Characterization of the Type-Specific and Cross-Reactive B-Cell Responses Elicited by a Live-Attenuated Tetravalent Dengue Vaccine

• Published in: The Journal of infectious diseases 2021-02, Vol.223 (2), p.247-257
• Main Authors: Michlmayr, Daniela, Andrade, Paulina, Nascimento, Eduardo J M, Parker, Allan, Narvekar, Parnal, Dean, Hansi J, Harris, Eva
• Format: Article
• Language: English
• Subjects: Clinical trials; Dengue fever; Immunization; Immunological memory; Leukocytes (mononuclear); Lymphocytes B; Memory cells; Peripheral blood mononuclear cells; Quantitation; Serotypes; Vaccination; Vaccines
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jiaa346

Abstract Background Dengue is caused by 4 antigenically distinct serotypes of dengue virus (DENV1–4). Takeda’s live attenuated tetravalent dengue vaccine (TAK-003) candidate is composed of an attenuated DENV2 and chimeric viruses containing prM/E of DENV1, 3 and 4 on the DENV2 backbone. The multicolor FluoroSpot (MCF) assay enables quantitation of serotype-specific and cross-reactive individual memory B cells (MBCs) secreting DENV-specific antibodies in a polyclonal mixture. Methods Using the MCF assay, we determined the type-specific and cross-reactive MBC response in peripheral blood mononuclear cells collected pre- and postvaccination from 7 macaques and 15 randomly selected individuals who received TAK-003 (8 DENV seronegative and 7 DENV seropositive) in a phase 2 clinical trial in Singapore (DEN-205 study). Results Preexisting DENV-specific MBC responses were detected only in seropositive vaccine recipients at day 0. Following vaccination, both type-specific and cross-reactive MBCs to all 4 DENV serotypes were observed in all macaques and clinical trial participants. The proportion of type-specific MBCs was higher than cross-reactive MBCs and remained stable between day 30 and 360 post vaccination. Conclusions These results demonstrate that, unlike primary or secondary natural DENV infection, tetravalent vaccination elicits tetravalent type-specific MBCs, and thus all 4 components of TAK-003 contribute to the DENV-specific MBC response following vaccination. Clinical Trials Registration NCT02425098. Multicolor FluoroSpot was used for single-cell analysis of polyclonal memory B cells (MBCs) in recipients of Takeda’s tetravalent dengue virus (DENV) vaccine. Both type-specific and cross-reactive MBCs to all 4 DENV serotypes were observed in macaques and clinical trial participants.