Here, we demonstrate that electroporation-enhanced immunization with a rationally designed HPV DNA vaccine (GX-188E), preferentially targeting HPV antigens to dendritic cells, elicits a significant E6/E7-specific IFN-γ-producing T-cell response in all nine cervical intraepithelial neoplasia 3 (CIN3) patients. Importantly, eight out of nine patients exhibit an enhanced polyfunctional HPV-specific CD8 T-cell response as shown by an increase in cytolytic activity, proliferative capacity and secretion of effector molecules. Notably, seven out of nine patients display complete regression of their lesions and viral clearance within 36 weeks of follow up. GX-188E administration does not elicit serious vaccine-associated adverse events at all administered doses. These findings indicate that the magnitude of systemic polyfunctional CD8 T-cell response is the main contributing factor for histological, cytological and virological responses, providing valuable insights into the design of therapeutic vaccines for effectively treating persistent infections and cancers in humans.

Interleukin-7 (IL-7) is a heavily glycosylated cytokine with a molecular mass of 25 kDa, and it is a member of the common ␥-chain receptor (CD132) cytokine family. IL-7 is secreted mainly by nonhematopoietic cells, such as thymic and intestinal epithelial cells, bone marrow stromal cells, keratinocytes, and reticular cells (1, 2). The receptor for IL-7, comprised of IL-7 receptor alpha (IL-7R␣; CD127) and the common ␥ chain, is expressed on various immune cells, including immature B cells, early thymocyte progenitors, and most mature T lymphocytes. IL-7 plays a role in the development of T cells, B cells, certain subsets of NK cells, and dendritic cells (DCs), as well as in the homeostasis of naive and memory T cells. In addition, IL-7 is important for ␥␦ T cell proliferation and NKT cell maintenance. However, the role of IL-7 in the differentiation of T follicular helper (Tfh) cells and the induction of humoral immunity remains unclear.Tfh cells are the unique CD4 ϩ T helper (Th) cells that provide cognate help to B cells to induce high-affinity antibody production in germinal centers (GCs) (3). GCs are specialized structures that develop within B cell follicles of secondary lymphoid tissues. GCs support intense B cell clonal expansion, somatic hypermutation, selection of high-affinity B cells, and class switching of immunoglobulin genes. These B cells ultimately are differentiated into both memory B cells and long-lived plasma cells that secrete high-affinity antibodies (2, 4).The differentiation of Tfh cells depends on the expression of a master transcriptional repressor, Bcl-6, which inhibits non-Tfh lineage differentiation (Th1, Th2, and Th17) by repressing Blimp-1 (5). Tfh cells express CXCR5 and a number of costimulatory molecules, such as ICOS and PD-1 (6). In addition, IL-6 and IL-21 have been shown to be important soluble regulators for the differentiation of Tfh cells (7-9). Recently, IL-27 was shown to increase the Tfh cell differentiation by upregulating IL-21 production (10). However, there have been conflicting reports that the absence of either IL-6 or IL-21 exhibits significant, moderate, or minimal effects on Tfh cell differentiation. The absence of both cytokines resulted in a more significant decrease in Tfh cell generation than each cytokine alone in vivo (11), indicating that IL-6 and IL-21 have redundant and/or additive functions in Tfh differentiation. It remains to be determined whether exogenous IL-6 or IL-21 induces the expansion of Tfh cells, as previous findings mentioned above were based on the experiments using knockout mice and/or blockade antibodies. Moreover, the generation of Tfh cells is not completely impaired even in the absence of IL-6 and IL-21 (11). These results indicate that these

The unprecedented and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has motivated the need for a rapidly producible and scalable vaccine. Here, we developed a synthetic soluble SARS-CoV-2 spike (S) DNA-based vaccine candidate, GX-19. In mice, immunization with GX-19 elicited not only S-specific systemic and pulmonary antibody responses but also Th1-biased T cell responses in a dose-dependent manner. GX-19-vaccinated nonhuman primates seroconverted rapidly and exhibited a detectable neutralizing antibody response as well as multifunctional CD4+ and CD8+ T cell responses. Notably, when the immunized nonhuman primates were challenged at 10 weeks after the last vaccination with GX-19, they had reduced viral loads in contrast to non-vaccinated primates as a control. These findings indicate that GX-19 vaccination provides a durable protective immune response and also support further development of GX-19 as a vaccine candidate for SARS-CoV-2.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease caused by SFTS virus (SFTSV) infection. Despite a gradual increase of SFTS cases and high mortality in endemic regions, no specific viral therapy nor vaccine is available. Here, we developed a single recombinant plasmid DNA encoding SFTSV genes, Gn and Gc together with NP-NS fusion antigen, as a vaccine candidate. The viral antigens were fused with Fmslike tyrosine kinase-3 ligand (Flt3L) and IL-12 gene was incorporated into the plasmid to enhance cell-mediated immunity. Vaccination with the DNA provides complete protection of IFNAR KO mice upon lethal SFTSV challenge, whereas immunization with a plasmid without IL-12 gene resulted in partial protection. Since we failed to detect antibodies against surface glycoproteins, Gn and Gc, in the immunized mice, antigen-specific cellular immunity, as confirmed by enhanced antigen-specific T cell responses, might play major role in protection. Finally, we evaluated the degree of protective immunity provided by protein immunization of the individual glycoprotein, Gn or Gc. Although both protein antigens induced a significant level of neutralizing activity against SFTSV, Gn vaccination resulted in relatively higher neutralizing activity and better protection than Gc vaccination. However, both antigens failed to provide complete protection. Given that DNA vaccines have failed to induce sufficient immunogenicity in human trials when compared to protein vaccines, optimal combinations of DNA and protein elements, proper selection of target antigens, and incorporation of efficient adjuvant, need to be further investigated for SFTSV vaccine development.

HB-110 was safe and tolerable in CHB patients. In contrast to results in animal models, HB-110 in Korean patients exhibited weaker capability of inducing HBV-specific T-cell responses and HBeAg seroconversion than HB-100 in Caucasian patients. As Asian patients, who are generally infected via vertical transmission, appeared to have higher level of immune tolerance than Caucasian, novel approaches for breaking immune tolerance rather than enhancing immunogenicity may be more urgently demanded to develop effective therapeutic HBV DNA vaccines.