Dataset Information

Analysis of Neutralizing Antibodies as a Correlate of Instantaneous Risk of Hospitalized Dengue in Placebo Recipients of Dengue Vaccine Efficacy Trials.

ABSTRACT:

Background

In the CYD14 (NCT01373281) and CYD15 (NCT01374516) dengue vaccine efficacy trials, month 13 neutralizing antibody (nAb) titers correlated inversely with risk of symptomatic, virologically confirmed dengue (VCD) between month 13 (1 month after final dose) and month 25. We assessed nAb titer as a correlate of instantaneous risk of hospitalized VCD (HVCD), for which participants were continually surveilled for 72 months.

Methods

Using longitudinal nAb titers from the per-protocol immunogenicity subsets, we estimated hazard ratios (HRs) of HVCD by current nAb titer value for 3 correlate/endpoint pairs: average titer across all 4 serotypes/HVCD of any serotype (HVCD-Any), serotype-specific titer/homologous HVCD, and serotype-specific titer/heterologous HVCD.

Results

Baseline-seropositive placebo recipients with higher average titer had lower instantaneous risk of HVCD-Any in 2- to 16-year-olds and in 9- to 16-year-olds (HR, 0.26 or 0.15 per 10-fold increase in average titer by 2 methods [95% confidence interval {CI}, .14-.45 and .07-.34, respectively]) pooled across both trials. Results were similar for homologous HVCD. There was evidence suggesting increased HVCD-Any risk in participants with low average titer (1:10 to 1:100) compared to seronegative participants (HR, 1.85 [95% CI, .93-3.68]).

Conclusions

Natural infection-induced nAbs were inversely associated with hospitalized dengue, upon exceeding a relatively low threshold.

SUBMITTER: Huang Y

PROVIDER: S-EPMC8915240 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

Analysis of Neutralizing Antibodies as a Correlate of Instantaneous Risk of Hospitalized Dengue in Placebo Recipients of Dengue Vaccine Efficacy Trials.

Huang Ying Y Williamson Brian D BD Moodie Zoe Z Carpp Lindsay N LN Chambonneau Laurent L DiazGranados Carlos A CA Gilbert Peter B PB

The Journal of infectious diseases 20220101 2

<h4>Background</h4>In the CYD14 (NCT01373281) and CYD15 (NCT01374516) dengue vaccine efficacy trials, month 13 neutralizing antibody (nAb) titers correlated inversely with risk of symptomatic, virologically confirmed dengue (VCD) between month 13 (1 month after final dose) and month 25. We assessed nAb titer as a correlate of instantaneous risk of hospitalized VCD (HVCD), for which participants were continually surveilled for 72 months.<h4>Methods</h4>Using longitudinal nAb titers from the per-p ...[more]

PMID: 34174082

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Project description:Any potential dengue virus (DENV) vaccine needs to elicit protective immunity against strains from all four serotypes to avoid potential antibody-dependent enhancement (ADE). In this study, four independent DENV envelope (E) glycoproteins were generated using wild-type E sequences from viruses isolated between 1943 and 2006 using computationally optimized broadly reactive antigen (COBRA) methodology. COBRA and wild-type E antigens were expressed on the surface of subvirion viral particles (SVPs). Four separate wild-type E antigens were used for each serotype. Mice vaccinated with wild-type DENV SVPs had anti-E IgG antibodies that neutralized serotype-specific viruses. COBRA DENV SVPs elicited a broader breadth of antibodies that neutralized strains across all four serotypes. Two COBRA DENV vaccine candidates that elicited the broadest breadth of neutralizing antibodies in mice were used to vaccinate rhesus macaques (Macaca mulatta) that either were immunologically naive to any DENV serotype or had preexisting antibodies to DENV. Antibodies elicited by COBRA DENV E immunogens neutralized all 12 strains of DENV in vitro, which was comparable to antibodies elicited by a tetravalent wild-type E SVP vaccination mixture. Therefore, using a single DENV COBRA E protein can elicit neutralizing antibodies against strains representing all four serotypes of DENV in both naive and dengue virus-preimmune populations.IMPORTANCE Dengue virus infects millions of people living in tropical areas of the world. Dengue virus-induced diseases can range from mild to severe with death. An effective vaccine will need to neutralize viruses from all four serotypes of dengue virus without inducing enhanced disease. A dengue virus E vaccine candidate generated by computationally optimized broadly reactive antigen algorithms elicits broadly neutralizing protection for currently circulating strains from all four serotypes regardless of immune status. Most dengue vaccines in development formulate four separate components based on prM-E from a wild-type strain representing each serotype. Designing a monovalent vaccine that elicits protective immunity against all four serotypes is an effective and economical strategy.

Dataset Information

Analysis of Neutralizing Antibodies as a Correlate of Instantaneous Risk of Hospitalized Dengue in Placebo Recipients of Dengue Vaccine Efficacy Trials.

Background

Methods

Results

Conclusions

Publications

Analysis of Neutralizing Antibodies as a Correlate of Instantaneous Risk of Hospitalized Dengue in Placebo Recipients of Dengue Vaccine Efficacy Trials.

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