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Pediatric measles vaccine expressing a dengue antigen induces durable serotype-specific neutralizing antibodies to dengue virus.

ABSTRACT: Dengue disease is an increasing global health problem that threatens one-third of the world's population. Despite decades of efforts, no licensed vaccine against dengue is available. With the aim to develop an affordable vaccine that could be used in young populations living in tropical areas, we evaluated a new strategy based on the expression of a minimal dengue antigen by a vector derived from pediatric live-attenuated Schwarz measles vaccine (MV). As a proof-of-concept, we inserted into the MV vector a sequence encoding a minimal combined dengue antigen composed of the envelope domain III (EDIII) fused to the ectodomain of the membrane protein (ectoM) from DV serotype-1. Immunization of mice susceptible to MV resulted in a long-term production of DV1 serotype-specific neutralizing antibodies. The presence of ectoM was critical to the immunogenicity of inserted EDIII. The adjuvant capacity of ectoM correlated with its ability to promote the maturation of dendritic cells and the secretion of proinflammatory and antiviral cytokines and chemokines involved in adaptive immunity. The protective efficacy of this vaccine should be studied in non-human primates. A combined measles-dengue vaccine might provide a one-shot approach to immunize children against both diseases where they co-exist.

SUBMITTER: Brandler S

PROVIDER: S-EPMC2154386 | biostudies-literature | 2007

REPOSITORIES: biostudies-literature

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Pediatric measles vaccine expressing a dengue antigen induces durable serotype-specific neutralizing antibodies to dengue virus.

Brandler Samantha S Lucas-Hourani Marianne M Moris Arnaud A Frenkiel Marie-Pascale MP Combredet Chantal C Février Michèle M Bedouelle Hugues H Schwartz Olivier O Desprès Philippe P Tangy Frédéric F

PLoS neglected tropical diseases 20071212 3

Dengue disease is an increasing global health problem that threatens one-third of the world's population. Despite decades of efforts, no licensed vaccine against dengue is available. With the aim to develop an affordable vaccine that could be used in young populations living in tropical areas, we evaluated a new strategy based on the expression of a minimal dengue antigen by a vector derived from pediatric live-attenuated Schwarz measles vaccine (MV). As a proof-of-concept, we inserted into the ...[more]

PMID: 18160988

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Project description:UnlabelledDengue virus serotype 2 (DENV2) is widespread and responsible for severe epidemics. While primary DENV2 infections stimulate serotype-specific protective responses, a leading vaccine failed to induce a similar protective response. Using human monoclonal antibodies (hMAbs) isolated from dengue cases and structure-guided design of a chimeric DENV, here we describe the major site on the DENV2 envelope (E) protein targeted by neutralizing antibodies. DENV2-specific neutralizing hMAb 2D22 binds to a quaternary structure epitope. We engineered and recovered a recombinant DENV4 that displayed the 2D22 epitope. DENV2 neutralizing antibodies in people exposed to infection or a live vaccine tracked with the 2D22 epitope on the DENV4/2 chimera. The chimera remained sensitive to DENV4 antibodies, indicating that the major neutralizing epitopes on DENV2 and -4 are at different sites. The ability to transplant a complex epitope between DENV serotypes demonstrates a hitherto underappreciated structural flexibility in flaviviruses, which could be harnessed to develop new vaccines and diagnostics.ImportanceDengue virus causes fever and dengue hemorrhagic fever. Dengue serotype 2 (DENV2) is widespread and frequently responsible for severe epidemics. Natural DENV2 infections stimulate serotype-specific neutralizing antibodies, but a leading DENV vaccine did not induce a similar protective response. While groups have identified epitopes of single monoclonal antibodies (MAbs), the molecular basis of DENV2 neutralization by polyclonal human immune sera is unknown. Using a recombinant DENV displaying serotype 2 epitopes, here we map the main target of DENV2 polyclonal neutralizing antibodies induced by natural infection and a live DENV2 vaccine candidate. Proper display of the epitope required the assembly of viral envelope proteins into higher-order structures present on intact virions. Despite the complexity of the epitope, it was possible to transplant the epitope between DENV serotypes. Our findings have immediate implications for evaluating dengue vaccines in the pipeline as well as designing next-generation vaccines.

Project description:BackgroundAntibodies are critical responses to protect the host from dengue virus(DENV) infection. Antibodies target DENV by two pathologic mechanisms: virus neutralization and infection enhancement. In dengue patients, the absence of neutralizing activity in the presence of FcγR implies that infection-enhancing activity hampers the neutralizing activity of antibodies, which could potentially lead to symptomatic presentations and severe clinical outcomes.MethodsA total of 100 pair serum samples from adult healthy volunteers were obtained during the dengue season in Ha Noi in 2015 for evaluation of neutralizing and infection-enhancing activity. Additionally, 20 serum samples from acute secondary DENV infection patients were also used as the patient group in this study. PRNT was performed on BHK cells and FcγR-expressing BHK cell lines for all serum samples.ResultsOut of 100 residents, positive neutralizing antibodies (N.A) were found in 44.23 and 76.92% for DENV-1; 38.46 and 75% for DENV-2; 19.23 and 15.38% for DENV-3; and 1.92 and 9.62% for DENV-4 for pre and post-dengue season respectively. The percentage of post-exposure residents having positive responses against single, two, or more than three DENV serotypes were 38.46, 44.23 and 15.38%, respectively. A total of 34 residents were DENV seropositive before the dengue season and these individuals demonstrated further elevation of IgG antibodies after the dengue season. At the end of the season, 18 residents were confirmed to be new asymptomatic DENV infection cases. In both groups, N.A titers determined on BHK cells were higher than that on FcγR-expressing BHK cells. In heterotypic N.A responses, N.A titers to the infecting serotype from the samples obtained from pre-exposure group were significantly higher than those of the patient group. However, fold enhancement to the infecting serotypes from the samples in the pre-exposure group was substantially lower as compared to that of the patient group.ConclusionBefore and after the dengue season, serum samples from healthy volunteers demonstrated high levels of neutralizing antibodies and low or absence of infection-enhancement activity. The results suggest that while infection-enhancement activity hampers neutralizing activity of antibodies, high levels of DENV neutralizing antibodies set a critical threshold in facilitating the prevention of disease progression.

Dataset Information

Pediatric measles vaccine expressing a dengue antigen induces durable serotype-specific neutralizing antibodies to dengue virus.

Publications

Pediatric measles vaccine expressing a dengue antigen induces durable serotype-specific neutralizing antibodies to dengue virus.

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