Closer is better

From the Gilbert group, Vaccine and Infectious Disease Division
Image of a Dengue viral particle and its cross section. Image from wiki commons.

Dengue virus (DENV) is a mosquito borne pathogen that infects humans and horses. It causes mild to severe disease with potentially deadly hemorrhagic fever being the most extreme. There are four serotypes of DENV (1-4) and multiple genotypes within each serotype. This makes treatment and prevention difficult. Each serotype differs sufficiently to allow for repeat infections with different serotypes in one person. Another caveat with DENV infection is that secondary infection is often more severe than primary due to antibody dependent enhancement, which is when antibody recognition increases viral entry into cells. With the warming of the global climate and thus the spread of Aedes aegypti mosquitoes, the reservoir, DENV presents a global threat. To combat the spread, Sanofi Pasteur created a recombinant live attenuated tetravalent dengue vaccine that has been tested in two phase 3 clinical trials, showing 60% vaccine efficacy. This vaccine consists of four recombinant viruses each containing one of the four DENV serotypes. In a retrospective study, researchers from the Gilbert group in Vaccine and Infectious Disease Division at Fred Hutch assessed the serotype-specific vaccine efficacy in these two trials, matching end point virus (virus serotype that infected participants) with vaccine serotype.

In a study published in the journal Proceedings of the National Academy of Sciences the group conducted a sieve analysis of data from the two trials. A sieve analysis can be used to assess how vaccine efficacy differs between vaccine-matched versus vaccine-mismatched genotypes. This can be focused on whole genotype, a known epitope or a specific set of amino acids. Sieve analysis of the DENV vaccine revealed statistically greater vaccine efficacy in DENV3 and DENV4 compared to DENV 1 and DENV2 and overall reduction with more mismatched residues. However, this could be attributed to the fact that DENV3 and DENV4 in the vaccine were more closely matched with the currently circulating strain of DENV than DENV1 or DENV2. Further breaking down the mismatches into genotypes, the sieve analysis demonstrated that infection with DENV4-II genotype, which matched the vaccine genotype, led to better outcomes. The authors also found specific residues within this genotype that were important for this increased efficacy and attributed them to potential protective epitopes.

This suggests that vaccines that produce antibodies targeting these specific epitopes could increase overall protective effect of the vaccine. Regarding this finding Dr. Juraska states, “We also found eight dengue amino acid signature sites with differential vaccine efficacies against DENV4, which generated novel hypotheses about amino acid residues that are part of protective epitopes. These results led to a collaboration with Dr. Aravinda de Silva’s immunology group at UNC Chapel Hill, and they are in the process of conducting follow-up experiments, guided by our amino acid signature findings, to directly test the role of single amino acid residues and combinations of residues in viral neutralization escape. This research holds promise for guiding design of improved dengue vaccines that can confer greater protection, especially in young children”. Another caveat of this analysis is the fact that baseline serostatus is known to have an effect on vaccine outcome. Because this information was not known at the time of the trial but assumed instead, it was not taken into account and could thus also influence the vaccine efficacy outside the sieve analysis. In conclusion, Dr. Juraska states, “This paper studied how vaccine efficacy in these trials varied based on features of dengue amino acid sequences from the several-hundred observed primary dengue disease cases. We found that amino acid sequence match between vaccine strains and circulating strains was important for achieving high vaccine efficacy because it was lower against dengue viruses more distant in their sequence to the 4 dengue strains represented in the vaccine.”

Juraska M, Magaret CA,  Shao J, Carpp LN, Fiore-Gartland AJ, Benkeser D, Girerd-Chambaz Y, Langevin E, Frago C, Guy B, Jackson N, Duong Thi Hue K, Simmons CP, Edlefsen PT, Gilbert PB. 2018. Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials. Proceedings of the National Academy of Sciences. 4;115(36):E8378-E8387.

Funding was provided by the National Institutes of Health and Sanofi Pasteur.   

Fred Hutch/UW Cancer Consortium faculty members Paul Edlefsen and Peter Gilbert contributed to this work.