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GlaxoSmithKline Biologicals S.A. (Rixensart, Belgium) under a Cooperative Research and Development Agreement with Fiocruz(Rio de Janeiro, Brazil). GlaxoSmithKline Biologicals S.A. was involved in the study design, data collection and analysis, decision to publish and preparation of the manuscript. PFCV was partially supported by MoH and CNPq (457664/2013-4 and 303999/ 2016-0) Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. GSK. Rockville, Maryland, United States of America. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. GSK. Rockville, Maryland, United States of America. GSK. Rockville, Maryland, United States of America. GSK. Rixensart, Belgium. GSK. Rixensart, Belgium. GSK. Rixensart, Belgium. Funda??o Oswaldo Cruz. Rio de Janeiro, RJ, Brazil. GSK. Rixensart, Belgium. The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model?s predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-? and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans.

BACKGROUND: Unprecedented spread between birds and mammals of highly pathogenic avian influenza viruses (HPAI) of the H5N1 subtype has resulted in hundreds of human infections with a high fatality rate. This has highlighted the urgent need for the development of H5N1 vaccines that can be produced rapidly and in sufficient quantities. Potential pandemic inactivated vaccines will ideally induce substantial intra-subtypic cross-protection in humans to warrant the option of use, either prior to or just after the start of a pandemic outbreak. In the present study, we evaluated a split H5N1 A/H5N1/Vietnam/1194/04, clade 1 candidate vaccine, adjuvanted with a proprietary oil-in- water emulsion based Adjuvant System proven to be well-tolerated and highly immunogenic in the human (Leroux-Roels et al. (2007) The Lancet 370:580-589), for its ability to induce intra-subtypic cross-protection against clade 2 H5N1/A/Indonesia/5/05 challenge in ferrets. METHODOLOGY AND PRINCIPAL FINDINGS: All ferrets in control groups receiving non-adjuvanted vaccine or adjuvant alone failed to develop specific or cross-reactive neutralizing antibodies and all died or had to be euthanized within four days of virus challenge. Two doses of adjuvanted split H5N1 vaccine containing >or=1.7 microg HA induced neutralizing antibodies in the majority of ferrets to both clade 1 (17/23 (74%) responders) and clade 2 viruses (14/23 (61%) responders), and 96% (22/23) of vaccinees survived the lethal challenge. Furthermore lung virus loads and viral shedding in the upper respiratory tract were reduced in vaccinated animals relative to controls suggesting that vaccination might also confer a reduced risk of viral transmission. CONCLUSION: These protection data in a stringent challenge model in association with an excellent clinical profile highlight the potential of this adjuvanted H5N1 candidate vaccine as an effective tool in pandemic preparedness.