Abstract
The four-dengue virus (DENV) serotypes infect several hundred million people annually. For the greatest safety and efficacy, tetravalent DENV vaccines are designed to stimulate balanced protective immunity to all four serotypes. However, this has been difficult to achieve. Clinical trials with a leading vaccine demonstrated that unbalanced replication and immunodominance of one vaccine component over others can lead to low efficacy and vaccine enhanced severe disease. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a live attenuated tetravalent DENV vaccine (TV003), which is currently being tested in phase 3 clinical trials. Here we report, our study to determine if TV003 stimulate balanced and serotype-specific (TS) neutralizing antibody (nAb) responses to each serotype. Serum samples from twenty-one dengue-naive individuals participated under study protocol CIR287 (ClinicalTrials.gov NCT02021968) are analyzed 6 months after vaccination. Most subjects (76%) develop TS nAbs to 3 or 4 DENV serotypes, indicating immunity is induced by each vaccine component. Vaccine-induced TS nAbs map to epitopes known to be targets of nAbs in people infected with wild type DENVs. Following challenge with a partially attenuated strain of DENV2, all 21 subjects are protected from the efficacy endpoints. However, some vaccinated individuals develop post challenge nAb boost, while others mount post-challenge antibody responses that are consistent with sterilizing immunity. TV003 vaccine induced DENV2 TS nAbs are associated with sterilizing immunity. Our results indicate that nAbs to TS epitopes on each serotype may be a better correlate than total levels of nAbs currently used for guiding DENV vaccine development.
Highlights
The four-dengue virus (DENV) serotypes infect several hundred million people annually
A TS response is the fraction of Abs against a particular serotype that remained after using heterologous DENV serotypes to remove all cross-reactive Abs
When the sample was depleted using a mix of DENV1, 3 and 4 antigens, we observed complete loss of DENV1, 3 and 4, but not DENV2 binding and neutralizing antibody (nAb) indicating that the subject had DENV2 TS Abs (Fig. 1a, b)
Summary
The four-dengue virus (DENV) serotypes infect several hundred million people annually. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a live attenuated tetravalent DENV vaccine (TV003), which is currently being tested in phase 3 clinical trials. In Dengvaxia clinical trials, vaccine efficacy was highest against DENV414,22 These observations indicate that independent replication of each vaccine component above a threshold is required for protection. We analyze immune serum samples from subjects who received a live-attenuated tetravalent DENV vaccine to test if DENV serotype-specific Abs, which are linked to the balanced replication and immunogenicity of each vaccine component are elicited by the vaccine. The vaccinated subjects were challenged with a partially attenuated strain of DENV2 to determine if the binding specificity of vaccine-induced nAbs is a better correlate of protection than the total level of nAbs currently used for vaccine evaluation
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