Two immunogenic recombinant protein vaccine candidates showed disparate protective efficacy against Zika virus infection in rhesus macaques.

Zika virus (ZIKV) infection has caused major public health problems recently. To develop subunit vaccines for ZIKV, we have previously constructed recombinant ZIKV envelope protein domain III (EDIII), and the entire ectodomain (E80, which comprises EDI, EDII and EDIII), as vaccine candidates and showed both of them being immunogenic and protective in murine models. In this follow-up study, we compared these vaccine candidates in non-human primates. Both of them elicited neutralizing antibody responses, but only E80 immunization inhibited ZIKV infection in both peripheral blood and monkey tissues, whereas EDIII increased blood ZIKV RNA through possibly antibody-dependent enhancement. Further investigations revealed that the virion-binding antibody response in E80 immunized monkeys persisted longer and stronger than in EDIII immunized monkeys. These results demonstrate that E80 is superior to EDIII as a vaccine candidate, and that the magnitude, quality and durability of virion-binding neutralizing antibodies are correlates of protection.

ZIKV infection induces robust Th1-like Tfh cell and long-term protective antibody responses in immunocompetent mice.

Induction of long-lived antibody responses during infection or vaccination is often essential for subsequent protection, but the relative contributions of T follicular helper (Tfh) cells and T helper 1 (Th1) cells for induction of antigen specific antibody responses to viruses are unclear. Here, we establish an acute Zika virus (ZIKV) infection model in immunocompetent mice, and show that ZIKV infection elicits robust Th1-like Tfh cell and protective antibody responses. While these Th1-like Tfh cells share phenotypic and transcriptomic profiles with both Tfh and Th1 cells, they also have unique surface markers and gene expression characteristics, and are dependent on T-bet for their development. Th1-like Tfh cells, but not Th1 cells, are essential for class switching of ZIKV-specific IgG2c antibodies and maintenance of long-term neutralizing antibody responses. Our study suggests that specific modulation of the Th1-like Tfh cell response during infection or vaccination may augment the induction of antiviral antibody response to ZIKV and other viruses.

Recombinant Zika virus envelope protein elicited protective immunity against Zika virus in immunocompetent mice.

Zika virus (ZIKV) has caused great public concerns due to its recent large outbreaks and a close association with microcephaly in fetus and Guillain-Barre syndrome in adults. Rapid development of vaccines against ZIKV is a public health priority. To this end, we have constructed and purified recombinant ZIKV envelope protein using both prokaryotic and eukaryotic expression systems, and then tested their immunogenicity and protective efficacy in immune competent mice. Both protein immunogens elicited humoral and cellular immune responses, and protected immune competent mice from ZIKV challenge in vivo. These products could be further evaluated either as stand-alone vaccine candidate, or used in a prime-and-boost regimen with other forms of ZIKV vaccine.

Guiding dengue vaccine development using knowledge gained from the success of the yellow fever vaccine.

Flaviviruses comprise approximately 70 closely related RNA viruses. These include several mosquito-borne pathogens, such as yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), which can cause significant human diseases and thus are of great medical importance. Vaccines against both YFV and JEV have been used successfully in humans for decades; however, the development of a DENV vaccine has encountered considerable obstacles. Here, we review the protective immune responses elicited by the vaccine against YFV to provide some insights into the development of a protective DENV vaccine.

Systematic Analysis of the Functions of Lysine Acetylation in the Regulation of Tat Activity.

The Tat protein of HIV-1 has several well-known properties, such as nucleocytoplasmic trafficking, transactivation of transcription, interaction with tubulin, regulation of mitotic progression, and induction of apoptosis. Previous studies have identified a couple of lysine residues in Tat that are essential for its functions. In order to analyze the functions of all the lysine residues in Tat, we mutated them individually to alanine, glutamine, and arginine. Through systematic analysis of the lysine mutants, we discovered several previously unidentified characteristics of Tat. We found that lysine acetylation could modulate the subcellular localization of Tat, in addition to the regulation of its transactivation activity. Our data also revealed that lysine mutations had distinct effects on microtubule assembly and Tat binding to bromodomain proteins. By correlation analysis, we further found that the effects of Tat on apoptosis and mitotic progression were not entirely attributed to its effect on microtubule assembly. Our findings suggest that Tat may regulate diverse cellular activities through binding to different proteins and that the acetylation of distinct lysine residues in Tat may modulate its interaction with various partners.