- History of VaccinesA Parthasarathy, Hitt Sharma, Sameer Parekh
- Vaccination in India: Past, Present, and FutureChandrakant Lahariya
- Vaccine ImmunologyDeepak Kamat, Ambika Mathur
- Immunological Correlates of Protection Induced by VaccinesAaqib Zaffar Banday, Amit Rawat, Surjit Singh
- Epidemiology in Relation to VaccinologyShilpa Khanna Arora, Piyush Gupta
- Vaccine-preventable Diseases SurveillanceMeeta D Vashi, Vivek R Pardeshi
- General Recommendations on ImmunizationTanu Singhal
- Scheduling of VaccinesLate Panna Choudhury, Ajay Kalra,Vipin M Vashishtha
- Mucosal Immunity: Implications fonnnr Vaccine DevelopmentMonjori Mitra
- Mucosal Immunity to PoliovirusNicholas C Grassly
- Herd Immunity and Herd ProtectionYash Paul
- Adverse Events Following ImmunizationAjay Kalra, Premashish Mazumdar
- Cold Chain and Vaccine StorageSatish K Gupta, Digant D Shastri
- Vaccine Safety and Misinformation about VaccinationAnuradha Bose
- New Methods in Vaccine CommunicationsZulkifli Ismail
- Vaccine HesitancyChandrakant Lahariya, Vipin M Vashishtha
- Disease Elimination and EradicationAlok Gupta
- Adjuvants
ABSTRACT
Vaccination is one of the best disease prevention techniques. Vaccines are special from other medical products as they are mainly given to healthy individuals in preventing diseases, they may or may not encounter. Before 20th century, several infectious diseases were threatening lives of millions of people. Since then, number of serious infectious diseases have been prevented and eliminated due to increase in research and development, and widespread use of vaccines. The vaccine developments intend to protect the individual as well as the community health. Because of the significant contribution from vaccines, the diseases that were once termed as childhood diseases are now called vaccine-preventable diseases.
However, challenges exist specifically in implementing vaccine policies, execution and accomplishment of immunization schedule, developing and integrating new technologies and public perception. In this chapter, we have narrated origin and development of vaccines and various innovative technologies for future vaccine development.
Keywords: Vaccination, smallpox, combination vaccines, genetic engineering.
INTRODUCTION
Vaccination is one of the greatest discovery in the modern medicine. The development of vaccines has a short history. In spite of this, vaccines have significant impact in terms of reduction of mortality and increase in human longevity. Compared to other public health majors vaccination has more profound effect on the health of the world's people especially children. In the past 50 years, it has saved more lives worldwide than any other medical products or procedures. In the 1970s worldwide vaccination program by WHO eradicated smallpox, one of the most fearful and deadliest diseases. In 1988, Global Polio Eradication Initiative (GPEI) was launched with the goal to eradicate the poliomyelitis. Strengthening the routine immunization of infants against polio is one of the key strategies under this initiative. Childhood vaccination has greatly reduced the morbidity and mortality from infectious diseases in many of the developed and developing countries. While vaccination is a proven cost-effective public health tool, the future presents continued challenges. Researchers have been unable to find effective vaccines against human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), malaria, leishmaniasis, and for many more other diseases. In some parts of the world, where infrastructure is poor or nonexistent, the logistics of even the currently available vaccines poses challenges. Even though some vaccines are the most needed in poor countries, the cost of vaccines is not affordable. Although, many of the current vaccines are highly effective, researchers continue to explore new possibilities to develop new vaccine formulations targeting broader range of diseases. Higher effectiveness, lower cost, and convenient delivery are some of the main goals.
DEVELOPMENT OF THE WORLD'S FIRST VACCINE
The smallpox vaccine was the first successful vaccine developed in the world. Edward Jenner, an English physician also known as “Father of Immunology” introduced smallpox vaccine in 1796. Before that, for many years during the 1770s, Edward Jenner heard a story of a milkmaid that she would never have the deadly or disfiguring disease 4smallpox, because she had already had cowpox (a disease similar to smallpox, but much less virulent). Fascinated by this common belief, Jenner postulated that the pus in the blisters, which milkmaids received from cowpox, protected them from smallpox. He demonstrated scientific evidence by actively inoculating subjects with cowpox followed by intentionally exposing them to smallpox to determine the immunity. In May 1796, Jenner found a dairymaid, Sarah Nelms, contracted cowpox and had fresh cowpox lesions on her hands.
On May 14, 1796, he inoculated an 8-year-old boy, James Phipps using matter from Nelms’ cowpox pustules and observed its reaction. In July 1796, he inoculated him with the pus from a man with smallpox lesions but the boy did not contract the smallpox. The experiment was repeated after few months, and again the boy did not develop the disease. This had resolved the mystery of dreadful smallpox epidemic and the disease was totally eradicated two centuries later. Since cowpox was also called vaccinia, this process was called vaccination, and the inoculum was termed as “vaccine”.
In the 19th century, vaccines were considered a matter of national pride, and compulsory vaccination laws were passed. In 1885, Louis Pasteur, a French microbiologist generalized Jenner's idea by developing a rabies vaccine. Many would consider Louis Pasteur to be the progenitor of immunology but Edward Jenner with his pioneering work, remains the first to test the hypothesis based on scientific experiments.
The 20th century saw the introduction of several successful vaccines, including those against diphtheria, measles, mumps and rubella (Table 1). Development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s were the major achievements. In 1988, GPEI was launched with the ambitious goal of polio eradication. Since the launch of GPEI, the number of polio cases across the world have decreased by more than 99%. In 2016, a shift to eliminate vaccine-derived type 2 polio began. As a part of this strategy, in approximately 145 countries using oral polio vaccine, all immunization programs were directed to stop using trivalent oral polio vaccine and begin using bivalent (types 1 and 3) vaccine. The switch to bivalent vaccine was designed to eliminate circulating vaccine-derived type 2 polio strains.1 Practice of transferring protective antibodies was developed when it was discovered that vaccines protected through the action of antibodies. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including malaria and HIV.
DEVELOPMENT OF MONOVALENT AND COMBINATION FORMULATIONS
Vaccines may be “monovalent” or “polyvalent” (also called “combination”). A monovalent vaccine (e.g. tetanus toxoid vaccine, measles vaccine) is designed to immunize against a single antigen or single microorganism. In certain cases, a monovalent vaccine may be desirable for rapid development of strong immune response.
Combination vaccines are expected to have significant impact on disease prevention globally. As more vaccines are being developed (Table 2), combination vaccines merge multiple antigens into single product to avoid multiple injections and minimize the complications in the regular immunization schedules. The advantages of combination vaccines are that they simplify pediatric routine immunization schedules, decrease the discomfort of vaccine recipients, improve parent compliance and also reduce the delivery of cost of vaccines. Combination vaccines are of two types: (1) multidisease—mixtures of different types of vaccines [e.g. diphtheria, tetanus, polio (DTP)/hepatitis B (HB)/Haemophilus influenzae type b (Hib)] and (2) multivalent—mixtures of different serotype vaccines for the same vaccine target (e.g. pneumococcal vaccine). Some combination vaccines are both multidisease and multivalent [e.g. DTP/Hib/inactivated poliovirus (IPV)]. However, there are numerous challenges and unknown pitfalls in successfully developing new combination vaccines, which include physical incompatibility, instability, and potential immunological interference.
Vaccines cannot be combined at random. Safety and effectiveness of each combination vaccine must be evaluated in well-designed clinical trials. Ideal combination vaccines have to be as safe and effective as each of their single-component counterpart is. It should be appropriate for the currently recommended schedule and route of administration; components should be compatible; and be easily stored and easy to administer. With the combination vaccines, the amount of adjuvants and preservatives is lowered when compared with multiple, single-antigen products.
Safety and Efficacy of Combination Vaccines
Each component in a combination vaccine has to demonstrate established parameters of protection before approval.5
Immune responses to specific antigens in combined vaccines may be either stronger or weaker than those to separately administered single antigens. Combination vaccines should have an equal or less incidence of adverse reactions than administering single-antigen products separately.
Complexities of Combination Vaccines
Combination vaccines are crucial for continued success of vaccination programs. Though several possible combinations are being considered, each new combination must be carefully evaluated in clinical trials to ensure comparable safety and immunogenicity of the individual components.6
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The measurement of potency and antigen content of combination vaccines is more complex. Even a single, temporary problem in the production of an individual component of a combination product could affect the production of combined vaccine and thus leading to shortage in vaccine supply for multiple diseases. In the context of combination products, the effects of adjuvants may be difficult to assess. In case of an allergic or other significant adverse event it may difficult to identify the vaccine component responsible for it.
FUTURE VACCINES IN STORE
In the 21st century, combination vaccines have become necessary and an essential part of routine immunization.
Research and development is in progress with a variety of combination vaccines including varicella, pneumococcal. AIDS, malaria and tuberculosis together cause more than 5 million deaths per year, worldwide. They represent one of the serious global public health challenges as we enter the second decade of the 21st century (Fig. 1). Vaccine development against these diseases is ongoing. Recent early phase studies have provided evidence of high possibility of vaccine development to prevent HIV and malaria infections. Furthermore, various novel technologies including newer adjuvants and strategies for intracellular antigen presentation have led to progress in the development of vaccine against tuberculosis.2 Till date, a vaccine was considered for prophylactic use but now considerable serious attempts are made to develop vaccines for therapeutic use. The basic idea is to develop cellular responses that will suppress infection.
New delivery techniques are going to play major role in the future of vaccines. Inhaled vaccines, for example, influenza vaccines have been made in the form of a nasal spray. These new live-attenuated vaccines given intranasal route, which can lead to local and systemic immunity and gives broader protection against antigenically drifted strains. Oral immunization has been used to prevent diseases like polio and typhoid. Now, rectal and vaginal routes are also investigated for vaccination. Other possibilities of new delivery methods include, a patch application, where a skin patch containing a matrix with dissolving microneedles delivers a vaccine without the use of a syringe. This novel method of delivery is very helpful, particularly in remote areas, as its application would not require trained medical person for delivery. Research on vaccine delivery through skin has been promising and many devices have been developed for antigen release across skin. Skin is one of our best barrier against infection. But it also includes large numbers of certain immune system cells, called dendritic cells (DCs), which are specialized antigen presenting cells. These cells can react to a vaccine antigens placed on the skin. Transdermal patch vaccines are being evaluated travelers’ diarrhea, tetanus, anthrax, and seasonal flu.
The new vaccine developments stem from advances in a broad range of interrelated technical fields, including recombinant DNA (rDNA) and molecular biology, analytical chemistry and biochemistry, protein and polysaccharide chemistry, fermentation, macromolecular purification, formulation, immunology and related techniques, virology and bacteriology. They have extended this scope to vaccines for noninfectious diseases (e.g. autoimmune diseases, cancer, allergy, drug addiction) and therapeutic vaccines (e.g. certain infectious diseases as well as noninfectious disease). This broadening of scope is continuing to redefine the term vaccine.7
Fig. 1: Potential vaccines. Area of circles is proportional to the number of deaths (2008 data). Shaded areas are proportional to the number of deaths prevented by vaccination. (AIDS: acquired immunodeficiency syndrome; EPI: expanded program on immunization; HIV: human immunodeficiency virus)Source: Adapted from Serdobova I, Kieny MP. Assembling a global vaccine development pipeline for infectious diseases in the developing world. Am J Public Health. 2006;96(9):1554-9.
A number of innovative vaccines are also in development and in use:
Dendritic cell vaccines: Dendritic cells are efficient antigen presenting cells. DC vaccines combine DCs with antigens in order to present the antigens to the body's white blood cells. These cells activate naive and memory CD4+ and CD8+ T cells which could be used for the induction of a specific antitumor immunity. These vaccines might be used for treatment of chemotherapy and radiotherapy resistant endocrine cancers such as metastasized medullary thyroid carcinomas and other neuroendocrine carcinomas.3
Live recombinant vaccines use attenuated viruses as vectors: Immunity against complex infectious diseases can be augmented by using rDNA technology. Recombinant vectors are developed by combining the physiology of one microorganism and the deoxyribonucleic acid (DNA) of the other. Thus, an immunogenic protein from one infectious agent can be presented using other disease causing virus or bacterium as a vector. This approach may be used to enhance the immune response or development of new vaccines. For example, HIV cannot be attenuated enough to be given as a vaccine in humans—it could cause AIDS. Vaccination with live-attenuated viruses, in general, offers an effective and a durable immune response. Using recombinant approach, complete presentation of the antigenic components of the pathogen to the immune system is possible near future. Both structural and nonstructural antigens are available to stimulate humoral and cell-mediated immune responses.4
DNA vaccines: Recently, a completely new approach to vaccination has been developed. It involves the direct introduction into of a plasmid DNA sequence encoding the antigen(s) is introduced into appropriate tissues in the body which leads to expression of desired antigens and elicits specific immune responses.5 This new type of vaccine called “DNA vaccination”, created from an infectious agent's DNA, has been developed. It consists 8of DNA coding for a particular antigen, which is directly injected into the muscle. The DNA after inserting into the individual's cells produces the antigen from the infectious agent and stimulates the immune system. Because these cells have very long life, if the pathogen expressing these antigens is encountered at a later time, they will be attacked immediately by the immune system. These types of vaccines may be able to generate immunity against parasitic diseases such as malaria, mycoplasma, etc. Though DNA vaccines are advantageous in terms of production and storage, they are still experimental because no DNA-based vaccines have been shown to elicit the considerable immune response required to prevent infection. The first such vaccines licensed for marketing are likely to use plasmid DNA derived from bacterial cells. Ribonucleic acid (RNA) or other complexes of nucleic acid molecules may be used for other vaccines in future. Recently, a meningococcal group B vaccine has been developed which consists of four proteins identified by genomic analysis. These proteins together with an outer membrane vesicle of the organism induce bactericidal antibodies. Rappuoli and coworkers developed this vaccine by the innovative technique called reverse vaccinology which uses genomic analysis for selection of proteins that induce protective immune responses.6
T-cell receptor peptide vaccines: T-cell receptor (TCR) peptide vaccines are under evaluation for several diseases using models of stomatitis and atopic dermatitis, multiple sclerosis. Their mechanism of action is by modulation of cytokine production and enhancement of cell-mediated immunity. Basically, it engages the TCR and has immunoregulatory and immunostimulatory activities. In animal studies, TCR vaccine has restored cell-mediated immunity, normalized T-helper type 1/2 (Th1/Th2) balance, and reduced viral pathology.
CHALLENGES FOR PUBLIC HEALTH DEPARTMENT AND VACCINATION
In future, universally, there is an increased risk of facing new infectious diseases or increase outbreaks of existing diseases. These pose challenges in the area of immunization. The public health infrastructure must be able to handle these emerging threats effectively. Highly skilled professionals, modern laboratories and technology need to be in place to provide rapid response to the threat of epidemics. An integrated strategy is necessary to understand, detect, control, prevent and eradicate or eliminate infectious diseases. Below are some specific emerging issues:
- Appropriate preventive health care which is also culturally acceptable an immense responsibility that will grow over the decade.
- As the aging population is increasing, expansion of public healthcare systems is needed to control communicable diseases.
- New infectious agents and diseases continue to be detected. There is increase in international travel and trade, import of food and agriculture products, migration as a part of globalization. Hence, infectious diseases [e.g. severe acute respiratory syndrome (SARS) and H1N1] must be looked at in a global context due to increasing globalization.
- Infectious diseases are a critical public health, humanitarian and safety concern; nationally and internationally coordinated efforts will protect people across the nation and around the world.
SUMMARY
The future of immunization depends on the success of medical research for vaccines that are easy to administer, will have convenient logistics and storage characteristics and will provide a more substantial and durable immune response. However, the success of vaccination depends upon maintaining widespread public awareness and trust, without which vaccination programs cannot succeed.
REFERENCES
- WHO. (2018). Replacing trivalent OPV with bivalent OPV. [online]. Available from: https://www.who.int/immunization/diseases/poliomyelitis/endgame_objective2/oral_polio_vaccine/en/ [Last accessed May, 2019].
- Rappuoli R, Aderem A. A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature. 2011;473(7348):463–9.
- Schott M, Seissler J. Dendritic cell vaccination: new hope for the treatment of metastasized endocrine malignancies. Trends Endocrinol Metab. 2003;14(4):156–62.
- Spaete RR. Recombinant live attenuated viral vaccines. In: Ellis RW (Ed). New Vaccine Technologies, 1st edition. Texas, USA: Landes Bioscience; 2001.
- World Health Organization. (2013). Biologicals: DNA vaccines. [online] Available from: www.who.int/biologicals/areas/vaccines/dna/en/index.html [Last accessed May, 2019].
- Plotkin S. History of vaccination. Proc Natl Acad Sci U S A. 2014;111(34):12283–7.