Australasian Biotechnology (backfiles) AusBiotech ISSN: 1036-7128 Vol. 8, Num. 5, 1998

CONFERENCE PAPER

A. Sasson,

United Nations Educational, Scientific and Cultural Organization (UNESCO): Place de Fontenoy, 75352 Paris 07 SP - France

Code Number:AU98039
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In 1973, Stanley Cohen of Stanford University, Herbert Boyer of the University of California Medical School (San Francisco), and their colleagues succeeded in designing the method for the transfer of a gene from one organism to another, thus establishing the basis of recombinant DNA technology. In 1981, the first US-approved biotechnology product reached consumers: a monoclonal antibody-based diagnostic test kit. The following year, the first recombinant DNA pharmaceutical, Genentech Incs.'s (Eli Lilly & Co.) Humulin®, recombinant human insulin, was approved for sale in the USA and United Kingdom. That same year, the first recombinant animal vaccine against colibacillosis was approved in Europe.

Since then, there has been an exponential increase in the number of marketable recombinant products, a trend that should continue well into the twenty-first century. Recombinant proteins have had, by far, their largest repercussion in the pharmaceutical area. Among the most successful of the antibody-based diagnostics are pregnancy test kits, which are so simple to use that they can be purchased over-the-counter in the USA and used at home. Human immunodeficiency virus testing kits are being sold world-wide and are manufactured in many parts of the world. The US market for monoclonal antibodies, the majority of which are used in such test kits, was estimated at $1.2 billion in 1994 and to be nearly $4 billion by the turn of the century.

The applications of recombinant proteins are also becoming customary in the food and detergent areas, as well as in the production of pesticides. Other products include more than 300 DNA modifying enzymes, such as different restriction endonucleases and methyltransferases.

Infectious diseases account for 17 million of the 50 million deaths in the world each year. The ten-biggest killing infectious diseases are: acute respiratory infections, 4.4 million deaths per year; tuberculosis, 3.1 million, diarrhoeal diseases, 3.1 million, malaria, 2.1 million, hepatitis B, 1.1 million, AIDS, more than 1 million, measles, more than 1 million, neonatal tetanus, 500,000; whooping
cough, 355,000; roundworm and hookworm, 165,000. According to the World Health Organization estimates, nearly 9 million children under 14 years of age die every year from infectious diseases, and at least one-third of them would be saved if existing vaccines were more widely used, but the rest only if suitable new vaccines were developed.

The only effective approach against viral diseases has been, and still largely is, prevention (eg sanitation/hygiene, vaccination) in spite of the recent production of a few medicines for treating viral diseases. Analysis of health interventions published in the 1993 World Bank Report on World Development, showed basic childhood vaccination to be the most cost-effective health intervention in terms of averted disease burden and economic savings for low and middle-income countries.

Public health needs requiring the development and large-scale production of vaccines stem from:

• a group of re-emerging diseases once conquered or nearly conquered, now staging a come-back (eg tuberculosis);
• a group of simmering diseases with a high probability of breaking out in epidemic form given appropriate conditions;
• a group of new diseases exemplified by AIDS.

In addition, increasing resistance to pathogens is part of the challenge in public health. Vaccine development is therefore propelled by the twin forces of societal need on the one hand and scientific discovery and technological innovation on the other. Their range of usefulness is widening in the prevention not only of infectious diseases but also of certain forms of cancer.

In 1996-1997, there were 30 vaccines which were mainly given prophylactically to prevent or minimize acute viral and bacterial infections. There was a lesser number at an advanced stage of clinical investigation. They are mainly of three types: live attenuated preparations, inactivated whole organisms or subunit preparations. The 1986 US Food and Drug Administration's approval of Merck, Sharpe and Dohme's hepatitis B vaccine blazed the trail for biotechnology-derived vaccines. Recombinant vaccine potential lies in genetically engineering harmless bacterial or viral vectors to present the pathogenic antigens (immunogens).

The main achievements of the vaccine industry in recent years are:

• first recombinant DNA vaccine for hepatitis B (1985-1990); the disease caused by this virus, which cannot be cultured in vitro, can be controlled thanks to the expression of the HBV surface antigen, responsible for protective immunity, either in yeast or mammalian cells, and subsequent generalized vaccination;
• vaccine against tick-borne encephalitis;
• vaccine against Haemophilus influenza
• development of conjugated vaccines, ie making antigens (in this case, polysaccharides, which are major antigenic elements of encapsulated bacteria) immunogenic for children and making them thymo-dependent by adding epitopes recognized by the T-lymphocytes; conjugated vaccines against Hib meningitis and against A/C serotypes of Neisseria meningitis are the results of this approach;
• vaccine against hepatitis A (1990-1995) and improved vaccine against whooping cough with fewer side-effects and increased efficacy;
• oral vaccines against cholera (1990-1995).

In the medium or long term, improved vaccines may be needed for viral diseases, such as influenza or measles (early childhood vaccine). The other major viral diseases for which there is greatest need for the development of new vaccines include HIV/AIDS, hepatitis C, dengue, respiratory syncitial virus and papillomavirus. Among bacterial diseases, tuberculosis accounts for the highest mortality and morbidity burden. Its close liaison with the HIV virus as an opportunistic infection may further increase its impact on human health. Because of the restricted efficacy of the existing vaccine (BCG), new candidates are sought. Other priorities include the major respiratory (conjugated pneumococcal vaccine) and gastro-intestinal infectious agents (Shigella, ETEC, Helicobacter pylori). The diphtheria, tetanus and pertussis (DTP) combination vaccine should be improved and the number of antigens included increased if possible. For parasitic diseases no functional vaccines for human use exist as yet.

If a cause-effect relationship could be established between defined infectious agents and certain cancer or other chronic diseases, vaccines against the causative infectious agent could be developed. Accumulating evidence links hepatitis B virus with liver cancer, papillomaviruses with cervical cancer, Epstein-Barr virus with Burkitt's lymphoma and nasopharyngeal carcinoma and enteroviruses with juvenile-type diabetes. In addition, a number of research teams and biotechnology companies are researching and testing various ways for immunizing against cancer. Collectively, these therapies are referred to as cancer vaccines.

It is generally accepted that a majority of infectious diseases gain entry through the mucosae. Nevertheless, mucosal immunology has received limited attention, because of the difficulties of studying the different mucosal tracts. A major challenge will be to develop effective vaccines that can be delivered via mucosal routes.

World sales of biotechnology-derived products would jump from a few tens of billion US dollars in 1996 to $110-220 billion in the year 2006. In the USA alone, the annual growth rate (1996) of medical bio-industry was 12% and sales amounted to $10.8 billion.

In the USA, and to a lesser extent in Canada and Europe, bio-industry was focused on the medical area. The proportion was 68% in the USA, mainly for medicines and diagnostics, 43.7% in Canada and about 43% in Europe. In 1994, the US bio-industry spent an overall $7 billion on research and development (+23%). The time needed to put a new drug on the market is approximately ten years with costs of research and development around $200 million or even more. For the majority of US biotechnology companies research and development expenses were still higher than earnings from sales. In 1994, the US bio-industry recorded sales of $7.7 billion. Of these sales, the following market segments were: 42% for therapeutic products, 26% for diagnostics, 15% for supplies, 9% for chemical and environmental services and 8% for agrobiotechnologies. In comparison, the total US pharmaceutical industry spent $13.8 billion on research and development, recorded sales of $84.8 billion and employed 353,800 people.

Sales for human insulin in the USA were about $560 million in 1993, whereas by 1997 its world-wide market increased to $1,035 million. Since 1983 the sales of recombinant pharmaceutical proteins have increased considerably, reaching $5,462 million during 1994 in the USA. The period with the highest growth rate was between 1984 to 1987, with a compounded annual growth rate of around 146%. Between 1987 and 1993, such growth decreased to an average annual rate of about 45% and from 1994 to 2000 sales in recombinant pharmaceuticals will grow at a relatively constant rate of about 15%. Thus, the projected sales of such products in the USA for the year 2000 are estimated to be above $7 billion.

Although the biopharmaceutical products (therapeutic proteins) represented, in the early 1990s a very small fraction of the overall pharmaceutical products (only about 1% and a market value of $7.6 billion world-wide), by the year 2003 they should account for at least 10% of such a market ($18.5 billion in 2000).

Research and development on new vaccines has become rather similar to research for new drugs:

• the time frame is at least ten years;
• the risk of failures is great due to the complexity of the diseases at stake, and it is only when efficacy has been proven in humans, using very complex studies, that there is any guarantee for success;
• the costs are on the average $200 to $300 million per vaccine;
• patent protection is essential, as such vast sums can not be earmarked for research without guaranteed return on investment.

The US National Institutes of Health are the world's biggest single funder of vaccine research, spending more than $300 million annually. The US Center for Disease Control and Prevention spends another $528 million on vaccine purchase, research and testing. European investment in research and development is of similar if not bigger size.

The world market value for pharmaceuticals was over $267 billion in 1994, of which the European Union accounted for $91 billion in the year 2000. In 1994, the world market value for human vaccines was estimated at $4.5 billion, of which Europe accounted for $1.260 billion, compared to $1.2 billion for the world annual sales of human recombinant erythropoietin. The current growth rate of the world market for human vaccines is 7% (based on doses rather than value) and in Europe is 12% (value figures). The number of vaccine doses used globally would be of the order of 1.8 billion, of which a very large share would be for viral diseases. Industrialized countries, ie Europe, Japan and North America, together account for less than 16% of global vaccine use, compared to more than 60% for the developing countries, mainly supplied through UNICEF, PAHO and WHO; other countries account for the remaining 24%.

In terms of volume, the best customers for vaccines are the developing countries. Each year there are tens of millions of children that are vaccinated with a vaccine costing about ten dollars, but there are 120 million children who cannot afford this. How can we solve this dilemma? The vaccine industry is looking for a new equilibrium and considers it its duty to supply these new products at reasonable prices for the developing world and at higher prices in the developed countries.

Copyright 1998 Australian Biotechnology Association Ltd.