Biomedical subjects
S A Plotkin
Publications and source records attributed to S A Plotkin.
Meta-analysis of typhoid vaccine efficacy trials showed that whole cell vaccines are more effective than either the oral, attenuated vaccine or the Vi polysaccharide vaccine.
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Involvement of a p53-dependent pathway in rubella virus-induced apoptosis.
In light of the important role of apoptotic cell death in the pathogenesis of several viral infections, we asked whether the cytopathogenicity evoked by rubella virus (RV) might also involve apoptotic mechanisms. The To-336 strain of RV induced apoptosis in Vero and RK-13 cells, but not in fibroblast cell lines. UV-inactivated RV virions did not elicit the apoptotic response, indicating that productive infection is required for the induction of cell death. Both p53 and p21 protein levels were highly elevated in RV-infected Vero cells. The level of p21 mRNA was increased, while expression of the p53 gene was unaffected by RV infection. A dominant-negative p53 mutant (p53(W248)) conferred partial protection from RV-induced apoptosis. These data implicate a p53-dependent apoptotic pathway in the cytopathogenicity of RV, thereby suggesting a mechanism by which RV exerts its teratogenic effects.
The eradication of rubella.
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Incidence of Lyme borreliosis in the Würzburg region of Germany.
To assess the incidence of Lyme borreliosis in Central Europe, a 12-month, prospective, population-based surveillance study of Lyme borreliosis was conducted in the Wurzburg region of central Germany, following an aggressive awareness campaign. The diagnosis of Lyme borreliosis required the presence of (i) erythema migrans (diameter > or =5 cm); (ii) lymphocytoma; or (iii) another specific manifestation including Lyme arthritis, neuroborreliosis, carditis or acrodermatitis chronica atrophicans in conjunction with serological confirmation. A total of 313 cases of Lyme borreliosis was diagnosed, giving an incidence of 111 cases/100000 inhabitants, the highest rates occurring in children and elderly adults living in wooded as opposed to agricultural areas. The incidence in city dwellers and inhabitants of rural areas was not significantly different. Erythema migrans was the only manifestation in 279 (89%) patients. Of the 34 patients with manifestations other than erythema migrans alone, 15 had arthritis, nine neuroborreliosis, six lymphocytoma, four acrodermatitis chronica atrophicans and one carditis. Children were more likely than adults to have manifestations other than erythema migrans alone. Lyme borreliosis was very common in central Germany, and one of the most frequent bacterial infections. The observation of more cases of arthritis than neuroborreliosis was similar to that in the USA. These results may be representative for many parts of central Europe and suggest the need for development of a vaccine against borreliosis caused by European strains of Borrelia species.
Cytomegalovirus vaccine.
Congenital cytomegalovirus disease is an unsolved public health problem, unlikely to be solved by means other than immune prophylaxis. Development of a vaccine has been hampered by low awareness of the problem, which is caused by the often delayed detection of abnormalities after birth. Nevertheless, cytomegalovirus vaccine development is active. An attenuated, live vaccine has been studied extensively, and an improved strain may result from genetic manipulation. An immunogenic viral glycoprotein (gB) vaccine is currently in clinical trial to determine if antibodies alone will be protective. The idea of a combined vaccine has been proposed, in which a canarypox recombinant containing several cytomegalovirus genes is used both to generate cellular immunity and to prime for augmented antibody responses to the viral glycoprotein. Finally, DNA plasmids containing cytomegalovirus genes are being investigated for their utility as vaccines.
Induction of human cytomegalovirus (HCMV)-glycoprotein B (gB)-specific neutralizing antibody and phosphoprotein 65 (pp65)-specific cytotoxic T lymphocyte responses by naked DNA immunization.
Plasmids expressing the human cytomegalovirus (HCMV) glycoprotein B (gB) (UL55) or phosphoprotein 65 (pp65) (UL83) were constructed and evaluated for their ability to induce immune responses in mice. The full-length gB as well as a truncated form expressing amino acids 1-680 of gB, and lacking the fragment encoding amino acids 681 907 including the transmembrane domain of gB (gB680) were evaluated. Immunization of mice with plasmids coding for gB or gB680 induced ELISA and neutralizing antibodies, with the highest titres in mice immunized with the gB680 plasmid. Mice immunized with the gB plasmid predominantly produced IgG2a gB-specific antibody, while the gB680 plasmid raised mostly IgG1 anti-gB antibody. Mice immunized with the pp65 plasmid developed pp65-specific cytotoxic T lymphocytes (CTL) and ELISA antibodies. Immunization with a mixture of both gB and pp65 plasmids raised antibodies to both proteins and pp65-specific CTL, indicating a lack of interference between these two plasmids. These results suggest that DNA immunization is a useful approach for vaccination against HCMV disease.
Vaccination against the major infectious diseases.
The reputation of vaccination rests on a 200-year-old history of success against major infectious diseases. That success has led to the doctrine of 'for each disease, a vaccine'. Although some diseases have proved frustrating, this doctrine carries considerable truth. However, when one reviews the vaccines now available it is apparent that most successes have been obtained when the microbe has a bacteremic or viremic phase during which it is susceptible to the action of neutralizing antibodies, and before replication in the particular organ to which it is tropic. Poliomyelitis and infections by capsulated bacteria are examples where vaccination has worked efficiently. However, some success has also been achieved against agents replicating on respiratory or gastrointestinal mucosae. Influenza, pertussis and rotavirus vaccines are examples of such agents, against which it has been possible to induce immune responses acting locally as well as systemically. In addition, when bacteria produce disease through exotoxins, purification and chemical or genetic inactivation of those toxins has yielded highly efficacious vaccines. Control of intracellular pathogens has not been achieved, except partly with the BCG vaccine against tuberculosis, and modern efforts are directed towards pathogens against which cellular immune responses are critical. In general, two achievements have been crucial to the success of vaccines: the induction of long-lasting immunological memory in individuals and the stimulation of a herd immunity that enhances control of infectious diseases in populations.
A canarypox vector expressing cytomegalovirus (CMV) glycoprotein B primes for antibody responses to a live attenuated CMV vaccine (Towne).
To develop a vaccine against cytomegalovirus (CMV), a canarypox virus (ALVAC) expressing CMV glycoprotein (gB) was evaluated alone or in combination with a live, attenuated CMV vaccine (Towne). Three doses of 106.5 TCID50 of ALVAC-CMV(gB) induced very low neutralizing or ELISA antibodies in most seronegative adults. However, to determine whether ALVAC-CMV(gB) could prime for antibody responses, 20 seronegative adults randomly received either 106.8 TCID50 of ALVAC-CMV(gB) or 106.8 TCID50 of ALVAC-RG, expressing the rabies glycoprotein, administered at 0 and 1 month, with all subjects receiving a dose of 103.5 pfu of the Towne vaccine at 90 days. For subjects primed with ALVAC-CMV(gB), neutralizing titers and ELISA antibodies to CMV(gB) developed sooner, were much higher, and persisted longer than for subjects primed with ALVAC-RG. All vaccines were well tolerated. These results demonstrate that ALVAC-CMV(gB) primes the immune system and suggest a combined-vaccine strategy to induce potentially protective levels of neutralizing antibodies.
Vaccination against cytomegalovirus, the changeling demon.
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Where rubella is still a problem.
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Cost of varicella in France: a study in day care centers.
To assess the cost of varicella in young children in France, a prospective study was done in day care centers. Children (1263), who were 3 months to 3 years old and attending day care, were followed over a varicella season. For every child who developed varicella (n = 200), detailed information was obtained by use of parental questionnaires. Questions concerned medical care, days missed from work for parents, and the need for extra baby-sitting. On average, each sick child had one consultation with a physician and received three medications. In half of the families (52%), at least 1 parent had to miss work an average of 4.5 days to care for a sick child. Total costs to society were estimated to be US$352 per family, with medical costs accounting for 22% of the cost. The average eventual cost to parents was $89 per family, including $80 of non-medical costs. This study emphasizes the important socioeconomic impact of varicella in the day care setting in France.
Antibody persistence following preexposure regimens of cell-culture rabies vaccines: 10-year follow-up and proposal for a new booster policy.
Subjects (n = 312) received either the human diploid cell rabies vaccine (HDCV) or the purified Vero cell rabies vaccine (PVRV) according to either two-injection (days 0 and 28) or three-injection (days 0, 7, and 28) primary regimens. They received a booster injection at 1 year. Rabies antibody levels were measured after the primary series and the booster and then each year for the next 10 years. The results confirm the superior long-term immunogenicity of the three-injection over the two-injection protocol. HDCV and PVRV in three doses were equally immunogenic. A booster injection at 1 year provides long-term seroconversion (titer > or = 0.5 IU/mL). Antibody titers 2 weeks after the 1-year booster allowed prediction of long-term immunity. Good responders, with titers > or = 30 IU/mL, were protected for at least 10 years. An algorithm for differentiation between good responders and poor responders with respect to vaccine booster strategies is proposed.
Safety and immunogenicity of the Towne strain cytomegalovirus vaccine.
BACKGROUND: Women with naturally acquired serum antibodies to cytomegalovirus (CMV) are usually protected against both frequent secondary infection and giving birth to infants severely affected by intrauterine CMV infection. OBJECTIVE: To determine the feasibility of using a live attenuated strain of CMV (Towne) to achieve immunity similar to that provided by wild-type infection, we evaluated a new lot of the Towne strain of CMV in 3 open label trials involving 68 men, 63 women of childbearing age and 13 children, respectively. RESULTS: Mild local reactions occurred among approximately one-third of subjects. There were no systemic reactions. All 45 subjects tested developed lymphoproliferative responses to CMV. CD8+ class I-restricted cytotoxic T cell responses specific for CMV antigens were detected in three of four subjects and persisted for 6 months. Neutralizing titers were maximal at 2 to 4 months postimmunization, were dose-dependent and were comparable to those induced by natural infection. CONCLUSION: These results support further evaluation of the Towne strain of CMV in women at risk for acquiring CMV infection during pregnancy or among children transmitting CMV to pregnant women.
Human diploid cell strains (HDCS) viral vaccines.
Since the development in 1961 by Hayflick and Moorhead of a human diploid cell strain (HDCS) culture system for isolating viruses, HDCS-derived human vaccines have been licensed worldwide for polio IPV and OPV (multiple strains), rabies (Pitman-Moore L503 3M strain); rubella (RA27/3 strain); measles (Edmonston-Zagreb strain); varicella-zoster (Oka strain); mumps (Rubini strain) and hepatitis A (HM-175, CR-326-F', and GBM strains). Many of these widely-used vaccines now have at least a 20-year record of safety after extensive, ongoing pharmacovigilance. Serious vaccine-associated events are rare, and appear to reflect the activity of the live viruses replicated in the HDCS or of the inactivated viruses or other proteins added during manufacture. There is no credible association of reactions to the HDCS substrate or a hypothetical contaminant derived from it.
Polio vaccine production.
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Randomised feasibility trial of pre-exposure rabies vaccination with DTP-IPV in infants.
BACKGROUND: Pre-exposure vaccination against rabies generally simplifies treatment and could be especially beneficial to children in countries where the disease is enzootic. We studied the feasibility of administering to infants pre-exposure rabies vaccination with combined diphtheria, tetanus, whole-cell pertussis, and inactivated poliomyelitis vaccine (DTP-IPV). METHODS: 84 Vietnamese infants were randomly assigned to groups that received three doses of DTP-IPV vaccine at 2, 3, and 4 months of age alone (n = 43) or with two doses of purified Vero cell rabies vaccine (PVRV) at 2 and 4 months (n = 41). The safety and immunogenicity data of the groups were compared. FINDINGS: All infants in both groups developed protective antibody concentrations against diphtheria, tetanus, pertussis, and polio. All infants who received the PVRV vaccine developed protective antibody concentrations against rabies. No serious adverse effects were reported, nor did systemic reactions differ between groups. INTERPRETATION: Administration of PVRV with DTP-IPV proved safe, and elicited what are presumed to be protective antibody concentrations to all antigens in all 41 infants. Confirmation of these results could lead to integration of pre-exposure rabies vaccination into Expanded Programme on Immunisation (EPI) sessions in selected countries where rabies is enzootic.