Vaccines, Types of Vaccines

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Chapter: Pharmaceutical Microbiology : The Manufacture And Quality Control Of Immunological Products

The vaccines currently used for the prevention of infectious diseases of humans are all derived, directly or indirectly, from pathogenic microorganisms.



The vaccines currently used for the prevention of infectious diseases of humans are all derived, directly or indirectly, from pathogenic microorganisms. The basis of vaccine manufacture thus consists of procedures which produce from infectious agents, their components or their products, immunogenic preparations that are devoid of pathogenic properties but which, nonetheless, can still induce a protective response in their recipients. The methods that are used in vaccine manufacture are constrained by technical limitations, cost, problems of delivery to the recipient/patient, by regulatory issues and, most of all, by the biological properties of the pathogens from which vaccines are derived. Those vaccines currently in use in conventional immunization programmes are of several readily distinguishable types.


Types Of Vaccines


A)  Live Vaccines


These are preparations of live bacteria, viruses or other agents which, when administered by an appropriate route, cause subclinical or mild infections. In the course of such an infection the components of the microorganisms in the vaccine evoke an immune response which provides protection against the more serious natural disease. Live vaccines have a long history, dating from the development of smallpox vaccine. Initially, material from mild cases of smallpox was used for inoculation. This process of ‘variolation’ was hazardous and could produce fatalities and secondary smallpox cases. A much safer alternative was introduced in 1796 by the Gloucestershire physician Edward Jenner, following observations made by Benjamin Jesty, a local farmer, that an attack of the mild condition known as cowpox (probably a rodent pox) protected milkmaids from smallpox during epidemics of this dreaded disease. For many years the cowpox vaccine was propagated by serial transfer from person to person and at some point evolved into a distinctive virus, vaccinia, with some features of both cowpox and small-pox viruses but quite probably derived from a now extinct poxvirus. Vaccinia was eventually used to eradicate small-pox. Its significance was that it could stimulate a high degree of immunity to smallpox while producing only a localized infection in the recipient.


The natural occurrence of cross-protective organisms of low pathogenicity seems to be a rare event and attenuated strains have usually had to be selected by laboratory manipulation. Thus the bacille Calmette-Guérin (BCG) strain of Mycobacterium bovis used to protect against human tuberculosis caused by the related species M. tuberculosis, was produced by many sequential subcultures on ox bile medium. This process resulted in deletion of many genes present in virulent M. bovis, including some essential for pathogenicity. Similarly, treatment of a virulent strain of Salmonella enterica serovar Typhi with nitrosoguanidine, which produced multiple mutations, gave rise to the live attenuated typhoid vaccine strain Ty21A. More recently developed attenuated strains of S. entericaserovar Typhi and Vibrio cholerae have been selected by directed mutagenesis processes which can produce defined mutations in specific genes.


Perhaps surprisingly, nearly all of the most successful attenuated viral vaccine strains in current use were produced by empirical methods long before the genetic basis of pathogenesis by the specific pathogen was understood. Thus, attenuated strains of polio virus for use as a live, oral vaccine (Sabin) were selected by growth of viruses isolated from human cases under cultural conditions that did not permit replication of neuropathogenic virus. Comparable procedures were used to select the attenuated virus strains that are currently used in live measles, mumps, rubella and yellow fever vaccines. A more recent approach has been to use genetic reassortants to produce live rotavirus vaccines.


Now, attenuated strains of pathogens can be selected by deliberate selective modification of genes responsible for encoding factors determining pathogenesis, such as toxins or immunomodulators, or metabolites essential for in vivo growth. Live vaccine strains can also be genetically modified by incorporating genes that encode protective antigens of other infectious agents. Several of these are under evaluation at present e.g. for vaccination against malaria and tuberculosis.


B)   Killed Vaccines


Killed vaccines are suspensions of bacteria, viruses or other pathogenic agents that have been killed by heat or by disinfectants such as phenol, ethanol or formaldehyde. Killed microorganisms obviously cannot replicate and cause an infection and so it is necessary for each dose of a killed vaccine to contain sufficient antigenic material to stimulate a protective immune response. Killed vaccines therefore usually have to be relatively concentrated suspensions. Even so, such preparations are often rather poorly protective, possibly because of partial destruction of protective antigens during the killing process or inadequate expression of these during in vitro culture. At the same time, because they contain all components of the microorganism they can be somewhat toxic. It is thus often necessary to divide the total amount of vaccine that is needed to induce protection into several doses that are given at intervals of a few days or weeks. Such a course of vaccination takes advantage of the enhanced ‘secondary’ response that occurs when a vaccine is administered to an individual person whose immune system has been sensitized (‘primed’) by a previous dose of the same vaccine. The best-known killed vaccines are whooping cough (pertussis), typhoid, cholera, plague, inactivated polio vaccine (Salk type) and rabies vaccine. The trend now is for these rather crude preparations to be phased out and replaced by better-defined subunit vaccines containing only relevant protective antigens, e.g. acellular pertussis and typhoid Vi polysaccharide vaccines.


C)  Toxoid vaccines


Toxoid vaccines are preparations derived from the toxins that are secreted by certain species of bacteria. In the manufacture of such vaccines, the toxin is separated from the bacteria and treated chemically to eliminate toxicity without eliminating immunogenicity, a process termed ‘toxoiding’.


A variety of reagents have been used for toxoiding, but by far the most widely employed and generally successful has been formaldehyde. Under carefully controlled conditions this reacts preferentially with the amino groups of proteins although many other functional groups potentially may be affected. Ideally the toxoided protein will be rendered non-toxic but retain its immunogenicity.


The treated toxins are sometimes referred to as formol toxoids. Toxoid vaccines are very effective in the prevention of those diseases such as diphtheria, tetanus, botulism and clostridial infections of farm animals, in which the infecting bacteria produce disease through the toxic effects of secreted proteins which enzymically modify essential cellular components. Many of the clostridial toxins are lytic enzymes with very specific substrates such as neural proteins. Detoxification is also required for the pertussis toxin component of acellular pertussis vaccines.


Anthrax adsorbed vaccine is not toxoided but relies on the use of cultural conditions that favour production of the protective antigen (binding and internalization factor) rather than the lethal factor (protease) and oedema factor (adenyl cyclase) components of the toxin. Selective adsorption to aluminium hydroxide or phosphate also slows release of residual toxin.


D)   Bacterial Cell Component Vaccines


Rather than use whole cells, which may contain undesirable and potentially reactogenic components such as lipopolysaccharide endotoxins, a more precise strategy is to prepare vaccines from purified protective components. These are of two main types, proteins and capsular polysaccharides. Often more than one component may be needed to ensure protection against the full range of prevalent serotypes. The potential advantage of such vaccines is that they evoke an immune response only to the component, or components, in the vaccine and thus induce a response that is more specific and effective. At the same time, the amount of unnecessary material in the vaccine is reduced and with it the likelihood of adverse reaction. Vaccines that have been based on one or more capsular polysaccharides include Hib vaccine; the Neisseria meningitidis ACWY vaccines; the 23-valent pneumococcal polysaccharide vaccine; and the typhoid Vi vaccine. These have the disadvantage that they are T-cell-independent antigens and thus do not evoke immunological memory or effective protective responses in the very young. This problem can be overcome by chemically coupling the polysaccharides to T-cell-dependent protein carriers.

The pertussis vaccine is another example where, traditionally, whole bacterial cells have been used, but recent developments have led to an acellular pertussis vaccine that may contain detoxified toxin, either alone or combined with several other bacterial antigens.


E)   Conjugate vaccines


The performance of certain types of antigen that give weak or inappropriate immune responses can often be improved by chemically conjugating them to more immunogenic carriers. Among others, polysaccharide-protein, peptide-protein, protein-protein, lipid-protein and alkaloid-protein conjugate vaccines may be prepared in this way. These have a wide range of applications, including prevention of infection, tumour therapy, fertility control and treatment of addictions. This approach has been very successful against infections caused by bacteria that produce polysaccharide capsules. The latter are T-independent antigens and induce weak responses without immunological memory. They are particularly ineffective in the very young.


F)   Viral Subunit Vaccines


Three viral subunit vaccines are widely available, two influenza vaccines and a hepatitis B vaccine. The influenza vaccines are prepared by treating intact influenza virus particles from embryonated hens’ eggs infected with influenza virus with a surface-active agent such as a non-ionic detergent. This disrupts the virus particles, releasing the virus subunits. The two types that are required in the vaccine, haemagglutinin and neuraminidase, can be recovered and concentrated by centrifugation methods. The hepatitis B vaccine was, at one time, prepared from hepatitis B surface antigen (HbsAg) obtained from the blood of carriers of hepatitis B virus. This very constrained source of antigen has been replaced by production in yeast or mammalian cells that have been genetically engineered to express HbsAg during fermentation. The human papillomavirus (HPV) vaccines for prevention of genital warts and cervical cancer also contain recombinant viral proteins.


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