Early transcriptional responses after dengue vaccination mirror the response to natural infection and predict neutralizing antibody titers

Abstract

BackgroundSeveral promising live attenuated virus (LAV) dengue vaccines are in development, but information about innate immune responses and early correlates of protection are lacking.\n\nMethodsWe characterized human genome-wide transcripts in whole blood from 10 volunteers at 11 time-points after immunization with the dengue virus type 3 (DENV-3) component of the NIH dengue vaccine candidate TV003 and from 30 hospitalized children with acute primary DENV-3 infection. We compared day-specific gene expression patterns with subsequent neutralizing antibody (NAb) titers.\n\nResultsThe transcriptional response to vaccination was largely confined to days 5-20 and was dominated by an interferon-associated signature and a cell cycle signature that peaked on days 8 and 14, respectively. Changes in transcript abundance were much greater in magnitude and scope in symptomatic natural infection than following vaccination (maximum fold-change >200 versus 21 post-vaccination; 3,210 versus 286 transcripts with significant fold-change), but shared gene modules were induced in the same sequence. The abundance of 131 transcripts on days 8 and 9 post-vaccination was strongly correlated with NAb titers measured 6 weeks post-vaccination.\n\nConclusionsLAV dengue vaccination elicits early transcriptional responses that mirror those found in symptomatic natural infection and provide candidate early markers of protection against DENV infection.\n\nClinical Trial Registration Number: NCT00831012 (available at clinicaltrials.gov)\n\nSummary: Interferon- and cell cycle-associated gene transcript abundance levels in the peripheral blood of dengue vaccine recipients on days 8 and 9 post-vaccination were associated with dengue neutralizing antibody titers on day 42, and mirrored responses in primary dengue infection, suggesting the possibility of predicting protective immunity.