A subunit vaccine is a type of vaccine that contains only specific pieces (or subunits) of a virus or bacteria—usually proteins or sugars—that are enough to trigger an immune response without including the whole pathogen. This makes the vaccine safer and reduces the risk of side effects.
Source: https://pubs.acs.org/cms/10.1021/jacs.1c06600/asset/images/jacs.1c06600.social.jpeg_v03
Why need Subunit vaccine: problem with the traditional vaccine
Traditional vaccines often use whole pathogens—either: Live attenuated (weakened) organisms and Inactivated (killed) organisms. While these can be effective, they come with risks, such as:
- Reactivation of Live Pathogens: In rare cases, weakened live vaccines (like for polio or TB) can revert to a harmful form and cause disease.
- Stronger Side Effects: Whole-organism vaccines may cause fever, inflammation, or other immune-related side effects because they expose the body to all parts of the pathogen, not just the safe or important parts.
- Unsuitability for Immunocompromised Individuals: People with weakened immune systems (due to HIV, cancer treatment, etc.) can’t safely receive live vaccines.
- Difficulties in Manufacturing and Storage: Growing whole pathogens under controlled, safe conditions can be complex and expensive.
These components are selected based on their ability to induce a strong and specific immune response without causing disease.
what can be used for subunit vaccine candidate?
For a subunit vaccine candidate, the following components can be used:
- Proteins – Specific proteins from the pathogen, such as surface proteins or toxins, that the immune system can recognize (e.g., the spike protein in SARS-CoV-2).
- Peptides – Short fragments of proteins that contain important immune-targeting regions (epitopes).
- Polysaccharides – Sugar molecules from the surface of bacteria that can stimulate an immune response (common in bacterial vaccines like for Streptococcus pneumoniae).
- Protein-polysaccharide conjugates – Polysaccharides linked to a protein carrier to improve immune recognition (used in conjugate vaccines).
so based on what part or molecule of organism used for the vaccination development it can be classified into different types –
Types of Subunit Vaccines
There are three main types of subunit vaccines:
Toxoid Vaccines (Inactivated Exotoxins)
Some bacteria produce harmful toxins (exotoxins) that cause disease symptoms, like in diphtheria and tetanus.
In these vaccines, the toxins are purified and then inactivated using a chemical (formaldehyde), turning them into toxoids. The toxoids can’t cause disease but can train the immune system to produce antibodies that neutralize the real toxin if it enters the body.
Producing these vaccines must be carefully controlled to keep the immune-triggering parts (epitopes) intact while fully deactivating the toxin.
Capsular Polysaccharide Vaccines
Some bacteria, such as Streptococcus pneumoniae and Neisseria meningitidis, have a sugar coating (capsule) that helps them avoid being destroyed by immune cells. Vaccines made from these purified sugar capsules can help the immune system make antibodies that “tag” the bacteria for destruction.
Example: The PCV13 vaccine for S. pneumoniae contains 13 different sugar capsule types and is given to infants.
Surface Glycoprotein Vaccines
Viruses often have proteins on their outer surface (called glycoproteins) that help them infect cells. These glycoproteins can be used in vaccines to trigger an immune response.
Example: Glycoprotein-D from HSV-2 (herpes simplex virus type 2) has shown promising results in preventing genital herpes
Limitations of Some Subunit Vaccines
Problem with Polysaccharide-Only Vaccines
- Polysaccharide vaccines (sugar-based) often fail to activate helper T cells (TH cells). Without T cell help: The body mainly produces a basic type of antibody (IgM).
- There is little to no immune memory or long-term protection.
- There is no improvement in antibody quality (no affinity maturation).
Solution to this problem is Conjugate Vaccines
By linking the sugar (polysaccharide) to a protein, the immune system can better recognize it and involve T cells.
- This leads to: Stronger, longer-lasting immunity.
- Production of better-quality antibodies.
- Memory cell formation.
Use of Recombinant DNA Technology in Subunit Vaccines
We now know that there are certain proteins or peptides that are important for pathogen and it is now possible to identify the genes that produce these proteins. These genes are inserted into cultured cells (like yeast or bacteria) to produce the protein in large amounts.
The proteins are then purified and used in vaccines.
Example: Hepatitis B Vaccine: The gene for the hepatitis B surface antigen (HBsAg) was inserted into yeast cells. These yeast cells were grown in fermenters to produce large amounts of HBsAg.
The antigen was purified and used in a vaccine.
This recombinant vaccine is safe and effective and has been widely used around the world.
Steps in Subunit Vaccine Preparation
The process of preparing a subunit vaccine typically involves the following steps:
1. Identification of the Target Antigen : Scientists first identify which part of the pathogen (protein, polysaccharide, or glycoprotein) can safely and effectively trigger an immune response.
2. Gene Cloning (for recombinant vaccines) : If the antigen is a protein, the gene coding for it is isolated and inserted into a host organism (like bacteria or yeast) using recombinant DNA technology.
3. Protein Expression: The host organism is cultured in large quantities (e.g., in a bioreactor or fermenter), where it produces the antigen in bulk.
4. Antigen Purification: The produced antigen is extracted and purified using biochemical techniques to ensure it’s free of contaminants.
5. Inactivation (if necessary): For toxoid vaccines, the antigen (toxin) is chemically inactivated (e.g., with formaldehyde) to make it harmless while keeping its immune-stimulating structure.
6. Formulation : The purified antigen may be combined with adjuvants (substances that boost the immune response) and stabilizers. For conjugate vaccines, the antigen is chemically linked to a protein carrier to improve T-cell activation.
7. Quality Control and Testing : The vaccine undergoes strict testing to confirm safety, purity, and effectiveness before approval for human use.
Note: The above steps is only for the molecule or subunit that have a gene and can be produce by genetic engineering. otherwise cultivation of pathogen will be the steps between identification of potential vaccine candidate and antigen purification.
Thus in short the subunit vaccines offer a safer choice to whole-organism vaccines by using only the parts of a pathogen needed to stimulate the immune system. They can be made using purified toxins, sugar capsules, or proteins, often with the help of genetic engineering. While they sometimes need enhancements like conjugation with proteins to be fully effective.
References
rtega-Rivera, O. A., Shin, M. D., Chen, A., Beiss, V., Moreno-Gonzalez, M. A., Lopez-Ramirez, M. A., Reynoso, M., Wang, H., Hurst, B. L., Wang, J., Pokorski, J. K., & Steinmetz, N. F. (2021). Trivalent subunit vaccine candidates for COVID-19 and their delivery devices. Journal of the American Chemical Society, 143(36), 14748–14765. https://doi.org/10.1021/jacs.1c06600
Julie Baillet, John H. Klich, Ben S. Ou, Emily L. Meany, Jerry Yan, Theodora U.J. Bruun, Ashley Utz, Carolyn K. Jons, Sebastien Lecommandoux, Eric A. Appel. Sustained exposure to multivalent antigen-decorated nanoparticles generates broad anti-coronavirus responses. Matter 2025, 8 (4) , 102006. https://doi.org/10.1016/j.matt.2025.102006