The impact of genetic engineering on vaccine technology

The advent of recombinant DNA technology has rendered possible the large-scale production of polypeptides normally present on the surface of virtually any pathogen. These polypeptides, when purified from the producer organism (e.g. E. coli, Saccharomyces cerevisiae) can then be used as 'subunit' vaccines. This method of vaccine production exhibits several advantages over conventional vaccine production methodologies. These include:

• Production of a clinically safe product; the pathogen-derived polypeptide now being expressed in a non-pathogenic recombinant host. This all but precludes the possibility that the final product could harbour undetected pathogen.

• Production of subunit vaccine in an unlimited supply. Previously, production of some vaccines was limited by supply of raw material (e.g. hepatitis B surface antigen; see below).

• Consistent production of a defined product that would thus be less likely to cause unexpected side effects.

A number of such recombinant (subunit) vaccines have now been approved for general medical use (Table 13.9). The first such product was that of hepatitis B surface antigen (rHBsAg), which gained marketing approval from the FDA in 1986. Two billion people are infected with hepatitis B worldwide, 350 million individuals suffer from life-long chronic infection, and more

Table 13.9 Recombinant subunit vaccines approved for human use

Product

Company

Indication

Recombivax (rHBsAg produced in S. cerevisiae) Comvax (combination vaccine, containing rHBsAg produced in S. cerevisiae, as one component) Engerix B (rHBsAg produced in S. cerevisiae) Tritanrix-HB (combination vaccine, containing rHBsAg produced in S. cerevisiae as one component)

Lymerix (rOspA, a lipoprotein found on the surface of Borrelia burgdorferi, the major causative agent of Lyme's disease. Produced in E. coli) Infanrix-Hep B (combination vaccine, containing rHBsAg produced in S. cerevisiae as one component) Infanrix-Hexa (combination vaccine, containing rHBsAg produced in S. cerevisiae as one component) Infanrix-Penta (combination vaccine, containing rHBsAg produced in S. cerevisiae as one component) Ambirix (combination vaccine, containing rHBsAg produced in S. cerevisiae as one component) Twinrix, adult and pediatric forms in EU (combination vaccine containing rHBsAg produced in S. cerevisiae as one component)

Primavax (combination vaccine, containing rHBsAg produced in S. cerevisiae as one component) Procomvax (combination vaccine, containing rHBsAg as one component) Hexavac (combination vaccine, containing rHBsAg produced in S. cerevisiae as one component) Triacelluvax (combination vaccine containing r(modified) pertussis toxin Hepacare (r S, pre-S and pre-S2 hepatitis B surface antigens, produced in a mammalian (murine) cell line) HBVAXPRO (rHBsAg produced in

S. cerevisiae) Dukoral (combination vaccine containing rCholera toxin B subunit as one component

Merck Merck

Smithkline Beecham Smithkline Beecham

Hepatitis B prevention Vaccination of infants against

H. influenzae type b and hepatitis B Vaccination against hepatitis B Vaccination against hepatitis B, diphtheria, tetanus and pertussis

Smithkline Beecham Lyme disease vaccine

Smithkline Beecham

Smithkline Beecham

Smithkline Beecham

Glaxo SmithKline

Smithkline Beecham (EU)

Glaxo Smithkline (USA) Pasteur Merieux MSD

Pasteur Merieux

MSD Aventis Pasteur

Chiron SpA Medeva Pharma

Aventis Pharma SBL Vaccin AB

Immunization against diphtheria, tetanus, pertussis and hepatitis B

Immunization against diphtheria, tetanus, pertussis, polio, H. influenzae b and hepatitis B Immunization against diphtheria, tetanus, pertussis, polio, and hepatitis B Immunization against hepatitis A and B

Immunization against hepatitis A and B

Immunization against diphtheria, tetanus and hepatitis B

Immunization against H. influenzae type b and hepatitis B Immunization against diphtheria, tetanus, pertussis, hepatitis B, polio and H. influenzae type b Immunization against diphtheria, tetanus and pertussis Immunization against hepatitis B

Immunization of children &

adolescents against hepatitis B Active immunization against diseases caused by Vibrio cholerae than 1 million infected patients die each year from the associated complications of liver cirrhosis and/or liver cancer. Prior to its approval, hepatitis B vaccines consisted of HBsAg purified directly from the blood of hepatitis B sufferers. When present in blood, HBsAg exists not in monomeric form, but in characteristic polymeric structures that display a diameter of 22 ^m. Production of hepatitis B vaccine by direct extraction from blood suffered from two major disadvantages:

• The supply of finished vaccine was restricted by the availability of infected human plasma.

• The starting material will likely be contaminated by intact, viable hepatitis B viral particles (and perhaps additional viruses, such as HIV). This necessitates introduction of stringent purification procedures to ensure complete removal of any intact viral particles from the product stream. A final product QC test to confirm this entails a 6-month safety test on chimpanzees.

The HBsAg gene has been cloned and expressed in a variety of expression systems, including E. coli, S. cerevisiae and a number of mammalian cell lines. The product used commercially is produced in S. cerevisiae. The yeast cells are not only capable of expressing the gene, but also assembling the resultant polypeptide product into particles quite similar to those found in the blood of infected individuals. This product proved safe and effective when administered to both animals and humans. An overview of its manufacturing process is presented in Figure 13.10.

Various other companies have also produced recombinant HBsAg-based vaccines. SmithKline Beecham secured FDA approval for such a product (tradename Engerix-B) in 1989 (Figure 13.11 and Box 13.4). Subsequently, SmithKline Beecham have also generated various combination vaccines in which recombinant HBsAg is a component. Twinrix (tradename), for example, contains a mixture of inactivated hepatitis A virus and recombinant HBsAg. Tritanrix, on the other hand, contains diphtheria and tetanus toxoids (produced by traditional means), along with recombinant HBsAg. Dukoral is the tradename given to an additional recombinant protein-containing vaccine now on the market. Indicated for active immunization against disease caused by Vibrio cholerae (serogroup 01), the product contains recombinant cholera toxin subunit B and four whole (heat- or formalin-inactivated) V. cholerae strains.

It seems likely that many such (recombinant) subunit vaccines will gain future regulatory approval. One such example is that of Bordetella pertussis subunit vaccine. B. pertussis is a Gramnegative coccobacillus. It is transmitted by droplet infection and is the causative agent of the upper respiratory tract infection commonly termed 'whooping cough'.

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