Current overview of the pathogenesis and prophylaxis of measles with focus on practical implications.

Measles is one of the most important diseases of mankind, which is so highly contagious and evokes such persistent immunity that the virus cannot be sustained in a population of less than about 500,000 persons. The first of the licensed live virus vaccines against measles was developed empirically and was approved in 1963. It provides high level and lasting immunity and is a paradigm for solving major medical problems without really understanding them. In spite of means for control by prophylactic immunization, research on measles infection continues to be part of the effort to understand the pathogenesis of many different viruses, which may have important similarities and differences and provide important insights. Measles, usually, is spontaneously reversible and is a prime model for understanding virus-induced immunodeficiency disease (AIDS) which is rarely reversible. Much has been learned of basic immunology and vaccinology in measles through observation of the inappropriate use of vaccines of appropriate composition, and through inappropriate host response to measles vaccines of inappropriate composition. This review provides a current overview of selected highlights of measles, the virus, its immunopathogenesis, and its control by use of live virus vaccine which may lead to elimination of the disease and eventually to eradication of the virus.

Overview of the pathogenesis, prophylaxis and therapeusis of viral hepatitis B, with focus on reduction to practical applications.

Hepatitis B is the most important of several hepatitis viruses of man because of the number of cases of the disease and the frequent occurrence of persistent infection that may lead to cirrhosis and cancer of the liver. The pathology of hepatitis B infection results mainly from the self-destructive cytotoxic T cell response of the host. This may be modulated by soluble pre-core e antigen of the virus that induces immune tolerance and by cytokines elaborated by cytotoxic T cells, which suppress viral replication in the infected cell. Pathogenesis of the disease is markedly influenced by viral mutations. Persistent hepatitis B virus infection may be controlled in a minority of patients by passive alpha-interferon therapy, and in a majority of patients by the nucleoside lamivudine until resistance develops. The best means to control the disease is by prevention through application of the highly effective vaccine prepared using surface antigen of the virus. It is anticipated that the gradually increasing application of the vaccine throughout the world may lead to elimination of hepatitis B as an important medical problem. This paper is intended to provide a cursory overview of the contemporary knowledge relating to pathogenesis, prophylaxis and therapeusis of human hepatitis B.

Overview of vaccinology with special reference to papillomavirus vaccines.

Viruses that belong to six different families are a significant cause for neoplasia in man and animals. Among them are the Papillomaviruses that cause uterine cervical cancer in women. Efforts to develop prophylactic vaccines against viruses that cause cancer are now a major research engagement. Vaccinology, the science of vaccines, engages the sciences of immunology and of microbiology, both relying heavily on molecular biology. Successful development of vaccines relies on extensive knowledge of immunology and vaccinology. Present efforts to develop vaccines against cervical cancer caused by Papillomaviruses are focused on use of the structural antigens L1 and L2 of the virus and on the oncoproteins E6 and E7. Work on Papillomavirus vaccines has been brilliantly conceived and executed and some of vaccines are now in clinical trial. Success may follow and Papillomavirus vaccine may join with the hepatitis B virus anti-cancer vaccine in the battle against cancers of man.

Vaccines in historic evolution and perspective: a narrative of vaccine discoveries.

The sciences of vaccinology and immunology were created only two centuries ago by Jenner's scientific studies of prevention of smallpox through inoculation with cowpox virus. This rudimentary beginning was expanded greatly by the giants of late 19th- and early 20th-century biomedical sciences. The period from 1930 to 1950 was a transitional era, with the introduction of chick embryos and minced tissues for propagating viruses and rickettsiae in vitro for vaccines. Modern vaccinology began about 1950 as a continuum following notable advances made during the 1940s and World War II. Its pursuit has been based largely on breakthroughs in cell culture, bacterial polysaccharide chemistry, molecular biology, and immunology which have yielded many live and killed viral and bacterial vaccines plus the recombinant-expressed hepatitis B vaccine. The present paper was presented as a lecture given at a Meeting of the Institute of Human Virology entitled A Symposium on HIV-AIDS and Cancer Biology, Baltimore, Maryland, on August 30, 1999 and recounts, by invitation, more than 55 years of vaccine research from the venue of personal experience and attainment by the author. The paper is intentionally brief and truncated with focus only on highlights and limited referencing. Detailed recounting and referencing are given elsewhere in text references 1 and 2. This narration will have achieved its purpose if it provides a background of understanding and guidelines that will assist others who seek to engage in creation of new vaccines.

Vaccines in historic evolution and perspective: a narrative of vaccine discoveries.

The sciences of vaccinology and of immunology were created just two centuries ago by Jenner's scientific studies of prevention of smallpox through inoculation with cowpox virus. This rudimentary beginning was expanded greatly by the giants of late 19th and early twentieth centuries biomedical sciences. The period from 1930 to 1950 was a transitional era with the introduction of chick embryos and minced tissues for propagating viruses and Rickettsiae in vitro for vaccines. Modern era vaccinology began about 1950 as a continuum following notable advances made during the 1940s and World War II. Its pursuit has been based largely on breakthroughs in cell culture, bacterial polysaccharide chemistry, molecular biology and immunology, which have yielded many live and killed viral and bacterial vaccines plus the recombinant-expressed hepatitis B vaccine. The present paper was presented as a lecture given(1) on August 30, 1999 and recounts, by invitation, more than five-and-half decades of vaccine research from the venue of personal experience and attainment by the author. The paper is intentionally brief and truncated with focus only on highlights and limited referencing. Detailed recounting and referencing are given elsewhere in text references [Hilleman MR. Six decades of vaccine development - a personal history. Nat. Med. 1998;4 (Vaccine Suppl.): 507-14] and [Hilleman MR. Personal historical chronicle of six decades of basic and applied research in virology, immunology and vaccinology. Immunol. Rev. (in press)]. This narration will have achieved its purpose if it provides a background of understanding and guidelines that will assist others who seek to engage in creation of new vaccines.

Personal historical chronicle of six decades of basic and applied research in virology, immunology, and vaccinology.

The sciences of vaccinology and of immunology were created just two centuries ago by Jenner's studies of prevention of smallpox by inoculation with cowpox virus. This rudimentary beginning was expanded greatly by the giants of late 19th and early 20th centuries biomedical sciences. The period from 1930 to 1950 was a transitional era with the introduction of chick embryos and minced tissues for propagating viruses and rickettsiae in vitro for vaccines. Modern era vaccinology began about 1950 as a continuum of notable advances made during the 1940s and World War II. Present vaccinology is based largely on breakthroughs in cell culture, bacterial polysaccharide chemistry, molecular biology, and immunology. By invitation, the author, who is a microbe hunter in fact, was asked to chronicle his six decades of pioneering achievements in basic and applied virology, bacteriology, immunology, molecular biology, epidemiology, and cancer, with special reference to the pioneering creation of most of the present day vaccines. Knowledge of the past may guide the present and future. This chronicle will have achieved its legacy if it helps others to understand the why and how of the past that may help to create the substance of the future.

The business of science and the science of business in the quest for an AIDS vaccine.

This paper simplifies and encapsulates the past, present and future for developing vaccines, especially against AIDS. Needed technical information and how it can best be obtained are delineated. The views are my own and may not be shared by others. The science enterprise, including that for vaccines, is enmeshed in the major evolution and restructuring of many of the world's institutions. Changes brought by the knowledge revolution impinge on scientific information, technology, public policy, societal demands, private and public funding, academic and industrial organization and economic opportunity. Public-supported research is not an entitlement. It is in the scientific establishment's best interest to organize for greatest efficiency and effectiveness to bring paybacks commensurate with public investment.

International biological standardization in historic and contemporary perspective.

Recounting the origination and development of the concepts and institutions to foster and control new and existing biological products is a fertile subject for historical review. It describes what was a necessary and functional activity that needed to be brought into being. The earliest examples of biologicals regulation were created by the eighteenth century inventors themselves and became progressively institutionalized by the creation of national control authorities which increased in number and sophistication during the past century. In 1948, the World Health Organization (WHO) was established and created biological standards and regulations as an advisory to member nations. This too has grown in sophistication and is now of central importance in the biologicals enterprise worldwide. The field of biological standardization and regulation can be viewed in its need and role to foster technological development and to assure that the products of that endeavour are worthy and are retained. In many respects, it is a tale of troubles, tragedies, and triumphs and this is recounted in the text.

Vaccines, human experimentation, and ethics in evolutionary perspective.

Clinical testing of unlicensed biological products is woven into issues of ethics and technology that reflect the state of the art. Materials for human testing must be of best possible quality and content, and must be safe. Testing of vaccines demands fulfillment of three ethical principles established since World War II. Thus, autonomy (informed consent), beneficence (optimize benefit to risk, and do no harm), and justice (equitable distribution of benefits and burden among volunteer participants). Ethical and technical considerations are the driving force for regulation, by National Control Authorities, of both products and clinical testing. Regulation is facilitated by guidelines promulgated by the larger National Control Authorities, by the European Community, and by the World Health Organization. Sane and sensible regulation is best achieved by well-trained and informed regulatory staffs and is optimized by their continuing hands-on conduct of research. The difficulties of the past products have been diminished by increasing technical sophistication. The future bodies well for improved and new vaccines that will be based mainly on the established technologies of the past. New technologies will be approved slowly.

Discovery of simian virus 40 (SV40) and its relationship to poliomyelitis virus vaccines.

Simian Virus 40 (SV40) was discovered in 1959 as a covert contaminant of poliovirus vaccines prepared using Macacus monkey renal cell cultures. This inapparent polyoma virus of monkeys was detected using Cercopithecus renal cell cultures and was eliminated from poliovaccines. There has been no evidence to implicate SV40 virus of vaccine origin in long- or short-term consequences in human subjects. Of importance, SV40 virus provided a new model for basic studies of viral pathogenesis and for cell transformation and neoplasia. Neoplastic transformation is fixed on the promiscuous binding of SV40 large T antigen to anti-oncogene cellular protein elements. SV40 also served as a valuable model for defining the immunology of virus-induced cancer and in its prevention and cure. Further, it has been a prime tool for elucidating the molecular details of eukaryotic cell processes. Numerous techniques now used in molecular biology were pioneered in the SV40 system. The SV40 promoter is commonly used in vector expression constructs and it has continued to be a model to develop new tools for site-specific mutagenesis. The virus has been critically important to studies in modern genetics and in molecular biology.

A simplified vaccinologists' vaccinology and the pursuit of a vaccine against AIDS.

Vaccinology is the science and engineering of developing vaccines to prevent infectious diseases. Guidelines come from knowledge of pathogenesis and from successful past vaccines. The vaccine enterprise relies on the evolution of appropriate science and technology. Governmental support and industrial participation are key to successful development of new vaccines. A large challenge for vaccinology is a vaccine which protects against AIDS. Though misguided in its first decade, current vaccine research is directed to use of any and all viral antigens and to elicit both cell-mediated and humoral immune responses that are resident, with memory, at the mucosal sites of viral entry. Recent seminal discoveries guiding the future include selective elicitation of both Type 1 and Type 2 immune responses, and prime-boosting using recombinant viral or DNA vectors and expressed antigens. Success in vaccinology depends on simplification of the complex and on iterative processes in a well-defined pathway. The present and future of vaccinology are discussed in depth.

Overview of viruses, cancer, and vaccines in concept and in reality.

Cancer is a consequence of malfunction of the replicative cell cycle caused by acquisition of independence from proliferative and restrictive controls in the process. Such alteration may be driven by unrepaired mutations in proto-oncogenes and anti-oncogenes or by genetic insults of environmental, infectious, or spontaneous origin. The consequence of mutations may be reflected at any of a number of locations in the transductive pathways from receptor to nucleus which upset normal homeostatic balance between the opposing forces for promotion or restraint of cell proliferation. About 15% of human cancers are caused primarily by viruses that bring about aberrations in gene structure and function or that express proteins that bind to cell regulatory proteins. The means for achieving immunoprophylaxis of viral cancers, such as hepatitis B or Marek's disease, are based on prior specific perturbation of the immune system, causing it to respond rapidly and effectively in preventing infection on subsequent contact with the corresponding agent. Existing cancers of viral origin and those of nonviral causation come together in attempted immunotherapy. Cure is far more difficult to achieve than prevention and relies on the principle that tumor cells can display abnormal markers on the cell surface that are capable of being detected and engaged by an effective immune response. Efforts to prevent and cure cancer of viral, spontaneous, or environmental origin are a worthy pursuit and must take account of the most advanced information relating to the chemistry of the cell cycle and to the function of the immune system.

Overview: practical insights from comparative immunology and pathogenesis of AIDS, hepatitis B, and measles for developing an HIV vaccine.

Combined effects of viral mutation, beneficial and adverse host immune responses, and alterations in immune function strongly fashion the pathogenesis and outcome of HIV infection. Understanding HIV can be aided by understanding hepatitis B and measles. Clinical remission and exacerbation in persistent hepatitis B virus infection is determined by the triad of viral mutation, induction of anergy, and host immune responses. Measles virus infects many of the same kinds of cells as HIV and causes an immunodeficiency as well that usually is spontaneously reversible. Lessons learned from comparative studies can assist in plotting approaches and strategies for immunoprophylactic and therapeutic interventions in HIV infections and AIDS.

Comparative biology and pathogenesis of AIDS and hepatitis B viruses: related but different.

AIDS (HIV) and hepatitis B viruses are remarkably similar in their sharing of reverse transcription, in their ancestral origins and common genetic elements, and in their modes of transmission. Both are hypermutable and exist as quasispecies due primarily to errors in reverse transcription, though there is severe restriction in the replicative competence of most hepatitis B mutants. They differ in the lack of an integrase in hepatitis B virus and in their pathogenesis in the infected host. HIV survives mainly by antigenic variability, immune evasion, and impairment of immune function though viral regulatory control elements seek to restrict fatal damage to the host. Hepatitis B virus survives primarily by mutation of e antigen/core genes that directly obviates cytotoxic T cell destruction of infected liver cells, or indirectly limits destruction of infected cells through induction of anergy in the cytotoxic T cell response. Most persons infected with hepatitis B virus recover completely while recovery from HIV infection is rare if ever. Hepatitis B is highly preventable by vaccine while HIV vaccine is still seeking a meaningful immunoprophylactic target. AIDS and hepatitis B represent an extreme example, among the viruses of man, in their close similarities but distinct differences. In depth details and perspectives are presented in this review.