Vaccine that contains antigenic parts of the pathogen.
A subunit vaccine is a
vaccine that contains purified parts of the
pathogen that are
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
immunocompromised individuals.[2] Disadvantages include being relatively complex to manufacture compared to some vaccines, possibly requiring
adjuvants and
booster shots, and requiring time to examine which antigenic combinations may work best.[2]
After
injection, antigens trigger the production of antigen-specific
antibodies, which are responsible for recognising and neutralising foreign substances. Basic components of recombinant subunit vaccines include recombinant subunits,
adjuvants and carriers. Additionally, recombinant subunit vaccines are popular candidates for the development of
vaccines against
infectious diseases (e.g.
tuberculosis,[9]dengue[10])
Recombinant subunit vaccines are considered to be safe for injection. The chances of
adverse effects vary depending on the specific type of
vaccine being administered. Minor side effects include injection site pain, fever, and
fatigue, and serious
adverse effects consist of
anaphylaxis and potentially fatal
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
pathogen-associated molecular patterns which are common to a class of pathogen. These
molecular structures may be used by
immune cells for danger recognition, so without them, the immune response may be weaker. Another drawback is that the antigens do not infect
cells, so the immune response to the subunit vaccines may only be
antibody-mediated, not
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]
A
protein subunit is a
polypeptide chain or
protein molecule that assembles (or "coassembles") with other protein molecules to form a
protein complex.[12][13][14] Large assemblies of proteins such as
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-based vaccines are being used for
hepatitis B and 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
Vi capsular polysaccharide vaccine (ViCPS) against
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]
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]
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]
Selection of appropriate cell lines for the cultivation of subunits is time-consuming because microbial proteins can be incompatible to certain
expression systems.[35]
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:
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]
Memory B cells and
T cells are formed post-infection.[37] The
antigens are memorised by these cells so that subsequent exposure to the same type of antigens will stimulate a
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
vaccines are given initially, followed by additional doses named
booster doses. Boosters can effectively maintain the level of
memory cells in the human body, hence extending a person's
immunity.[34][35][44]
Manufacturing
The manufacturing process of recombinant subunit
vaccines are as follows:
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.
Mammalian cells are well known for their ability to perform therapeutically essential
post-translational modifications and express properly folded,
glycosylated and functionally active proteins.[50][53][54] However, efficacy of mammalian cells may be limited by
epigeneticgene 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
Chinese Hamster Ovary (CHO) cells utilised for the synthesis of recombinant
varicella zoster virus surface glycoprotein (gE) antigen for
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]
Throughout history, extraction and
purification methods have evolved from standard
chromatographic methods to the utilisation of
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.
Adjuvants increase the magnitude of
adaptive response to the
vaccine and guide the activation of the most effective forms of
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]
Recombinant subunit
vaccines are
contraindicated to people who have experienced
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.
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
vaccination of healthy individuals is associated with ≥90% seroprotection rates for
ENGERIX-B, despite decreasing with older age. Lower seroprotection rates are also associated with presence of underlying
chronic diseases and
immunodeficiency. Yet, GSK HepB still has a clinically acceptable
safety profile in all studied populations.[79]
Human Papillomavirus (HPV)
Cervarix,
GARDASIL and
GARDASIL9 are three recombinant subunit
vaccines licensed for the protection against
HPV infection. They differ in the
strains which they protect the patients from as
Cervarix confers protection against type 16 and 18,[57]Gardasil confers protection against type 6, 11, 16 and 18,[80] and Gardasil 9 confers protection against type 6, 11, 16, 18, 31, 33, 45, 52, 58[5] respectively. The
vaccines contain purified
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 (
Cervarix) is associated with
pain (OR 3.29; 95% CI: 3.00–3.60),
swelling (OR 3.14; 95% CI: 2.79–3.53) and
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]
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]
While the practice of
immunisation can be traced back to the
12th century, in which ancient
Chinese at that time employed the technique of
variolation to confer
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.[citation needed] Rapid technological advancements during this period of time enabled scientists to cultivate
cell culture under controlled environments in laboratories,[88] subsequently giving rise to the production of vaccines against
poliomyelitis,
measles and various
communicable diseases.[citation needed] Conjugated vaccines were also developed using
immunologic markers including capsular
polysaccharide and
proteins.[88] Creation of products targeting common illnesses successfully lowered infection-related
mortality and reduced
public healthcare burden.
As the
manufacturing methods continue to evolve, vaccines with more complex constitutions will inevitably be generated in the future to extend their therapeutic applications to both infectious and
non-infectious diseases,[citation needed] in order to safeguard the health of more people.
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 receptor-binding domain (RBD) recombinant protein as a human
vaccine against
COVID-19. The theory is supported by evidence that
convalescentserum from
SARS-CoV patients have the ability to neutralise
SARS-CoV-2 (corresponding virus for
COVID-19) and that amino acid similarity between
SARS-CoV and
SARS-CoV-2 spike and RBD protein is high (82%).[91]
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