Although the incidence of severe fever with thrombocytopenia syndrome virus (SFTSV) infection has increased from its discovery with a mortality rate of 10–20%, no effective vaccines are currently available. Here we describe the development of a SFTSV DNA vaccine, its immunogenicity, and its protective efficacy. Vaccine candidates induce both a neutralizing antibody response and multifunctional SFTSV-specific T cell response in mice and ferrets. When the vaccine efficacy is investigated in aged-ferrets that recapitulate fatal clinical symptoms, vaccinated ferrets are completely protected from lethal SFTSV challenge without developing any clinical signs. A serum transfer study reveals that anti-envelope antibodies play an important role in protective immunity. Our results suggest that Gn/Gc may be the most effective antigens for inducing protective immunity and non-envelope-specific T cell responses also can contribute to protection against SFTSV infection. This study provides important insights into the development of an effective vaccine, as well as corresponding immune parameters, to control SFTSV infection.

GATA-1 is an erythroid activator that binds β-globin gene promoters and DNase I hypersensitive sites (HSs) of the β-globin locus control region (LCR). We investigated the direct role of GATA-1 interaction at the LCR HS2 enhancer by mutating its binding sites within minichromosomes in erythroid cells. Loss of GATA-1 in HS2 did not compromise interaction of NF-E2, a second activator that binds to HS2, nor was DNase I hypersensitivity at HS2 or the promoter of a linked ε-globin gene altered. Reduction of NF-E2 using RNAi confirmed the overall importance of this activator in establishing LCR HSs. However, recruitment of the histone acetyltransferase CBP and RNA pol II to HS2 was diminished by GATA-1 loss. Transcription of ε-globin was severely compromised with loss of RNA pol II from the transcription start site and reduction of H3 acetylation and H3K4 di- and tri-methylation in coding sequences. In contrast, widespread detection of H3K4 mono-methylation was unaffected by loss of GATA-1 in HS2. These results support the idea that GATA-1 interaction in HS2 has a prominent and direct role in co-activator and pol II recruitment conferring active histone tail modifications and transcription activation to a target gene but that it does not, by itself, play a major role in establishing DNase I hypersensitivity.

Direct-acting antiviral treatment for hepatitis C virus (HCV) infection is costly and does not protect from re-infection. For human and chimpanzees, recovery from acute HCV infection correlates with host CD4+ and CD8+ T cell responses. DNA plasmids targeting the HCV non-structural antigens NS3, NS4, and NS5, were previously reported to induce robust and sustained T cell responses in mice and primates. These plasmids were combined with a plasmid encoding cytokine IL-28B, together named as VGX-6150. The dose-dependent T cell response and safety of VGX-6150 administered intramuscularly and followed by electroporation was assessed in mice. Immune responses plateaued at 20 μg/dose with IL-28B demonstrating significant immunoadjuvant activity. Mice administered VGX-6150 at 40, 400, and 800 μg given either as a single injection or as 14 injections given bi-weekly over 26 weeks showed no vaccine related changes in any clinical parameter compared to placebo recipients. There was no evidence of VGX-6150 accumulation at the injection site or in any organ 1 month following the 14th vaccination. Based on these studies, the approximate lethal dose (ALD) exceeds 800 μg/dose and the NOAEL was 800 μg/dose in mouse. In conclusion, VGX-6150 appears safe and a promising preventive vaccine candidate for HCV infection.

SARS-CoV-2 is the third pathogenic coronavirus to emerge since 2000. Experience from prior outbreaks of SARS-CoV and MERS-CoV has demonstrated the importance of both humoral and cellular immunity to clinical outcome, precepts that have been recapitulated for SARS-CoV-2. Despite the unprecedented rapid development and deployment of vaccines against SARS-CoV-2, more vaccines are needed to meet global demand and to guard against immune evasion by newly emerging SARS-CoV-2 variants. Here we describe the development of pGO-1002, a novel bi-cistronic synthetic DNA vaccine that encodes consensus sequences of two SARS-CoV-2 antigens, Spike and ORF3a. Mice immunized with pGO-1002 developed humoral and cellular responses to both antigens, including antibodies and capable of neutralizing infection by a clinical SARS-CoV-2 isolate. Rats immunized with pGO-1002 by intradermal (ID) injection followed by application of suction with our GeneDerm device also developed humoral responses that included neutralizing antibodies and RBD-ACE2 blocking antibodies as well as robust cellular responses to both antigens. Significantly, in a Syrian hamster vaccination and challenge model, ID+GeneDerm-assisted vaccination prevented viral replication in the lungs and significantly reduced viral replication in the nares of hamsters challenged with either an ancestral SARS-CoV-2 strain or the B.1.351 (Beta) variant of concern. Furthermore, vaccinated immune sera inhibited virus-mediated cytopathic effects in vitro. These data establish the immunogenicity of the SARS-CoV-2 vaccine candidate pGO-1002 which induces potent humoral and cellular responses to the Spike and ORF3a antigens and may provide greater protection against emerging variants.