Essay on Vaccines: History, Development and Limitations!
Introduction or History of Vaccines:
A vaccine is a collection of immunological determinants which are presented to the immune system as killed or live antigens which provoke protective immune responses. The development of vaccines against viral and bacterial diseases is one of the greatest achievements of human endeavours. Vaccination is the most cost effective and efficient way to control viral diseases. The use of conventional viral vaccines has saved humans and animals from dreaded disease epidermics.
Infectious diseases which account for about 30-50% deaths due to lack of effective chemotherapeutic agents and that do exists are often too costly. Thus vaccines have become important tools for fighting infectious diseases in many parts of the world. On the other hand, in developed countries these infectious diseases account only 4-8% of all deaths. This low incidence of infectious diseases is largely due to the wide spread use of vaccination. The well-known example is eradication of smallpox with the help of smallpox vaccine.
Similarly use of several other vaccines like diphtheria, poliomyelitis, measles and rubella resulted dramatic decrease of diseases incidence and mortality. Further vaccination is much inexpensive than treating people who are already sick with modern antibiotics and other chemotherapeutic agents. Some of the commonly used vaccines are listed in Table 19.1.
Vaccines continue to play an important role in veterinary medicine. However, sometimes these traditional vaccines become serious problem. Recombinant DNA techniques and synthetic organic chemistry have had major impact in overcoming, some of these problems and developing vaccines of a new type. Apart from this, some modern molecular approaches (Table 19.2) are applied. These methods enabled us to develop vaccines against diseases for which traditional vaccines do not exist.
Development of Vaccines:
Some of the noval approaches currently in the process of development of vaccines are:
1. Synthetic vaccines,
2. Recombinant subunit vaccine,
3. Genetically altered live vaccines,
4. Vectored vaccines,
5. DNA vaccines, and
6. Plant and plant viruses based vaccines.
7. Vaccines against bacteria, and
Two decades long research have revealed that small synthetic peptide having sequences of immunogenic epitopes on a protein will react with antibody to the intact native antigen and in some cases neutralize the biological activity. Anderer and Schlumberger (1965) demonstrated that chemically synthesized peptides corresponding to protein fragment would also produce the virus neutralizing antibody.
This observation led to an extensive research on synthetic antigens. Sale et al. (1992) demonstrated that a synthetic fragment of 20 amino acids corresponding to 89-108 of the coat protein of MS2 (a bacteriophage) elicited antibodies which reacted with the intact virus particle. These initial observations provided a ground for the subsequent exploration of peptide immunogen.
The identification of genes encoding immunogenic proteins and availability of nucleic acid sequences allowed derivation of amino acid sequence of the immunogenic peptides.
There are several advantages of synthetic peptide vaccines:
(i) They possess indefinite shelf life,
(ii) Would have precise composition,
(iii) No possibility for the adventitious presence of live virus, and
(iv) Costly handling facilities are not necessary. A number of different diseases have been the target for synthetic vaccines e.g. FMDV, influenza and Hepatitis B.
Though significant protective immune responses have been achieved in experimental conditions, the synthetic vaccines are far from the commercialization mainly due to poor immunogenicity, short-term immunity and high cost of vaccination. Now the focus is on improving the immunogenicity by incorporating B and T lymphocyte epitopes and better adjuvants in the synthetic peptides.
The understanding that isolated proteins of viruses can provoke protective immune response, led to application of genetic engineering in cloning, expression of critical viral genes in prokaryotic and eukaryotic expression vectors. Thus, the immunogenic peptides of the viral origins could be expressed in bacteria and yeasts. The concept of a subunit vaccine contain only those immunogenic components that are necessary to elicit a protective response and excluding unnecessary that has several alternative features.
Subunit vaccines lack infectivity and hence no complication of arising out of vaccination in immunocompromised individuals. Subunit vaccination eliminates allogenic immunosuppressive and other undesirable reactogenicity. These vaccines also exhibit a great deal of stability.
The first successful recombinant vaccine was produced against hepatitis B. This has paved the way for the development of other recombinant peptide vaccines. The other recombinant vaccine which is in advanced stage of development is against parvovirus B19. Though the recombinant subunit vaccines are quite safe, there are still considerable problems like poor immunogenicity, high cost of production, short term immunity etc. Until these problems are tackled effectively, it is unlikely that the recombinant subunit vaccines will hit the market in near future.
Conventionally attenuated or naturally found avirulent strains of viruses have been used to develop live vaccines. Now with the development of rDNA technology, it is possible to attenuate a virus by deleting or altering the virulent genes. This kind of gene manipulation reduces its virulence or makes it unable to replicate completely and thus make a live vaccine with precisely defined modifications.
A live Simian Immunodeficiency Virus (SIV) vaccine, attenuated by deleting net gene exhibited the most impressive protection against SIV in macaques. Investigations are in progress to generate live attenuated vaccines for the use in human including improved polio and dengue vaccines. Recently Pirkin et al. (1997) demonstrated the feasibility of using genetically modified live vaccine against influenza-A. Genetically altered live vaccines could be used veterinary vaccines but human factors are to be considered. The clinical trials of such products in human have not been carried out.
Vectored vaccines approach allows expression of heterogenous genes into an avirulent viral/ bacterial organism which are harmless to vaccinated animals and induce cellular and humoral immune response against the foreign product. This approach also enables expression of more than one foreign genes encoding immunogenic proteins, thus paving the way for development of multivalent recombinant vaccines against human and animal viral infection. In the past one decade, a wide range of viruses and bacteria have been used for expression of relevant foreign genes. The most extensively used vector has been vaccinia virus.
Vectored vaccines against viral diseases are generally based on infectious, semi infected viral, bacterial vectors into which the genes of interest have been cloned. Vaccinia virus has been used as a vector for development of vaccine against rabies and rinderpest. A number of relevant genes of other viruses have been expressed in a variety of vectors and their vaccine potential has been studied extensively.
Relatively recent approaches in vaccine development are based on the observation that when plasmid containing suitable promoters and the genes encoding immunogenic proteins are injected into tissues, the gene may be expressed and generate humoral and cellular immune responses. The same response can be generated by inoculating relevant nucleic acid into the skin or mucosa.
This approach has generated a great deal of commercial interest due to several advantages including duration of immunity generated and stability of the vaccine. DNA vaccine technology provides exciting new approach for prevention and control of variety of viral diseases.
Delivery of DNA vaccines requires expression of immunogenic proteins in tissues accessible immuno system such as muscle or skin or mucous membranes. For effective transfection and expression of the gene within these tissues, it is imperative that the introduced DNA is supercoiled and it includes strong tissue specific promoter and the transcribed mRNA has poly. A tail to ensure its stability in the host cell. Like plasmid DNA, naked mRNA encoding immunogenic protein can also be directly inoculated into host to induce immune response against the protein product.
Though the nucleic acid vaccine approach appears very attractive, there are a number of constrains including the possibility of integration of the nucleic acid, persistence and immunotolerance, which can be addressed.
The results of recent studies have suggested that genetically engineered plants and plant viruses could be used as vaccines. In recent years, several attempts have been made to produce various antigens and antibodies in plants. Antigens and antibodies expressed in plants can be administered orally as any edible part of the plant, or by parenteral route after isolation and purification from the plant tissue.
The edible part of the plant to be used as a vaccine is fed raw to experimental animals or humans to prevent possible denaturation during cooking and avoid cumbersome purification protocols. Thus, plants like tomato, banana and cucumbers are generally, the plants of choice. Virus based vectors can also be used to express the gene transiently to develop the products in a short period.
Plant system has the capability of producing any vaccine in large amounts and in a less expensive manner. However, the purification of the product may require the use of existing or even more cumbersome procedures. Attention, therefore, has been paid to mainly those antigens that stimulate mucosal immune system to produce secretory IgA (S-IgA) at mucosal surface, such as gut and respiratory epithelia.
Thus, an antigen produced in the edible part of plant can serve as a vaccine against several infectious agents which invade epithelial membranes. The first report of the production of edible vaccine (a surface protein from Streptococcus) in tobacco appeared in 1990 in the form of patent application. Subsequently, a number of attempts were made to express various antigens in plants.
One of the utilities of producing antigens in plants in large amounts is in treatment of autoimmune diseases like diabetes mellitus which involve production of antibodies against glutamic acid dehydrogenase (GAD) and insulin, leading to destruction of insulin producing pancreatic cells. The antigens targeted for autoimmune response can be fed to the animals to induce immune tolerance.
Due to readily availability of wide range of antibiotics against bacterial diseases, not much effort is put on the development of vaccines against these diseases.
Need of such vaccines being felt due to following reasons:
(1) Not all bacterial diseases are readily treated with antibiotics
(2) The use of antibiotics has resulted in purification of bacterial strains that are resistant to several antibiotics.
(3) Refrigeration facilities for the storage of such antibiotics are not available in many tropical countries.
(4) It is often difficult to ensure that individuals receiving antibiotic therapy have to undergo the full course of treatment.
Thus different strategies have to be adapted depending upon the type of bacterial disease. For instance Rocky Mountain spotted fever caused by Rickettsiae rickeltsie cannot be cultured. In this case a cloned 155-Kda protein that is a major surface antigen of R.rickettsie was used as a subunit vaccine. The incidence of bacterial diseases of man has resulted total eradication or reduced to near total (Table 19.7).
In view of these facts, several other vaccines for the control of other bacterial diseases have also been permitted (Table 19.8).
The developments in the past ten years have clearly pointed towards immense possibility of developing more efficacious, safer, thermostable and economically affordable viral vaccines using molecular approaches. Already some efficacious recombinant human and animal viral vaccines have been commercialized and some are at different stages of development. Recombinant plants carrying viral immunogens could easily immunize humans and animals against the targeted viral diseases.
Despite the great strides in vacciniology, a number of problems related to stability, safety, efficacy, environmental concern and economic feasibility remain unresolved. Once technical problems are solved regulatory and public issues must be tackled.
Limitations of Traditional Vaccines:
Live and attenuated vaccines of either bacteria or viruses are sometimes ineffective or not entirely safe. The other possibility that the organism or the toxin in the vaccine may not be completely killed or inactivated. Sometimes the vaccines revert to the virulence strain. Live attenuated vaccines may cause clinical disease if not attenuated sufficiently or revert back to virulence. The over attenuation of the virus may render it less immunogenic.
The inactivated vaccines are often unable to generate protective levels of immune response due to loss of important antigenic determinants during inactivation and poor antigen load. Further, we lack vaccines for many important diseases. Another risk runs by the workers who cultivate dangerous pathogens in large amounts to manufacture the virus vaccines. Over 200 years ago, Edward Jenner (1796) could demonstrate virulent human disease such as small pox could be checked with infections with mild cowpox by inoculating James Phipps, an 8-year old boy with exudate from a cowpox pustule.
Communicable diseases such as tuberculosis, small pox, cholera, typhus, bubonic plague and poliomyelitis have in the part been a scourge for humankind. With advent of vaccination, antibiotics and effective public health measures these epidemic diseases have for the most part been brought under control (Fig. 19.1).
However, occasionally protective measures become ineffective and devastating new outbreaks occur. Further, for many diseases of man and animals there are no vaccines (Table 19.4).
In addition an acquired immune deficiency syndrome (AIDS) for which vaccine might be useful. Live viral vaccines are developed to some of human diseases (Table 19.5).
To control some other viral diseases, non-infectious viral vaccines are developed (Table 19.6).
Notwithstanding the considerable success that has been achieved in creating effective vaccines against diseases such as German measles, diphtheria, whooping cough, tetanus, smallpox and poliomyelitis, there are number of limitations to the current mode of vaccine production such as:
1. All infectious agents cannot be grown in culture and so no vaccines have been developed for a number of diseases.
2. Production of animal and human vaccines requires animal cell culture which is expensive.
3. Both yield, rate of production of animal and human vaccines in culture are often quite low, thereby making vaccine production costly.
4. Extensive safety precautions are necessary to ensure that laboratory and production personnel are not exposed to a pathogenic agent.
5. Some diseases such as AIDS cannot be prevented through traditional vaccines.
6. Most current vaccines have a limited shelf life and often require refrigeration to maintain potency. This requirement creates storage problem in countries with large un-electrified rural areas.
The development of recombinant DNA technology has provided the possibility of creation of new generation of vaccines that overcome the drawbacks of traditional vaccines. The availability of gene cloning has enabled research to contemplate various noval strategies for vaccine development.
(1) Virulence genes could be deleted from infectious agents that retain the availability to stimulate an immunological response.
(2) Live nonpathogenic carrier systems that carry discrete antigenic determinants of unrelated pathogenic agent can be created. In this form the carrier system facilitates the induction of storing immunological response directed against the pathogenic agent.
(3) For infectious agents that cannot be maintained in culture, the genes for the proteins that have critical antigenic determinants can be isolated, cloned and expressed in an alternative host system such as E.coli or mammalian cell line. These cloned gene proteins can be formulated into a subunit vaccine.
(4) There are some infectious agents that do not damage host cells directly. Instead the disease condition results when the host immune system attacks its own (infected) cells. For these diseases it may be possible to create targeted cell specific killing system. Although not a true vaccine, this type of system attacks only infected cells, thereby removing the source of the adverse immunological response. In these cases, the gene for a fusion protein is constructed. First, one part of this fusion protein binds to an infected cell, while the other part kills the infected cell.
Though these vaccines developed on recombinant DNA technique, that are being utilized for immunization of animal diseases but gradually they are improved to cure human diseases.
Recombinant technology can be used in various ways to create reliable vaccines. Immunologically active, non-infectious agents can be produced by deleting the genes that cause virulence. With this deletion a live vaccine would never be able to revert to the infectious form. It is possible to clone gene(s) that encodes the major antigenic determinant(s) from a pathogenic organism that can be harvested, purified and used as a vaccine. With this strategy, complete genes produce subunit vaccines and cloned domains of major antigenic determinants produce peptide vaccines. Peptide vaccines may also be produced by chemical peptide synthesis.
Modern molecular methodologies have provided hope for designing better vaccines which will be devoid of the problems associated with existing conventional vaccines. The advent of recombinant DNA (r DNA) technology created a revolutionary impact on the science of vaccinology.