A genetic vaccine (also ''gene-based vaccine'') is a

vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...

that contains

nucleic acids Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main clas ...

such as DNA or

RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

that lead to

protein biosynthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...

s within a cell. Genetic vaccines thus include

DNA vaccine A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response. DNA vaccines work by injecting genetically engineered plasmid containing the D ...

RNA vaccine An mRNA vaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen-encoding mRNA into immune cells, which use the designed mRNA as a blueprin ...

s and

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. , six viral v ...

Properties

Most vaccines other than

live attenuated vaccine An attenuated vaccine (or a live attenuated vaccine, LAV) is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or "live"). Attenuation takes an infectious agent and alters it so that it becomes harmless or less ...

s and genetic vaccines are not taken up by

MHC-I MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on pla ...

-presenting cells, but act outside of these cells, producing only a strong

humoral immune response Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it in ...

via

antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

. In the case of intracellular pathogens, an exclusive humoral immune response is ineffective.Eckhart Buddecke: ''Molekulare Medizin.'' ecomed-Storck GmbH, 2002, ISBN 3609160918. S. 162. Genetic vaccines are based on the principle of uptake of a nucleic acid into cells, whereupon a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

is produced according to the nucleic acid template. This protein is usually the immunodominant antigen of the

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

or a surface protein that enables the formation of

neutralizing antibodies A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibod ...

that inhibit the infection of cells. Subsequently, the protein is broken down at the

proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...

into short fragments (

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

s) that are imported into the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

via the

transporter associated with antigen processing Transporter associated with antigen processing (TAP) protein complex belongs to the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules. T ...

, allowing them to bind to MHCI-molecules that are subsequently

secreted 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...

to the cell surface. The presentation of the peptides on MHC-I complexes on the cell surface is necessary for a

cellular immune response Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in ...

. As a result, genetic vaccines and live vaccines generate

cytotoxic T-cell A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...

s in addition to antibodies in the vaccinated individual. In contrast to live vaccines, only parts of the pathogen are used, which means that a reversion to an infectious pathogen cannot occur as it happened during the polio vaccinations with the Sabin vaccine.Wolfram Gerlich: ''Medizinische Virologie.'' Georg Thieme Verlag, 2010, ISBN 3131139625. S. 466.

Administration

Genetic vaccines are most commonly administered by

injection Injection or injected may refer to: Science and technology * Injective function, a mathematical function mapping distinct arguments to distinct values * Injection (medicine), insertion of liquid into the body with a syringe * Injection, in broadca ...

(intramuscular or subcutaneous) or

infusion Infusion is the process of extracting chemical compounds or flavors from plant material in a solvent such as water, oil or alcohol, by allowing the material to remain suspended in the solvent over time (a process often called steeping). An inf ...

, and less commonly and for DNA, by

gene gun In genetic engineering, a gene gun or biolistic particle delivery system is a device used to deliver exogenous DNA (transgenes), RNA, or protein to cells. By coating particles of a heavy metal with a gene of interest and firing these micro-projec ...

electroporation Electroporation, or electropermeabilization, is a microbiology technique in which an electrical field is applied to cells in order to increase the permeability of the cell membrane, allowing chemicals, drugs, electrode arrays or DNA to be introdu ...

. While viral vectors have their own mechanisms to be taken up into cells, DNA and RNA must be introduced into cells via a method of

transfection Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: "transformation" is typically used to desc ...

. In humans, the cationic

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...

SM-102 SM-102 is a synthetic amino lipid which is used in combination with other lipids to form lipid nanoparticles. These are used for the delivery of mRNA-based vaccines, and in particular SM-102 forms part of the drug delivery system for the Moderna ...

ALC-0159 ALC-0159 is a PEG/lipid conjugate (i.e. PEGylated lipid), specifically, it is the ''N,N''-di myristylamide of 2-hydroxyacetic acid, O-pegylated to a PEG chain mass of about 2 kilodaltons (corresponding to about 45-46 ethylene oxide units per mole ...

and

ALC-0315 ALC-0315 ( 4-hydroxybutyl)azanediyli(hexane-6,1-diyl) bis(2-hexyldecanoate)) is a synthetic lipid. A colorless oily material, it has attracted attention as a component of the SARS-CoV-2 vaccine, BNT162b2, from BioNTech and Pfizer. Specifically, it ...

are used in conjunction with electrically neutral helper lipids. This allows the nucleic acid to be taken up by endocytosis and then released into the cytosol.

Applications

Examples of genetic vaccines approved for use in humans include the RNA vaccines tozinameran and

mRNA-1273 The Moderna COVID19 vaccine (INN: elasomeran), sold under the brand name Spikevax, is a COVID-19 vaccine developed by American company Moderna, the United States National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedi ...

, the DNA vaccine

ZyCoV-D ZyCoV-D is a DNA vaccine, DNA plasmid-based COVID-19 vaccine developed by Indian pharmaceutical company Cadila Healthcare, with support from the Biotechnology Industry Research Assistance Council. It is emergency use authorisation, approved ...

as well as the viral vectors AZD1222, Ad26.COV2.S,

Ad5-nCoV AD5-nCOV, trade-named Convidecia, is a single-dose viral vector vaccine for COVID-19 developed by CanSino Biologics. It conducted its Phase III trials in Argentina, Chile, Mexico, Pakistan, Russia, and Saudi Arabia with 40,000 participants. I ...

, and

Sputnik V Sputnik V (russian: Спутник V, the brand name from RDIF) or Gam-COVID-Vac (russian: Гам-КОВИД-Вак, the name under which it is legally registered and produced) is an adenovirus viral vector vaccine for COVID-19 developed by t ...

. In addition, genetic vaccines are being investigated against proteins of various infectious agents, protein-based

toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849– ...

s, as

cancer vaccine A cancer vaccine is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as ''therapeutic'' cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", ...

s,Freda K. Stevenson, Gianfranco di Genova, Christian H. Ottensmeier, Natalia Savelyeva: ''Cancer Immunotherapy.'' Elsevier Inc., 2013, ISBN 0128059117. Kapitel IX: ''Clinical Trials of DNA vaccines''. and as tolerogenic vaccines for

hyposensitization Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies, such as insect bites, and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergen in ...

of type I

allergies Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

History

The first use of a viral vector for vaccination – a Modified Vaccinia Ankara Virus expressing

HBsAg HBsAg (also known as the Australia antigen) is the surface antigen of the hepatitis B virus (HBV). Its presence in blood indicates current hepatitis B infection. Structure and function The viral envelope of an enveloped virus has different sur ...

– was published by

Bernard Moss Bernard Moss (born July 26, 1937 in Brooklyn) is a virologist at the National Institute of Allergy and Infectious Diseases, part of the United States National Institutes of Health. He is the Chief of the NIAID Laboratory of Viral Diseases and of ...

and colleagues. DNA was used as a vaccine by Jeffrey Ulmer and colleagues in 1993. The first use of RNA for vaccination purposes was described in 1993 by Frédéric Martinon, Pierre Meulien and colleaguesRein Verbeke, Ine Lentacker, Stefaan C. De Smedt, Heleen Dewitte
''Three decades of messenger RNA vaccine development.''
In: ''Nano Today.'' 28, 2019, S. 100766, . and in 1994 by X. Zhou, Peter Liljeström, and colleagues in mice. Martinon demonstrated that a cellular immune response was induced by vaccination with an RNA vaccine. In 1995, Robert Conry and colleagues described that a humoral immune response was also elicited after vaccination with an RNA vaccine. While DNA vaccines were more frequently researched in the early years due to their ease of production, low cost, and high stability to degrading enzymes, but sometimes produced low vaccine responses despite containing immunostimulatory

CpG site The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...

s,L. Li, N. Petrovsky: ''Molecular mechanisms for enhanced DNA vaccine immunogenicity.'' In: ''Expert review of vaccines.'' Band 15, Nummer 3, 2016, S. 313–329, , PMID 26707950, {{PMC, 4955855. more research was later conducted on RNA vaccines, whose

immunogenicity Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injectio ...

was often better due to inherent

adjuvants In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analgesi ...

and which, unlike DNA vaccines,Matthias Giese: ''Molecular Vaccines.'' Springer Science & Business Media, 2013, ISBN 3319009788. S. 497. cannot insert into the genome of the vaccinated. Accordingly, the first RNA- and DNA-based vaccines approved for humans were RNA and DNA vaccines used as

COVID vaccine A COVID19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus that causes coronavirus disease 2019 ( COVID19). Prior to the COVID19 pandemic, an e ...

s. Viral vectors had previously been approved as

ebola vaccine Ebola vaccines are vaccines either approved or in development to prevent Ebola. As of 2022, there are only vaccines against the Zaire ebolavirus. The first vaccine to be approved in the United States was rVSV-ZEBOV in December 2019. It had been ...

References

Vaccines Nucleic acid vaccines Gene delivery