentation pathways. This induces a robust adaptive immune response.{{sfn|McCann|O'Connor|Lambe|Pollard|2022|p=2}}{{sfn|Ura|Okuda|Shimada|2014|p=624-625}} Viral vector vaccines also have intrinsic [[Immunologic adjuvant|adjuvant properties]] via innate immune system activation and the expression of [[pathogen-associated molecular patterns]], negating the need for any additional adjuvant.{{sfn|McCann|O'Connor|Lambe|Pollard|2022|p=1}}{{sfn|Wang|Liang|Wang|Li|2023|p=1}} In addition to a more robust immune response in comparison to other vaccine types, viral vectors offer efficient gene transduction and can target specific cell types.{{sfn|Ura|Okuda|Shimada|2014|p=624}} Pre-existing immunity to the virus used as the vector, however, can be a significant issue.{{sfn|Ura|Okuda|Shimada|2014|p=625}} 

Prior to 2020, viral vector vaccines were widely administered but confined to veterinary medicine.{{sfn|McCann|O'Connor|Lambe|Pollard|2022|p=1}} In the global response to the [[COVID-19 pandemic]], viral vector vaccines played a fundamental role and were administered to billions of people, particularly in low and middle-income nations.{{sfn|McCann|O'Connor|Lambe|Pollard|2022|pp=1,6-7}}

==Types==
===Retroviruses===
{{main|Retroviruses}}
[[Retroviruses]]—enveloped RNA viruses—are popular viral vector platforms due to their ability to integrate genetic material into the host genome.{{sfn|Labbé|Vessillier|Rafiq|2021|p=1}} Retroviral vectors comprise two general classes: gamma retroviral and lentiviral vectors. The fundamental difference between the two are that gamma retroviral vectors can only infect dividing cells, while lentiviral vectors can infect both dividing and resting cells.{{sfn|Labbé|Vessillier|Rafiq|2021|p=2}} Notably, retroviral genomes are composed of single-stranded RNA and must be converted to proviral double-stranded DNA, a process known as [[reverse transcription]]—before it is integrated into the host genome via viral proteins like [[integrase]].{{sfn|Milone|O'Doherty|2018|pp=1530-1531}}

The most commonly used gammaretroviral vector is a modified [[Moloney murine leukemia virus]] (MMLV), able to transduce various mammalian cell types. MMLV vectors have been associated with some cases of carcinogenesis.{{sfn|Gruntman|Flotte|2018|pp=1734}} Gammaretroviral vectors have been successfully applied to ''ex vivo'' hematopoietic stem cell to treat multiple genetic diseases.{{sfn|Gruntman|Flotte|2018|pp=1733}}

====Lentiviral vectors====
{{further|Lentiviral vector in gene therapy}}
[[Image:Lentiviral vector.png|thumb|right|400px|Packaging and transduction by a lentiviral vector.]]
Most lentiviral vectors are derived from [[HIV|human immunodeficiency virus type 1]] (HIV-1), although modified [[simian immunodeficiency virus]] (SIV), the [[feline immunodeficiency virus]] (FIV), and the [[equine infectious anaemia virus]] (EIAV) have also been utilized.{{sfn|Labbé|Vessillier|Rafiq|2021|p=2}} As all functional genes are removed or otherwise mutated, the vectors are not [[cytopathic effect|cytopathic]] and can be engineered to be non-integrative.{{sfn|Nemirov|Bourgine|Anna|Wei|2023|p=1}} 

Lentiviral vectors are able to carry up to 10 kb of foreign genetic material, although 3-4 kb was reported as optimal as of 2023.{{sfn|Labbé|Vessillier|Rafiq|2021|p=2}}{{sfn|Nemirov|Bourgine|Anna|Wei|2023|p=1}} Relative to other viral vectors, lentiviral vectors possess the greatest transduction capacity, due to the formation of a three-stranded "DNA flap" during retro-transcription of the single-strand lentiviral RNA to DNA within the host.{{sfn|Nemirov|Bourgine|Anna|Wei|2023|p=1}}

Although largely non-inflammatory,{{sfn|Nemirov|Bourgine|Anna|Wei|2023|pp=1, 4}} lentiviral vectors can induce robust adaptive immune responses by memory-type [[cytotoxic T cells]] and [[T helper cells]].{{sfn|Nemirov|Bourgine|Anna|Wei|2023|pp=1-2}} This is largely due to lentiviral vectors' high tropism for [[dendritic cells]], which activate T cells.{{sfn|Nemirov|Bourgine|Anna|Wei|2023|pp=1-2}} However, they can infect all types of antigen-presenting cells.{{sfn|Nemirov|Bourgine|Anna|Wei|2023|p=4}} Moreover, as they are the only retroviral vectors able to efficiently transduce both dividing and non-dividing cells, make them the most promising vaccine platforms.{{sfn|Nemirov|Bourgine|Anna|Wei|2023|p=4}} They have also been trialed as vaccines against cancer.{{sfn|Nemirov|Bourgine|Anna|Wei|2023|p=7}}

Lentiviral vectors have been used as ''[[in vivo]]'' therapies, such as directly treating genetic diseases like [[haemophilia B]] and for ''[[ex vivo]]'' treatments like immune cell modification in [[CAR T cell therapy]].{{sfn|Labbé|Vessillier|Rafiq|2021|p=2}} In 2017, the [[US Food and Drug Administration]] (FDA) approved [[tisagenlecleucel]], a lentiviral vector, for [[acute lymphoblastic leukaemia]].{{sfn|Li|Samulski|2020|p=255}}

===Adenoviruses===
{{main|Adenovirus}}
[[File:Icosahedral Adenoviruses.jpg|upright=1.5|thumb|[[Adenoviruses]] (visualized via electron micrograph at left and right and depicted graphically at center) are commonly used as viral vector platforms. Note the [[icosahedron]] capsid structure.]]
Adenoviruses are double-stranded DNA viruses belonging to the family ''[[Adenoviridae]]''.{{sfn|Elkashif|Alhashimi|Sayedahmed|Sambhara|2021|p=2}}{{sfn|Farhad|Neves|Arbuthnot|Maepa|2022|p=2}} Their relatively large genomes, of approximately 30-45 kb, make them ideal candidates for genetic delivery;{{sfn|Elkashif|Alhashimi|Sayedahmed|Sambhara|2021|p=2}} newer adenoviral vectors can carry up to 37 kb of foreign genetic material.{{sfn|Nemirov|Bourgine|Anna|Wei|2023|pp=3-4}} Adenoviral vectors display high transduction efficiency and transgene expression, and can infect both dividing and non-dividing cells.{{sfn|Ura|Okuda|Shimada|2014|p=628}} 

The adenoviral capsid, an [[icosahedron]], features a fibre "knob" at each of its 12 vertices. These fibre proteins mediate cell entry—greatly affecting efficacy and contribute to its broad tropism—notably via [[coxsackie–adenovirus receptors]] (CARs).{{sfn|Elkashif|Alhashimi|Sayedahmed|Sambhara|2021|p=2}}{{sfn|Ura|Okuda|Shimada|2014|p=628}} Adenoviral vectors can induce robust innate and adaptive immune responses.{{sfn|Elkashif|Alhashimi|Sayedahmed|Sambhara|2021|p=3}} Its strong immunogenicity is particularly due to the transduction of dendritic cells (DC), upregulating the expression of both MHC I and II molecules and activating the DCs.{{sfn|Elkashif|Alhashimi|Sayedahmed|Sambhara|2021|pp=3-4}} They have a strong adjuvant effect, as they display several [[pathogen-associated molecular patterns]].{{sfn|Elkashif|Alhashimi|Sayedahmed|Sambhara|2021|p=3}} One disadvantage is that pre-existing immunity to adenovirus serotypes is common, reducing efficacy.{{sfn|Ura|Okuda|Shimada|2014|p=628}}{{sfn|Elkashif|Alhashimi|Sayedahmed|Sambhara|2021|p=8}} The use of chimpanzee adenoviruses may circumvent this issue.{{sfn|Ewer|Sebastian|Spencer|Gilbert|2017|p=3020}}

While the activation of both innate and adaptive immune responses is an obstacle for many therapeutic applications, it makes adenenoviral vectors an ideal vaccine platform.{{sfn|Farhad|Neves|Arbuthnot|Maepa|2022|p=2}} The global response to the COVID-19 pandemic saw the development and use of multiple adenoviral vector vaccines, including [[Sputnik V COVID-19 vaccine|Sputnik V]], the [[Oxford–AstraZeneca COVID-19 vaccine|Oxford–AstraZeneca vaccine]], and the [[Janssen COVID-19 vaccine|Janssen vaccine]].{{sfn|Elkashif|Alhashimi|Sayedahmed|Sambhara|2021|pp=10,11}}

===Adeno-associated viruses===
{{main|Adeno-associated virus}}
[[File:Viral mediated delivery of genes to neurons 2.jpg|thumb|350px|left|'''Lentivirus (upper panel)''' –  To produce lentiviruses with the gene of interest as the lentiviral DNA construct, first transfect cells with a packaging plasmid and the envelope vector (VSVG).
'''Adeno Associated Virus (AAV) (lower panel)''' – To produce AAV, package a gene of interest into the AAV-ITR vector and transfect cells with a Helper vector and the Rep/Cap DNA integration vector.]]
Adeno-associated viruses (AAVs) are relatively small single-stranded DNA viruses belonging to ''[[Parvoviridae]]'' and, like lentiviral vectors, AAVs can infect both dividing and non-dividing cells.{{sfn|Haggerty|Grecco|Reeves|Atwood|2019|p=69}} AAVs, however, require the presence of a "helper virus" such as an adenovirus or herpes simplex virus to replicate within the host, although it can do so independently if [[cellular stress]] is induced or the helper virus genes are carried by the vector.{{sfn|Haggerty|Grecco|Reeves|Atwood|2019|pp=69-70}} 

AAVs insert themselves into a specific site in the host genome, particularly ''AAVS1'' on [[chromosome 19]] in humans. However, recombinant AAVs have been designed that do not integrate. These are instead stored as episomes that, in non-dividing cells, can last for years.{{sfn|Haggerty|Grecco|Reeves|Atwood|2019|p=70}} One disadvantage is that they are not able to carry large amounts of foreign genetic materials. Furthermore, the need to express the complementary strand for its single-stranded genome may delay transgene expression.{{sfn|Haggerty|Grecco|Reeves|Atwood|2019|p=70}} 

As of 2020, 11 different AAV serotypes—differing by capsid structure and consequently by tropism—had been identified.{{sfn|Haggerty|Grecco|Reeves|Atwood|2019|p=69}} The tropism of adeno-associated viral vectors can be tailored by creating recombinant versions from multiple serotypes, termed pseudotyping.{{sfn|Haggerty|Grecco|Reeves|Atwood|2019|p=69}} Due to their ability to infect and induce longlasting effects within nondividing cells, AAVs are commonly used in basic neuroscience research.{{sfn|Haggerty|Grecco|Reeves|Atwood|2019|pp=71-74, 78}} Following the approval of the AAV [[Alipogene tiparvovec]] in Europe in 2012,{{sfn|Haggerty|Grecco|Reeves|Atwood|2019|p=75}} in 2017, the FDA approved the first AAV-based in vivo gene therapy—[[voretigene neparvovec]]—which treated [[RPE65-associated Leber congenital amaurosis]].{{sfn|Li|Samulski|2020|p=255}} As of 2020, 230 clinical trials using AAV-based treatments were either underway or had been completed.{{sfn|Haggerty|Grecco|Reeves|Atwood|2019|p=75}}

===Vaccinia===
{{Main|Vaccinia}}
[[File:VaccHeuser.jpg|thumb|upright=1.1|An electron micrograph of [[vaccinia]]]]
[[Vaccinia virus]], a [[poxvirus]], is another promising candidate for viral vector development.{{sfn|Zhang|Dong|Zhao|Zheng|2021|p=1578}} Its use as the [[smallpox vaccine]]—first reported by [[Edward Jenner]] in 1798—led to the eradication of [[smallpox]] and demonstrated vaccinia as safe and effective in humans.{{sfn|Ura|Okuda|Shimada|2014|p=626}}{{sfn|Zhang|Dong|Zhao|Zheng|2021|p=1578}} Moreover, manufacturing procedures developed to mass-produce smallpox vaccine stockpiles may expedite vaccinia viral vector production.{{sfn|Ura|Okuda|Shimada|2014|p=627}}

Vaccinia possesses a large DNA genome and can consequently carry up to 40 kb of foreign DNA.{{sfn|Ura|Okuda|Shimada|2014|p=626}}{{sfn|Kaynarcalidan|Mascaraque|Drexler|2021|p=1}}{{sfn|Guo|Lu|Guo|Giehl|2019|p=4}}{{sfn|Kaynarcalidan|Mascaraque|Drexler|2021|p=1}} Further, vaccinia are unlikely to integrate into the host genome, decreasing the chance of carcinogenesis.{{sfn|Kaynarcalidan|Mascaraque|Drexler|2021|p=1}} Attenuated strains—replicating and non-replicating—have been developed.{{sfn|Ura|Okuda|Shimada|2014|p=626}} Although widely characterized due to its use against smallpox, as of 2019 the function of 50 percent of the vaccinia genome was unknown. This may lead to unpredictable effects.{{sfn|Guo|Lu|Guo|Giehl|2019|p=4}}

As a vaccine platform, vaccinia vectors display highly effective transgene expression and create a robust immune response.{{sfn|Ura|Okuda|Shimada|2014|p=627}} The virus fast-acting: its life cycle produces mature progeny vaccinia within 6 hours, and has three viral spread mechanisms.{{sfn|Guo|Lu|Guo|Giehl|2019|p=4}} Vaccinia also has an [[Immunologic adjuvant|adjuvant effect]], activating a strong [[Innate immune system|innate response]] via [[toll-like receptors]].{{sfn|Ura|Okuda|Shimada|2014|p=627}} A significant disadvantage that can reduce its efficacy, however, is pre-existing immunity against vaccinia in those who received the smallpox vaccine.{{sfn|Ura|Okuda|Shimada|2014|p=627}}

===Herpesviruses===
{{Main|Herpesviridae}}
[[File:Herpes simplex virus pap test 2.jpg|thumb|left|Herpes simplex virus I]]
Of the nine [[Human herpesviruses|herpesviruses]] that infect humans, herpes simplex virus 1 (HSV-1) is the most well characterized and most commonly used as a viral vector.{{sfn|Mody|Pathak|Hanson|Spencer|2020|p=1}} HSV-1 offers several advantages: it has broad tropism and can deliver therapeutics via specialized expression systems.{{sfn|Mody|Pathak|Hanson|Spencer|2020|pp=3-4}} Moreover, HSV-1 can cross the blood brain barrier if medically-disrupted, enabling it to target neurological diseases. Also, HSV-1 does not integrate into the host genome and can carry large amounts of foreign DNA. The former feature prevents harmful mutagenesis, as can occur with retroviral and adeno-associated vectors. Replication-deficient strains have been developed.{{sfn|Mody|Pathak|Hanson|Spencer|2020|p=4}}

In 2015, [[talimogene laherparepvec]]—an HSV-1 vector that triggers an anti-tumor immune response—was approved by the FDA to treat [[melanoma]].{{sfn|Khushalani|Harrington|Melcher|Bommareddy|2023|p=1}} As of 2020, HSV-1 vectors have been experimentally applied against [[sarcomas]] and cancers of the brain, colon, prostate, and skin.{{sfn|Hromic-Jahjefendic|Lundstrom|2020|p=631}} 

[[Cytomegalovirus]] (CMV), a herpesvirus, has also been developed for use as a viral vector.{{sfn|Ura|Okuda|Shimada|2014|p=631}} CMV can infect most cell types and can thus proliferate throughout the body. Although a CMV-based vaccine provided significant immunity against SIV—closely related to HIV—in macaques, development of CMV as a reliable vector was reported to still be in early stages as of 2020.{{sfn|Sasso|D'Alise|Zambrano|Scarselli|2020|p=10}}{{sfn|Schaefer|Robbins|Nzilambi|Louis|2005|p=1446}}

===Plant viruses===
{{main|Plant virus}}
[[Plant viruses]] are also engineered viral vectors for use in agriculture, horticulture, and [[Biology|biologic]] production.{{sfn|Abrahamian|Hammond|Hammond|2020|pp=513-515}} These vectors have been employed for a range of applications, from increasing the aesthetic quality of [[ornamental plants]] to [[Biological pest control|pest biocontrol]], rapid expression of recombinant proteins and peptides, and to accelerate crop breeding.{{sfn|Pasin|Menzel|Daròs|2019|pp=1010-1011}} The use of engineered plant viruses has been proposed to enhance crop performance and promote sustainable production.{{sfn|Pasin|Uranga|Charudattan|Kwon|2024|p=1}}

Replicating virus-based vectors are typically used.{{sfn|Zaidi|Mansoor|2017|p=1}} RNA viruses used for monocots include [[wheat streak mosaic virus]] and [[barley stripe mosaic virus]] and, for dicots, [[tobacco rattle virus]]. Single-stranded DNA viruses like [[geminiviruses]] have also been utilized.{{sfn|Zaidi|Mansoor|2017|p=1}} Viral vectors can be administered to plants via several pathways termed "agro-inoculation", including via rubbing, a [[Gene gun|biolistic delivery system]], agrospray, agroinjection, and even via [[insect vectors]].{{sfn|Abrahamian|Hammond|Hammond|2020|pp=520-523}}{{sfn|Pasin|Menzel|Daròs|2019|pp=1010-1011}} However, ''[[Agrobacterium]]''-mediated delivery of viral vectors—in which bacteria are transformed with [[plasmid DNA]] encoding the viral vector construct—is the most common approach.{{sfn|Abrahamian|Hammond|Hammond|2020|pp=522-528}}

===Bacteriophages===
{{Main|Bacteriophage}}
Chimeric vectors combining both bacteriophages and eukaryotic viruses have been developed and are capable of infecting eukaryotic cells.{{sfn|Petrov|Dymova|Richter|2022|p=9}}{{sfn|Pranjol|Hajitou|2015|p=269}} Unlike eukaryotic virus-based vectors, such bacteriophage vectors have no innate tropism for eukaryotic cells, allowing them to be engineered to be highly specific for cancer cells.{{sfn|Petrov|Dymova|Richter|2022|p=1}}

Bacteriophage vectors are also commonly used in molecular biology.{{sfn|Elois|Silva|Pilati|Rodriguez-Lazaro|2023|p=1}} For instance, bacteriophage vectors are used in [[phage-assisted continuous evolution]], promoting rapid mutagenesis of bacteria.{{sfn|Abril|Carrera|Notario|Sanchez-Perez|2022|p=11}} Although limited to [[mycobacteriophages]] and some phages of [[gram-negative bacteria]], bacteriophages can be used for direct cloning.{{sfn|Abril|Carrera|Notario|Sanchez-Perez|2022|p=12}}

==Manufacture==
[[File:Bioreactor principle.svg|thumb|upright|A typical suspension culture bioreactor]]
Viral vector manufacturing methods often vary by vector, although most utilize an adherent or suspension-based system with mammalian cells.{{sfn|van der Loo|Wright|2016|p=44}} For viral vector production on a smaller, laboratory setting, static cell culture systems like Petri dishes are typically used.{{sfn|Merten|Schweizer|Chahal|Kamen|2014|p=184}} 

Those techniques used in the laboratory are difficult to scale, requiring different approaches on an industrial scale.{{sfn|van der Loo|Wright|2016|p=44}} Large single-use disposable culture systems and [[bioreactors]] are commonly used by manufacturers.{{sfn|van der Loo|Wright|2016|p=44}} Vessels such as those with gas permeable surfaces are used to maximize cell culture density and solution transducing units.{{sfn|van der Loo|Wright|2016|p=44}} Depending on the vessel, viruses can be directly isolated from the supernatant or isolated via chemical lysis of the cultured cells or microfluidization.{{sfn|van der Loo|Wright|2016|p=45}} In 2017, ''The New York Times'' reported a manufacturing backlog of inactivated viruses, delaying some gene therapy trials by years.{{sfn|Kolata|2017}}

==History==
{{multiple image
 | align = right
 | total_width = 310
 | image1 = Paul Berg in 1980.jpg
 | alt1 = Portrait of Paul Berg
 | image2 = Asilomar Chapel interior - 2023-02-21.jpg
 | alt2 = Wooden church room
 | footer = [[Paul Berg]]'s creation of the first viral vector in 1972 led to the [[Asilomar Conference on Recombinant DNA|Asilomar Conference]], which established a moratorium on [[recombinant DNA]] research.
}}
In 1972, [[Stanford University]] biochemist [[Paul Berg]] developed the first viral vector, incorporating DNA from the [[lambda phage]] into the polyomavirus [[SV40]] to infect kidney cells maintained in culture.{{sfn|Travieso|Li|Mahesh|Mello|2022|p=1}}{{sfn|Lukiw|2023|p=1}}{{sfn|Jackson|Symons|Berg|1972|pp=2904–2909}} The implications of this achievement troubled scientists like [[Robert Pollack (biologist)|Robert Pollack]], who convinced Berg not to transduce DNA from SV40 into ''E. coli'' via a bacteriophage vector. They feared that introducing the purportedly cancer-causing genes of SV40 would create carcinogenic bacterial strains.{{sfn|Carmen|1985|pp=61–62}}{{sfn|Lukiw|2023|p=2}} These concerns and others in the emerging field of [[recombinant DNA]] led to the [[Asilomar Conference on Recombinant DNA|Asilomar Conference]] of 1975, where attendees agreed to a voluntary moratorium on [[Molecular cloning|cloning DNA]].{{sfn|Moss|2013|p=4220}}

In 1977, the [[National Institutes of Health]] (NIH) issued formal guidelines confining viral DNA cloning to rigid [[BSL-4]] conditions, practically preventing such research. However, the NIH loosened these rules in 1979, permitting [[Bernard Moss]] to develop a viral vector utilizing [[vaccinia]].{{sfn|Moss|2013|p=4220}} In 1982, Moss reported the first use of a viral vector for transient gene expression.{{sfn|Ura|Okuda|Shimada|2014|p=625}} The following year, Moss used the vaccinia vector to express a [[hepatitis B]] antigen, creating the first viral vector vaccine.{{sfn|McCann|O'Connor|Lambe|Pollard|2022|p=1}}

{{quote box |bgcolor = powderblue | width = 28em |align = left
| quote = Every realm of medicine has its defining moment, often with a human face attached. [[Polio]] had [[Jonas Salk]]. [[In vitro fertilization]] had [[Louise Brown]], the world's first test-tube baby. [[Transplant surgery]] had [[Artificial heart|Barney Clark]], the Seattle dentist with the artificial heart. AIDS had [[Magic Johnson]]. Now gene therapy has [[Jesse Gelsinger]].
| source = — [[Sheryl Gay Stolberg]], ''[[The New York Times Magazine]]''{{sfn|Stolberg|1999}} 
| style = padding:1.5em
| fontsize=85%
}}
Although a failed gene therapy attempt utilizing wild-type [[Shope papilloma virus]] had been made as early as 1972, [[Martin Cline]] attempted the first gene therapy utilizing recombinant DNA in 1980. It proved unsuccessful.{{sfn|Wirth|Parker|Ylä-Herttuala|2013|p=164}}{{sfn|Bulcha|Wang|Ma|Tai|2021|p=1}} In the 1990s, as genetic diseases were further characterized and viral vector technology improved, there was overoptimism about the capabilities the technology. Many clinical trials proved failures.{{sfn|Sheridan|2011|p=121}} There were some successes, such as the first effective gene therapy for [[severe combined immunodeficiency]] (SCID); it employed a retroviral vector.{{sfn|Bulcha|Wang|Ma|Tai|2021|p=1}} 

However, during a 1999 clinical trial at the [[University of Pennsylvania]], [[Jesse Gelsinger]] died from a fatal reaction to an adenoviral vector-based gene therapy.{{sfn|Stolberg|1999}}{{sfn|Sheridan|2011|p=121}} It was the first death related to any form of gene therapy.{{sfn|Sibbald|2001|p=1612}} Consequently, the FDA suspended all gene therapy trials at the University of Pennsylvania and investigated 60 others across the US.{{sfn|Sibbald|2001|p=1612}} An anonymous editorial in ''[[Nature Medicine]]'' noted that it represented a "loss of innocence" for viral vectors.{{sfn|Sheridan|2011|p=121}} Shortly thereafter, the field's reputation was further damaged when 5 children treated with a SCID gene therapy developed [[leukemia]] due to an issue with the retroviral vector.{{sfn|Sheridan|2011|p=121}}{{efn|group=note|One child ultimately died. According to Cormac Sheridan, the backlash was unfair as the overall mortality rate for the viral vector therapy was lower than equivalent approaches.{{sfn|Sheridan|2011|p=121}}}}

Viral vectors experienced a resurgence when they were successfully employed for ''ex vivo'' hematopoietic gene delivery in clinical settings.{{sfn|Bezeljak|2022|pp=2,10}} In 2003, China approved the first gene therapy for clinical use: [[Gendicine]], an adenoviral vector encoding [[p53]].{{sfn|Wirth|Parker|Ylä-Herttuala|2013|p=165}}{{sfn|Bezeljak|2022|p=23}} In 2012, the European Union issued its first approval of a gene therapy, an adeno-associated viral vector.{{sfn|Wirth|Parker|Ylä-Herttuala|2013|pp=166-167}} During the [[COVID-19 pandemic]], viral vector vaccines were used to an unprecedented extent: administered to billions of people.{{sfn|Bezeljak|2022|p=2}}{{sfn|McCann|O'Connor|Lambe|Pollard|2022|p=1}} As of 2022, all approved gene therapies were viral vector-based and over 1000 viral vector clinical trials targeting cancer were underway.{{sfn|Bezeljak|2022|pp=2,10}}

==In popular culture==
[[File:I am legend.jpg|thumb|upright|alt=Burnt and abandoned car props are situated near post-apocalyptic Washington Square Park in New York City as part of a set for the film I am Legend.|The film ''[[I Am Legend (film)|I Am Legend]]'' (set pictured) depicts a viral vector-created apocalypse.]]
In film, viral vectors are often portrayed as unintentionally causing a pandemic and civilizational catastrophe.{{sfn|Sánchez-Angulo|2023|pp=1,16}} The 2007 film ''[[I Am Legend (film)|I Am Legend]]'' depicts a cancer-targeting viral vector as unleashing a [[zombie apocalypse]].{{sfn|Reuters|2020}}{{sfn|Feldman|Clayton|2022|pp=2,5}} Similarly, a viral vector therapy for [[Alzheimer's disease]] in ''[[Rise of the Planet of the Apes]]'' (2011) becomes a deadly pathogen and causes an [[Planet of the Apes|ape uprising]]. Other films featuring viral vectors include ''[[The Bourne Legacy (film)|The Bourne Legacy]]'' (2012) and ''[[Resident Evil: The Final Chapter]]'' (2016).{{sfn|Sánchez-Angulo|2023|p=16}}

==Notes and references==
===Notes===
{{notelist|group=note}}

===Citations===
{{reflist}}

===Works cited===
====Journal articles====
{{Refbegin|30em}}
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{{Refend}}

====News articles====
{{Refbegin}}
*{{cite news|work=Reuters|date=December 18, 2020|title=Fact check: A vaccine did not turn characters in the movie 'I Am Legend' into zombies |url=https://www.reuters.com/article/idUSKBN28S23O/|access-date=27 April 2024|ref={{sfnref|Reuters|2020}} }}
*{{cite news|last=Kolata|first=Gina|date=27 November 2017|title=Gene Therapy Hits a Peculiar Roadblock: A Virus Shortage|url=https://www.nytimes.com/2017/11/27/health/gene-therapy-virus-shortage.html|work=The New York Times|access-date=20 May 2024|archive-url=https://web.archive.org/web/20230425132019/https://www.nytimes.com/2017/11/27/health/gene-therapy-virus-shortage.html|archive-date=25 April 2023|url-status=live}}
*{{cite news| vauthors = Stolberg SG |date=28 November 1999|title=The Biotech Death of Jesse Gelsinger|url=https://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html|work=The New York Times Magazine|access-date=29 April 2024|archive-url=https://web.archive.org/web/20121025034826/https://www.nytimes.com/1999/11/28/magazine/the-biotech-death-of-jesse-gelsinger.html|archive-date=25 October 2012|url-status=live}}
{{Refend}}

====Books and protocols====
{{Refbegin}}
*{{cite book| vauthors = Carmen I |date=1985|title=Cloning and the Constitution: An Inquiry into Governmental Policymaking and Genetic Experimentation|publisher=University of Wisconsin Press|isbn=9780299103408}}
*{{cite book|vauthors=Kayser FH, Bienz KA, Eckert J, Zinkernagel RM|date=2005|title=Medical Microbiology|publisher=Thieme|edition=10|isbn=1588902455}}
*{{cite book|last1=Warnock|first1=James N.|last2=Daigre|first2=Claire|last3=Al-Rubeai|first3=Mohamed|date=2011|editor-last1=Manfredsson|editor-first1=Fredric P.|editor-last2=Benskey|editor-first2=Matthew J.|title=Viral Vectors for Gene Therapy: Methods and Protocols|publisher=Springer|pages=1–25|chapter=Introduction to Viral Vectors|isbn=9781493990641}}
{{Refend}}

{{Virus topics|state=expanded}}
{{Self-replicating organic structures|state=collapsed}}


[[Category:Cell culture techniques]]
[[Category:Gene delivery]]
[[Category:Molecular genetics]]
[[Category:Virotherapy]]