Non-Living Vaccines: Whole Organisms
An early approach for preparing vaccines is the inactivation of whole bacteria or viruses. A number of reagents (e.g., formaldehyde, glutaraldehyde) and heat are commonly used for inactivation. Examples of this first generation approach are pertussis, cholera, typhoid fever, and inactivated polio vaccines. These non-living vaccines have the disadvantage that little or no CMI is induced. Moreover, they more frequently cause adverse effects as compared to live attenuated vaccines and second and third generation non-living vaccines.
Some bacteria such as Corynebacterium diphtheriae and
Clostridium tetani form toxins. Antibody-mediated immunity to the toxins is the main protection mechanism against infections with these bacteria. Both toxins are proteins. Around the beginning of the twentieth century, a combination of diphtheria toxin and antibodies to diphtheria toxin was used as diphtheria vaccine. This vaccine was far from ideal and was replaced in the 1920s with formaldehyde-treated toxin. The chemically treated toxin is devoid of toxic properties and is called toxoid. The immuno-genicity of this preparation was relatively low and was improved after adsorption of the toxoid to a suspension of aluminum salts. This combination of an antigen and an adjuvant is still used in existing combination vaccines. Similarly, tetanus toxoid vac-cines have been developed.
Diphtheria toxin has also been detoxified by chemical mutagenesis of Corynebacterium diphtheriae with nitrosoguanidine. These diphtheria toxoids are referred to as cross-reactive materials (e.g., CRM197).
The relatively frequent occurrence of side effects of whole-cell pertussis vaccine was the main reason to develop subunit vaccines in the 1970s, which are referred to as acellular pertussis vaccines. These vaccines were prepared by either extraction of the bacterial suspension followed by purification steps, or purification of the cell-free culture supernatant. These second generation vaccines showed relatively large lot-to-lot variations, as a result of their poorly controlled production processes.
The development of third generation acellular pertussis vaccines in the 1980s exemplifies how a better insight into factors that are important for pathogenesis and immunogenicity can lead to an improved vaccine. It was conceived that a subunit vaccine consisting of a limited number of purified immunogenic components and devoid of (toxic) lipopolysaccharide would significantly reduce unde-sired effects. Four protein antigens important for protection have been identified. However, as yet there exists no consensus about the optimal composition ofan acellular pertussis vaccine. Current vaccines con-tain different amounts of two to four of these proteins.
Bacterial capsular polysaccharides consist of patho-gen-specific multiple repeating carbohydrate epi-topes, which are isolated from cultures of the pathogenic species. Plain capsular polysaccharides (second generation vaccines) are thymus-independent antigens that are poorly immunogenic in infants and show poor immunological memory when applied in older children and adults. The immunogenicity of polysaccharides is highly increased when they are chemically coupled to carrier proteins containing Th-epitopes. This coupling makes them T-cell dependent, which is due to the participation of Th-cells that are activated during the response to the carrier. Examples of such third generation polysaccharide conjugate vaccines include meningococcal type C, pneumococ-cal and Haemophilus influenzae type b (Hib) polysac-charide vaccines that have recently been introduced in many national immunization programs. Four differ-ent conjugated Hib polysaccharide structures are presently available, i.e., chemically linked to either tetanus toxoid, diphtheria toxoid, CRM197 (mutagenically detoxified diphtheria toxin, see above) or meningococcal outer membrane complexes. Apart from the carrier, the four structures vary in the size of the polysaccharide moiety, the nature of the spacer group, the polysaccharide-to-protein ratio, and the molecular size and aggregation state of the conjugates. As a result, they induce different immunological responses. This illustrates that not only the antigen, but also its presentation form determines the im-munogenicity of a vaccine. Therefore, the determina-tion of optimal conjugation procedures, the standardization of conjugation, as well as the separa-tion of conjugates from free proteins and polysacchar-ides are of utmost importance.
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