Viral vector

Viruses have evolved specialized molecular mechanisms to transport their genomes into infected hosts, a process termed transduction.

Further development was temporarily halted by a recombinant DNA research moratorium following the Asilomar Conference and stringent National Institutes of Health regulations.

Although the 1990s saw significant advances in viral vectors, clinical trials had a number of setbacks, culminating in Jesse Gelsinger's death.

Viruses, infectious agents composed of a protein coat that encloses a genome, are the most numerous biological entities on Earth.

[11] Viral vector gene therapies may also be used for plants, tentatively enhancing crop performance or promoting sustainable production.

[11][13] Relative to other non-integrative gene therapy approaches, transgenes introduced by viral vectors offer multi-year long expression.

[15][16] Conventional vaccines are not suitable for protection against some pathogens due to unique immune evasion strategies and differences in pathogenesis.

[22] 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.

[23] Retroviruses—enveloped RNA viruses—are popular viral vector platforms due to their ability to integrate genetic material into the host genome.

[25] The most commonly used gammaretroviral vector is a modified Moloney murine leukemia virus (MMLV), able to transduce various mammalian cell types.

[26] Gammaretroviral vectors have been successfully applied to ex vivo hematopoietic stem cell to treat multiple genetic diseases.

[36] Adenoviral vectors display high transduction efficiency and transgene expression, and can infect both dividing and non-dividing cells.

[38] 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.

[41] 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.

[43] The tropism of adeno-associated viral vectors can be tailored by creating recombinant versions from multiple serotypes, termed pseudotyping.

[43] Due to their ability to infect and induce longlasting effects within nondividing cells, AAVs are commonly used in basic neuroscience research.

[49][48] Moreover, manufacturing procedures developed to mass-produce smallpox vaccine stockpiles may expedite vaccinia viral vector production.

[52] As a vaccine platform, vaccinia vectors display highly effective transgene expression and create a robust immune response.

[50] The virus fast-acting: its life cycle produces mature progeny vaccinia within 6 hours, and has three viral spread mechanisms.

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.

[61] These vectors have been employed for a range of applications, from increasing the aesthetic quality of ornamental plants to pest biocontrol, rapid expression of recombinant proteins and peptides, and to accelerate crop breeding.

[72] For viral vector production on a smaller, laboratory setting, static cell culture systems like Petri dishes are typically used.

[74] In 2017, The New York Times reported a manufacturing backlog of inactivated viruses, delaying some gene therapy trials by years.

[75] 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.

[76][77][78] The implications of this achievement troubled scientists like Robert Pollack, who convinced Berg not to transduce DNA from SV40 into E. coli via a bacteriophage vector.

[81] 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.

[11] 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.

[84] 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.

[84][note 1] Viral vectors experienced a resurgence when they were successfully employed for ex vivo hematopoietic gene delivery in clinical settings.

CDC poster explaining viral vector vaccines
A 2021 U.S. Centers for Disease Control and Prevention poster on the COVID-19 viral vector vaccines
Structure of a virus
Structure of a virus, specifically the hepatitis C virus
Genetically engineered mice glowing green
Mice transduced by a lentiviral vector fluoresce under UV-illumination [ 7 ]
Viral vector-based gene therapy
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.
Packaging and transduction by a lentiviral vector.
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.
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.
An electron micrograph of vaccinia
Herpes simplex virus I
A typical suspension culture bioreactor
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 (set pictured) depicts a viral vector-created apocalypse.