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The invention and evolution of vaccination as a method for fostering long-term protection against certain pathogens has had an immense positive effect on public health. Throughout the 20th century, vaccines allowed reducing the global incidence of some deadly diseases, including smallpox and congenital rubella syndrome, by at least 99% (Orenstein & Ahmed, 2017). By providing protection against many life-threatening viruses and bacteria and preventing serious morbidity, vaccination not only assists in promoting individual and community well-being but also serves as the most cost-effective method for the elimination of many infectious diseases.
Regardless of vaccines’ multiple positive impacts, the contemporary anti-vaccination movement is gathering momentum. It is valid to say that the rising negative attitude to artificial immunization is largely due to the misunderstanding of the mechanisms through which vaccines act, their interactions with the immune system, and potential vaccine-related risks to individuals’ health. Considering this, the present paper will aim to explore the concept of vaccination and explain how it stimulates responses at different levels of the immune system. Additionally, different types of vaccines will be reviewed along with the most recent developments in the field of immunization.
Although the science of vaccination commenced advancing merely by the end of the 18th century, evidence shows that first attempts to create vaccines were made in antiquity. It is known that the process of variolation was practiced in ancient China: people tried to induce immunity by intranasally inhaling small pieces of scabs collected from smallpox lesions of infected persons (Davies, Schmidt & Sheikh 2012). In the 18th century, Lady Mary Montagu introduced and promoted variolation in Western Europe and Britain after observing how this procedure was successfully implemented in Turkey (Davies, Schmidt & Sheikh 2012).
However, a significant milestone in the field of vaccinology was marked by Edward Jenner’s discovery. The scientist found out that a related but less dangerous pathogen, such as cowpox, could be utilized to prevent a more deadly infection, such as smallpox (Davies, Schmidt & Sheikh 2012). After his finding, a large number of other experiments were conducted by using a plethora of disparate bacteria and virus species including those causing cholera and tuberculosis (Davies, Schmidt & Sheikh 2012).
All of the carried-out experiments invariably revealed that a weakened pathogen could induce an immune response without actually causing disease. This observation is fundamental to the understanding of how vaccines work, and it will be further explained through an overview of different components and actions of the immune system.
Components and Functions of the Immune System
Overall, the human immune system has two large subsystems: the innate system and the adaptive system. These subsystems are in a constant process of interaction, and vaccines usually aim to stimulate responses in both of them (Clem 2011). Nevertheless, it is valid to say that the core target of vaccines is the adaptive system. Unlike the innate system that is responsible for general, first-line defense of the organism, the adaptive system protects against specific infections and, after one or a few sequential exposures to pathogens, develops memory necessary to respond to them more quickly and effectively (Clem 2011). This capability of the adaptive system for learning and memorizing its previous experiences is the main reason why after vaccination people become immune to different viruses and bacteria for a substantial time or even obtain lifelong immunity.
The scope of each immune subsystem’s response is defined by its basic components and functions. For example, protective elements of the innate system are anatomic barriers (skin, mucous membranes, and so forth), physiological barriers (body temperature, interferons, lysozymes, and so forth), inflammatory response, complement pathways (triggered by IgM/IgG antibodies, properdin, and lectin), pattern recognition receptors, mononuclear phagocytes, and granulocytic cells (Clem 2011). Neither of these protective measures can recognize specific pathogenic agents.
However, pattern recognition receptors serve to detect lipoproteins found in bacterial capsules, double-stranded DNA found in viruses, and many other general, pathogen-related molecular patterns (Clem 2011). In a way, this generalized recognition function serves as a restrictive measure, without which the innate immunity would attack host cells and disrupt the work of other body systems (Clem 2011). However, even without the ability to discern various kinds of toxins and pathogens precisely, the actions of defense mechanisms included in the innate immune system are often enough to remove pathogenic agents from the organism. The adaptive system usually gets involved when an infection is particularly aggressive and persistent.
The abovementioned evidence indicates that immune responses to pathogens, in general, and vaccines, in particular, always start at the innate system level with the activation of the pathogen recognition receptors. The further response depends on the type of pathogen detected by these receptors. However, they are all linked to the production of proinflammatory cytokines and chemokines, as well as the stimulation of antigen-presenting cells, such as phagocytes (Kang & Compans 2009). These antigens play an essential role in the initiation of the adaptive system and the further development of immune memory.
The adaptive system consists of two arms: the humoral immunity, also known as the antibody-mediated immunity, comprised of B-cells, and the cell-mediated immunity comprised of T-cells (Clem 2011). The first arm provides defense against the extracellular pathogens, whereas the second arm protects against intracellular pathogens (Clem 2011).
Most of the modern vaccines target the humoral immunity and aim to stimulate the production of antibodies by B-cells, which are considered to hold the main responsibility for the development of long-term immune memory (Kang & Compans 2009). However, although B-cells can be activated without the involvement of T-cells, it is suggested that “activation of B-cells with T-helper cell activation results in a much better immune response and more effective memory” (Clem 2011, p. 75). So far, some types of vaccines have been more efficient in triggering both T and B cell activation simultaneously than others.
Conventional Types of Vaccines
The majority of vaccines that are commonly used nowadays can be categorized as either live attenuated vaccines or non-living, non-replicating vaccines. The first type refers to vaccines that contain weakened forms of real pathogenic organisms (Titball & Atkins 2012). Considering that pathogens included in those vaccines are similar to the original, they tend to result in strong immune responses that usually do not differ from reactions to natural infections.
Following the injection of a live attenuated vaccine, the pattern recognition receptors of the innate immune system become activated, which leads to a consequent release of the pathogen-associated signals, as well as dendritic cells, macrophages, and other agents involved in the cellular immune response (Kang & Compans 2009). In this way, the innate system triggers the initiation of both arms of the adaptive immune system.
The route of live vaccine administration does not seem to define the intensity of the adaptive immune memory stimulation. In either case, live vaccines widely disseminate throughout the organism and pass all stages of natural infection development (Kang & Compans 2009). For example, when a vaccine is administered orally or through the nose, pathogens replicate in the mucosal lining, which induces a multi-site activation of antigen-presenting cells and impacts a larger number of lymph nodes where naïve B-cells are contained (Kang & Compans 2009; Clem 2011).
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These naïve B-cells then commence interacting with antigens during the process of somatic hypermutation of B-cells, leading to a further maturation of the latter and their transformation into plasma cells or memory cells that start to produce specific antibodies (IgM, IgD, IgA, or IgE) needed to eradicate a certain pathogen (Clem 2011). At the phase of B-cell maturation, dendritic cells also become involved in the differentiation of CD4 (T-helper) cells, which serve to strengthen the memory capacity of the adaptive system (Kang & Compans 2009). Overall, the described process demonstrates that live attenuated vaccines substantially impact both subsystems of the immune system.
As for inactive or non-replicating vaccines, their ability to induce innate immune response is rather limited. Non-living vaccines contain pathogens that are killed by using chemicals, heat, and other laboratory-based methods (Clem 2011). Thus, compared to live vaccines, the non-replicating ones are more stable, associated with fewer risks for immunocompromised individuals, have a longer shelf life, and do not require strictly controlled storage conditions for the preservation of their potency (Clem 2011; Titball & Atkins 2012).
Regardless of these advantages, inactive vaccines usually stimulate innate immune responses only at the site of injection because the process of replication (natural infection development) is not possible in killed pathogens (Kang & Compans 2009). Moreover, unlike the case with the live attenuated vaccines, the route of administration seems to play a big role in defining the intensity of protective immune responses to non-living vaccines. For example, intradermal immunization against rabies and influenza are empirically proved to be more effective compared to other routes of injection of vaccines against these viruses (Kang & Compans 2009).
Nevertheless, even when the best site and route of administration are considered, non-living vaccines usually fail to target the cell-mediated immunity and initiate a T-cell response (although it is reported that irradiated non-living vaccines can potentially attain a high degree of T-cell activity) (Kang & Compans 2009; Clem 2011). Thus, non-replicating vaccines do not foster long-term immune protection and require additional shots over time.
New Types of Vaccines in Development
With a greater understanding of various DNA mechanisms and advanced awareness of how vaccination impacts the immune system, new types of vaccines have emerged. Two of them are naked DNA vaccines and recombinant vector vaccines. The former type implies that purified DNA of certain antigens or, in other words, DNA that is not molecularly protected and developed as a result of releasing genetic information into the environment, would be used to activate immune responses (Rouse et al. 2012).
According to Clem (2011), after the injection of a naked DNA vaccine, the body cells would consume the introduced DNA and consequently commence generating the required antigen, which would eventually result in the desired immune response. This type of new vaccines can potentially foster strong, long-term immune protection by affecting both arms of the adaptive system (Clem 2011). Besides, naked DNA vaccines will also likely be cheap to produce, yet at the present developmental stage, they are characterized by low therapeutic efficacy since naked DNA tends to degrade rapidly (Clem 2011; Hobernik & Bros 2018). The improvement of the transfection process during the vaccine design is thus the primary goal of researchers involved in the development of this type of vaccines nowadays.
The recombinant vector vaccines are also still being investigated by scientists. This type of vaccines will utilize DNAs of live viruses and bacteria and transfer them into host cells (Clem 2011). It means that their effects would be similar to those produced by conventional live attenuated vaccines and would induce immune responses that typically occur in natural infections. Evaluating recombinant vector vaccines in the context of virus/bacteria replication, they seem to be associated with a significant safety risk.
As validly noted by Bull, Nuismer, and Antia (2019), “vaccine revertants that delete or inactivate the transgene may evolve to dominate the vaccine virus population both during the process of manufacture of the vaccine as well as during the course of host infection” (p. 1). It means that besides addressing the issues of therapeutic efficiency, researchers will need to find a way to reduce the risk of viral replication when designing recombinant vector vaccines.
The analysis revealed that vaccination is indeed an efficient method for the prevention of infectious diseases and the protection of public health. Live attenuated vaccines are particularly effective in this regard. By mimicking natural infections and stimulating pathogen recognition receptors in the innate system along with B-cell and T-cell activities in the adaptive system, they promote the development of long-term immune memory that protects hosts from initial infections. While the injection of these vaccines may be detrimental to immunocompromised individuals, it may be expected that further developments in the field of vaccinology will eventually help to resolve this issue.
Bull, JJ, Nuismer, S & Antia, R 2019, ‘Recombinant vector vaccines and within-host evolution’, PLoS Computational Biology, vol. 15, no. 7, pp. 1-20.
Clem AS 2011, ‘Fundamentals of vaccine immunology’, Journal of Global Infectious Diseases, vol. 3, no. 1, pp. 73-78.
Davies, DH, Schmidt, CS & Sheikh, NA 2012, ‘Concept and scope of modern vaccines’, in WJW Morrow, NA Sheikh, CS Schmidt & DH Davies (eds), Vaccinology: principles and practice, Blackwell Publishing, Chichester, UK, pp. 3-14.
Hobernik, D & Bros, M 2018, ‘DNA vaccines-how far from clinical use?’, International Journal of Molecular Sciences, vol. 19, no. 3605, pp. 1-28.
Kang, SM & Compans, RW 2009, ‘Host responses from innate to adaptive immunity after vaccination: molecular and cellular events’, Molecules and Cells, vol. 27, no. 1, pp. 5-14.
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Titball, RW & Atkins, HS 2012, ‘Attenuated bacterial vaccines’, in WJW Morrow, NA Sheikh, CS Schmidt & DH Davies (eds), Vaccinology: principles and practice, Blackwell Publishing, Chichester, UK, pp. 181-195.