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European Biopharmaceutical Review

Virus Control

Adel Mahmoud at Princeton University looks at the future of vaccine discovery

Vaccination has been the cornerstone of major global efforts to control infectious disease. While it was probably practiced many years ago in China and India, its recent introduction in the practice of preventative medicine dates back to 1796, with the discovery of the capacity of cowpox to immunise against smallpox. For most of the past 200 years, the practice has been firmly established, and serious scientific efforts have been undertaken to investigate how to develop vaccines against multitudes of viral and bacterial infections. In developed countries, we currently enjoy the benefits of controlling many of the scourges of times past, such as poliomyelitis, measles, bacterial pneumonia, meningitis and many others. Similar but less successful efforts have reduced the burden of illness in developing countries, but the challenge is still facing many: approximately three million children die each year from vaccine-preventable diseases, and many more are threatened by infections for which no vaccines have yet been developed, such as malaria, TB and HIV/Aids.

The pathway to vaccine discovery in the past depended mainly on using the whole organism as the immunising agent. This approach was taken by Edward Jenner after his observation that milkmaids who were exposed to cowpox in the process of milking cows were resistant to human smallpox. In spite of not knowing the etiology of either disease, this observation led to the development of the modern concept of vaccination. Almost 200 years later, it led to the complete disappearance of human smallpox. The scientific basis of this observation was later confirmed by the discovery that virus infections of animals which may not cause disease in humans but are genetically close enough to human pathogens can be used for immunisation. Subsequent attempts to repeat this observation led to the development of a partially effective vaccine against childhood tuberculosis using attenuated cow mycobacterium. Most subsequent efforts to discover and develop effective vaccines were, however, directed at reducing the harmful effects of human viral or bacterial infectious agents to allow their use as vaccines. This was accomplished by either killing the organisms or attenuating their pathogenicity to humans. Attenuation was introduced by Louis Pasteur and later adopted in the production of vaccines against viral infection, such as measles, hepatitis A, influenza, rabies or bacterial infections such as cholera or typhoid. In subsequent years, von Behring discovered that extracts of bacterial cultures may be equally effective in inducing protection. This concept is used today for immunisation against diphtheria.

A major scientific achievement occurred in the mid-twentieth century in the discovery by Enders, Robbins and Weller that viruses may be grown not in eggs but in cells in in vitro culture. This observation led to the development of two polio vaccines, one made of killed virus and the other by attenuating the human organisms. The success of both vaccines is amply demonstrated globally by the disappearance of poliomyelitis in most countries. Two additional discoveries bring us to today’s scientific accomplishments in vaccine development. These include the conjugation of the polysaccharide capsule of several bacterial infectious organisms to a protein backbone which resulted in effective vaccination strategies against bacterial pneumonia and meningitis, particularly in infants and children. The other recent discovery was based on the ability to clone the segment of viral DNA encoding the protective components of two viral infections. Success was accomplished with the hepatitis B and human papillomavirus resulting in two remarkably effective and molecularly defined vaccines.

With a background of such tremendous success against many human infectious pathogens, the most challenging question is what comes next in vaccine science and discovery? And why do we not yet have vaccines against some of the most devastating infections in humans? The magnitude of scientific efforts to discover vaccines against malaria, TB and HIV/Aids has been tremendous, but with little success to show. One sobering assessment indicates the necessity to go back to basics and to attempt a more fundamental understanding of microbes and their tactics for causing infection and disease in humans. We must admit that over 200 years of vaccine discovery and development were based on one or two fundamental concepts, and relied heavily on using the whole organism or partially characterised components of their structures. Going forward, the discovery of which components of a viral, bacterial or parasitic infectious agent provide the linchpin for an effective immune response will not come unless we understand and dissect the structure, molecular organisation and role of microbial genome. The use of simplistic reductionist approaches to discover protective antigens has uniformly failed. Even in the case of the recent discovery, development and launching of effective vaccines against human papillomavirus and hepatitis B virus, the cloned proteins are not significantly immunogenic or protective by themselves. Immunogenicity of these cloned molecules was determined to relate to their self assembly into virus-like particles and the maturation and stabilisation of these particles.

Future vaccine discovery and development is most likely to be dependent on exploring new scientific horizons. First, acquiring basic information and clear functional understanding of microbial genomes. We are approaching the discovery of immunogens in a hit and miss fashion. This is not to denigrate the serious and herculean efforts of past decades, but it is a call for a much more fundamental understanding of microbial structures and functions. There is an urgent need to appreciate the survival mechanisms and metabolic pathways of microorganisms. This begins with the sequencing of many microorganisms, studying their genes, genomics and metabolomics. Only then can we define the most susceptible component of these organisms. By inducing human immune responses against this, we will be able to arm ourselves to combat the invaders.

Equally important is a much more sophisticated understanding and recognition of the imperatives of evolutionary biology and its implications for microorganisms. Infectious agents of any class are co-inhabitants of this globe: they have developed extremely elaborate survival mechanisms, and it is clear that, in their own self-interest, they will not expose their most vulnerable structures or molecules to our immunologic protective system. Therefore, discovery of new vaccine targets will only come from a better understanding and meticulous dissection of their genomes. It is highly likely that new molecularly defined vaccine candidates will be made of several critical structural or metabolic components of each microorganism.

The second concept is a recognition that antigen presentation to our immune system is an essential step in vaccine development. The unfolded protein in the two molecularly defined vaccines, hepatitis B and human papillomavirus, are poor immunogens and do not elicit an effective protective immune response. It is only by assembly of these proteins as virus-like particles, and only when the structure is rigid enough, stable enough and contains the necessary disulphide bonds, that a robust protective immune response can be elicited in immunised animals and humans. The multiple attempts to use single protein molecules or deliver them as DNA vaccines have not met with uniform success in most studies in humans.

Thirdly, our appreciation of the mechanisms of protection in any of the available successful vaccines is in its infancy. The science of immunology is progressing towards quantitative approaches and definitions of immune responsiveness. Such developments are essential to understanding what responses need to be induced and in what manner and quantities. Examining the difference in immune recognition and responses to the different classes of human infections is crucial to proceed with new methods of vaccine discovery. Immune responses to intracellular invaders must be differentiated from those mounted against extracellular organisms, just as responses to unicellular parasites need to be differentiated from those directed at large multicellular organisms. Furthermore, pathogens that integrate in the human genomes such as HIV have to be examined immunologically in completely novel ways. This understanding of our immune mechanisms will not be complete without an additional quantitative assessment of innate as well as adaptive immunity. In this context comes the necessity to understand and discover new adjuvants. It is highly likely that we will need multiple approaches to enhance the immunogenicity, duration and protection induced by new molecularly defined vaccines.

Human-microbe interplay is the struggle dictated by coinhabiting this globe. The future of vaccine discovery is linked to the phrase that Joshua Lederberg coined some years back: “our wit against their genes”!

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Adel A F Mahmoud, MD, PhD, is at The Woodrow Wilson School of Public and International Affairs and The Department of Molecular Biology at Princeton University. He has recently retired as President of Merck Vaccines. Prior to that, he served at Case Western Reserve University and University Hospitals of Cleveland as Chairman of Medicine and Physician-in-Chief. Adel’s academic pursuits focused on investigations of host resistance to helminthic infections and strategies for their control. At Merck, Adel led the effort to develop four new vaccines including: a combination of measles, mumps, rubella and varicella; rota virus; shingles; and human papillomavirus. He was elected to membership of the Institute of Medicine of the National Academy of Sciences in 1987. He received the Bailey K Ashford Award of the American Society of Tropical Medicine and Hygiene, and the Squibb Award of the Infectious Diseases Society of America. He is a past president of the International Society for Infectious Diseases.
Adel AF Mahmoud
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