Introductory Chapter: Current Trends in Vaccine Development

1. Introduction

Ever since Edward Jenner proposed in 1796 a prophylactic inoculation of cowpox using the lymph of a diseased animal as a vaccine [1], vaccination of humans has become widespread. Currently, millions of people around the world receive vaccines against viral and bacterial infections. The first generation of vaccines were whole particles of pathogens, attenuated and inactivated in various ways. The whole virion lives attenuated and inactivated vaccines have the longest history of use. Inactivated vaccines contain non-viable viruses, and repeated injections are often required to form an immune response. Although, the experience of eliminating dangerous viral infections, such as smallpox, measles, and poliomyelitis suggests that the use of live vaccines provides the necessary epidemic efficiency and effectiveness of anti-epidemic measures.

Live attenuated influenza vaccines (LAIVs) have been used in Russia since the 1960s. In the early days of LAIV production, the serial passage in chick embryos (CE) produced attenuated viruses, which were host-range (hr-) mutants. Serial passages in CE at a temperature lowered to 25–28°C made it possible to regularly obtain cold-adapted (ca-) vaccine strains from all varieties of influenza A and B viruses which were safe for children [2]. Based on data on the segmented genome of the influenza virus, it became possible to develop vaccine strains production using genetic reassortment of epidemic influenza viruses and an attenuated master donor strain (MDS) [3]. The main features of reassortant vaccine strains—safety for susceptible people and genetic stability—are determined by the properties of MDS. A cold-adapted MDS A/Leningrad/134/57 (H2N2) is currently used in Russia to prepare the reassortant A/H1N1 and A/H3N2 LAIV vaccine strains [4]. The MDS B/USSR/60/69 was developed for the production of vaccine strains of type B influenza viruses [5]. In 2003, the American LAIV was manufactured by MedImmune. Inc. was licensed for use in North America and Europe [6]. LAIV has been shown to be particularly effective in preventing influenza among young children [7]. Differences between Russian and American MDSs are both in the total number of passages and in the cell model.

Until recently, influenza viruses were considered the main causative agents of pandemics and annual epidemics in the modern world. Influenza epidemics have resulted in approximately 3–5 million cases of severe infection and between 290,000 and 650,000 deaths worldwide annually [8]. New coronavirus infection disease (COVID-19), which was first reported on December 31, 2019, in Wuhan, China, caused more than 378 million cases and more than 5.6 million deaths worldwide [https://github.com/CSSEGISandData/COVID-19] as have been reported on February 1st, 2022.

Back in 2015, a chimeric virus expressing the spike of bat coronavirus SHC014 based on a mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV) backbone was reported to have been able efficiently bind to human ACE2 receptor and replicate efficiently in primary human airway cells. In mice, the double-inactivated whole SARS-CoV vaccine failed to neutralize and protect from infection with CoVs with the novel spike protein [9]. However, the use of modern technologies has made it possible to prepare and apply a number of vaccines against this infection in the shortest possible time.

A large part of the development of prototypes of COVID-19 vaccines is based on the use of viral vectors. The technology for this approach is based on the insertion of a gene encoding the target viral protein into the genome of a viral vector. A vector is another virus that does not cause disease in humans. For example, to create a vaccine against COVID-19, a gene encoding a coronavirus protein is inserted into an adenovirus [10]. An obstacle to the use of such vaccines is the presence of antibodies to the viral vector in humans. In this case, to obtain a full-fledged immune response is to adjust vaccination regimens, such as priming boosting is applied.

The production of vaccines based on both non-replicating mRNA and self-amplifying mRNA is a promising new direction in vaccinology. DNA and RNA vaccines are preparations based on the nucleic acid to deliver viral genetic material into the cells of the body. This was limited the use of DNA and RNA vaccine as and for a long time no nucleic acid-based preparation has been used in clinical practice in humans. The emergence of the COVID-19 pandemic has dramatically accelerated this research and RNA vaccines are now widely used.

There are several advantages of mRNA vaccines over conventional methods, namely: minimization of the potential risk of infection and mutagenesis due to the natural degradation of mRNA in the cellular microenvironment; high efficiency of the immunogen due to structural modifications of mRNA increases its stability and translation efficiency; highly effective mRNA-based vaccines able to generate antiviral neutralizing antibodies; recombinant mRNA facilitates large-scale production of sufficient doses vaccines needed to treat large population groups. These factors make an mRNA vaccine more suitable for rapid pandemic response [11].

The SARS-Cov-2 mutates rapidly, with the formation of new variants with increased transmissibility such as Delta (B.1.617.2 and AY lineages) and Omicron (B.1.1.529 and BA lineage [https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html#anchor_1632158924994]. Therefore, the development of universal or polyepitope vaccines is relevant. Antigen selection is a key aspect of any vaccine design. Developing computer and bioinformatic technologies and applied mathematical analysis help to predict antigenic determinants SARS-CoV-2 and immune responses to them. The concept of a multi-epitope vaccine against SARS-CoV-2 is in the identification and assembly of epitopes for B cells, CTL CD8+ and T-helpers CD4 + .B- and T-cell epitopes into a single immunogen, which can induce a more effective response of both parts of immunity—humoral and cellular [12].

Another concern with the high variability of SARS-Cov-2 is the possible need for frequent and repeated vaccinations. This raises the question of which vaccines will be safe and effective for these purposes. In general, the information accumulated to date on the pathogenesis of COVID-19 infection indicates the central role of the mucous membranes and mucosa-associated lymphoid tissues in the initiation, clinical development, and spread of the [13]. As evidenced by studies of taxonomically and structurally similar coronaviruses (SARS-CoV and MERS-CoV), mucosal vaccination may provide a safe and effective way to induce not only long-term mucosal immunity but also systemic immune protection against SARS-CoV-2 [14, 15]. It is considered that genetically modified microorganisms, including probiotic strains, are attractive agents for oral administration or mucosal delivery of vaccine antigens. Several studies have shown that mucosal administration of antigens is capable of eliciting an immune response mediated by mucosal-specific serum IgG and IgA along with mucosal cell-mediated immune responses that effectively neutralize and eradicate infections [16, 17, 18]. Thus, advances in modulating mucosal immune responses, and in particular the use of probiotics as live delivery vectors, may encourage prospective studies to evaluate the efficacy of genetically engineered probiotics in SARS-CoV-2 infection [19, 20]. Controversial aspects of the use of genetically modified probiotics lie in overcoming interference between mucosal delivery of therapeutic agents and the immune system.

Along with this, it is worth mentioning the development of vaccines against bacterial infections. The number of bacterial vaccines against common pathogens such as whooping cough, Streptococcus pneumoniae, and Haemophilus influenzae are also widely used and updated. Pneumococcal polysaccharide or conjugate vaccines are currently used, which are based on a limited set of polysaccharide antigens of the bacterial capsule. Although, polysaccharide vaccines require a constant change in composition in view of the fact that when vaccinating the population, bacterial serotypes that are not included in the vaccine begin to dominate and cause disease [21, 22]. Therefore, pneumococcal vaccines include more and more components, for example, pneumococcal conjugate vaccine Prevnar was first prepared as a 7-component preparation, then as a 13-component preparation, and now it is being prepared as a 20-component preparation [23]. The inclusion of a large number of components and their modification with a protein adjuvant makes the vaccine difficult to control in terms of quality and safety, and also expensive. In addition, the polysaccharide components of the vaccine do not provide a long immunological memory, which requires their modification with adjuvants or repetitive revaccination [23]. Current trends in the development of vaccines against pneumococcal infection include the use of protein factors of bacterial pathogenicity, such as highly conservative lipoprotein or enzymes (nucleases, proteases, hemolysin, peptidase) which are preferable over polysaccharide vaccines due to the lower variability and higher immunogenicity [24, 25].

Finally, a number of areas include the development of vaccines against a number of somatic diseases, which, as it turned out, are closely related to a number of pathogens. For example, even 50 years ago, no one could have imagined that such diseases as stomach and duodenal ulcers are of infectious origin and are related to Helicobacter pylori. The development of an anti-Helicobacter pylori vaccine turned out to be a rather complicated project due to the number of pathophysiological, immunological, and technological difficulties. Nevertheless, a promising direction in improving H. pylori vaccines is the search for effective mucosal adjuvants and the use of immunostimulatory probiotics during the administration of a vaccine. Perhaps in the future, it will be possible to prevent somatic diseases by vaccinating against the corresponding infections.

In conclusion, it should be noted that vaccination is the most effective and cost-effective means of protection against infectious diseases known to modern medicine. The use of vaccines has reduced, and in some cases completely eliminated, a number of diseases from which tens of thousands of children and adults previously suffered and died. Vaccines represent the most powerful defense tool in reducing the risk of a pandemic outbreak and will play a critical role in response to any future pandemic. The development and testing of new vaccine platforms contribute to the rapid release of vaccines against new pathogens that continually arise and regenerate. To fight new emerging infections, the creation and deposit of prototype vaccine candidates can also help. When developing new vaccines, the future of the drug is determined by such factors as the possibility of reducing the incidence and the benefits of using the vaccine, the risk of complications and possible damage from vaccination, the cost of the vaccine, and economic benefits. The cost of vaccination for any vaccine with proven efficacy is about 10 times less than the cost of treating infectious diseases.