Traditional vaccine preparations

For the purposes of this discussion, the term 'traditional' refers to those vaccines whose development predated the advent of recombinant DNA technology. Approximately 30 such vaccines

Table 13.5 Some diseases against which effective/more effective vaccines are urgently required. Diseases more prevalent in developing world regions differ from those that are most common in developed countries

Developing world regions

Developed world regions

AIDS

AIDS

Malaria

Respiratory syncytial virus

Tuberculosis

Pneumococcal disease

remain in medical use (Table 13.6). These can largely be categorized into one of several groups, including:

• live, attenuated bacteria (e.g. bacillus Calmette-Guerin (BCG), used to immunize against tuberculosis);

• dead or inactivated bacteria (e.g. cholera and pertussis vaccines);

• live attenuated viruses (e.g. measles, mumps and yellow fever viral vaccines);

• inactivated viruses (hepatitis A and polio (Salk) viral vaccines);

• toxoids (e.g. diphtheria and tetanus vaccines);

• pathogen-derived antigens (e.g. hepatitis B, meningococcal, pneumococcal and Haemophilus influenzae vaccines).

Table 13.6 Some traditional vaccine preparations that find medical application. In addition to being marketed individually, a number of such products are also marketed as combination vaccines. Examples include diphtheria, tetanus and pertussis vaccines and measles, mumps and rubella vaccines

Product

Description

Application

Anthrax vaccines

BCG (bacillus Calmette-

Guérin) vaccine Brucellosis vaccine Cholera vaccine Cytomegalovirus vaccines

Diphtheria vaccine

Japanese encephalitis vaccine H. influenzae vaccine

Hepatitis A vaccine Hepatitis B vaccine

Influenza vaccines

Bacillus anthracis-derived antigens found Active immunization against anthrax in a sterile filtrate of cultures of this microorganism. Live attenuated strain of Mycobacterium tuberculosis Antigenic extract of Brucella abortus Dead strain(s) of Vibrio cholerae Live attenuated strain of human cytomegalovirus Diphtheria toxoid formed by treating diphtheria toxin with formaldehyde Inactivated Japanese encephalitis virus

Purified capsular polysaccharide of H. influenzae type b (usually linked to a protein carrier, forming a conjugated vaccine)

(Formaldehyde)-inactivated hepatitis A virus

Suspension of hepatitis B surface antigen (HBsAg) purified from the plasma of hepatitis B sufferers

Mixture of inactivated strains of influenza

Active immunization against tuberculosis Active immunization against brucellosis Active immunization against cholera Active immunization against cytomegalovirus Active immunization against diphtheria

Active immunization against viral agents causing Japanese encephalitis Active immunization against H. influenzae type b infections (major causative agent of meningitis in young children) Active immunization against hepatitis A Active immunization against hepatitis B (note: this preparation has largely been superseded by HBsAg preparations produced by genetic engineering) Active immunization against influenza

(Continued)

Table 13.6 (Continued)

Product

Description

Application

Leptospira vaccines

Measles vaccines Meningococcal vaccines

Mumps vaccine

Pertussis vaccines

Plague vaccine Pneumococcal vaccines

Poliomyelitis vaccine

(Sabin vaccine: oral) Poliomyelitis vaccine (Salk vaccine: parenteral) Rabies vaccines Rotavirus vaccines

Rubella vacines

Tetanus vaccines

Typhoid vaccines

Typhus vaccines

Killed strain of Leptospira interogans

Live attenuated strains of measles virus Purified surface polysaccharide antigens of one or more strains of Neisseria meningitidis Live attenuated strain of the mumps virus

(Paramyxovirus parotitidus) Killed strain(s) of B. pertussis

Formaldehyde-killed Yersinia pestis Mixture of purified surface polysaccharide antigens obtained from differing serotypes of Streptococcus pneumoniae Live attenuated strains of poliomyelitis virus

Inactivated poliomyelitis virus

Inactivated rabies virus

Live attenuated strains of rotavirus

Live attenuated strain of Rubella virus

Toxoid formed by formaldehyde treatment of toxin produced by C. tetani Killed Salmonella typhi

Killed epidemic Rickettsia prowazekii

Varicella zoster vaccines Live attenuated strain of Herpes virus varicellae

Yellow fever vaccines Live attenuated strain of yellow fever virus

Active immunization against leptospirosis icterohaemorrhagica (Weil's disease) Active immunization against measles Active immunization against

N. meningitidis (can cause meningitis and septicaemia) Active immunization against mumps

Active immunization against whooping cough

Active immunization against plague Active immunization against Streptococcus pneumoniae

Active immunization against polio

Active immunization against polio

Active immunization against rabies Active immunization against rotavirus (causes severe childhood diarrhoea) Active immunization against rubella

(German measles) Active immunization against tetanus

Active immunization against typhoid fever

Active immunization against louse-borne typhus Active immunization against chickenpox Active immunization against yellow fever

13.4.1.1 Attenuated, dead or inactivated bacteria

Attenuation (bacterial or viral) represents the process of elimination or greatly reducing the virulence of a pathogen. This is traditionally achieved by, for example, chemical treatment or heat, growing under adverse conditions or propagation in an unnatural host. The attenuated product should still immunologically cross-react with the wild-type pathogen. Although rarely occurring in practice, a theoretical danger exists in some cases that the attenuated pathogen might revert to its pathogenic state. An attenuated bacterial vaccine is represented by BCG. BCG is a strain of tuberculae bacillus that fails to cause tuberculosis, but retains much of the antigenicity of the pathogen. Killing or inactivation of pathogenic bacteria usually renders them suitable as vaccines. This is usually achieved by:

• treatment with formaldehyde or acetone;

• treatment with phenol or phenol and heat;

• treatment with propiolactone.

13.4.1.2 Attenuated and inactivated viral vaccines

Viral particles destined for use as vaccines are generally propagated in a suitable animal cell culture system. Although true cell culture systems are sometimes employed, many viral particles are grown in fertilized eggs or cultures of chick embryo tissue (Table 13.7).

Many of the more prominent vaccine preparations in current medical use consist of attenuated viral particles (Table 13.6). Mumps vaccines consist of live attenuated strains of Paramyxovirus parotitidis. In many world regions, it is used routinely to vaccinate children, often a part of a combined measles, mumps and rubella vaccine.

Several attenuated strains have been developed for use in vaccine preparations. The most commonly used is the Jeryl Linn strain, which is propagated in chick embryo cell culture. This vaccine has been administered to well over 50 million people worldwide and, typically, results in seroconversion rates of over 97 per cent. The Sabin (oral poliomyelitis) vaccine consists of an aqueous suspension of poliomyelitis virus, usually grown in cultures of monkey kidney tissue. It contains approximately 1 million particles of poliomyelitis strains 1, 2 or 3 or a combination of all three strains.

Hepatitis A vaccine exemplifies vaccine preparations containing inactivated viral particles. It consists of a formaldehyde-inactivated preparation of the HM 175 strain of hepatitis A virus. Viral particles are normally propagated initially in human fibroblasts.

13.4.1.3 Toxoids and antigen-based vaccines

Diphtheria and tetanus vaccines are two commonly used toxoid-based vaccine preparations. The initial stages of diphtheria vaccine production entail the growth of Corynebacterium diphtheriae.

Table 13.7 Some cell culture systems in which viral particles destined for use as viral vaccines are propagated

Viral particle/vaccine

Typical cell culture system

Yellow fever virus Measles virus (attenuated) Mumps virus (attenuated) Polio virus (live, oral, i.e. Sabin, and

Chick egg embryos Chick egg embryo cells Chick egg embryo cells Monkey kidney tissue culture inactivated injectable, i.e. Salk) Rubella vaccine

Duck embryo tissue culture, human

Hepatitis A viral vaccine

V. zoster vaccines (chickenpox vaccine)

tissue culture Human diploid fibroblasts Human diploid cells

Table 13.8 Some vaccine preparations that consist not of intact attenuated/ inactivated pathogen, but of surface antigens derived from such pathogens

Vaccine

Specific antigen used

Anthrax vaccines

Antigen found in the sterile filtrate of B. anthracis

H. influenzae vaccines

Purified capsular polysaccharide of

H. influenzae type B

Hepatitis B vaccines

Hepatitis B surface antigen (HBsAg) purified

from plasma of hepatitis B carriers

Meningococcal vaccines

Purified (surface) polysaccharides from

N. meningitidis (groups A or C)

Pneumococcal vaccine

Purified polysaccharide capsular antigen from up

to 23 serotypes of S. pneumoniae

The toxoid is then prepared by treating the active toxin produced with formaldehyde. The product is normally sold as a sterile aqueous preparation. Tetanus vaccine production follows a similar approach. Clostridium tetani is cultured in appropriate media. The toxin is recovered and inactivated by formaldehyde treatment. Again, it is usually marketed as a sterile aqueous-based product.

Traditional antigen-based vaccine preparations consist of appropriate antigenic portions of the pathogen (usually surface-derived antigens; Table 13.8). In most cases, the antigenic substances are surface polysaccharides. Many carbohydrate-based substances are inherently less immunogenic than protein-based material. Poor immunological responses are thus often associated with administration of carbohydrate polymers to humans, particularly to infants. The antigenicity of these substances can be improved by chemically coupling (conjugating) them to a protein-based antigen. Several conjugated H. influenzae vaccine variants are available. In these cases, the Haemophilus capsular polysaccharide is conjugated variously to diphtheria toxoid, tetanus toxoid or an outer membrane protein of Neisseria meningitidis (group B).

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