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Biomedical subjects

M R Hilleman

Publications and source records attributed to M R Hilleman.

At least 37 records · Page 2Linked to original sources
PubMed1994

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.

AIDS Vaccines↗
PubMed1994

Vaccinology, immunology, and comparative pathogenesis of measles in the quest for a preventative against AIDS.

Current approaches to the prevention and control of AIDS by vaccines and by chemotherapy have failed to provide satisfactory solutions to this important medical problem and have failed, in addition, to provide definitive guidelines for future research endeavor. Vaccine research must and will continue but it is possible that a safe and effective vaccine may never be developed and it may be timely to explore, in addition, alternative means for immunological intervention in AIDS. Both immunoprophylactic and immunotherapeutic efforts might be assisted by manipulating the T helper 1 (Th1) and T helper 2 (Th2) subsets of CD4+ T helper cells, which is therefore worthy of exploration. Selective control of immune response by the two T helper subsets is by release of different cytokines that promote either cellular or humoral immunity, the latter of which may be associated with inappropriate immune responses and with immune dysfunction. Discovery of the Th1 and Th2 subsets and definition of the cytokines they release provide a new avenue toward possible development of a safe and effective vaccine and an approach, in addition, to correction of immune dysfunction by selective cytokine administration or by cytokine ablation by antagonists or antibodies. AIDS pathogenesis and immune dysfunction are complex and understanding them may be overwhelmed by an excess of possibilities. Simplification of the endeavor might benefit from comparative studies of the pathogenesis of measles, in which there also is immune deficiency but usually with spontaneous viral clearance, reversal of immune dysfunction, and total recovery. In addition, measles presents as a single disease and is caused by antigenically stable virus. Identification of the process whereby measles immunodeficiency is spontaneously reversed might be of importance in attempting to devise means for similar reversal in AIDS.

AIDS Vaccines↗
PubMed1994

Recombinant vector vaccines in vaccinology.

The development of recombinant vector vaccines will be guided by nearly two centuries of research in vaccinology and immunology. Experimental vector vaccines may be of viral, bacterial or genetic composition and their acceptability will depend on safety, efficacy, and practicality as seen by the user, the developer, and the licensing authority. Recombinant vector vaccines will need to compete with alternative vaccine approaches and may find special use for non-propagable agents, immunization in early life, fertility control, and emerging infectious agents. Needs of the developing nations that include low cost, temperature stability, and ease of administration may be met, in part at least, by the vector vaccine approach.

Antibody Formation↗
PubMed1993

Hepatitis and hepatitis A vaccine: a glimpse of history.

Human hepatitis has been recognized since the dawn of recorded history, but proof of infectious etiology and delineation of hepatitis A (infectious hepatitis) from hepatitis B (serum hepatitis) were not established until the first half of the present century. Development of the present killed hepatitis A vaccine depended on a series of breakthrough discoveries made during the last 25 years. These were marmoset propagation (1967); definition of virus attributes (1974-1975); development of diagnostic tests and seroepidemiology (1974-1975); and the preparation and proof of efficacy of a prototype killed hepatitis A vaccine (1976). Successful cultivation of hepatitis A virus in cell culture in 1979 quickly led to development of both live and killed hepatitis A vaccines for tests in human beings (1980-1990). The year 1991 marks the initiation of protective efficacy trials of two different killed virus vaccines in human beings. The safety and protective efficacy of the first vaccine (Merck) is reported in this symposium and the findings in tests of a second vaccine (SKB) are awaited. Hepatitis A is clearly a conquerable disease, initially in its elimination as an important disease entity and eventually in its eradication.

Hepatitis A Vaccines↗
PubMed1992

Impediments, imponderables and alternatives in the attempt to develop an effective vaccine against AIDS.

A personal view is presented that current successful vaccines against 'ordinary' viruses do not provide the guidelines needed for development of effective vaccines against the 'extraordinary' viruses that cause AIDS. Present 'candidate' AIDS vaccines fail to recognize the special attributes that are needed to make them successful. There is an urgent need for intensive studies of pathogenesis to seek and find the clues needed for vaccine attack that are at present unknown. Also needed is a targeted Research and Development organization comprising a cadre of capable scientists of requisite disciplines in adequate facilities, dedicated solely to the development of a vaccine against AIDS. The urgency imposed by the AIDS pandemic merits a new dedication to targeted basic research discovery and an effectively concentrated and coordinated applied research initiative.

AIDS Vaccines↗
PubMed1992

The dilemma of AIDS vaccine and therapy. Possible clues from comparative pathogenesis with measles.

AIDS viruses, because of their unique properties, are extraordinary. Past successes achieved with vaccines against ordinary viruses do not provide the guidelines needed to develop successful vaccines against HIV. Neither vaccines nor drugs can be relied upon to provide an answer to AIDS. AIDS is a disease of immune dysfunction and destruction, and an alternative to prevention of infection or cure might lie with elimination of the clinical consequences of infection. This might find a basis in precise definition of its pathogenesis. The enormity of possible pathogenetic changes in HIV infection invites simplification, and might be aided by a search for clues among ordinary viruses in which there is a less complicated biology and spontaneous recovery from infection. Measles virus infection presents analogies to AIDS, especially in the induction of anergy and increased mortality, in the long term, from diseases other than measles as observed in children infected during early life. This was demonstrated recently in increased deaths, all causes, during a three-year period among infants who were given live measles virus vaccine of high infectivity titer during early infancy, sometimes in the presence of maternal antibody. AIDS and measles may be diseases of similar pathogenesis, but with the difference that AIDS immunopathology is progressive while that for measles is regressive.

AIDS Vaccines↗
PubMed1990

History, precedent, and progress in the development of mammalian cell culture systems for preparing vaccines: safety considerations revisited.

The use of cell substrates to propagate viruses or recombinant plasmids for vaccine productions has been the subject of long evolutionary conflict, primarily from the standpoint of product safety, and especially from the viewpoint of cancer induction. The present concern is for safety of vaccines made using transformed or neoplastic mammalian cells that may contain endogenous contaminating viruses or integrated gene sequences from oncogenic viruses. There is also concern for use of plasmid vectors employing promoter elements from oncogenic viruses. The principal concern for safety lies with retention of residual DNA in the vaccine, especially since induction of cancer is a single-cell phenomenon, and a single functional unit of foreign DNA integrated into the host cell genome might serve to induce cell transformation as a single event or part of a series of multifactorial events. Current proposed standards for vaccines would permit contamination with up to 100 pg of heterologous DNA per dose. This is equivalent to about 10(8) "functional lengths" of DNA. Total safety would seem to require complete absence of DNA from the product. While preparation of biologicals used to treat serious disease might demand the use of mammalian cells, this is not the situation with vaccines that are given prophylactically to persons who might be given equally efficacious vaccines produced in bacterial cells or in yeast that have attributes for greater safety. Careful assessment of safety and risk vs. benefit of continuous mammalian cell-produced vaccines should be made by technically expert scientists in the relevant disciplines and a consensus needs to be evolved in the scientific community at large.

Animals↗
PubMed1988

Hepatitis B and AIDS and the promise for their control by vaccines.

Human hepatitis B virus and human immunodeficiency virus (HIV), that causes AIDS, share attributes and possible evolutionary relationships. The specific requirements for inducing effective immunity against hepatitis B and HIV are discussed. Lessons learned in studies of hepatitis B and its vaccine may find application in creating a vaccine against HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Haemophilus influenzae type b polysaccharide-protein conjugate vaccine.

An Haemophilus influenzae type b capsular polysaccharide-protein conjugate has been prepared. The polysaccharide was coupled to the serotype II protein of group B meningococcus through the spacer 6-aminocaproic acid using cyanogen bromide and water soluble carbodiimide. The conjugate can be shown to be reproducible and is stable and highly immunogenic in mice and African green monkeys. Clinical evaluation of this conjugate in children 3 months to 4 years of age showed that it elicited an antibody titer to the polysaccharide moiety greater than 1000 ng/ml in children 8 months of age or older.

Animals↗
PubMed1986

The science of vaccines in present and future perspective.

Vaccinology, while affording great opportunities in the prevention of infectious diseases, also poses the problem of stretching the possible beyond the practicable. Politics, economics, and technology all come together at the point of resource allocation. It is important to maintain a balance between expenditure for the development of vaccines and for the application of vaccines if maximal good is to be achieved in this new era of technical opportunity. A promising approach is to include in single "polytopic" vaccines the largest number of immunogenic epitopes for the greatest number of important diseases.

Antibodies, Monoclonal↗