A randomized, placebo-controlled, blinded phase 1 study investigating a novel inactivated, Vero cell-culture derived Zika virus vaccine.

BACKGROUND: Zika virus (ZIKV) is an emerging public health threat, rendering development of a safe and effective vaccine against the virus a high priority to face this unmet medical need. Our vaccine candidate has been developed on the same platform used for the licensed vaccine IXIARO®, a vaccine against Japanese Encephalitis virus, another closely related member of the Flaviviridae family. METHODS: Between February 24, 2018 and November 16, 2018, we conducted a randomized, observer-blinded, placebo controlled, single center phase 1 study to assess the safety and immunogenicity of an adjuvanted, inactivated, purified whole-virus Zika vaccine candidate in the U.S. A total of 67 healthy flavivirus-naïve adults aged 18 to 49 years were randomly assigned to one of five study arms to receive two immunizations of either high dose or low dose (6 antigen units or 3 antigen units) with both dose levels applied in two different immunization regimens or placebo as control. RESULTS: Our vaccine candidate showed an excellent safety profile independent of dose and vaccination regimen with predominantly mild adverse events. No serious adverse event has been reported. The ZIKV vaccine induced neutralizing antibodies in all tested doses and regimens with seroconversion rates up to 85.7% (high dose), which remained up to 40% (high dose) at 6 months follow-up. Of note, the rapid regimen triggered a substantial immune response within days. CONCLUSIONS: The rapid development and production of a ZIKV vaccine candidate building on a commercial Vero-cell manufacturing platform resulted in a safe and immunogenic vaccine suitable for further clinical development. To optimize antibody persistence, higher doses and a booster administration might be considered.

Nucleation and spreading of a heterochromatic domain in fission yeast.

Outstanding questions in the chromatin field bear on how large heterochromatin domains are formed in space and time. Positive feedback, where histone-modifying enzymes are attracted to chromosomal regions displaying the modification they catalyse, is believed to drive the formation of these domains; however, few quantitative studies are available to assess this hypothesis. Here we quantified the de novo establishment of a naturally occurring ∼20-kb heterochromatin domain in fission yeast through single-cell analyses, measuring the kinetics of heterochromatin nucleation in a region targeted by RNAi and its subsequent expansion. We found that nucleation of heterochromatin is stochastic and can take from one to ten cell generations. Further silencing of the full region takes another one to ten generations. Quantitative modelling of the observed kinetics emphasizes the importance of local feedback, where a nucleosome-bound enzyme modifies adjacent nucleosomes, combined with a feedback where recruited enzymes can act at a distance.