Analyzing the Human Serum Antibody Responses to a Live Attenuated Tetravalent Dengue Vaccine Candidate

Swanstrom, Jesica; Henein, Sandra; Plante, Jessica A.; Yount, Boyd; Widman, Douglas G.; Gallichotte, Emily N.; Dean, Hansi; Osorio, Jorge E.; Partidos, Charalambos D.; Silva, Aravinda M. de; Baric, Ralph S.

doi:10.1093/infdis/jiy063

Cited by 25 publications

(19 citation statements)

References 34 publications

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“…In a previous study, we analyzed specimens from Takeda studies 104 and 203 to understand the specificity of vaccine induced serum Nabs in individuals who were DENV seronegative or seropositive at baseline (34). In individuals who were seronegative at baseline, we observed high levels of DENV2 Nabs that tracked with TS epitopes on serotype 2.…”

Section: Discussionmentioning

confidence: 91%

Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

White

Young

Stoops

et al. 2020

Preprint

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The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naïve adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. We conclude that the DENV2 component in the vaccine is immunodominant because of the high levels of serum neutralizing antibodies targeting type-specific epitopes. We also conclude that DENV1, 3 and 4 vaccine components are less immunogenic because most study subjects did not develop type-specific serum neutralizing antibodies to these serotypes. While DENV vaccine development has been guided by the presence of neutralizing antibodies to each serotype as a benchmark, our results indicate that the presence of neutralizing antibodies alone are not a reliable indicator of the immunogenicity of each vaccine component.Author summaryThe development of tetravalent dengue vaccines has been guided by neutralizing antibodies to each serotype as a correlate of safe and effective vaccine induced immunity. However, the absolute levels of neutralizing antibodies to each serotype has proven to be an unreliable correlate of protection. Levels of antibodies to epitopes that are unique to each serotype, which are measures of immunity independently stimulated by each vaccine component, rather than total quantity of neutralizing antibodies, are likely to be better correlates of protection. Here, we mapped the specificity of antibodies induced by the Takeda tetravalent dengue vaccine TAK-003 in monkeys and humans with no prior immunity to dengue. The TAK-003 vaccine induces high levels of serotype 2 specific neutralizing antibodies that map to known protective epitopes. In contrast, the serotype 1, 3 and 4 neutralizing antibody responses are lower and mainly consist of cross-reactive antibodies binding to epitopes conserved between serotypes. These heterotypic antibodies, which are most likely derived from the serotype 2 component, may not provide long term protection in vivo.

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Section: Discussionmentioning

confidence: 91%

Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

White

Young

Stoops

et al. 2020

Preprint

Self Cite

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“…Human sera or MAbs were serially diluted 3-fold and mixed with sufficient virus to cause 15% infection in U937 cells expressing dendritic cell-specific Intercellular adhesion molecule-3-Grabbing Non-Integrin (U937+DC-SIGN) or 50 foci per well in Vero-81 cells. Assays were performed as previously described by our group [32, 33]. Using the 50% neutralization (Neut 50 ) titers, the percentage of cross-reactive (CR) and type-specific (TS) nAbs against each serotype were calculated using the following formulas:…”

Section: Methodsmentioning

confidence: 99%

Beyond Neutralizing Antibody Levels: The Epitope Specificity of Antibodies Induced by National Institutes of Health Monovalent Dengue Virus Vaccines

Swanstrom

Nivarthi

Patel

et al. 2019

The Journal of Infectious Diseases

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“…It is thus unsurprising that we observed no correlation between ED III ELISA results and 13month neutralization titers, although our phage display results do suggest sero-reactivity to parts of NS3 and NS5 as candidate biomarkers. The functional significance of the differential sero-reactivity to EDIII we observe is unclear, but at least two DENV vaccine do appear to target this region and interest remains in EDIII-based vaccination strategies (33,34) (35)(36)(37). Finally, independent of its role in neutralization, the fact that the region we identify contains multiple reported Class I epitopes does support its immunological relevance.…”

Section: Discussionmentioning

confidence: 80%

Inoculation by mosquito induces durable differences in serological profile in non-human primates infected with DENV1

Rajan

McCracken

Mandel‐Brehm

et al. 2020

Preprint

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Natural dengue virus (DENV) infections are delivered by mosquito bite but how the route of inoculation route could shape the humoral immune response is not well understood. Here, we serologically profiled 20 non-human primates (NHP) from a prior study of DENV1 infection in which the animals were inoculated by mosquito (N=10) or subcutaneous injection (N=10). Using a comprehensive, densely tiled and highly redundant pan-flavivirus programmable phage library containing 91,562 overlapping 62 amino acid peptides, we produced a high-resolution map of linear peptide sequences enriched during DENV seroconversion. We found that serological profiles in mosquito-inoculated and subcutaneously-inoculated animals were similar up to 90 days after primary infection, but diverged at 1 year. We found differences in sero-reactivity, as indicated by the median area under the curve (AUC) in the Envelope (E; residues 215-406; p < 0.08), and Nonstructural-3 (NS3; residues 549-615; p < 0.05) proteins in mosquito-inoculated versus subcutaneously-inoculated animals. Within the E protein, residues 339-384 in domain III accounted for >99% of the total AUC difference across residues 215-406. Antibody breadth did not vary by mode of inoculation. The differential reactivity to E domain III (EDIII) seen by phage display validated orthogonally by ELISA, but did not correlate with late neutralization titers. Serological profiling of humoral immune responses to DENV infection in NHP by programmable phage display demonstrated durable differences in sero-reactivity by route of inoculation. These findings could have implications for DENV diagnostics and evaluation of vaccines.

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Analyzing the Human Serum Antibody Responses to a Live Attenuated Tetravalent Dengue Vaccine Candidate

Abstract: Here we provide qualitative measures of the magnitude and epitope specificity of the nAb responses to TDV. This information will be useful for understanding the performance of TDV in clinical trials and for identifying correlates of protective immunity.

Cited by 25 publications

References 34 publications

Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

Beyond Neutralizing Antibody Levels: The Epitope Specificity of Antibodies Induced by National Institutes of Health Monovalent Dengue Virus Vaccines

Inoculation by mosquito induces durable differences in serological profile in non-human primates infected with DENV1

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