Subunit vaccine

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(Redirected from
Recombinant subunit vaccine
)

A subunit vaccine is a

antigenic, or necessary to elicit a protective immune response.[1][2] Subunit vaccine can be made from dissembled viral particles in cell culture or recombinant DNA expression,[3]
in which case it is a recombinant subunit vaccine.

A "subunit" vaccine doesn't contain the whole pathogen, unlike live attenuated or inactivated vaccine, but contains only the antigenic parts such as proteins, polysaccharides[1][2] or peptides.[4] Because the vaccine doesn't contain "live" components of the pathogen, there is no risk of introducing the disease, and is safer and more stable than vaccines containing whole pathogens.[1] Other advantages include being well-established technology and being suitable for

booster shots, and requiring time to examine which antigenic combinations may work best.[2]

The first recombinant subunit vaccine was produced in the mid-1980s to protect people from

Coronavirus disease 2019
).

After

infectious diseases (e.g. tuberculosis,[9] dengue[10]
)

Recombinant subunit vaccines are considered to be safe for injection. The chances of

allergic reaction. The contraindications are also vaccine-specific; they are generally not recommended for people with the previous history of anaphylaxis
to any component of the vaccines. Advice from medical professionals should be sought before receiving any vaccination.

Discovery

The first certified subunit vaccine by clinical trials on humans is the hepatitis B vaccine, containing the surface antigens of the hepatitis B virus itself from infected patients and adjusted by newly developed technology aiming to enhance the vaccine safety and eliminate possible contamination through individuals plasma.[11]

Mechanism

Subunit vaccines contain fragments of the pathogen, such as protein or polysaccharide, whose combinations are carefully selected to induce a strong and effective immune response. Because the immune system interacts with the pathogen in a limited way, the risk of

side effects is minimal.[2]
An effective vaccine would elicit the immune response to the antigens and form immunological memory that allows quick recognition of the pathogens and quick response to future infections.[1]

A drawback is that the specific antigens used in a subunit vaccine may lack

cell-mediated
, and as a result, is weaker than those elicited by other types of vaccines. To increase immune response, adjuvants may be used with the subunit vaccines, or booster doses may be required.[2]

Types

Summary of subunit vaccine types[1][2]
Types Description Examples
Protein subunit contains isolated proteins from pathogens (virus or bacteria)
acellular pertussis vaccines
Polysaccharide contains chains of
cell walls of some bacteria
 pneumococcal polysaccharide vaccine, meningococcal vaccine preventing diseases from Neisseria meningitidis group A, C, W-135, and Y
Conjugate contains polysaccharide chains bound to
tetanus toxoid, to boost the immune response
 pneumococcal conjugate vaccine, haemophilus influenzae type b conjugate vaccine, meningococcal conjugate vaccine

Protein subunit

A

viruses often use a small number of types of protein subunits as building blocks.[15] A key step in creating a recombinant protein vaccine is the identification and isolation of a protein subunit from the pathogen which is likely to trigger a strong and effective immune response, without including the parts of the virus or bacterium that enable the pathogen to reproduce. Parts of the protein shell or capsid of a virus are often suitable. The goal is for the protein subunit to prime the immune system response by mimicking the appearance but not the action of the pathogen.[16] Another protein-based approach involves self‐assembly of multiple protein subunits into a virus-like particle (VLP) or nanoparticle. The purpose of increasing the vaccine's surface similarity to a whole virus particle (but not its ability to spread) is to trigger a stronger immune response.[17][16][18]

Protein subunit vaccines are generally made through

baculovirus, or mammalian cell cultures can be used to produce large amounts of proteins in vitro.[16][19][20]

Protein-based vaccines are being used for

human papillomavirus (HPV).[17][16] The approach is being used to try to develop vaccines for difficult-to-vaccinate-against viruses such as ebolavirus and HIV.[21] Protein-based vaccines for COVID-19 tend to target either its spike protein or its receptor binding domain.[17] As of 2021, the most researched vaccine platform for COVID-19 worldwide was reported to be recombinant protein subunit vaccines.[16][22]

Polysaccharide subunit

typhoid caused by the Typhi serotype of Salmonella enterica.[23] Instead of being a protein, the Vi antigen is a bacterial capsule polysacchide, made up of a long sugar chain linked to a lipid.[24] Capsular vaccines like ViCPS tend to be weak at eliciting immune responses in children. Making a conjugate vaccine by linking the polysacchide with a toxoid increases the efficacy.[25]

Conjugate vaccine

Main article: Conjugate vaccine

A conjugate vaccine is a type of vaccine which combines a weak antigen with a strong antigen as a carrier so that the immune system has a stronger response to the weak antigen.[26]

Peptide subunit

A peptide-based subunit vaccine employs a peptide instead of a full protein.[27] Peptide-based subunit vaccine mostly used due to many reasons,such as, it is easy and affordable for massive production. Adding to that, its greatest stability, purity and exposed composition.[28] Three steps occur leading to creation of peptide subunit vaccine;[29]

  1. Epitope recognition
  2. Epitope optimization
  3. Peptide immunity improvement

Features

When compared with conventional attenuated vaccines and inactivated vaccines, recombinant subunit vaccines have the following special characteristics:

  • They contain clearly identified compositions which greatly reduces the possibility of presence of undesired materials within the vaccine.[30]
  • Their pathogenicities are minimized as only fragments of the pathogen are present in the vaccine which cannot invade and multiply within the human body.[31]
  • They have better
    safety profiles[32] and are suitable to be administered to immunocompromised patients.[33]
  • They are suitable for mass production due to the use of recombinant technologies.[30]
  • They have high stability so they can withstand environmental changes and are more convenient to be used in community settings.[31]

However, there are also some drawbacks regarding recombinant subunit vaccines:

Pharmacology

Simplified overview of the processes involved in the primary immune response

infectious diseases.[36]

Active immunity can be acquired artificially by vaccination as a result of the body's own defense mechanism being triggered by the exposure of a small, controlled amount of pathogenic substances to produce its own antibodies and memory cells without being infected by the real pathogen.[37]

The processes involved in primary immune response are as follows:

  1. Pre-exposure to the
    antigen-presenting cells (APCs), such as dendritic cells and macrophages, via phagocytosis.[37][38]
  2. The APCs will travel to lymph nodes, where immature B cells and T cells are present.[39]
  3. Following antigen processes by APCs, antigens will bind to either MHC class I receptors or MHC class II receptors on the cell surface of the cells based on their compositional and structural features to form complexes.[37]
  4. cytotoxic T cells (CD8+) or helper T cells (CD4+).[40][41]
  5. Cytotoxic CD8+ cells can directly destroy the infected cells containing the antigens that were presented to them by the APCs by releasing lytic molecules, while helper CD4+ cells are responsible for the secretion of cytokines that activates B cells and cytotoxic T cells.[38][42]
  6. B cells can undergo activation in the absence of T cells via the B cell receptor signalling pathway.[38]
  7. After
    Isotype switching can take place during B cell development for the formation of different antibodies, including IgG, IgE and IgA.[38]
  8. secondary response, in which a higher concentration of antibodies specific for the antigens are reproduced rapidly and efficiently in a short time for the elimination of the pathogen.[39]

Under specific circumstances, low doses of

immunity.[34][35][44]

Manufacturing

The manufacturing process of recombinant subunit vaccines are as follows:

  1. Identification of immunogenic subunit
  2. Subunit expression and synthesis
  3. Extraction and purification
  4. Addition of adjuvants or incorporation to vectors
  5. Formulation and delivery.

Identification of immunogenic subunit

Candidate subunits will be selected primarily by their immunogenicity.[45] To be immunogenic, they should be of foreign nature and of sufficient complexity for the reaction between different components of the immune system and the candidates to occur.[46] Candidates are also selected based on size, nature of function (e.g. signalling) and cellular location (e.g. transmembrane).[45]

Subunit expression and synthesis

Upon identifying the target subunit and its encoding gene, the gene will be isolated and transferred to a second, non-pathogenic organism, and cultured for mass production.[47] The process is also known as heterologous expression.

A suitable expression system is selected based on the requirement of post-translational modifications, costs, ease of product extraction and production efficiency. Commonly used systems for both licensed and developing recombinant subunit vaccines include bacteria, yeast, mammalian cells, insect cells.[48]

Bacterial cells

Escherichia coli

Bacterial cells are widely used for cloning processes, genetic modification and small-scale productions.[49] Escherichia coli (E. Coli) is widely utilised due to its highly explored genetics, widely available genetic tools for gene expression, accurate profiling and its ability to grow in inexpensive media at high cell densities.[50]

E. Coli is mostly appropriate for structurally simple proteins owing to its inability to carry out

protein secretary system and the potential for producing inclusion bodies that require additional solubilisation.[49][50][51] Regarding application, E.Coli is being utilised as the expression system of the dengue vaccine.[10]

Yeast

soluble proteins and has the ability to perform post-translational modifications similar to mammalian cells.[51]

Saccharomyces cerevisiae colonies on yeast extract glucose chloramphenicol agar (YGC).

Notably, yeast incorporates more

VLPs) of the major capsid protein L1 of human papillomavirus type 6, 11, 16, 18 are produced by Saccharomyces cerevisiae
.

Mammalian cells

glycosylated and functionally active proteins.[50][53][54] However, efficacy of mammalian cells may be limited by epigenetic gene silencing and aggresome formation (recombinant protein aggregation).[50] For mammalian cells, synthesised proteins were reported to be secreted into chemically defined media, potentially simplifying protein extraction and purification.[49]

The most prominent example under this class is

SHINGRIX.[7] CHO cells are recognised for rapid growth and their ability to offer process versatility. They can also be cultured in suspension-adapted culture in protein-free medium, hence reducing risk of prion-induced contamination.[49][50]

Baculovirus (insect) cells

Schematic representation of baculovirus structure and infection cycle.

The

toxicological risks.[49] A notable feature is the existence of elements of control that allow for the expression of secreted and membrane-bound proteins in Baculovirus-insect cells.[49][55]

Licensed recombinant subunit

influenza viruses).[6]

Extraction and purification

Throughout history, extraction and

affinity tags.[58] However, the final extraction and purification process undertaken highly depends on the chosen expression system
. Please refer to subunit expression and synthesis for more insights.

Addition of adjuvants

Adjuvants are materials added to improve immunogenicity of recombinant subunit vaccines.[59]

immunity for each specific pathogen (e.g. increasing generation of T cell memory).[59][60][61][62] Addition of adjuvants may confer benefits including dose sparing and stabilisation of final vaccine formulation.[59][62]

Appropriate

immunostimulatory molecules (e.g. AS01B).[59][61]

Formulation and delivery

microspheres and liposomes) and live delivery systems (gram-positive bacteria, gram-negative bacteria and viruses
)

Polymer-based delivery systems

Vaccine antigens are often encapsulated within microspheres or liposomes. Common microspheres made using Poly-lactic acid (PLA)[63] and poly-lactic-co-glycolic acid (PLGA)[63] allow for controlled antigen release by degrading in vivo while liposomes including multilamellar or unilamellar vesicles allow for prolonged release.[61]

Polymer-based

Shringrix
.

Live delivery systems

Live

mucosal immune system.[47]

Advantages and disadvantages

Advantages

Disadvantages

Adverse effects and contraindications

Recombinant subunit

physical health condition, age, gender and genetic predisposition.[73][74]

Recombinant subunit

allergic reactions and anaphylaxis to antigens or other components of the vaccines previously.[75][76] Furthermore, precautions should be taken when administering vaccines to people who are in diseased state and during pregnancy,[75]
in which their injections should be delayed until their conditions become stable and after childbirth respectively.

Licensed vaccines

Hepatitis B

Engerix B (Hepatitis B) vaccine

RECOMBIVAX HB (produced by merck) are two recombinant subunit vaccines licensed for the protection against hepatitis B. Both contain HBsAg harvested and purified from Saccharomyces cerevisiae and are formulated as a suspension of the antigen adjuvanted with alum.[77][78]

Antibody concentration ≥10mIU/mL against HBsAg are recognized as conferring protection against hepatitis B infection.[77][78]

It has been shown that primary 3-dose

safety profile in all studied populations.[79]

Human Papillomavirus (HPV)

Gardasil vaccine and box

VLP of the major capsid L1 protein produced by recombinant Saccharomyces cerevisiae
.

It has been shown in a 2014 systematic quantitative review that the bivalent HPV vaccine (

redness (OR 2.41; 95% CI: 2.17–2.68) being the most frequently reported adverse effects. For Gardasil, the most frequently reported events were pain (OR 2.88; 95% CI: 2.42–3.43) and swelling (OR 2.65; 95% CI: 2.0–3.44).[81]

Gardasil was discontinued in the U.S. on May 8, 2017, after the introduction of Gardasil 9[82] and Cervarix was also voluntarily withdrawn in the U.S. on August 8, 2016.[83]

Influenza

Flublok Quadrivalent is a licensed recombinant subunit vaccine for active immunisation against influenza. It contains HA proteins of four strains of influenza virus purified and extracted using the Baculovirus-insect expression system. The four viral strains are standardised annually according to United States Public Health Services (USPHS) requirements.[6]

Flublok Quadrivalent has a comparable safety profile to traditional trivalent and quadrivalent vaccine equivalents. Flublok is also associated with less local reactions (RR = 0.94, 95% CI 0.90–0.98, three RCTs, FEM, I2 = 0%, low‐ certainty evidence) and higher risk of chills  (RR = 1.33, 95% CI 1.03–1.72, three RCTs, FEM, I2 = 14%, low‐certainty evidence).[84]

Herpes Zoster

VZV gE antigen component extracted from CHO cells, which is to be reconstituted with adjuvant suspension AS01B.[7]

safety profile.[85][86]

COVID-19

SARS-CoV-2 spike protein produced using the baculovirus expression system, which is eventually adjuvanted with the Matrix M adjuvant.[8]

History

While the practice of

immunity to smallpox infection,[citation needed] the modern era of vaccination has a short history of around 200 years. It began with the invention of a vaccine by Edward Jenner in 1798 to eradicate smallpox by injecting relatively weaker cowpox
virus into the human body.

The middle of the 20th century marked the golden age of vaccine science.[

public healthcare
burden.

Emergence of

recombinant vaccines apart from traditional whole-cell vaccine, for instance Hepatitis B vaccine, which uses the viral antigens to initiate immune responses.[88]

As the

non-infectious diseases,[citation needed
] in order to safeguard the health of more people.

Future directions

Recombinant subunit vaccines are used in development for tuberculosis,[9] dengue fever,[10] soil-transmitted helminths,[89] feline leukaemia[90] and COVID-19.[91]

Subunit vaccines are not only considered effective for SARS-COV-2, but also as candidates for evolving immunizations against malaria, tetanus, salmonella enterica, and other diseases.[11]

COVID-19

Research has been conducted to explore the possibility of developing a heterologous

SARS-CoV-2 spike and RBD protein is high (82%).[91]

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