Detection of post-vaccination enhanced dengue virus infection in macaques: An improved model for early assessment of dengue vaccines

Abstract

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro ), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.

Cell-Mediated Immunity Generated in Response to a Purified Inactivated Vaccine for Dengue Virus Type 1

“…While the data presented here suggest that PIV-1 vaccination induces a T cell response that is similar to that induced by other vaccines known to confer protection, whether the PIV-1 product, or its tetravalent counterpart (51), is efficacious for preventing dengue is unknown. Previous studies in nonhuman primates demonstrated that tetravalent PIV vaccination followed by live DENV challenge resulted in most animals developing breakthrough RNAemia (52). In that same study, individual animals showed higher viremia than unvaccinated controls as well as differences from the unvaccinated controls in cytokine responses; the low number of animals with enhanced viremia prevented statistically significant conclusions, but in light of the Dengvaxia experience, this finding is of potential concern.…”

Route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in rhesus macaques

“…[22] Furthermore, we showed that when assessing vaccine efficacy by combining viremia and RNAemia measurement with characterization of changes in relevant biological markers, safety signals associated with a dengue vaccine could be detected in the SC-inoculated macaque model. [23] However, despite these improvements, the model did not demonstrate clinical signs, and viremia/RNAemia, onset of which occurred 1-2 days post-challenge, remained low both in terms of magnitude and duration compared to viremia/RNAemia reported in severe dengue patients.…”

Safety and Immunogenicity of an AS03B-Adjuvanted Inactivated Tetravalent Dengue Virus Vaccine Administered on Varying Schedules to Healthy U.S. Adults: A Phase 1/2 Randomized Study

“…Although improvements following non-human primate assessments of CYD-TDV and DPIV+AS03 B have been noted, the studies also suggest a risk of enhanced viremia and disease many months following vaccination. 11,12 Two DPIV+AS03 B doses administered 1 M apart were well tolerated and induced robust neutralizing antibody (Nab) titers against all four DENV types in dengue-seronegative 13 and dengue-seropositive adults. 14 Although antibody titers waned considerably within 6 M after vaccination in seronegative participants, 13 they remained high in seropositive participants.…”