Over the past few years, even people who are normally not biologically inclined have become interested in the issue of vaccination. The event we are all familiar with created many experts on either side of the opposing views on the topic. Interestingly enough, the vast majority of the population are not fully familiar with how many vaccine types are out there or how they are made. A strong opinion on any topic should be backed by a strong understanding of the subject. Here, we will try to introduce primarily non-immunologists to the topic of vaccine production. Why “non-immunologists” only? Because immunologists should know this stuff inside out and in much greater detail than presented below. This post will soon be accompanied by a video (in production) that will provide a good visual explanation of the process.
If one is to immunize a person or an animal against a virus, one needs to induce the humoral response (1). Humoral response relies on ANTI-body GEN-erating molecules, or antigens (2). To get the antigens, one can do the following:
Whole virus approach
- Crush the whole virus and either inject the fragments “as is” or fractionate the components in order to obtain what is considered the “best” fraction.
- Weaken the whole virus (attenuated virus). It could be done by heat treatment or formaldehyde for example.
The advantage of the whole virus approach is its simplicity. The first vaccines were developed this way. These vaccines can be highly efficient, yet some of them can be ineffective in the case of attenuated viruses. Attenuation can destroy the epitopes (the antigenic part of the virus protein), so the vaccine is not potent. The downside of this approach is reactogenicity, i.e., activation of the innate immune response through other molecules present in the mix.
Recombinant approach
- Produce only the surface molecules using recombinant technology. Production of proteins in expression systems such as bacterial, yeast, or insect cells is straightforward. What is not straightforward is epitope selection, or in other words, finding the “best” parts of the antigen. It could be done empirically or computationally, with limited success (3).
- The gene of interest is cloned into a plasmid and then injected. This is practically a “naked DNA” vaccine.
- The gene of interest is inserted into a live carrier vector (less harmful virus). This is a DNA vaccine but not “naked”.
- mRNA vaccines. These are the vaccines that everyone is talking about. mRNA is encapsulated in lipoprotein nanoparticles (LNP) and released in the cytosol of a cell. Its main advantage over DNA vaccines is that it doesn’t need to go to the nucleus and integrate into the host DNA (4). They are cheap and easy to produce. The obvious downside is RNA’s notorious instability, so transport and storage are complicated. Efficacy and other potential issues are yet to be impartially analyzed.
Peptide approach
- In this approach, antigenic peptides are synthesized by combining some structural elements and some linear (loop) elements of the original antigen. The original antigen is usually too big to replicate by pure chemical synthesis, so only the selected parts of the original antigen are used. Once the peptides are selected and synthetically produced, they are usually too small to induce an immune response. They need to be coupled to a bigger protein, which in many cases complicates things and leads to an ineffective vaccine in the end (5).
So, which one is the best? It depends on how the word “best” is defined. The whole virus vaccines have been used for a long time, therefore their efficacy and drawbacks are much better known than the mRNA vaccines. On the other hand, if one needs millions of doses they can’t be produced quickly by the traditional methods. Testing protocols for the safety and efficacy of new biologics are very strict and take time. However, we have witnessed accelerated production and testing of the new technology vaccines. Speaking from a purely scientific perspective, one great thing is that there have been many early adopters willing to test this technology so we should have plenty of data to analyze in the years to come.
References:
- Mantovani A, Garlanda C. Humoral Innate Immunity and Acute-Phase Proteins. N Engl J Med. 2023 Feb 2;388(5):439-452. doi: 10.1056/NEJMra2206346. PMID: 36724330; PMCID: PMC9912245.
- Strugnell, Richard & Zepp, Fred & Cunningham, Anthony & Tantawichien, Terapong. (2011). Vaccine antigens. Perspectives in Vaccinology. 1. 61–88. 10.1016/j.pervac.2011.05.003.
- Flower DR, Macdonald IK, Ramakrishnan K, Davies MN, Doytchinova IA. Computer aided selection of candidate vaccine antigens. Immunome Res. 2010 Nov 3;6 Suppl 2(Suppl 2):S1. doi: 10.1186/1745-7580-6-S2-S1. PMID: 21067543; PMCID: PMC2981880.
- Ramachandran S, Satapathy SR, Dutta T. Delivery Strategies for mRNA Vaccines. Pharmaceut Med. 2022 Feb;36(1):11-20. doi: 10.1007/s40290-021-00417-5. Epub 2022 Jan 30. PMID: 35094366; PMCID: PMC8801198.
- Francis MJ. Recent Advances in Vaccine Technologies. Vet Clin North Am Small Anim Pract. 2018 Mar;48(2):231-241. doi: 10.1016/j.cvsm.2017.10.002. Epub 2017 Dec 6. PMID: 29217317; PMCID: PMC7132473