Contribution to hepatitis B prevention Jean Stephenne Hepatitis B is widely recognized as an important public health problem. The only effective way to control hepatitis B is by vaccination. First generation plasma-derived hepatitis B vaccines have limitations. Advances in recombinant DNA technology have led to the development of yeast-derived recombinant hepatitis B vaccine which is now used extensively in the developed worM. This article reviews the development of this new generation vaccine and the efforts to facilitate universal vaccination programmes particularly in the developing world. The issue of the cost of new generation vaccines, in relation to the major investment required for research and development and also the quality of the final product, is discussed. Keywords: Hepatitis B; vaccine; recombinant DNA technology
INTRODUCTION There are at least five forms of viral hepatitis, designated A, B, C, D and E. Hepatitis B is the most prevalent and severe form, for which there is no specific cure. The causative agent, the hepatitis B virus (HBV), is a DNA virus whose only natural host is man. Each complete virion (or Dane particle) consists of an inner core of DNA, protein and DNA polymerase surrounded by an outer protein envelope. HBV is spread by contact with infected body fluids. Blood is the primary vehicle for infection but the virus is also detectable in saliva, seminal fluid, vaginal secretions, breast milk, sweat and tears 1. The main modes of transmission of the virus are parenteral/percutaneous, perinatal and through sexual contact. Individuals at risk from parenteral/percutaneous infection include haemophiliacs, intravenous drug users and health care workers. The risk of HBV transmission to neonates of mothers who are seropositive for both surface (HBsAg) and " e " (HBeAg) viral antigens is very high 2. Hepatitis B is also recognized as a sexually transmitted disease in both heterosexual and homosexual populations 3. HBV infection not only causes acute disease but also leads to chronic conditions including chronic liver disease, cirrhosis or primary hepatocellular carcinoma, one of the commonest malignant turnouts 4'5. The outcome of infection with HBV is dependent upon the age at which it occurs. Infection during infancy, most commonly perinatally, leads to a chronic carrier state in 60-95% of cases. During adulthood infection rarely leads to the carrier status. Although carrier infants appear healthy, considerable numbers of these children go on to develop chronic disease during adulthood. Currently it is estimated that there are more than 300 million carriers of hepatitis B worldwide 6. The prevalence of HBV infection, based on serological evidence of previous or current infection, varies significantly in different geographical regions of the world. The highest prevalence SmithKline Beecham Biologicals, 89 Rue de I' Institut, B-1330 Rixensart, Belgium 026~410X/92/130900434 ~ 1992 Butterworth-HeinemannLtd 900
Vaccine, Vol. 10, Issue 13, 1992
is in the developing world with 70-90% of the population infected in South East Asia and 20-40% of the population in Central America, North Africa and parts of Southern and Eastern Europe. Northern Europe, USA and Australia have 4 6% of the population with evidence of infection. In terms of mortality and morbidity, the burden of hepatitis B exceeds that of diphtheria, pertussis, polio, cholera, rotavirus diarrhoea and AIDS. Thus the need for control of hepatitis B infection is recognized worldwide as a major healthcare objective. Hepatitis B vaccination The only way to effectively control hepatitis B infection is by vaccination. The first hepatitis B vaccine, developed in the early 1980s, was based on hepatitis B surface antigen (HBsAg) particles (the major component of the viral envelope) purified from the plasma of chronic HBV carriers 7's. Despite a good record of safety and efficacy the use of plasma-derived vaccines was limited. This was due to the relatively expensive production costs and also the theoretical fear that potentially pathogenic organisms which may be present in human plasma would escape inactivation during the manufacturing process. The advent of recombinant DNA technology provided an alternative safe source of HBsAg for hepatitis B vaccine and the successful expression of cloned HBsAg in yeast cells opened the way for production of unlimited quantities of recombinant hepatitis B vaccine 9'1°. In developed countries yeast-derived recombinant hepatitis B vaccine, which is the first and only recombinant DNA vaccine registered for humans, is now in routine use and has virtually replaced the plasma-derived vaccine. D E V E L O P M E N T O F E N G E R I X - B AT S M I T H K L I N E B E E C H A M B I O L O G I C A L S (SB B I O ) At SB Bio the research programme for hepatitis B vaccine was initiated in 1978 when the DNA sequence coding for the hepatitis B surface antigen (HBsAg) was isolated. Initially the HBsAg gene was cloned and expressed in Escherichia coll. However, the level of expression in
Contribution to hepatitis B prevention: J. Stephenne
E. coil was inadequate and the polypeptides produced were not properly assembled into particles analogous to the natural HBsAg particles derived from plasma. In 1981 the HBsAg was successfully expressed in Saccharomyces cerevisiae yeast cells which are capable of correctly synthesizing native HBsAg particles. Between 1983 and 1984 the yeast host strain was improved, the purification process was optimized and following characterization of the final recombinant HBsAg product, pilot batches of the candidate vaccine were prepared for initial clinical trials. Efforts were then concentrated, in parallel, on clinical development and scale-up of the production process. Engerix-B was first registered in 1986 ; however, this was not the end of investment in research and development. Thereafter the large-scale production process was initiated and clinical development was continued to cover specific licensing requirements and new indications for the vaccine. Today continuous efforts are being made to optimize manufacturing and to explore all potential for improvement. This experience with Engerix B illustrates that, as with pharmaceutical drugs, 10 12 years of intensive research and development are required to translate an initial concept into a final marketable product. One important consideration is whether the system chosen for production of recombinant hepatitis B vaccine is the most economical one available. Apart from yeast, HBsAg particles can also be expressed in other eucaryotic host systems such as mammalian or insect cells. However, the efficiency of production achieved using yeast cell technology is far superior to that achieved with other cell systems. Factors which lead to higher productivity in the yeast system include larger culture volumes, faster rates of replication and greater product concentrations. Today the SB Bio plant has the capacity to produce more than 150 million doses of Engerix B per annum and, if required, this capacity can be further increased. CLINICAL EXPERIENCE WITH YEAST-DERIVED RECOMBINANT HEPATITIS B VACCINE The yeast-derived recombinant hepatitis B vaccine Engerix-B (SB Bio), first registered in 1986, has undergone intensive clinical development for the evaluation of safety, optimal dose level, different vaccination schedules and protective efficacy 1~. Since 1984, more than 175 clinical studies with this vaccine have been carried out worldwide in all populations from neonates to the elderly. Many of these studies have focused on the protective efficacy in high risk neonates since perinatal transmission of HBV accounts for a large proportion of the total number of chronic carriers worldwide. It has been demonstrated that administration of hepatitis B vaccine in combination with hepatitis B immune globulin (HBIg) is highly effective in preventing perinatal acquisition of HBV carriage ~2'13. The largescale use of HBIg, however, is prohibitive due to high cost and limited availability, thus the most cost-effective method for control of vertical transmission is the administration of hepatitis B vaccine alone. The results of clinical trials have shown that administration of recombinant hepatitis B vaccine alone can considerably reduce the risk of perinatal HBV infection, provided the correct vaccination scheme and dose level are used
Table 1 Protective efficacy studies with the yeast-derived hepatitis B vaccine in high risk neonates
Study
Schedule (months)
Dose (#g)
1 2 3 4
0,1,2,+ 12 0,2,6 0,1,2+12 0,1,2+12
5 6
0,1,6 0,2,4+12 0,1,6
10 20 10 10 20 20 10 10
HBIg
Carrier rate (%)
Protective efficacy" (%)
--+ + + + + +
2/59 (3.4) 16/137 (11.7) 1/65 (1.5) 1/56 (1.8) 3/50 (6.0) 2/59 (3.4) 6/53 (11.3) 2/59 (3.4) 0/60 ( < 1 . 7 )
95.8 85.5 98.1 97.8 92.5 95.8 85.9 95.8 >97.9
aCalculated using a theoretical infection rate without prophylaxis of 80%
(Table 1) 14. With regard to the primary three-dose vaccination schedule, the interval between the first and second doses of vaccine has been found to influence the protective efficacy. For maximum protection a 1 month interval is required. As demonstrated for plasma-derived hepatitis B vaccines, the optimum dose level is several times greater than the minimum dose required for seroconversion 15. Higher dose levels ( >~10/~g HBsAg) result in more rapid rates of seroconversion, higher final antibody titres and maximum protective efficacy. In addition to high risk neonates, clinical studies have also been carried out with healthy subjects, immunocompromised subjects (haemodialysis patients, haemophiliacs, thalassaemics, sickle cell anaemies, cirrhotics ) and other high risk subjects (intravenous drug users, homosexual men and institutionalized mentally handicapped). Initially the vaccination strategy was to target selective and accessible high risk groups such as patients receiving regular blood transfusions or being treated with blood derivatives and also health care workers. However, this strategy had little impact on the incidence of disease as it did not cover the large number of subjects who, according to epidemiological data, were being infected via heterosexual transmission 16 or as a consequence of other high risk behaviour. Thus, with the unlimited supply of recombinant hepatitis B vaccine now available, the current trend is not only to vaccinate identifiable subjects at risk but to aim for universal vaccination based on epidemiological data. Several countries, for example Italy, Israel, USA and some Asian countries, have now decided to implement universal vaccination programmes for adolescents and neonates. A task force has now been set up to oversee the integration of hepatitis B vaccination in the WHO Expanded Programme on Immunization (EPI). There are six vaccines (polio, measles, BCG, combined diphtheria, tetanus and pertussis) currently included in the EPI, the objective of which is to achieve universal vaccination against diseases that have a major impact on the health and survival of children, particularly in developing countries. With regard to universal vaccination in developing countries the vaccine industry has two objectives : 1 To provide vaccines of the same quality as for developed countries, particularly with respect to dose level since low dose vaccines are more likely to have
Vaccine, Vol. 10, I ssue 13, 1992
901
Contribution to hepatitis B prevention: J. Stephenne
their potency significantly altered by exposure to substandard conditions. 2 To provide these vaccines at a reasonable cost, today industry is already supplying vaccines to the developing world at 2.5-5% of the price in the developed world. SKILLS REQUIRED FOR D E V E L O P M E N T OF M O D E R N VACCINES The production of modern vaccines requires considerable biotechnological expertise. Recombinant DNA technology has allowed scientists to clone genes and express the gene products in foreign host cells, thus enabling the production of large quantities of protein antigens such as HBsAg. The efficient production of highly purified proteins on a commercial scale requires expertise in fermentation and protein purification technologies and also engineering. Analytical procedures must be developed to cover all steps in the manufacturing process; for Engerix-B this involved the development of analytical techniques for monitoring, for production and for determining product characteristics such as levels of contaminating DNA and protein. The clinical development of a vaccine is a complex and multi-step procedure which requires the participation of both experienced medical and experienced scientific personnel. Altogether more than 100 people worked over 10 years to achieve the development of Engerix-B. The total cost of this development is estimated to be between 150 and 200 million dollars. R E G U L A T O R Y ASPECTS F O R M O D E R N VACCINE P R O D U C T I O N The control of the production process for any vaccine is a critical element if quality is to be guaranteed. Such a guarantee of quality is essential as the vaccine may be administered prophylactically to millions of children. All aspects of production are subject to rigorous regulatory scrutiny. Production at high standards requires a modern facility which satisfies current requirements for good manufacturing practice (C-GMP). C-GMP, which includes extensive process validation and consistency of production within defined limits, must be implemented from phase 1 clinical trials. It is imperative to demonstrate that the whole production process is consistently reproducible. Furthermore, state-of-the-art technology must be developed and applied for product specification and characterization. There are also specific requirements for antigens produced by recombinant DNA technology which include assurance and control of the genetic stability of the host and vector and also the fidelity of expression of the polypeptide. Other regulations that must be strictly adhered to are those controlling the environmental impact of the production process. COST O F N E W V A C C I N E S Do new vaccines have to be made available at a cheap price? The cost of development of a new vaccine cannot be compared to that of older generation vaccines such as measles and polio. The development of present generation vaccines is very similar to that of drugs in terms of technologies and skills required and the
902
Vaccine, Vol. 10, Issue 13, 1992
complexities of research and development, but for manufacturing, vaccine inventories are generally more costly. The market for vaccines, however, is considerably smaller than for pharmaceuticals as a vaccine is only administered a few times during a lifetime. These factors must be taken into account when setting the price of new vaccines to ensure a normal return on investment for the industry. It must also be recognized that in terms of cost-benefit, vaccines provide an enormous return. The acceptance of realistic market prices, which reflect the huge capital investment required for research and development, is necessary to encourage the industry to remain committed and to continue to invest in the development of new vaccines. CONCLUSIONS Full advantage is not being taken of the unlimited quantities of vaccines available today, The supply of vaccines such as Engerix B is more than adequate to meet the demands of universal vaccination which is the best strategy for effective control of disease. Efforts are now being made to reduce administrative expenses which account for a large percentage of the cost of vaccination programmes. For the EPI, the vaccines only represent 10-15% of the total cost. Thus, while any further reduction in the price of the vaccines would jeopardize quality, guarantee of supply and long term research and development for new vaccines, the impact on the overall cost of the EPI would be minimal. To ease administration of hepatitis B vaccine, the industry is developing combinations with other paediatric vaccines; these formulations will be available within the next 2 years. For developing countries vaccines are currently supplied at 5% or less of the price in developed countries. The cost of manufacturing and the investment required for research and development make it impossible for the industry to reduce prices any further. It must also be acknowledged that the quality of vaccines cannot be sacrificed in order to reduce costs. For hepatitis B vaccine, high antigen dose levels must be maintained so that complete and long term protection is guaranteed. The industry cannot use double standards; the vaccines supplied for the developing world must be of the same quality as those supplied for the developed world. In the past, industry has contributed substantially to the success of all EPI programmes; however, the continuation of this commitment is dependent upon the application of normal rules of economy. For the future, industry and the World Health Organization must work together towards the prevention of diseases such as non-A-non-B hepatitis, malaria and AIDS. The skills and technology needed to develop these new vaccines are in place but it will be a long, complex and expensive process. REFERENCES 1
2
3
Dienstag, J.L. The epidemiology of hepatitis B. In : Hepatitis B. The Virus, the Disease and the Vaccine (Ed. Millman, I.), Plenum Press, 1984, pp 55-65 Okada, K., Kamiyama, I., Inomata, M., Imai, M., Miyakawa, Y. and Mayumi, M. e antigen and anti e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N. Engl. J. Med. 1976, 294, 746 Alter, M.J., Ahtone, J., Weisfuse, I. et al. Hepatitis B virus transmission between heterosexuals. J. Am. Med. Assoc. 1986, 256, 1307-1310
Contribution to hepatitis B p r e v e n t i o n : J. Stephenne
4
Iwarson, S.A. Chronic hepatitis B, In: Hepatitis B. (Ed. Gerety, R.J.) Academic Press Inc., Orlando, FL, USA, 1985, pp 119-153 5 Tabor, E. Hepatitis B virus and primary hepatocellular carcinoma. In: Hepatitis B. (Ed. Gerety, R.J.) Academic Press Inc., Orlando, FL, USA, 1985, pp 247-267 6 Maynard, J.E. Hepatitis B: global importance and need for control. Vaccine 1990, 8, S18 20 7 Hilleman, M.R., Berland, A.U., Buynak, E.B. et al. Clinical and laboratory studies of HBsAg vaccine. In: Viral Hepatitis, Franklin Institute Press, Philadelphia, 1978, p. 539 8 Maupas, Ph., Goudeau, A., Coureaget, P., Druker, J., Barin, F. and Andre, M. Immunization against hepatitis B in man: a pilot study of two years duration. In: Viral Hepatitis, Franklin Institute Press, Philadelphia, 1978, p. 525 9 Harford, N., Cabezon, T., Colau, B., Delisse, A.M, Rutgers, T. and De Wilde, M. Construction and characterization of a Saccharomyces cerevisiae strain (RIT4376) expressing hepatitis B surface antigen. Postgrad. Med. J. 1987, 63 (suppl. 2), 65 70 10 Petre, J., Van Wijnendaele, F., De Neys, B. et al. Development of a hepatitis B vaccine from transformed yeast cells. Postgrad. Med.
J. 1987, 6,3 (suppl. 2), 73 81 11 Andre, F.E. Summary of safety and efficacy data on a yeast derived hepatitis B vaccine. Am. J. Med. 1989, 87 (39), 14S 12 Beasley, R.P., Hwang, L.Y., Lee, G.C.Y. et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1984,1,1099-1102 13 Stevens, C.E., Taylor, P.E., Tong, M.J. et al. Yeast recombinant hepatitis B vaccine: efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission. J. Am. Med. Assoc. 1987, 257, 2612-2616 14 Poovorawan, Y., Sanpavat, S., Pongpunlert, W. et al. Comparison of a recombinant DNA hepatitis B vaccine alone or in combination with hepatitis B immune globulin for the prevention of perinatal acquisition of hepatitis B carriage. Vaccine 1990, 8, $56-59 15 Lee, C.Y., Hwang, L.Y. and Beasley, R.P. Low-dose hepatitis B vaccine. Lancet 1989, ii, 860 861 16 Alter, M.J. Heterosexual activity: A leading risk factor in the transmission of hepatitis B. In: Hepatitis B; A Sexually Transmitted Disease in Heterosexuals. (Eds Piot, P. and Andre, F.) Excerpta Medica, Amsterdam, New York, Oxford, 1990, pp. 17 22
Vaccine, Vol. 10, Issue 13, 1992
903
INTRODUCTION There are at least five forms of viral hepatitis, designated A, B, C, D and E. Hepatitis B is the most prevalent and severe form, for which there is no specific cure. The causative agent, the hepatitis B virus (HBV), is a DNA virus whose only natural host is man. Each complete virion (or Dane particle) consists of an inner core of DNA, protein and DNA polymerase surrounded by an outer protein envelope. HBV is spread by contact with infected body fluids. Blood is the primary vehicle for infection but the virus is also detectable in saliva, seminal fluid, vaginal secretions, breast milk, sweat and tears 1. The main modes of transmission of the virus are parenteral/percutaneous, perinatal and through sexual contact. Individuals at risk from parenteral/percutaneous infection include haemophiliacs, intravenous drug users and health care workers. The risk of HBV transmission to neonates of mothers who are seropositive for both surface (HBsAg) and " e " (HBeAg) viral antigens is very high 2. Hepatitis B is also recognized as a sexually transmitted disease in both heterosexual and homosexual populations 3. HBV infection not only causes acute disease but also leads to chronic conditions including chronic liver disease, cirrhosis or primary hepatocellular carcinoma, one of the commonest malignant turnouts 4'5. The outcome of infection with HBV is dependent upon the age at which it occurs. Infection during infancy, most commonly perinatally, leads to a chronic carrier state in 60-95% of cases. During adulthood infection rarely leads to the carrier status. Although carrier infants appear healthy, considerable numbers of these children go on to develop chronic disease during adulthood. Currently it is estimated that there are more than 300 million carriers of hepatitis B worldwide 6. The prevalence of HBV infection, based on serological evidence of previous or current infection, varies significantly in different geographical regions of the world. The highest prevalence SmithKline Beecham Biologicals, 89 Rue de I' Institut, B-1330 Rixensart, Belgium 026~410X/92/130900434 ~ 1992 Butterworth-HeinemannLtd 900
Vaccine, Vol. 10, Issue 13, 1992
is in the developing world with 70-90% of the population infected in South East Asia and 20-40% of the population in Central America, North Africa and parts of Southern and Eastern Europe. Northern Europe, USA and Australia have 4 6% of the population with evidence of infection. In terms of mortality and morbidity, the burden of hepatitis B exceeds that of diphtheria, pertussis, polio, cholera, rotavirus diarrhoea and AIDS. Thus the need for control of hepatitis B infection is recognized worldwide as a major healthcare objective. Hepatitis B vaccination The only way to effectively control hepatitis B infection is by vaccination. The first hepatitis B vaccine, developed in the early 1980s, was based on hepatitis B surface antigen (HBsAg) particles (the major component of the viral envelope) purified from the plasma of chronic HBV carriers 7's. Despite a good record of safety and efficacy the use of plasma-derived vaccines was limited. This was due to the relatively expensive production costs and also the theoretical fear that potentially pathogenic organisms which may be present in human plasma would escape inactivation during the manufacturing process. The advent of recombinant DNA technology provided an alternative safe source of HBsAg for hepatitis B vaccine and the successful expression of cloned HBsAg in yeast cells opened the way for production of unlimited quantities of recombinant hepatitis B vaccine 9'1°. In developed countries yeast-derived recombinant hepatitis B vaccine, which is the first and only recombinant DNA vaccine registered for humans, is now in routine use and has virtually replaced the plasma-derived vaccine. D E V E L O P M E N T O F E N G E R I X - B AT S M I T H K L I N E B E E C H A M B I O L O G I C A L S (SB B I O ) At SB Bio the research programme for hepatitis B vaccine was initiated in 1978 when the DNA sequence coding for the hepatitis B surface antigen (HBsAg) was isolated. Initially the HBsAg gene was cloned and expressed in Escherichia coll. However, the level of expression in
Contribution to hepatitis B prevention: J. Stephenne
E. coil was inadequate and the polypeptides produced were not properly assembled into particles analogous to the natural HBsAg particles derived from plasma. In 1981 the HBsAg was successfully expressed in Saccharomyces cerevisiae yeast cells which are capable of correctly synthesizing native HBsAg particles. Between 1983 and 1984 the yeast host strain was improved, the purification process was optimized and following characterization of the final recombinant HBsAg product, pilot batches of the candidate vaccine were prepared for initial clinical trials. Efforts were then concentrated, in parallel, on clinical development and scale-up of the production process. Engerix-B was first registered in 1986 ; however, this was not the end of investment in research and development. Thereafter the large-scale production process was initiated and clinical development was continued to cover specific licensing requirements and new indications for the vaccine. Today continuous efforts are being made to optimize manufacturing and to explore all potential for improvement. This experience with Engerix B illustrates that, as with pharmaceutical drugs, 10 12 years of intensive research and development are required to translate an initial concept into a final marketable product. One important consideration is whether the system chosen for production of recombinant hepatitis B vaccine is the most economical one available. Apart from yeast, HBsAg particles can also be expressed in other eucaryotic host systems such as mammalian or insect cells. However, the efficiency of production achieved using yeast cell technology is far superior to that achieved with other cell systems. Factors which lead to higher productivity in the yeast system include larger culture volumes, faster rates of replication and greater product concentrations. Today the SB Bio plant has the capacity to produce more than 150 million doses of Engerix B per annum and, if required, this capacity can be further increased. CLINICAL EXPERIENCE WITH YEAST-DERIVED RECOMBINANT HEPATITIS B VACCINE The yeast-derived recombinant hepatitis B vaccine Engerix-B (SB Bio), first registered in 1986, has undergone intensive clinical development for the evaluation of safety, optimal dose level, different vaccination schedules and protective efficacy 1~. Since 1984, more than 175 clinical studies with this vaccine have been carried out worldwide in all populations from neonates to the elderly. Many of these studies have focused on the protective efficacy in high risk neonates since perinatal transmission of HBV accounts for a large proportion of the total number of chronic carriers worldwide. It has been demonstrated that administration of hepatitis B vaccine in combination with hepatitis B immune globulin (HBIg) is highly effective in preventing perinatal acquisition of HBV carriage ~2'13. The largescale use of HBIg, however, is prohibitive due to high cost and limited availability, thus the most cost-effective method for control of vertical transmission is the administration of hepatitis B vaccine alone. The results of clinical trials have shown that administration of recombinant hepatitis B vaccine alone can considerably reduce the risk of perinatal HBV infection, provided the correct vaccination scheme and dose level are used
Table 1 Protective efficacy studies with the yeast-derived hepatitis B vaccine in high risk neonates
Study
Schedule (months)
Dose (#g)
1 2 3 4
0,1,2,+ 12 0,2,6 0,1,2+12 0,1,2+12
5 6
0,1,6 0,2,4+12 0,1,6
10 20 10 10 20 20 10 10
HBIg
Carrier rate (%)
Protective efficacy" (%)
--+ + + + + +
2/59 (3.4) 16/137 (11.7) 1/65 (1.5) 1/56 (1.8) 3/50 (6.0) 2/59 (3.4) 6/53 (11.3) 2/59 (3.4) 0/60 ( < 1 . 7 )
95.8 85.5 98.1 97.8 92.5 95.8 85.9 95.8 >97.9
aCalculated using a theoretical infection rate without prophylaxis of 80%
(Table 1) 14. With regard to the primary three-dose vaccination schedule, the interval between the first and second doses of vaccine has been found to influence the protective efficacy. For maximum protection a 1 month interval is required. As demonstrated for plasma-derived hepatitis B vaccines, the optimum dose level is several times greater than the minimum dose required for seroconversion 15. Higher dose levels ( >~10/~g HBsAg) result in more rapid rates of seroconversion, higher final antibody titres and maximum protective efficacy. In addition to high risk neonates, clinical studies have also been carried out with healthy subjects, immunocompromised subjects (haemodialysis patients, haemophiliacs, thalassaemics, sickle cell anaemies, cirrhotics ) and other high risk subjects (intravenous drug users, homosexual men and institutionalized mentally handicapped). Initially the vaccination strategy was to target selective and accessible high risk groups such as patients receiving regular blood transfusions or being treated with blood derivatives and also health care workers. However, this strategy had little impact on the incidence of disease as it did not cover the large number of subjects who, according to epidemiological data, were being infected via heterosexual transmission 16 or as a consequence of other high risk behaviour. Thus, with the unlimited supply of recombinant hepatitis B vaccine now available, the current trend is not only to vaccinate identifiable subjects at risk but to aim for universal vaccination based on epidemiological data. Several countries, for example Italy, Israel, USA and some Asian countries, have now decided to implement universal vaccination programmes for adolescents and neonates. A task force has now been set up to oversee the integration of hepatitis B vaccination in the WHO Expanded Programme on Immunization (EPI). There are six vaccines (polio, measles, BCG, combined diphtheria, tetanus and pertussis) currently included in the EPI, the objective of which is to achieve universal vaccination against diseases that have a major impact on the health and survival of children, particularly in developing countries. With regard to universal vaccination in developing countries the vaccine industry has two objectives : 1 To provide vaccines of the same quality as for developed countries, particularly with respect to dose level since low dose vaccines are more likely to have
Vaccine, Vol. 10, I ssue 13, 1992
901
Contribution to hepatitis B prevention: J. Stephenne
their potency significantly altered by exposure to substandard conditions. 2 To provide these vaccines at a reasonable cost, today industry is already supplying vaccines to the developing world at 2.5-5% of the price in the developed world. SKILLS REQUIRED FOR D E V E L O P M E N T OF M O D E R N VACCINES The production of modern vaccines requires considerable biotechnological expertise. Recombinant DNA technology has allowed scientists to clone genes and express the gene products in foreign host cells, thus enabling the production of large quantities of protein antigens such as HBsAg. The efficient production of highly purified proteins on a commercial scale requires expertise in fermentation and protein purification technologies and also engineering. Analytical procedures must be developed to cover all steps in the manufacturing process; for Engerix-B this involved the development of analytical techniques for monitoring, for production and for determining product characteristics such as levels of contaminating DNA and protein. The clinical development of a vaccine is a complex and multi-step procedure which requires the participation of both experienced medical and experienced scientific personnel. Altogether more than 100 people worked over 10 years to achieve the development of Engerix-B. The total cost of this development is estimated to be between 150 and 200 million dollars. R E G U L A T O R Y ASPECTS F O R M O D E R N VACCINE P R O D U C T I O N The control of the production process for any vaccine is a critical element if quality is to be guaranteed. Such a guarantee of quality is essential as the vaccine may be administered prophylactically to millions of children. All aspects of production are subject to rigorous regulatory scrutiny. Production at high standards requires a modern facility which satisfies current requirements for good manufacturing practice (C-GMP). C-GMP, which includes extensive process validation and consistency of production within defined limits, must be implemented from phase 1 clinical trials. It is imperative to demonstrate that the whole production process is consistently reproducible. Furthermore, state-of-the-art technology must be developed and applied for product specification and characterization. There are also specific requirements for antigens produced by recombinant DNA technology which include assurance and control of the genetic stability of the host and vector and also the fidelity of expression of the polypeptide. Other regulations that must be strictly adhered to are those controlling the environmental impact of the production process. COST O F N E W V A C C I N E S Do new vaccines have to be made available at a cheap price? The cost of development of a new vaccine cannot be compared to that of older generation vaccines such as measles and polio. The development of present generation vaccines is very similar to that of drugs in terms of technologies and skills required and the
902
Vaccine, Vol. 10, Issue 13, 1992
complexities of research and development, but for manufacturing, vaccine inventories are generally more costly. The market for vaccines, however, is considerably smaller than for pharmaceuticals as a vaccine is only administered a few times during a lifetime. These factors must be taken into account when setting the price of new vaccines to ensure a normal return on investment for the industry. It must also be recognized that in terms of cost-benefit, vaccines provide an enormous return. The acceptance of realistic market prices, which reflect the huge capital investment required for research and development, is necessary to encourage the industry to remain committed and to continue to invest in the development of new vaccines. CONCLUSIONS Full advantage is not being taken of the unlimited quantities of vaccines available today, The supply of vaccines such as Engerix B is more than adequate to meet the demands of universal vaccination which is the best strategy for effective control of disease. Efforts are now being made to reduce administrative expenses which account for a large percentage of the cost of vaccination programmes. For the EPI, the vaccines only represent 10-15% of the total cost. Thus, while any further reduction in the price of the vaccines would jeopardize quality, guarantee of supply and long term research and development for new vaccines, the impact on the overall cost of the EPI would be minimal. To ease administration of hepatitis B vaccine, the industry is developing combinations with other paediatric vaccines; these formulations will be available within the next 2 years. For developing countries vaccines are currently supplied at 5% or less of the price in developed countries. The cost of manufacturing and the investment required for research and development make it impossible for the industry to reduce prices any further. It must also be acknowledged that the quality of vaccines cannot be sacrificed in order to reduce costs. For hepatitis B vaccine, high antigen dose levels must be maintained so that complete and long term protection is guaranteed. The industry cannot use double standards; the vaccines supplied for the developing world must be of the same quality as those supplied for the developed world. In the past, industry has contributed substantially to the success of all EPI programmes; however, the continuation of this commitment is dependent upon the application of normal rules of economy. For the future, industry and the World Health Organization must work together towards the prevention of diseases such as non-A-non-B hepatitis, malaria and AIDS. The skills and technology needed to develop these new vaccines are in place but it will be a long, complex and expensive process. REFERENCES 1
2
3
Dienstag, J.L. The epidemiology of hepatitis B. In : Hepatitis B. The Virus, the Disease and the Vaccine (Ed. Millman, I.), Plenum Press, 1984, pp 55-65 Okada, K., Kamiyama, I., Inomata, M., Imai, M., Miyakawa, Y. and Mayumi, M. e antigen and anti e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N. Engl. J. Med. 1976, 294, 746 Alter, M.J., Ahtone, J., Weisfuse, I. et al. Hepatitis B virus transmission between heterosexuals. J. Am. Med. Assoc. 1986, 256, 1307-1310
Contribution to hepatitis B p r e v e n t i o n : J. Stephenne
4
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