Genetic vaccine

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A genetic vaccine (also gene-based vaccine) is a vaccine that contains nucleic acids such as DNA or RNA that lead to protein biosynthesis of antigens within a cell. Genetic vaccines thus include DNA vaccines, RNA vaccines and viral vector vaccines.

Contents

Properties

Most vaccines other than live attenuated vaccines and genetic vaccines are not taken up by MHC-I-presenting cells, but act outside of these cells, producing only a strong humoral immune response via antibodies. In the case of intracellular pathogens, an exclusive humoral immune response is ineffective. [1] Genetic vaccines are based on the principle of uptake of a nucleic acid into cells, whereupon a protein is produced according to the nucleic acid template. This protein is usually the immunodominant antigen of the pathogen or a surface protein that enables the formation of neutralizing antibodies that inhibit the infection of cells. Subsequently, the protein is broken down at the proteasome into short fragments (peptides) that are imported into the endoplasmic reticulum via the transporter associated with antigen processing, allowing them to bind to MHCI-molecules that are subsequently secreted to the cell surface. The presentation of the peptides on MHC-I complexes on the cell surface is necessary for a cellular immune response. As a result, genetic vaccines and live vaccines generate cytotoxic T-cells 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. [2]

Administration

Genetic vaccines are most commonly administered by injection (intramuscular or subcutaneous) or infusion, and less commonly and for DNA, by gene gun or electroporation. 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. In humans, the cationic lipids SM-102, ALC-0159 and ALC-0315 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 DNA vaccine ZyCoV-D as well as the viral vectors AZD1222, Ad26.COV2.S, Ad5-nCoV, and Sputnik V. In addition, genetic vaccines are being investigated against proteins of various infectious agents, protein-based toxins, [3] as cancer vaccines, [4] and as tolerogenic vaccines for hyposensitization of type I allergies. [5] [6]

History

The first use of a viral vector for vaccination – a Modified Vaccinia Ankara Virus expressing HBsAg – was published by Bernard Moss and colleagues. [7] [8] DNA was used as a vaccine by Jeffrey Ulmer and colleagues in 1993. [9] The first use of RNA for vaccination purposes was described in 1993 by Frédéric Martinon, Pierre Meulien and colleagues [10] [11] and in 1994 by X. Zhou, Peter Liljeström, and colleagues in mice. [12] [11] Martinon demonstrated that a cellular immune response was induced by vaccination with an RNA vaccine. [11] In 1995, Robert Conry and colleagues described that a humoral immune response was also elicited after vaccination with an RNA vaccine. [13] [11] 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 sites, [14] [15] more research was later conducted on RNA vaccines, whose immunogenicity was often better due to inherent adjuvants and which, unlike DNA vaccines, [16] 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 vaccines. Viral vectors had previously been approved as ebola vaccines.

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<span class="mw-page-title-main">Vaccine</span> Pathogen-derived preparation that provides acquired immunity to an infectious disease

A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future. Vaccines can be prophylactic, or therapeutic. Some vaccines offer full sterilizing immunity, in which infection is prevented completely.

<span class="mw-page-title-main">DNA vaccine</span> Vaccine containing DNA

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.

<span class="mw-page-title-main">Antiviral drug</span> Medication used to treat a viral infection

Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit its development.

<span class="mw-page-title-main">HIV vaccine development</span> In-progress vaccinations that may prevent or treat HIV infections

An HIV vaccine is a potential vaccine that could be either a preventive vaccine or a therapeutic vaccine, which means it would either protect individuals from being infected with HIV or treat HIV-infected individuals.

In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens irrespective of their antigenic make-up. Other components of the immune system adapt themselves to each new disease encountered and can generate pathogen-specific immunity.

<i>Adenoviridae</i> Family of viruses

Adenoviruses are medium-sized, nonenveloped viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from their initial isolation from human adenoids in 1953.

Antigenic drift is a kind of genetic variation in viruses, arising from the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies recognize. This results in a new strain of virus particles that is not effectively inhibited by the antibodies that prevented infection by previous strains. This makes it easier for the changed virus to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses.

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 describe non-viral DNA transfer in bacteria and non-animal eukaryotic cells, including plant cells. In animal cells, transfection is the preferred term as transformation is also used to refer to progression to a cancerous state (carcinogenesis) in these cells. Transduction is often used to describe virus-mediated gene transfer into eukaryotic cells.

Lentivirus is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lentiviruses are distributed worldwide, and are known to be hosted in apes, cows, goats, horses, cats, and sheep as well as several other mammals.

Viral vectors are tools commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism or in cell culture. Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect. Delivery of genes or other genetic material by a vector is termed transduction and the infected cells are described as transduced. Molecular biologists first harnessed this machinery in the 1970s. Paul Berg used a modified SV40 virus containing DNA from the bacteriophage λ to infect monkey kidney cells maintained in culture.

Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response, making it one of the mechanisms of antigenic escape. It is related to phase variation. Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response. If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. Antigenic variation can result from gene conversion, site-specific DNA inversions, hypermutation, or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype. Many of the proteins known to show antigenic or phase variation are related to virulence.

<i>Murine respirovirus</i> Species of virus

Murine respirovirus, formerly Sendai virus (SeV) and previously also known as murine parainfluenza virus type 1 or hemagglutinating virus of Japan (HVJ), is an enveloped,150-200 nm in diameter, a negative sense, single-stranded RNA virus of the family Paramyxoviridae. It typically infects rodents and it is not pathogenic for humans or domestic animals. Sendai virus (SeV) is a member of genus Respirovirus. The virus was isolated in the city of Sendai in Japan in the early 1950s. Since then, it has been actively used in research as a model pathogen. The virus is infectious for many cancer cell lines, has oncolytic properties demonstrated in animal models and in naturally-occurring cancers in animals. SeV's ability to fuse eukaryotic cells and to form syncytium was used to produce hybridoma cells capable of manufacturing monoclonal antibodies in large quantities. Recent applications of SeV-based vectors include the reprogramming of somatic cells into induced pluripotent stem cells and vaccines creation. For vaccination purpose the Sendai virus-based constructs could be delivered in a form of nasal drops, which may be beneficial in inducing a mucosal immune response. SeV has several features that are important in a vector for a successful vaccine: the virus does not integrate into the host genome, it does not undergo genetic recombination, it replicates only in the cytoplasm without DNA intermediates or a nuclear phase and it is not causing any disease in humans or domestic animals. Sendai virus is used as a backbone for vaccine development against Mycobacterium tuberculosis that causes tuberculosis, against HIV-1 that causes AIDS and against other viruses, including those that cause severe respiratory infections in children. The latter include Human Respiratory Syncytial Virus (HRSV), Human Metapneumovirus (HMPV) and Human Parainfluenza Viruses (HPIV). The vaccine studies against Mycobacterium tuberculosis, HMPV, HPIV1 and, HPIV2 are in pre-clinical stage, against HRSV phase I clinical trail has been completed. The phase I clinical studies of SeV-based vaccination were also completed for HPIV1. They were done in adults and in 3- to 6-year-old children. As a result of vaccination against HPIV1 the significant boost in virus-specific neutralizing antibodies was observed. The SeV-based vaccine development against HIV-1 have reached phase II clinical trial. Fudan University in collaboration with ID Pharma Co. Ltd. is engaged in development of the vaccine for COVID-19 prevention. SeV serves as a vaccine backbone vector in the project.

Antigenic escape, immune escape, immune evasion or escape mutation occurs when the immune system of a host, especially of a human being, is unable to respond to an infectious agent: the host's immune system is no longer able to recognize and eliminate a pathogen, such as a virus. This process can occur in a number of different ways of both a genetic and an environmental nature. Such mechanisms include homologous recombination, and manipulation and resistance of the host's immune responses.

<span class="mw-page-title-main">Virus</span> Infectious agent that replicates in cells

A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1892 article describing a non-bacterial pathogen infecting tobacco plants and the discovery of the tobacco mosaic virus by Martinus Beijerinck in 1898, more than 9,000 virus species have been described in detail of the millions of types of viruses in the environment. Viruses are found in almost every ecosystem on Earth and are the most numerous type of biological entity. The study of viruses is known as virology, a subspeciality of microbiology.

<span class="mw-page-title-main">Reverse genetics</span> Method in molecular genetics

Reverse genetics is a method in molecular genetics that is used to help understand the function(s) of a gene by analysing the phenotypic effects caused by genetically engineering specific nucleic acid sequences within the gene. The process proceeds in the opposite direction to forward genetic screens of classical genetics. While forward genetics seeks to find the genetic basis of a phenotype or trait, reverse genetics seeks to find what phenotypes are controlled by particular genetic sequences.

This glossary of virology is a list of definitions of terms and concepts used in virology, the study of viruses, particularly in the description of viruses and their actions. Related fields include microbiology, molecular biology, and genetics.

Julianna Lisziewicz is a Hungarian immunologist. Lisziewicz headed many research teams that have discovered and produced immunotheraputic drugs to treat diseases like cancer and chronic infections like HIV/AIDS. Some of these drugs have been successfully used in clinical trials.

mRNA vaccine Type of vaccine

An mRNAvaccine 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 blueprint to build foreign protein that would normally be produced by a pathogen or by a cancer cell. These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells.

<span class="mw-page-title-main">Viral vector vaccine</span> Type of vaccine

A viral vector vaccine is a vaccine that uses a viral vector to deliver genetic material (mRNA) coding for a desired antigen into the recipient's host cells. As of April 2021, six viral vector vaccines have been authorized for use in humans in at least one country: four COVID-19 vaccines and two Ebola vaccines.

<span class="mw-page-title-main">Recombinant subunit vaccine</span>

Recombinant subunit vaccines are biological preparations that are composed of microbial subunits produced using recombinant DNA technology. They act to provide active acquired immunity to infectious diseases. The first recombinant subunit vaccine was produced in the mid-1980s to protect people from Hepatitis B. Notable recombinant subunit vaccines licensed include ENGERIX-B, GARDASIL-9, FLUBLOK(influenza), SHINGRIX and NUVAXOVID.

References

  1. ↑ Eckhart Buddecke: Molekulare Medizin. ecomed-Storck GmbH, 2002, ISBN 3609160918. S. 162.
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  4. ↑ 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.
  5. ↑ R. Weiss, S. Scheiblhofer, J. Thalhamer: Allergens are not pathogens: why immunization against allergy differs from vaccination against infectious diseases. In: Human vaccines & immunotherapeutics. Band 10, Nummer 3, 2014, S. 703–707, doi : 10.4161/hv.27183, PMID 24280693, PMC   4130253.
  6. ↑ R. Weiss, S. Scheiblhofer, J. Thalhamer: Generation and Evaluation of Prophylactic mRNA Vaccines Against Allergy. In: Methods in molecular biology. Band 1499, 2017, S. 123–139, doi : 10.1007/978-1-4939-6481-9_7, PMID 27987146.
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  16. ↑ Matthias Giese: Molecular Vaccines. Springer Science & Business Media, 2013, ISBN 3319009788. S. 497.
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