Prospects for induction of CD8 T cell‐mediated immunity to Zika virus infection by yellow fever virus (YFV) vaccination.

The Zika virus epidemic represents an unprecedented health crisis affecting significant parts of the world [1]. On 1st February 2016, the WHO declared the reported clusters of Zika virus-induced microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC). The epidemic is currently ongoing in Latin America and the Caribbean, with impacts of the infection already seen in large populations of Brazil, Colombia, Mexico, Peru and beyond. No specific treatment or vaccine is available, although several candidates are under development [2]. The Zika virus is a mosquito-borne pathogen belonging to the flavivirus family (Flaviviridae). It is closely related to other flaviviruses such as, for example the yellow fever virus (YFV). Developing vaccines towards flaviviruses have been a major focus of concern during the last 75 years. In 1939, Max Theiler succeeded in attenuating the YFV. Based on his discoveries, a YFV vaccine was developed and distributed globally. To date, over 300 million doses of the vaccine have been administered to humans [3]. The YFV vaccine is still considered as one of the world's most efficient vaccines, as a single dose provides at least a 10-year (most likely lifelong) immunity to the infection [4]. More recently, flavivirus vaccines have also been developed towards tick-borne encephalitis virus (TBEV) and Japanese encephalitis virus (JEV), whilst efficient vaccines towards other flaviviruses including Zika virus are still under development. Given the significant challenges posed by the current Zika virus epidemic, it is of utmost importance to seek out possible immediate solutions to this global health concern. In such attempts, similarities between different flaviviruses might be used to our advantage. In particular, if these could yield beneficial cross-reactive immune responses, without negative side effects. The flaviviral NS5-protein is a multifunctional, conserved protein that constitutes the viral polymerase. Analysis of the NS5 protein sequences of the currently used live attenuated YFV vaccine, when compared to that of Zika virus [5], reveals that the YFV vaccine-derived NS5 protein has a 64% homology with Zika virus NS5. This close similarity led us to initiate studies on possible cross-reactive responses between CD8 T cells from recipients of YFV vaccination and Zika virus-specific antigens. The YFV vaccine (Stamaril®, 0.5 ml, Sanofi Pasteur) was administered to healthy volunteers and peripheral blood collected before (day 0) and 15 days after vaccination (day 15). Peripheral blood mononuclear cells (PBMC) were stimulated (according to standard methods [6]) with a Zika-NS5 peptides (NS5 covering peptide library including 15 NetCTL-predicted [7] CD8 T cell epitopes, Zika virus French Polynesia isolate; library 18 amino acids in length and ten amino acids overlapping, predicted epitopes nine amino acids in length, all from GenScript). Zika virus-specific CD8 T cells were subsequently identified as lymphocytes, singlets, lineage- (CD19, CD14 and dead cell marker), CD3+CD8+ and IFNγ+TNF+ cells. In contrast to day 0 CD8 T cells, IFN-γ and TNF-producing CD8 T cells were clearly identified at day 15 in response to the Zika-NS5 library (Fig. 1). These results demonstrate that the homology between the YFV vaccine and Zika virus-NS5 is close enough to induce Zika-specific CD8 T cells.