Broadening the horizons for yellow fever: new uses for an old vaccine.
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The vaccine against yellow fever is one of the safest and most effective ever developed. With an outstanding record in humans, has this live attenuated vaccine been overlooked as a promising vector for the development of vaccines against pathogens outside its own genus? Recent studies, including a report by Tao et al. on page 201 of this issue, have sparked renewed interest. (+info)
Yellow fever 17D as a vaccine vector for microbial CTL epitopes: protection in a rodent malaria model.
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The yellow fever vaccine 17D (17D) is safe, and after a single immunizing dose, elicits long-lasting, perhaps lifelong protective immunity. One of the major challenges facing delivery of human vaccines in underdeveloped countries is the need for multiple injections to achieve full efficacy. To examine 17D as a vector for microbial T cell epitopes, we inserted the H-2K(d)-restricted CTL epitope of the circumsporozoite protein (CS) of Plasmodium yoelii between 17D nonstructural proteins NS2B and NS3. The recombinant virus, 17D-Py, was replication competent and stable in vitro and in vivo. A single subcutaneous injection of 10(5) PFU diminished the parasite burden in the liver by approximately 70%. The high level of protection lasted between 4 and 8 wk after immunization, but a significant effect was documented even 24 wk afterwards. Thus, the immunogenicity of a foreign T cell epitope inserted into 17D mimics some of the remarkable properties of the human vaccine. Priming with 17D-Py followed by boosting with irradiated sporozoites conferred sterile immunity to 90% of the mice. This finding indicates that the immune response of vaccine-primed individuals living in endemic areas could be sustained and magnified by the bite of infected mosquitoes. (+info)
Randomized, double-blind, phase III, pivotal field trial of the comparative immunogenicity, safety, and tolerability of two yellow fever 17D vaccines (Arilvax and YF-VAX) in healthy infants and children in Peru.
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We conducted a randomized, double-blind, phase III yellow fever (YF) vaccine trial among 1,107 healthy children in Sullana in northern Peru. The safety and efficacy (by measurement of geometric mean neutralizing antibody titer responses) were determined for two YF vaccines, ARILVAX (n = 738) and YF-VAX(R) (n = 369). Serocon-version rates were higher (94.9%) in ARILVAX than in YF-VAX (90.6%) recipients. The two-sided 95% confidence interval (YF-VAX-ARILVAX) was (-12.8% to -2.5%), indicating that the higher seroconversion rate for Arilvax was significant. Post-vaccination (30-day) mean log(10) neutralization indices were found to be similar for both products: 1.32 for ARILVAX and 1.26 for YF-VAX (P = 0.1404, by analysis of variance). A similar number of subjects in each group reported at least one adverse event (AE); 441 (59.8%) for ARILVAX versus 211 (59.9%) for YF-VAX. Most (591; 96.7%) of these were of a mild nature and resolved without treatment. There were no treatment-related serious AEs. This is the first randomized, double-blind comparison of two YF vaccines in a pediatric population; both vaccines were shown to be highly immunogenic and well-tolerated. (+info)
Immunogenicity and safety of BERNA-YF compared with two other 17D yellow fever vaccines in a phase 3 clinical trial.
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BERNA-YF (Flavimun) is a live, attenuated yellow fever (YF) vaccine of the 17D strain produced by Berna Biotech Ltd. following a transfer of technology from the Robert Koch Institute (RKI) in Berlin, Germany. In this phase 3 bridging study, the immunogenicity and safety of BERNA-YF were compared with the original RKI YF vaccine (RKI-YF) and to a current, commercially available YF vaccine, Stamaril (AP-YF; Aventis Pasteur, Lyon, France), in 304 healthy, adult volunteers. All three vaccines elicited an effective immune response with seroprotection achieved in 100% of individuals in each vaccine group at a neutralizing antibody titer > or = 1:10. BERNA-YF was shown to be comparable to the other two vaccine products, and subgroup analysis showed no differences in immune response between three consecutive production batches. The immune response to BERNA-YF and RKI-YF was very similar, with no significant difference in antibody titer between the two groups (P = 0.4634). However, AP-YF vaccination resulted in a significantly lower antibody titer (P < 0.0001 versus BERNA-YF). Males exhibited a higher antibody response than females to both BERNA-YF and RKI-YF, but not to AP-YF. All three vaccines were well tolerated and no serious adverse events were reported. (+info)
Antibody responses against wild-type yellow fever virus and the 17D vaccine strain: characterization with human monoclonal antibody fragments and neutralization escape variants.
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Human monoclonal antibody fragments neutralizing wild-type and vaccine strains of yellow fever (YF) virus (genotypes West Africa I + II, East/Central Africa, 17D-204-WHO) were generated by repertoire cloning from YF patients. Analysis of virus escape variants identified amino acid (aa) 71 in domain II of the envelope glycoprotein (E) as the most critical residue for neutralization, with aa 153-155 in domain I contributing to the epitope. These data confirm the previous mapping of YFV neutralizing epitopes using mouse monoclonal antibodies but suggest that a conformational epitope could be formed by amino acids from domains I and II opposing each other in the dimeric form of the E protein. While the sera of the YF patients showed up to 10-fold reduced neutralizing activity against the 17D escape variants, sera from 17D vaccinees retained their neutralizing titers. Mutations in this major neutralizing epitope of YFV thus do not seem to carry the risk of immune escape in persons immunized with the YFV-17D vaccine. (+info)
Attenuation of recombinant yellow fever 17D viruses expressing foreign protein epitopes at the surface.
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The yellow fever (YF) 17D vaccine is a live attenuated virus. Three-dimensional (3D) homology modeling of the E protein structure from YF 17D virus and its comparison with that from tick-borne encephalitis virus revealed that it is possible to accommodate inserts of different sizes and amino acid compositions in the flavivirus E protein fg loop. This is consistent with the 3D structures of both the dimeric and trimeric forms in which the fg loop lies exposed to solvents. We demonstrate here that YF 17D viruses bearing foreign humoral (17D/8) and T-cell (17D/13) epitopes, which vary in sequence and length, displayed growth restriction. It is hypothesized that interference with the dimer-trimer transition and with the formation of a ring of such trimers in order to allow fusion compromises the capability of the E protein to induce fusion of viral and endosomal membranes, and a slower rate of fusion may delay the extent of virus production. This would account for the lower levels of replication in cultured cells and of viremia in monkeys, as well as for the more attenuated phenotype of the recombinant viruses in monkeys. Testing of both recombinant viruses (17D/8 and 17D/13) for monkey neurovirulence also suggests that insertion at the 17D E protein fg loop does not compromise the attenuated phenotype of YF 17D virus, further confirming the potential use of this site for the development of new live attenuated 17D virus-based vaccines. (+info)
Reactogenicity of yellow fever vaccines in a randomized, placebo-controlled trial.
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OBJECTIVE: To compare the reactogenicity of three yellow fever (YF) vaccines from WHO-17D and Brazilian 17DD substrains (different seed-lots) and placebo. METHODS: The study involved 1,087 adults eligible for YF vaccine in Rio de Janeiro, Brazil. Vaccines produced by Bio-Manguinhos, Fiocruz (Rio de Janeiro, Brazil) were administered ("day 0") following standardized procedures adapted to allow blinding and blocked randomization of participants to coded vaccine types. Adverse events after immunization were ascertained in an interview and in diary forms filled in by each participant. Liver enzymes were measured on days 0, 4-20 and 30 of the study. Viremia levels were measured on days 4 to 20 of follow-up. The immune response was verified through serologic tests. RESULTS: Participants were mostly young males. The seroconversion rate was above 98% among those seronegative before immunization. Compared to placebo, the excess risk of any local adverse events ranged from 0.9% to 2.5%, whereas for any systemic adverse events it ranged from 3.5% to 7.4% across vaccine groups. The excess risk of events leading to search for medical care or to interruption of work activities ranged from 2% to 4.5%. Viremia was detected in 3%-6% of vaccinees up to 10 days after vaccination. Variations in liver enzyme levels after vaccination were similar in placebo and vaccine recipients. CONCLUSIONS: The frequency of adverse events post-immunization against YF, accounting for the background occurrence of nonspecific signs and symptoms, was shown for the first time to be similar for vaccines from 17D and 17DD substrains. The data also provided evidence against viscerotropism of vaccine virus. (+info)
Lymphocyte subset analyses in healthy adults vaccinated with yellow fever 17DD virus.
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In this study the kinetics of humoral and cellular immune responses in first-time vaccinees and re-vaccinees with the yellow fever 17DD vaccine virus was analyzed. Flow cytometric analyses were used to determine percentual values of T and B cells in parallel to the yellow fever neutralizing antibody production. All lymphocyte subsets analyzed were augmented around the 30th post vaccination day, both for first-time vaccinees and re-vaccinees. CD3+ T cells increased from 30.8% (SE +/- 4%) to 61.15% (SE +/- 4.2%), CD4+ T cells from 22.4% (SE +/- 3.6%) to 39.17% (SE +/- 2%) with 43% of these cells corresponding to CD4+CD45RO+ T cells, CD8+ T cells from 15.2% (SE +/- 2.9%) to 27% (SE +/- 3%) with 70% corresponding to CD8+CD45RO+ T cells in first-time vaccinees. In re-vaccinees, the CD3+ T cells increased from 50.7% (SE +/- 3%) to 80% (SE +/- 2.3%), CD4+ T cells from 24.9% (SE +/- 1.4%) to 40% (SE +/- 3%) presenting a percentage of 95% CD4+CD45RO+ T cells, CD8+ T cells from 19.7% (SE +/- 1.8%) to 25% (SE +/- 2%). Among CD8+CD38+ T cells there could be observed an increase from 15 to 41.6% in first-time vaccinees and 20.7 to 62.6% in re-vaccinees. Regarding neutralizing antibodies, the re-vaccinees presented high titers even before re-vaccination. The levels of neutralizing antibodies of first-time vaccinees were similar to those presented by re-vaccinees at day 30 after vaccination, indicating the success of primary vaccination. Our data provide a basis for further studies on immunological behavior of the YF 17DD vaccine. (+info)