Detection of post-vaccination enhanced dengue virus infection in macaques: An improved model for early assessment of dengue vaccines.

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.

Assessment of Prime-boost Vaccination Using an AS03B-adjuvanted Influenza A (H5N1) Vaccine: A Randomized Trial in Children of Three to Less Than Eighteen Years of Age.

BACKGROUND: Heterologous prime-boost vaccination is a pandemic response strategy utilizing subtype-matched vaccine at pandemic onset followed by strain-matched vaccine once available. Persistence of immune response and safety of influenza A (H5N1) vaccine adjuvanted with adjuvant system containing α-tocopherol and squalene in an oil-in-water emulsion (AS03B) were evaluated. METHODS: An open phase 3 active-controlled study (www.clinicaltrials.gov NCT01379937) assessed immunogenicity and reactogenicity of a heterologous booster dose of A/turkey/Turkey/1/2005-H5N1-AS03B in children 3 to <18 years of age, given 6 months after 2-dose priming with A/Indonesia/05/2005-H5N1-AS03B (H5N1(2) -H5N1 group) compared with a single dose of A/turkey/Turkey/1/2005-H5N1-AS03B in unprimed subjects (hepatitis A vaccine (HAV)-H5N1 group). Hemagglutinin inhibition responses and microneutralization antibodies were assessed to 6 months after booster vaccination. RESULTS: Hemagglutinin inhibition antibody responses against A/turkey/Turkey/1/2005-H5N1 were superior in the H5N1(2)-H5N1 versus the hepatitis A vaccine-H5N1 group overall and in each age strata (3 to <10 and 10 to <18 years). Anamnestic immune responses were demonstrated against vaccine-homologous/heterologous strains in the H5N1(2)-H5N1 group. Injection site pain and fever increased with consecutive doses for children <6 years (H5N1(2)-H5N1). Immune responses to vaccine-homologous/heterologous strains persisted to 6 months after booster vaccination in the H5N1(2)-H5N1 group. CONCLUSIONS: Heterologous H5N1-AS03B-adjuvanted booster vaccination in children/adolescents was immunogenic for vaccine-homologous and heterologous strains following 2-dose priming, with immune persistence for at least 6 months. Prime-boost strategies using H5N1-AS03 could be effectively employed in this age group.

Burden of symptomatic dengue infection in children at primary school in Thailand: a prospective study.

BACKGROUND: Dengue viruses are a major cause of morbidity and mortality in tropical and subtropical areas. Our aim was to assess prospectively the burden of dengue-related illness in children in Thailand. METHODS: We did a prospective study in a cohort of children at primary school in northern Thailand from 1998 to 2002. We assessed the burden of dengue illness as disability-adjusted life years (DALYs) and patient costs per illness. FINDINGS: Dengue accounted for 328 (11%) of the 3056 febrile cases identified in 2114 children during the study period. The mean burden of dengue was 465.3 (SD 358.0; range 76.5-954.0) DALYs per million population per year, accounting for about 15% of DALYs lost to all febrile illnesses (3213.1 [SD 2624.2] DALYs per million per year). Non-hospitalised patients with dengue illnesses represented a substantial proportion of the overall burden of disease, with 44-73% of the total DALYs lost to dengue each year due to such illness. The infecting dengue serotype was an important determinant of DALYs lost: DEN4 was responsible for 1% of total DALYs lost, DEN1 for 9%, DEN2 for 30%, and DEN3 for 29%. INTERPRETATION: Use of prospective data to estimate the burden of disease shows that most DALYs lost to dengue illness were the result of non-hospitalised illnesses of long duration. Thus, inclusion of non-hospitalised cases is critical to accurately assess the total burden of dengue illness.