Alternative routes of immunization for prevention of infectious diseases: a new paradigm for the 21st century.

The prevention of infectious diseases by the use of vaccines represents one of medicine's greatest triumphs during the 20th century. This era has witnessed the global eradication of smallpox as a result of Jennerian cowpox vaccination, the elimination of paralytic poliomyelitis from the western hemisphere, and within 5-10 years the anticipated eradication of poliomyelitis worldwide as a result of the poliovirus vaccines. Next slated for worldwide eradication is measles, the great killer of infants and children, which each year extracts a global mortality of one million victims. Throughout the 20th century the percutaneous (i.e., subcutaneous or intramuscular) route has almost exclusively been the preferred way to administer vaccines. However, as a result of several important scientific discoveries made during the 20th century, including new tissue-culturing techniques, the development of recombinant DNA technology, and genetic sequencing, a whole new generation of tailor-made modern vaccines has become available, including DNA vaccines and transgenic plant vaccines. Moreover, it became apparent that alternative routes of administration of vaccines, such as by aerosol immunization and transcutaneous skin patches, might be more appropriate and more effective than immunization via the parenteral route. This paper describes some of the recent advances relating to alternative methods of immunization and will focus primarily on the development and use of respiratory aerosolized vaccines.     

History of vaccination: from empiricism towards recombinant vaccines

PURPOSE: Two hundreds years after the discovery of the smallpox vaccine, immunization remains one of the most powerful tools of preventive medicine. CURRENT KNOWLEDGE AND KEY POINTS: Immunization was born with Jenner, then Pasteur and expanded during the 19th and 20th century. It started with the empirical observation of cross-immunity between two diseases, cowpox and smallpox. It became a real science, with pathogen isolation, culture and attenuation or inactivation, to prepare a vaccine. Together with clinical and biological efficacy studies and adverse events assessments, it constructed the concept of "vaccinology". Protein conjugation of polyosidic vaccines has made possible early immunisation of infants. Nowadays, recombinant, reassortant, or virus-like particles technologies open the road for new vaccines. FUTURE PROSPECTS: Ongoing research opens the way for the development of new vaccines that will help to control transmittable diseases for which we are lacking antimicrobial agents.     

Immunization update and hot topics in clinical immunology: how does this relate to my practice?

The prevention of infectious diseases by the use of vaccines represents one of medicine's greatest triumphs during the 20th century. This era has witnessed the global eradication of smallpox as a result of Jennerian cowpox vaccination, the elimination of paralytic poliomyelitis from the western hemisphere, and within 5-10 years the anticipated eradication of poliomyelitis worldwide as a result of the poliovirus vaccines. Next slated for worldwide eradication is measles, the great killer of infants and children, which each year extracts a global mortality of one million victims. Throughout the 20th century the percutaneous (i.e., subcutaneous or intramuscular) route has almost exclusively been the preferred way to administer vaccines. However, as a result of several important scientific discoveries made during the 20th century, including new tissue-culturing techniques, the development of recombinant DNA technology, and genetic sequencing, a whole new generation of tailor-made modern vaccines has become available, including DNA vaccines and transgenic plant vaccines. Moreover, it became apparent that alternative routes of administration of vaccines, such as by aerosol immunization might be more appropriate and more effective than immunization via the parenteral route. The overall success in vaccine development, however, has not been without cost. For every new vaccine that has been developed, an adverse effect has been seen. Thus, although modern vaccines are extremely safe and effective, they are neither completely safe nor completely effective. The goal of vaccine development, therefore, is to achieve the highest degree of protection and the lowest rate of adverse effects. This paper describes some of the recent advances in vaccine development and will focus on some hot topics relating to the recent development and use of respiratory aerosolized vaccines.     

Malaria vaccine developments

Large gains in the reduction of malaria mortality in the early 20th century were lost in subsequent decades. Malaria now kills 2-3 million people yearly. Implementation of malaria control technologies such as insecticide-treated bednets and chemotherapy could reduce mortality substantially, but an effective malaria vaccine is also needed. Advances in vaccine technology and immunology are being used to develop malaria subunit vaccines. Novel approaches that might yield effective vaccines for other diseases are being evaluated first in malaria. We describe progress in malaria vaccine development in the past 5 years: reasons for cautious optimism, the type of vaccine that might realistically be expected, and how the process could be hastened. Although exact predictions are not possible, if sufficient funding were mobilised, a deployable, effective malaria vaccine is a realistic medium-term to long-term goal.     

Tuberculosis vaccine development

If the end of the 20th century saw the flowering of genomics, the beginning of the 21st century is witnessing an equally rapid blossoming of proteomics. These twin technologies have had a dramatic influence on the study of tuberculosis (TB), and nowhere more so than in the development of new TB vaccines. Only a few years ago, it was generally accepted that clinical trials of new TB vaccines would not take place for at least a decade. However, the first trials are now scheduled to start within months. Much TB vaccine research has thus shifted from developing new vaccines, to selecting the best vaccines for human use from the increasing number of effective new candidates becoming available. This selection is being eased by the improved animal models that have been developed over the past few years and by our increasing understanding of immunity to TB.     

A review of licensed viral vaccines, some of their safety concerns, and the advances in the development of investigational viral vaccines

Viral vaccines could be considered among the most important medical achievements of the 20th century. They have prevented much suffering and saved many lives. Although some curative antiviral drugs exist, we desperately depend on efforts by academic, governmental and industrial scientists in the advancement of viral vaccines in the prevention and control of infectious diseases. In the next decade, we hope to see advancement in the development of current and investigational viral vaccines against childhood and adult infections. In this article, we will review the licensed viral vaccines, some of their safety concerns, and the advances in the development of investigational viral vaccines.     

Theories of carcinogenesis and their impact on surgical treatment of colorectal cancer

From the time of Hippocrates until the late 19th century, physicians and surgeons were convinced that surgical attempts at treating colorectal cancers were doomed to failure. This opinion stemmed from prevailing views on carcinogenesis. The three dominant theories, the humoral, mineral, and lymph theories, held that all cancers developed in tissue that had a diseased disposition. Thus, excision of the gross tumor mass alone seemed unlikely to cure the patient. Consequently, surgical treatment of all cancers, and in particular colorectal cancer, was vehemently condemned. The 19th century represented a transition period. Advances in surgical technique made excision of rectal cancers feasible. Unfortunately, classical views that resection of cancer was futile delayed the development of surgical treatment for colorectal cancer. Indeed, it was not until the late 19th century that a few individuals ignored these tenets of classical medicine and attempted local resections of rectal cancers. By the second quarter of the 20th century, a radical change occurred in the prevailing theories of carcinogenesis. Wide acceptance of the unicellular origin of cancer and the mucosal origin of colorectal cancers washed away admonitions against surgical treatment of colorectal cancers. It became axiomatic that all cancers, including colorectal cancers, could be cured surgically if treated while still local diseases.     

Paleoenvironmental history of the West Baray, Angkor (Cambodia)

Angkor (Cambodia) was the seat of the Khmer Empire from the 9th to 15th century AD. The site is noted for its monumental architecture and complex hydro-engineering systems, comprised of canals, moats, embankments, and large reservoirs, known as barays. We infer a 1,000-y, (14)C-dated paleoenvironmental record from study of an approximately 2-m sediment core taken in the largest Khmer reservoir, the West Baray. The baray was utilized and managed from the time of construction in the early 11th century, through the 13th century. During that time, the West Baray received relatively high rates of detrital input. In the 14th century, linear sedimentation rates diminished by an order of magnitude, yielding a condensed section that correlates temporally with episodes of regional monsoon failure during the late 14th and early 15th century, recorded in tree ring records from Vietnam. Our results demonstrate that changes in the water management system were associated with the decline of the Angkorian kingdom during that period. By the 17th century, the West Baray again functioned as a limnetic system. Ecologic and sedimentologic changes over the last millennium, detected in the baray deposits, are attributed to shifts in regional-scale Khmer water management, evolving land use practices in the catchment, and regional climate change.     

Twentieth century sea level: an enigma

Changes in sea level (relative to the moving crust) are associated with changes in ocean volume (mostly thermal expansion) and in ocean mass (melting and continental storage): zeta(t) = zeta(steric)(t) + zeta(eustatic)(t). Recent compilations of global ocean temperatures by Levitus and coworkers are in accord with coupled ocean/atmosphere modeling of greenhouse warming; they yield an increase in 20th century ocean heat content by 2 x 10(23) J (compared to 0.1 x 10(23) J of atmospheric storage), which corresponds to zeta(greenhouse)(2000) = 3 cm. The greenhouse-related rate is accelerating, with a present value zeta(greenhouse)(2000) approximately 6 cm/century. Tide records going back to the 19th century show no measurable acceleration throughout the late 19th and first half of the 20th century; we take zeta(historic) = 18 cm/century. The Intergovernmental Panel on Climate Change attributes about 6 cm/century to melting and other eustatic processes, leaving a residual of 12 cm of 20th century rise to be accounted for. The Levitus compilation has virtually foreclosed the attribution of the residual rise to ocean warming (notwithstanding our ignorance of the abyssal and Southern Oceans): the historic rise started too early, has too linear a trend, and is too large. Melting of polar ice sheets at the upper limit of the Intergovernmental Panel on Climate Change estimates could close the gap, but severe limits are imposed by the observed perturbations in Earth rotation. Among possible resolutions of the enigma are: a substantial reduction from traditional estimates (including ours) of 1.5-2 mm/y global sea level rise; a substantial increase in the estimates of 20th century ocean heat storage; and a substantial change in the interpretation of the astronomic record.     

Vaccination and systemic lupus erythematosus: the bidirectional dilemmas

Vaccination has been perhaps the most important achievement in medicine of the last century. A hoard of infectious diseases that used to claim the lives of many, especially children, have been prevented and some even eradicated. However, it is possible that within this gift there is hidden a 'Trojan Horse'. During the last decade increasing numbers of reports regarding possible autoimmune side effects of vaccination, have been published. The existing data does not link the vaccines and the autoimmune phenomena observed in a causal relationship, nevertheless a temporal connection has been described. In this article we wish to address in particular the possible link between vaccines and systemic lupus erythematosus (SLE), namely two aspects of this inter-relationship: the occurrence of SLE following vaccination and outcome of immunization of known SLE patients.     

Personal reflections on twentieth century vaccinology

The science of vaccinology was created in the late 18th and 19th centuries by "giants" of the time including Jenner, Pasteur, Koch, von Behring, Ehrlich and Lister. Relatively little technologic advance was made in the period leading to World War II except for yellow fever and influenza vaccines. Support for war efforts fueled developments which led to the modern era of vaccines of 1950 onwards. The author's career in vaccinology, which began in 1944, was recognized in the 2002 Prince Mahidol Award given in Bangkok, Thailand. This review presents the substance of the Award lecture delivered on January 29, 2003.     

Discovery of blood cells in the 17th century

Landmark works of the 17th century concerning observations of blood cells are quoted in the article. "Simple" and successively "compound" microscopes made their appearance in the late 16th century and early 17th century. In 1656, Frenchman Pierre Borel, physician-in-ordinary to the King Louis XIV, who first applied the microscope to medicine described a type of "worn" found in human blood. In 1657, Athanasius Kircher, a Jesuit priest and scientist from Germany, examined blood from plague victims, and described "worms" of plague. In 1661, 1664 and 1665, the blood cells were discerned by Marcello Malpighi. In 1678, the red blood corpuscles was described by Jan Swammerdam of Amsterdam, a Dutch naturalist and physician. The first complete account of the red cells was made by Anthony van Leeuwenhoek of Delft in the last quarter of the 17th century.     

Obesity: historical development of scientific and cultural ideas

The concept that obesity is a risk to health was clearly identified in the works of Hippocrates and frequently over the ensuing centuries. Obesity was originally discussed as part of more general texts. Scholarly theses on this subject began to appear in the late 16th century with the first monographs published in the 18th century. The value of dietary restriction, increasing exercise and reducing the amount of sleep were identified early in medical history dating at least from the time of Hippocrates. These concepts were often framed in a manner which implied a 'moral' weakness on the part of the overweight individual. The most spectacular dietary success was published by a layman in 1863 and was the forerunner to many subsequent diet books. Cases of massive obesity were identified in stone age carvings and have been described frequently since the time of Galen and the Roman Empire. More specific types of obesity began to be identified in the 19th century. Following the identification of the cell as the basic building block of animals and plants, fat cells were described and the possibility that obesity was due to too many fat cells was suggested. After the introduction of the calorimeter by Lavoisier, the suggestion that obesity might represent a metabolic derangement has been suggested and tested. Standards for measuring body weight appeared in the 19th century. The possibility that familial factors might also be involved was clearly identified in the 18th and 19th century. In conclusion, most of the concepts which are currently the basis for research in the field of obesity had their origin in the 19th century and often earlier.     

Gelenkpunktion und -injektion �C Die Geschichte

Up until the middle of the 20th century joint puncture was considered a dangerous surgical intervention performed primarily to drain pus. The differential diagnostic significance of synovial analysis only became clear in the second half of the 20th century. Thus it became possible to reliably distinguish between inflammatory and non-inflammatory diseases, and establish whether arthritides are bacterial or crystal-induced. Attempts to inject disinfecting or anti-inflammatory solutions into the joint go back to the end of the 19th century. In the mid 20th century, cortisone became the panacea of intraarticular therapy. After surgeons at the end of the 19th century succeeded in surgically removing the inflamed synovium, internal medicine specialists attempted to destroy the synovial membrane by injecting it with various chemicals around the mid 20th century; however, hardly any of these substances survived. Only with "internal radiation" by injecting radionuclides was a breakthrough seen in the middle of the 20th century. Since then radiosynoviorthesis and synovialectomy have become standard methods in the treatment of chronic inflammatory joint disease.     

The heterogeneity of mental representation: Ending the imagery debate

The possible ways that information can be represented mentally have been discussed often over the past thousand years. However, this issue could not be addressed rigorously until late in the 20th century. Initial empirical findings spurred a debate about the heterogeneity of mental representation: Is all information stored in propositional, language-like, symbolic internal representations, or can humans use at least two different types of representations (and possibly many more)? Here, in historical context, we describe recent evidence that humans do not always rely on propositional internal representations but, instead, can also rely on at least one other format: depictive representation. We propose that the debate should now move on to characterizing all of the different forms of human mental representation.     

Hospital admissions for peptic ulcer and indigestion in London and New York in the 19th and early 20th centuries

The occurrence of peptic ulcer increased rapidly in all Western countries from the 19th to the 20th century, attributed to a possible epidemic of Helicobacter pylori, a new pathogenic strain, or a change in host susceptibility. The early trends in hospital admissions for peptic ulcer and dyspepsia in London and New York during the 19th century are reviewed to test these hypotheses.     

Global control of hepatitis B virus infection

Worldwide about 350 million people are chronic carriers of the hepatitis B virus (HBV). The infection can cause acute and chronic liver disease including cirrhosis and hepatocellular carcinoma (HCC). Hepatocellular injuries of HBV infection are predominantly immune-mediated, and the natural history of chronic infection can be divided into three phases based on virus-host interactions-namely, immune tolerance, immune clearance, and viral integration phases. Four serotypes (adw, ayw, adr, and ayr) and seven genotypes (A to G) of HBV have been identified, and they show some distinct geographic distributions. The HBV genotypes may have clinical relevance and are currently under investigation. On the basis of disease burden and the availability of safe and effective vaccines, the WHO recommended that by the end of the 20th century hepatitis B vaccine be incorporated into routine infant and childhood immunisation programmes for all countries. The efficacy of universal immunisation has been shown in different countries, with striking reductions of the prevalence of HBV carriage in children. Most important, hepatitis B vaccination can protect children against HCC and fulminant hepatitis, as has been shown in Taiwan. Nevertheless, the implementation of worldwide vaccination against HBV requires greater effort to overcome the social and economic hurdles. Safe and effective antiviral treatments are available but are still far from ideal, a situation that, hopefully, will be improved soon. With hepatitis B immunisation, the global control of HBV infection is possible by the end of the first half of 21st century.