By Sabino Méndez Pastor
In 1796, Edward Jenner demonstrated that cowpox infection gave long term protection against the smallpox virus (Maruggi et al., 2019). Since then, vaccines have become one of the most effective public health tools ever developed by saving an estimate of 2.5 million lives each year from diseases like diphtheria, tetanus and measles (WHO, 2019). For instance, the widespread use of vaccination led to the complete eradication of smallpox. During these 200 years, vaccines have been developed based on the method of Jenner and Pasteur, which consists in injecting live-attenuated or inactivated (killed) pathogens into patients to establish an adaptative memory immune response against a pathogen (Wallis, Shenton & Carlisle, 2019). Although these approaches tend to be quite effective, making a pathogen safe to inject is a time-consuming process that carries important risks if the pathogen is not correctly attenuated or inactivated. That is why novel vaccine designs have emerged as promising alternatives to conventional vaccines, aiming to have the effectivity of live-attenuated and inactivated vaccines but without their risks and limitations. This review describes some of the new vaccine techniques that are currently under development or use.
In order to create long-term immunity against pathogens, vaccines must first introduce into the body molecules that can trigger an immune response, also known as antigens. Live-attenuated and inactivated vaccines insert a whole pathogen which contains a combination of pathogen associated molecular patterns (PAMPs) and antigens that activate the innate and adaptative arms of the immune system. This mechanism of action seems to suggest that introducing only some PAMPs and antigens of a pathogen could generate an immune response that results in long-term immunity. Indeed, antigens such as bacterial surface proteins and viral glycoproteins are purified and delivered as part of subunit vaccines. The Hepatitis B vaccine and pneumococcal vaccines are examples of this method. However, a single purified antigen or a few ones usually produce a much weaker and more short-lived response than injecting the whole pathogen, which is not sufficient to ensure long-term immunity (Wallis, Shenton & Carlisle, 2019). To overcome this challenge, additional chemicals known as adjuvants are added to subunit vaccines to elicit stronger responses by extending the time that the antigen survives and triggering immune innate responses. Repeated vaccinations that build up the immune responses to an adequate protective level named boosters are also used to increase the efficiency of subunit vaccines.
Bacterial capsular polysaccharides have long been a target of subunit vaccines. Bacteria synthesise hundreds of chemically and immunologically different polysaccharides that serve as a protective external layer. However, vaccines composed of purified polysaccharides failed to induce immune responses in children, the population for whom vaccines are generally most needed (Rappuoli, De Gregorio & Costantino, 2019). This was due to the way the immune system mounts an adaptative response. Polysaccharides are detected and phagocytosed by dendritic cells (DCs) which then migrate to secondary lymphoid tissues such as the lymphoid nodes and the spleen. Once there DCs present the antigen to both B and T lymphocytes. This leads to the formation of a germinal centre where B cells proliferate and mature to increase the affinity of their receptors and antibodies for the antigen. During this process B cells bind and take up the protein antigens presented by DCs, process them into small peptides and load them into Major Histocompatibility molecules that expose the peptides on the surface of the B cell. The B cells then present the peptide to T helper (Th) cells. Th cells can sense the affinity of the antigen for the MHC molecules. The higher this affinity is, the more they will stimulate the B cell to undergo more cycles of replication. The problem with polysaccharide subunit vaccines was that polysaccharide molecules cannot bind MHC molecules. In consequence, B cells that have B cell receptors (BCRs) and therefore can produce antibodies against polysaccharides are not recognised and stimulated by T helper cells which makes them undergo apoptosis. Conjugate vaccines have been developed to overcome that problem by using polysaccharides covalently conjugated to carrier proteins. This makes that when B cells recognise the polysaccharide, they internalise it with the carrier protein. Then they process them and load peptides from the carrier protein on their MHC, allowing presentation to the T cells. These are therefore activated, leading the creation of an adaptative immune response that produces plasma cells which secrete polysaccharide-specific antibodies and memory B cells (Rappuoli, De Gregorio and Costantino, 2019). Conjugate vaccines for haemophilus influenzae type B (Hib), meningococcus and malaria have been approved for use in humans (Wallis, Shenton and Carlisle, 2019).
On the other hand, mRNA vaccines are the newest and probably most promising new type of vaccines. Pfizer’s BNT162b1 and Moderna’s mRNA-1273 are some of the few vaccines currently approved to prevent SARS-CoV-2 infection and use this approach (European Medicines Agency, 2021; Sahin et al., 2020). To create an mRNA vaccine an antigen is selected, and its gene is sequenced and cloned into a DNA template plasmid. This is then transcribed in vitro into mRNA and the vaccine is delivered to a patient. The mRNA molecules enter the host cells (usually muscle cells) and use their translation machinery for in vivo translation into the corresponding antigen, mimicking a viral infection. The antigen can be expressed in the cytosol only, secreted or bound to the cell membrane and is able to elicit potent immune responses. There are two major types of mRNA vaccines (Maruggi et al., 2019). Conventional mRNA vaccines encode the antigen of interest flanked by 5’ and 3’ untranslated regions. They are simple and relatively cheap to manufacture but they present limitations in the duration and the level of expression they can achieve. In contrast, self-amplifying mRNA vaccines also encode the viral replication machinery for intracellular amplification of the antigen encoding RNA (Pardi et al., 2018). This results in higher levels of antigen expression. Self-amplifying RNA vaccines do not encode for structural genes of the virus so infectious virus particles are not produced (Wallis, Shenton and Carlisle, 2019). Both types of mRNA vaccines can lead to recognition of exogenous mRNA by a range of cell surface, endosomal and cytosolic innate immune receptors (Pardi et al., 2018). This provides adjuvant activity by producing robust innate immune responses including the production of chemokines and cytokines which are crucial to successfully trigger an adaptative response against the encoded antigen and therefore create long-term immunity (Maruggi et al., 2019). mRNA vaccines show many advantages as they can be produced rapidly and safely using a completely synthetic manufacturing process (no live pathogens are needed). Besides this, as they are synthetic, potentially any sequence can be designed in sillico, synthesised and tested rapidly in vivo in animal models. This makes them ideal to rapidly respond to newly emerging pathogens, such as SARS-CoV-2.
European Medicines Agency (2021). COVID-19 Vaccine Moderna. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/covid-19-vaccine-moderna (Accessed: 8 March 2021).
Maruggi, G. et al. (2019) ‘mRNA as a Transformative Technology for Vaccine Development to Control Infectious Diseases’, Molecular Therapy. Cell Press, pp. 757–772. doi: 10.1016/j.ymthe.2019.01.020.
Pardi, N. et al. (2018) ‘mRNA vaccines-a new era in vaccinology’, Nature Reviews Drug Discovery. Nature Publishing Group, pp. 261–279. doi: 10.1038/nrd.2017.243.
Rappuoli, R., De Gregorio, E. and Costantino, P. (2019) ‘On the mechanisms of conjugate vaccines’, Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, pp. 14–16. doi: 10.1073/pnas.1819612116.
Sahin, U. et al. (2020) ‘COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses’, Nature. Nature Research, 586(7830), pp. 594–599. doi: 10.1038/s41586-020-2814-7.
Wallis, J., Shenton, D. P. and Carlisle, R. C. (2019) ‘Novel approaches for the design, delivery and administration of vaccine technologies’, Clinical and Experimental Immunology. Blackwell Publishing Ltd, pp. 189–204. doi: 10.1111/cei.13287.
World Health Organization (2019). Immunization. Available from: https://www.who.int/news-room/facts-in-pictures/detail/immunization (Accessed: 8 March 2021).