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

Abstract

199 words 29 Text: 3501 words (not including Acknowledgements) 30 31 Summary: Interferon-and cell cycle-associated gene transcript abundance levels in the 32 peripheral blood of dengue vaccine recipients on days 8 and 9 post-vaccination were associated 33 with dengue neutralizing antibody titers on day 42, and mirrored responses in primary dengue 34 infection, suggesting the possibility of predicting protective immunity. 35 36 3 ABSTRACT 37 38 Background: Several promising live attenuated virus (LAV) dengue vaccines are in 39 development, but information about innate immune responses and early correlates of protection 40 are lacking.41 Methods: We characterized human genome-wide transcripts in whole blood from 10 volunteers 42 at 11 time-points after immunization with the dengue virus type 3 (DENV-3) component of the 43 NIH dengue vaccine candidate TV003 and from 30 hospitalized children with acute primary 44 DENV-3 infection. We compared day-specific gene expression patterns with subsequent 45 neutralizing antibody (NAb) titers. 46Results: The transcriptional response to vaccination was largely confined to days 5-20 and was 47 dominated by an interferon-associated signature and a cell cycle signature that peaked on days 48 8 and 14, respectively. Changes in transcript abundance were much greater in magnitude and 49 scope in symptomatic natural infection than following vaccination (maximum fold-change >200 50 versus 21 post-vaccination; 3,210 versus 286 transcripts with significant fold-change), but 51 shared gene modules were induced in the same sequence. The abundance of 131 transcripts 52 on days 8 and 9 post-vaccination was strongly correlated with NAb titers measured 6 weeks 53 post-vaccination.54 Conclusions: LAV dengue vaccination elicits early transcriptional responses that mirror those 55 found in symptomatic natural infection and provide candidate early markers of protection against 56 DENV infection.57 58 Clinical Trial Registration Number: NCT00831012 (available at clinicaltrials.gov) 59 60 of protection; interferon; neutralizing antibody 61 62 4 BACKGROUND 63 Each year, the four dengue virus serotypes (DENV-1-4) infect an estimated 390 million 64 individuals globally [1]. While most of these infections are asymptomatic, approximately 100 65 million individuals develop clinically apparent disease, from uncomplicated fever to life-66 threatening illness. Despite the high disease burden, there are no licensed therapeutics for 67 DENV infection. Several promising candidate dengue vaccines are in Phase III clinical trials, 68 and the live attenuated chimeric dengue vaccine Dengvaxia™ was recently licensed for use in 69 children 9 years of age and older in DENV endemic areas. However, the efficacy and duration 70 of protection were limited or uncertain, and DENV-naïve vaccine recipients were hospitalized for 71 dengue and severe dengue at a higher rate than placebo recipients, possibly due to antibody-72 dependent enhancement (ADE) [2]. 73 Studies of natural DENV infection and flavivirus LAVs have identifi...

Transcriptomic signatures induced by the Ebola virus vaccine rVSVΔG-ZEBOV-GP in adult cohorts in Europe, Africa, and North America: a molecular biomarker study

“…Interestingly, only the IFN-inducible gene IFI6 correlated positively with ZEBOV-GP-specific antibody titres. Consistent with our results, enrichment of IFN-signalling transcripts correlated with antibody titres after vaccination against influenza, 29,36 malaria, 37 dengue, 38 rubella, 39 and Ebola. 22 These results might be explained by the fact that IFNα and IFNβ, normally activated during infections or immunisations, also execute immunoregulatory activities, being able to modify the adaptive immune system by direct T-cell and B-cell activation, thereby enhancing the production of specific antibodies.…”

Integrative systems vaccinology identification of shared gene signatures between natural dengue infection and vaccination trials

“…Thus, our approach is part of a growing area of research that has provided a global picture of the host response to vaccination, identifying immunological signatures that can predict the immunogenicity of vaccines 26,50 . To date, several studies have characterized the immune response of dengue-infected patients or individuals enrolled in recent DVTs [51][52][53][54] . However, there is a growing effort to characterize molecular alterations and their association with disease phenotypes through multi-study cohorts to unravel consistent immunological signatures during dengue infection.…”