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Biomedical subjects

D T Karzon

Publications and source records attributed to D T Karzon.

At least 19 recordsLinked to original sources
PubMed1992

Development of a vaccine for the prevention of AIDS, a critical appraisal.

The pathogenesis and clinical expression of HIV-1 infection in humans is considered in terms of classical pathogenetic studies of viral infections for which successful vaccines have been produced. The unique features of HIV pathogenesis are defined, and gaps in knowledge identified as a framework for considering designs for immune intervention. Envelope-derived candidate vaccines have been used in immunization and challenge experiments in SIV/macaque or HIV/chimpanzee models, presented either as vaccinia recombinant vectors or as subunits, singly or in sequence. These studies have been paralleled by clinical trials for safety and immunogenicity in seronegative individuals. Data generated will permit comparison of immune responses to specific antigens and delivery systems in animal models and in humans. In limited studies conducted under optimized conditions, non-human primates have been protected against virus challenge when immunized with some candidate vaccines or following passive transfer of high-titred antibody. Consideration of current information suggests that in order to prevent HIV infection it may be necessary to devise new strategies capable of inducing and maintaining high threshold titres of biologically relevant antibody as well as persistence of active cytotoxic T cells recognizing multiple epitopes.

AIDS Vaccines↗
PubMed1991

Reinfection of mice with respiratory syncytial virus.

A BALB/c model of respiratory syncytial virus infection has been developed in which high-titered replication occurs in lung, immunological infiltrates in lung can be detected histologically, and illness can be consistently reproduced. The immunodeterminants of RSV reinfection in this system were investigated by rechallenging mice with RSV early (less than 2 months after primary infection) and late (16 to 21 months after primary infection) and correlating illness and titer of RSV isolated from lungs and noses with RSV-specific serological responses and lung histology. After early rechallenge, RSV was cleared within 24 hours from both nose and lung. After late rechallenge, RSV was isolated at 72 hours from nose in 21/24 mice, but from lung in only 5/24 mice. Isolation of RSV from lung after rechallenge was associated with low RSV-specific antibody titers measured by ELISA and plaque-reduction neutralization. The presence of lymphocyte aggregates around the bronchovascular bundles was associated with inability to isolate RSV from lung and lack of illness. The basophilic lymphocytes were small and uniform in size with dense nuclei and a small amount of cytoplasm. These studies demonstrate that nasal and pulmonary reinfection with RSV is possible in mice after late rechallenge. The studies also indicate the potential importance of RSV-specific antibody in protecting lung from reinfection.

Animals↗
PubMed1991

Respiratory syncytial virus infection in anti-mu-treated mice.

BALB/c mice were depleted of B cells by anti-mu treatment to investigate the pathogenesis of respiratory syncytial virus (RSV) infection in the absence of antibody. Termination of RSV replication after primary infection occurred with the same kinetics in anti-mu-treated mice as in phosphate-buffered saline (PBS)-treated controls. Yet, when rechallenged, anti-mu-treated mice were more permissive to RSV replication than PBS-treated controls. Anti-mu-treated mice also experienced greater illness than PBS-treated controls during both primary infection and rechallenge. Passive transfer of RSV-specific immune serum to anti-mu-treated mice before rechallenge reconstituted complete protection from RSV replication and diminished illness. Thus, RSV-specific antibody is not required to terminate RSV replication in primary infection, but without antibody, only partial immunity against rechallenge is induced. While it is unknown whether the mechanism is a direct effect on RSV titer or modulation of the illness-causing cellular immune response, the presence of RSV-specific antibody reduces illness in both primary RSV infection and rechallenge of mice.

Animals↗
PubMed1991

Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice.

The role of CD4+ and CD8+ T lymphocytes in terminating respiratory syncytial virus (RSV) replication, causing disease, and protecting from reinfection was investigated using a BALB/c mouse model in which CD4+ or CD8+ lymphocytes or both were depleted by injections of Mab directed against the respective mouse lymphocyte determinants. Kinetics of RSV replication, illness, and pathology were assessed after primary infection and rechallenge. Both CD4+ and CD8+ lymphocyte subsets were involved in terminating RSV replication after primary infection. When both T lymphocyte subsets were depleted RSV replication was markedly prolonged, yet no illness was evident, suggesting that host immune response rather than viral cytocidal effect was the primary determinant of disease in mice. Both CD4+ and CD8+ lymphocytes contributed to illness, although CD8+ lymphocytes appeared to play the dominant role in this particular system. Analysis of histological responses suggested that CD4+ lymphocytes were required for the appearance of peribronchovascular lymphocytic aggregates seen in normal mice after rechallenge, and that the presence of alveolar lymphocytes was correlated with illness. It is postulated that antibody is an illness-sparing mechanism for protecting mice from RSV infection, and that T lymphocytes are an important determinant of illness. Further delineation of RSV-induced immunopathogenesis in primary infection and reinfection will provide important information for the development of vaccine strategies.

Animals↗
PubMed1991

Differences in antibody response to whole-cell pertussis vaccines.

It has been assumed that whole-cell pertussis vaccines (WCVs) commercially distributed in the United States are of comparable immunogenicity, as all must comply with established standards for licensure. However, we have recently noted significant differences in antibody responses between groups of infants receiving the two WCVs commercially available in the United States. In separate studies performed concurrently under similar protocols at Vanderbilt and Johns Hopkins universities, infants were randomized to receive either an acellular pertussis vaccine or WCV. The acellular pertussis vaccine used at the two sites was identical, but the WCVs were from different manufacturers. Antibody responses to acellular pertussis vaccine did not differ between the two studies; responses to WCV differed dramatically, with infants receiving the Lederle WCV producing a 46-fold increase in antibody to pertussis toxin, compared with a 2.4-fold increase for infants receiving the Connaught WCV (P = .00003). Evaluation of other comparative data sets that were available provided further support for the conclusion that the two commercially available WCVs consistently differed in their ability to induce antibody to pertussis toxin. These findings have important implications for the design and interpretation of clinical trials comparing acellular and WCV products.

Adhesins, Bacterial↗
PubMed1990

Pertussis vaccines.

Concern over adverse reactions temporally associated with whole cell pertussis vaccine and advances in the understanding of the Bordetella pertussis organism have led to a new generation of more purified acellular vaccines. The biology of the pertussis organism, epidemiology of disease, vaccine development over the decades, and vaccine efficacy and adverse reaction data from whole cell and acellular vaccine trials are presented. Questions that remain to be answered before acellular vaccine replaces conventional vaccine are defined, and future studies addressing these questions are proposed.

Bordetella pertussis↗
PubMed1990

Natural history of pertussis antibody in the infant and effect on vaccine response.

To better characterize the transplacental transfer and persistence of pertussis antibodies and their role in the immune response to vaccine, concentrations of pertussis agglutinins and antibodies to lymphocytosis promoting factor (LPF) and filamentous hemagglutinin (FHA) were measured in three distinct groups of serum. Transplacental pertussis IgG antibody concentrations in newborns were found to be comparable to corresponding maternal concentrations and to decline with a half-life of approximately 6 weeks. By the age of 4 months, most infants had no detectable antibodies to LPF or FHA. Higher concentrations of maternally derived antibody to LPF were associated with a significantly weaker antibody response to conventional vaccine. In contrast, acellular vaccine stimulated superior antibody production, regardless of antecedent concentrations of antibody to LPF. The data support continuation of the current schedule of pertussis immunization and further efforts to develop an acellular vaccine for use in young infants.

Adult↗
PubMed1990

Development of an AIDS vaccine. Biological and ethical challenges.

The biologic, ethical, and social obstacles in AIDS vaccine development are explored. Current understanding of the immunodeterminants of HIV-1 pathogenesis is reviewed and ideal biological properties for an AIDS vaccine are proposed. Options for clinical trial design, criteria for entry into clinical trials, and provision for care of volunteers who experience vaccine-associated adversity are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Primary respiratory syncytial virus infection in mice.

A mouse model of respiratory syncytial virus (RSV) infection is described. A high-titered, large-volume inoculum results in replication of RSV to a high titer in lungs of BALB/c mice. Mice older than 15 weeks of age are more susceptible to RSV infection. Titers up to 10(6.9) plaque-forming units (pfu)/gram lung can be attained in 32-week-old mice. Older mice experience a clinical illness manifested by ruffled fur, reduced activity, and weight loss. Lung histology of older mice infected with RSV shows bronchiolitis and increased number of lymphocytes and macrophages in alveolar spaces compared with that of mice less than 8 weeks old. This model will serve as the basis for investigating immunodeterminants of recovery and protection from RSV infection.

Age Factors↗
PubMed1987

Candidate rotavirus vaccine (rhesus rotavirus strain) in children: an evaluation.

Fifty children, 3 months to 12 years of age, were given an experimental, orally administered, live attenuated rotavirus vaccine. Overall evidence of vaccine effectiveness as judged by vaccine virus shedding or a serologic response was seen in 82% of vaccinees. No clinical illness was seen in the rotavirus vaccinees when compared with 40 concurrently studied control children. No transmission to control children was observed even with close daily contact in a day-care setting. Young infants, generally less than 1 year of age, who had not previously experienced wild-type rotavirus infection shed significantly more vaccine virus. Limitation of virus shedding in those already exposed may be related to a prompt copro-IgA response which was significantly elevated by three days after vaccination. In summary, the development of this rotavirus vaccine, rhesus rotavirus-MMU-18006, is a promising step in the development of immunoprophylaxis against this major enteric pathogen.

Antibodies, Viral↗
PubMed1986

Serum and nasal-wash immunoglobulin G and A antibody response of infants and children to respiratory syncytial virus F and G glycoproteins following primary infection.

An enzyme-linked immunosorbent assay (ELISA) with immunoaffinity-purified fusion (F) or attachment (G) glycoprotein was used to measure the serum and secretory immune responses of 18 infants and children, 4 to 21 months of age, who underwent primary infection with respiratory syncytial virus (RSV). Most of the 10 older individuals (9 to 21 months of age) developed moderate levels of serum and nasal-wash immunoglobin A (IgA) and IgG F and G antibodies. These individuals developed a moderate level of serum or nasal-wash antibodies that neutralized virus infectivity. One of the eight younger individuals (4 to 8 months of age) failed to develop an F antibody response, while three failed to develop a G antibody response. The most notable difference in the responses of the two age groups involved the titer in convalescent sera of G, F, and neutralizing antibodies which were 8- to 10-fold lower in younger individuals. Most of the younger infants failed to develop a rise in serum or nasal-wash neutralizing antibody. It is possible that the presence of maternally derived antibody in the younger infants suppressed the immune response to RSV infection, and that this accounted, in part, for the low level of postinfection antibody titer in this group. This low level and the irregular response of the infants less than 8 months of age may contribute to the severity of their initial infection and may also be responsible, in part, for their failure to develop effective resistance to subsequent reinfection by RSV.

Antibodies, Viral↗
PubMed1985

Simultaneous administration of live, attenuated influenza A vaccines representing different serotypes.

Two live, attenuated cold-adapted influenza A vaccines representing current H1N1 and H3N2 serotypes were simultaneously administered intranasally to doubly seronegative children. No clinical illness resulted. Characterization of virus shedding demonstrated shedding of both original vaccine strains and of reassortant virus with the H3N1 and H1N2 phenotype. A serum immune response to both serotypes was demonstrated. The successful simultaneous administration of two influenza A vaccine strains enhances the potential usefulness of this approach to influenza prophylaxis.

Antibodies, Viral↗
PubMed1985

Cytotoxic T-cell response to respiratory syncytial virus in mice.

The role of the humoral and cellular arms of the immune response in protection against respiratory syncytial virus (RSV) infection and in the pathogenesis of the severe forms of this disease is poorly understood. The recent demonstration that some inbred mouse strains can be infected with RSV has opened the way to a detailed investigation of RSV immunity. We report here the finding of major histocompatibility complex-restricted, RSV-specific memory cytotoxic T cells in the spleens of BALB/c and C57BL mice after intranasal infection; these T cells recognize the Long, A2, and 8/60 (human) strains of RSV. Both K and D locus major histocompatibility complex alleles can restrict the cytotoxic response; however, in the two haplotypes tested, Dd is a low-responder allele and Kb is a nonresponder allele for RSV. UV-inactivated RSV (when given intraperitoneally) can prime mice for development of cytotoxic T cell memory, restimulate cytotoxic T cell cultures in vitro, and form a target for the cytotoxic cells.

Animals↗