Contemporary vaccine approaches and role of next-generation vaccine adjuvants in managing viral diseases
Shailendra K. Saxena, Vimal K. Maurya, Swatantra Kumar and Madan L.B. Bhatt Centre for Advanced Research (CFAR)-Stem Cell/Cell Culture Unit, King George’s Medical University (KGMU), Lucknow, India
18.1 Introduction Vaccine is the most efficient intervention of medical sciences to reduce both mortality and morbidity caused by infectious diseases. In modern medicine, vaccinology is the most important cornerstone that provides an improved quality of life by controlling the transmission of diseases across communities (Hajj Hussein et al., 2015). Vaccines are the most economical means for public health interference to focus the global health economic load related mainly with infectious diseases. Over the past century through global vaccination campaign, polio, tetanus, diphtheria, and measles are significantly restricted whereas smallpox has been successfully eradicated form the world. Similarly, other microbial infections that mainly affect the younger populations have been significantly decreased in developed countries (Doherty et al., 2016). Generally, pathogens for which new vaccines are required have extensive variability, complex pathogenesis, and immune evasion properties (Servı´n-Blanco et al., 2016). A conventional method for the vaccine development has several limitations such as they are slow, time consuming, and fail to meet the requirements of a new vaccine during pandemics (Khurana, 2018). Recent advancement in structural biology, systems biology, computational biology, molecular and cellular immunology, molecular genetics, nanotechnology, bioinformatics, and formulation technologies provides novel approaches in immunogenic design with appropriate adjuvant discovery for new diseases (Loomis and Johnson, 2015). Structural vaccinology, recombinant DNA, reverse vaccinology, polysaccharide chemistry, and synthetic RNA vaccines are novel technologies that have been employed to design next-generation vaccines in the last 30 years (Rappuoli et al., 2014) (Fig. 18.1). Genomics and Biotechnological Advances in Veterinary, Poultry, and Fisheries. DOI: https://doi.org/10.1016/B978-0-12-816352-8.00018-7 © 2020 Elsevier Inc. All rights reserved.
CHAPTER 18 Contemporary vaccine approaches
FIGURE 18.1 Evolution in vaccine development technologies: Meningococcal B (Men B), Group B Streptococcus (GBS), Haemophilus influenzae type b (Hib), Group A Streptococcus (GAS), and Bacillus Calmette-Guerin (BCG).
18.2 Structural vaccinology Structural vaccinology is the knowledge of structural biology, bioinformatics, and human immunology for rational engineering of immunogens (Liljeroos et al., 2015). Structural vaccinology based on the principle of single or multiple-selected epitopes detection, which may be enough to stimulate a protective immunity and efficient host immune response, does not require identification of the full antigenic protein. Structural vaccinology together with human immunology are fast rising approaches for the rational of designing newer vaccines containing various antigenic epitopes for the development of highly effective immunity (Delany et al., 2014). Recently, researchers have developed an immunogen specific to respiratory syncytial virus (RSV) by using a structure-based approach that produces defensive responses against the fusion glycoprotein of RSV (McLellan et al., 2013). Another major advantage of structural vaccinology is the development of a better antigen that prevents HIV infection by inhibiting HIV replication. The envelope protein of HIV is the main target of HIV neutralizing antibodies (Benjelloun et al., 2012).
18.4 Reverse vaccinology
18.3 Synthetic vaccines Synthetic vaccines are designed based on antigens, for example, synthetic peptides and carbohydrates. Synthetic vaccines are proposed to be safer than the conventional vaccines derived from cultures. In synthetic vaccinology, advancement of nucleic acid-based vaccines exhibits several advantages such as opportunities of in situ antigen expression and associated safety of subunit and inactivated vaccines (Skwarczynski and Toth, 2016). Higher rate of production, simple manufacturing method, and inexpensiveness are the other major advantages associated with synthetic vaccines that allow us to combat humanitarian emergencies. Recently, DNA-based vaccines have illustrated to be very promising in animals whereas immune response was poor in humans as compared to conventional vaccines. In order to increase the efficiency of DNA-based vaccines in humans, various strategies such as electroporation-mediated DNA delivery and use of genetic adjuvants for amplified immunity have been applied clinical trials with satisfactory preliminary responses (Villarreal et al., 2013). RNA vaccines are the substitute of DNA vaccines and are primarily comprised of mRNA and RNA replicons having self-amplifying capabilities. The direct translation of the RNA in the cytoplasm results in the desired peptides or antigens whereas the integration of the gene into the host genome has been completely abolished (Ulmer et al., 2012). The stability and effectiveness of RNA-based vaccines have been improved through the utilization of engineered viral-particle expressing nonhomologous antigens rather than the viral specific genes. Conquering the limitations of DNA vaccines and viral delivery technology, the self-amplifying RNA replicons have been shown to be really promising (Lundstrom, 2018). Novel synthetic delivery methods that unite the efficacy of live attenuated vaccines, enhanced safety profile than plasmid DNA vaccines and methods of manufacturing may define the future of improved RNA vaccines. Significant research is required for the advancement of a synthetic vaccine that offers a unique tool of vaccine availability during various pandemics (Vogel et al., 2018).
18.4 Reverse vaccinology Reverse vaccinology is the most recent approach of antigen discovery for the design of newer vaccines by using genome sequencing data of microorganisms and bioinformatics. Reverse vaccinology changes the perspective of vaccine design by permitting the detection of broad spectrum vaccine candidates and immunogenicity during infection (Bidmos et al., 2018). The simultaneous application of protein arrays genomics, proteomics, and bioinformatics can significantly increase the detection of vaccine targets and vaccine development process
CHAPTER 18 Contemporary vaccine approaches
(Galassie and Link, 2015). Meningococcal B are the first microorganisms for which reverse vaccinology was performed (Giuliani et al., 2006). Now this approach has also been useful to various bacterial pathogens such as Staphylococcus. aureus, Streptococcus. pneumoniae, Chlamydia, Streptococcus agalactiae, group A, and B streptococcus, Escherichia coli, and Leishmania major (Sette and Rappuoli, 2010). Reverse vaccinology involves sequencing the genome of an infectious organism and considering the whole antigenic repertoire for the identification of vaccine targets which can be evaluated for their appropriateness as vaccine candidate. Thus, the genome-based reverse vaccinology approaches can offer novel strategies for the design of vaccines, which was not possible to develop using conventional methods (Kanampalliwar et al., 2013). Other than reverse vaccinology, genomic-based antigen discovery can be increased by novel approaches enabling the investigation of entire antigenic repertoire with the help of antigenome analysis, that is, investigating the immunogenicity of proteins during infection and making the libraries of genetically expressed antigens (Furman and Davis, 2015). Furthermore, advancement in mass spectrometry has empowered the screening of existing and the amount of antigens present on surface of the pathogens (Sharma et al., 2018). Such advancements in antigen discovery technologies allowed identification of antigens for vaccine candidates that stimulate neutralizing antibody responses and assist the generation of vaccines based on T-lymphocytes (Koff et al., 2013) (Table 18.1).
18.5 Next-generation vaccine adjuvants Vaccine adjuvants are the substances that can advance the efficacy of vaccines by inducing vigorous immune responses in immunocompromised individuals, newborns, or the elderly. Adjuvants are usually required for subunit vaccines and not needed for live attenuated vaccines (Pe´rez et al., 2013). In vaccinology, adjuvants have various applications such as augmentation of immune response of the antigens by administering in native form, which diminishes the multiple immunization protocols to get protective immunity and to enhance the immune response in vaccinated individuals (Del Giudice et al., 2018). For vaccine formulation, currently, various categories of adjuvants with different mechanisms are used named as virosomes, oil emulsions, liposomes, mineral salts, immunestimulating complexes (ISCOM), virus-like particles, carbohydrate adjuvants, polymeric microparticle adjuvants, cytokines, and some bacterial derivatives (Aposto´licoJde et al., 2016).
18.5.1 Aluminum salts (Alum) Aluminum salts are commonly known as booster of Th2 immunity and they are extensively used adjuvants for human vaccines (Brewer, 2006). Aluminum is licensed for various human vaccines including human papilloma virus,
18.5 Next-generation vaccine adjuvants
Table 18.1 Merits and demerits of vaccine development technologies. Technology
• Activates all phases of the
• Secondary mutation can
• • •
• Recombinant DNA vaccines
• • • • • •
• • •
immune system. Provides more durable immunity, boosters are required less frequently. Low cost. Quick immunity. Some are easy to administer, for instance, polio can be taken orally. Vaccines have strong beneficial nonspecific effects. Rapid generation. Safe and long lived immunity. No need for protein expression and purification. Potentially generic and low-cost manufacturing processes. Thermostability. Leading technology for T cell induction. Vaccines are cost effectives. Prevents asymptomatic carriage of disease. Pathogens that remain protected by encapsulation are destroying, so vaccination is possible against encapsulated bacteria. Elicits long-term protection.
• Fast and efficient in silico approach.
• For detection of antibodies
Next generation technologies
• • •
produced as a result of infections, allergies, autoimmune diseases, or cancers. Induce both humoral and cellular immune responses. High degree of adaptability production does not require amplification in bacteria or cell cultures. Improved safety, efficiency, and stability.
cause a reversion to virulence. • Causes severe complications in immunocompromised patients. • Required special storage conditions.
• Affected by maternal antibody.
• Limited to protein immunogen only.
• Induction of immunologic tolerance.
• It is expensive.
• Loss of immunogenicity during conjugation.
• Immunogenic response is restricted to selected antigens. • Vaccine may cause mild side effects, these includes slight fever, allergic reaction, tenderness, swelling, and redness at the site of the shot. • Only proteins can be targeted using this process, other biomolecules like polysaccharide are not targeted.
• Required alternate delivery system.
• Vaccine uptake can be limited due to the presence of enzymes like RNases.
CHAPTER 18 Contemporary vaccine approaches
meningococcal, hepatitis B virus, tetanus, hepatitis A virus, diphtheria, and Haemophilus influenza type b. Aluminum has a lower toxicity profile than other vaccine adjuvants and is widely applicable for vaccine formulations to confirm antigen stabilization, high safety, and increase of high and long-lasting antibody response (Kanampalliwar et al., 2013).
18.5.2 Oil-in-water emulsions Augmentation of antibody titer and antigen dose-sparing are the main advantages associated with use of emulsion in vaccine formulations. Oil-in-water (o/w) emulsion based on squalene (AS03 and MF59) has been licensed for influenza vaccines both H1N1and H5N1in Europe. The efficacy of MF59 has been tested for various vaccine trials in conjunction with human immunodeficiency virus, cytomegalovirus, and herpes simplex virus (O’Hagan et al., 2012). Similarly, AS03 contains vitamin E (α-tocopherol) and is widely used for induction of nonspecific activation of the immune system (Morel et al., 2011).
18.5.3 Virosomes Virosomes are semisynthetic complexes derived from nucleic acid-free viral particles. Virosomes consist of two viral envelope glycoproteins: neuraminidase and influenza virus hemagglutinin are introduced between the phospholipids bilayers’ membrane. The various routes through which a virosomes can deliver an antigen in the biological system are intravenous, intramuscular, intradermal, and intranasal and depends upon intend of immunization with neglected side effects (Lee and Nguyen, 2015). Virosomes-based vaccine (Inflexal V) for influenza virus has been licensed for all age groups in Europe. Similarly, hepatitis A virus vaccine (Epaxal) has been licensed in South America, Europe, and Asia. The use of virosomes as vaccine adjuvants has various advantages like appropriateness to a wide range of population; improved antigen stability, excellent safety profile, and long-lasting antibody responses (Moser et al., 2007).
18.5.4 Monophosphoryl lipid and adjuvant System 04 Monophosphoryl lipid (MPL) is a toll-like receptor-4 (TLR4) receptor agonist and acts by increasing the expression of proinflammatory cytokines of Th1 immune responses specifically interferon gamma (IFN-γ) and interleukin-2 (IL-2). MPL, an immunostimulatory adjuvant is a detoxified form of bacterial lipopolysaccharide (LPS) obtained from Salmonella. minnesota R595 strain and one of the most promising adjuvant approved for human vaccines. Adjuvant System 04 (AS04) is made up of MPL impregnated on aluminum salts and now it became a second choice of adjuvant for human use after MF59. Currently, two AS04 containing vaccines, that is, human papilloma virus and hepatitis B virus, have been licensed for human use mainly in hemodialized patients (Ko et al., 2017).
18.5 Next-generation vaccine adjuvants
18.5.5 Carbohydrate adjuvants Various carbohydrates from natural sources can trigger the cells of immune system. γ-inulin is a potent carbohydrate adjuvant obtained from Compositae family and known for inducing cellular and humoral immunity with no side effects. Together with other adjuvants such as aluminum hydroxide, γ-inulin produces different types of adjuvants with a broad range of Th1 and Th2 activity. Acemannan is a natural polysaccharide carbohydrate adjuvant derived from mucilaginous gel of Aloe barbadensis and acts by stimulating the cytotoxic activity of natural killer cells and generation of cytotoxic T-lymphocytes-mediated responses (CTLs). The other mannose- and glucose-based polysaccharides that have adjuvant properties include galactomannans, lentanans, glucans, glucomannans, and dextrans (Mukherjee et al., 2013).
18.5.6 Cytokines adjuvants Various cytokines have been investigated for their ability to increase antigenspecific immune responses. To induce antigen-specific serum/mucosal antibody and cell-mediated immunity, a large number of cytokines have been studied. The most prominent cytokines adjuvants that have been evaluated to date for vaccine design include IL-1, IL-2, IL-6, IL-12, IL-15, IL-18, IFN, and granulocyte/macrophage colony stimulating factor (Taylor, 1995).
18.5.7 Nucleic acid-based mucosal adjuvants The mucosal adjuvants are the most promising strategy for vaccine design and are mainly obtained from toll-like receptor (TLR) ligands, novel small molecules, non-TLR immunostimulants, and bacterial toxins. Cholera toxin and Escherichia coli heat-labile enterotoxin are the most widely used mucosal adjuvants in animals. Various TLR agonists’ mucosal adjuvant such as AS04, MPL, TLR9 ligand CpG, and flagellin have been widely used for the development of newer vaccines (Chen et al., 2010).
18.5.8 Nanomaterial as adjuvants Implementation of nanotechnology in the field of vaccinology has reduced the dose and frequency of required immunizations due to the antigen-depot effect of nanocarriers. Various fascinating approaches such as the use of polycationic nanoparticles, cell-penetrating peptide-modified nanoparticles, and pH-dependent nanoparticles have been shown as promising for targeting the antibody and specific CTL responses during disease conditions and delivery of antigens into the cytosol. By controlling the physicochemical properties of these nonmaterials, they can use for antigen delivery that have high bioavailability, good targeting and imaging properties with sustained and controlled release profiles which are thought to be an advantage in the immune outcomes of vaccination (Shen et al., 2017) (Table 18.2).
CHAPTER 18 Contemporary vaccine approaches
Table 18.2 Adjuvants approved for human vaccines. Adjuvant type
Mechanism of action
1. Particulate delivery vehicle Liposomes
Contains synthetic phospholipids. Liposomesbased hepatitis A vaccine approved in Europe.
Immunestimulating complexes (ISCOM)
It contains a triterpenoid saponins obtained from Quillaia saponins, asterol and optionally a phospholipid. The saponins are Quil A or QS-21. It is made by biodegradable polymers. Antigens encapsulated inside the microparticles. It is considered as next generation of adjuvants. Potential for single shot vaccines.
Fuse with cell membrane of macrophages, enable antigen into the cytoplasm, enter major histocompatibility complex (MHC) class I path way and activate CD8 cytotoxic Tlymphocytes-mediated responses (CTL) response Generate CTL response, induce cytokines. Directly phagocytosed by macrophages.
Long-term depot effect from weeks to months. Pulsatile release of antigens. Target to antigen presenting cells.
2. Mineral salts Aluminum salts
Licensed and approved by USFDA for human use. Misreferred as alum. It is widely used as human and veterinary vaccines. Aluminum hydroxide is more potent than aluminum phosphate due to their adsorption property. Considered as the safest adjuvant. Calcium salts in the form of calcium phosphate has been used as human vaccine adjuvant especially DTP, polio, yellow fever, and Bacillus CalmetteGuerin (BCG) vaccines. Approved for human use in European countries.
Short-term depot effect and Induction of cytokine network. Complement activation. Delivery of antigens to different antigen presenting cell (APC). Strong Th2 response.
Short-term depot effect. Adsorbs soluble antigens and presents them in a particulate form to the immune system.
3. Oil emulsion Freund’s complete adjuvant (FCA) Freund’s incomplete adjuvant (FIA)
W/o type of emulsion adjuvant using paraffin oil mixed with killed mycobacteria. W/o type of emulsion adjuvant using paraffin oil mixed without killed mycobacteria.
Short-term depot effect. Strong Th1 and Th2 response. Short-term depot effect. It induces weak Th1 and Th2 response. (Continued)
18.6 Vaccine delivery technologies
Table 18.2 Adjuvants approved for human vaccines. Continued Adjuvant type
Mechanism of action
o/w type emulsion contains 4.3% of squalene oil, Tween 80, and span 85. Licensed for human use in European countries.
Inducing local immune stimulatory effect at the site of injection, regulates cytokines, chemokines, recruitment of CD11b 1 , MHC II 1 cells, and enhance antigen uptake by dendritic cells.
4. Microbial derivatives Adjuvant System 04 (ASO4)
It is 3-O-desacyl-40monophosphoryl lipid A obtained from the cell wall lipopolysaccharide (LPS) of Gram-negative Salmonella minnesota R595. Licensed for human use in European countries.
Local activation of NF-kB activity, cytokine production, optimal activation of APC, and generation of Th1 response.
18.6 Vaccine delivery technologies Advancements in vaccine delivery methods can provide great opportunity to develop the controlled release and targeted delivery of therapeutic agents against the broad range of pathogens. Delivery of vaccine via particulate carriers is a promising strategy for peptide and protein vaccines. Particulate delivery system mainly includes synthetic polymeric particles, lipid-based particles, and other colloidal structures for the delivery peptide and protein antigens. Delivering particulate antigens have various advantages over soluble antigens like internalization, processing, uptake via antigen presenting cells (APCs), and they can also mimic the particulate nature of pathogens (Liang et al., 2006). Discovery of a simple and efficient method to administer vaccines is another active area of research that improves immunization and extends lives (Saroja et al., 2011). Various novel vaccine delivery methods such as needle-free technologies which include edible vaccines, patches, and sprays have been investigated for their suitability in different age groups of individuals especially in children. Similarly, microscopic nanoparticles can serve as a transport mechanism for antigens for the targeted delivery into the immune cells. For the delivery of several types of vaccine-like DNA vaccines, viral vectors-based vaccines, inactivated and live attenuated vaccines, current nanotechnology-based delivery methods such as polymeric nanoparticles, liposomes, virosomes, dendrimer, micellar systems, and plant-derived viruses have been explored as vaccine delivery systems for humans and animals (Cordeiro and Alonso, 2016). Liposomes that can be used both as a delivery system and immunomodulator, offer a number of advantages in the development of novel hostdirected therapies and vaccines for various pathogens.
CHAPTER 18 Contemporary vaccine approaches
18.7 Conclusion Vaccination is the most efficient medical intervention that reduces both morbidity and mortality caused by various diseases. The recent outbreaks of Zika and Ebola have increased the global alertness to human health caused by newly emerging and reemerging pathogens that can also provide the impetus to get ready against future pandemics by encouraging the improvement of vaccine platforms ready to use in humanitarian emergencies. Development of novel adjuvants may allow the design of newer vaccines for the management of various infectious diseases during humanitarian emergencies. Currently, a few vaccine adjuvants are approved and several are in clinical trial for future human use. Vaccinology has been developed from empirical to next-generation vaccines in the last three decades. Newer technologies such as, reverse vaccinology, recombinant DNA, structural vaccinology, polysaccharide chemistry, and synthetic RNA vaccines have significantly improved the effectiveness of target detection, selection, and designing of next-generation vaccines. Advancements in vaccine delivery methods can provide great opportunity to develop the controlled release and targeted delivery of therapeutic agents against the broad range of pathogens. Persistent advances should be made in the 21st century to develop novel vaccines that have a potential to save lives, contributing extensively to provide an improved quality of life.
18.8 Future perspectives The attempts required to accomplish the extensive demands for next-generation vaccines designed for emerging pathogens are only achieved by sustainable research development models. Increasing the international cooperation and modernization of technologies to encourage design, development, and manufacturing will permit an ongoing shift to a more efficient and cost- effective production of vaccines. This will altogether add to the worldwide efforts to anticipate infectious diseases, prevent vulnerable populations, and acquire a more rapid response to future outbreaks, forming human health.
Acknowledgments The authors are grateful to the Vice Chancellor, King George’s Medical University, Lucknow for the encouragement and support for this work. S.K. Saxena is also supported by CCRH, Government of India, and US NIH grants: R37DA025576 and R01MH085259. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Further reading HogenEsch, H., O’Hagan, D.T., Fox, C.B., 2018. Optimizing the utilization of aluminium adjuvants in vaccines: you might just get what you want. NPJ Vaccines 3 (51), 1 10.