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Hantaviruses, members of the order Bunyavirales, family Hantaviridae, have a world-wide distribution and are responsible for greater than 150,000 cases of disease per year. The spectrum of disease associated with hantavirus infection include hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) also known as hantavirus cardiopulmonary syndrome (HCPS). There are currently no FDA-approved vaccines or treatments for these hantavirus diseases. This review provides a summary of the status of vaccine and antiviral treatment efforts including those tested in animal models or human clinical trials.

A SARS-CoV-2 DNA vaccine targeting the spike protein and delivered by jet injection, nCOV-S(JET), previously shown to protect wild-type and immunosuppressed Syrian hamsters ( Mesocricetus auratus ), was evaluated via two needle-free delivery methods in rhesus macaques ( Macaca mulatta ). The methods included intramuscular delivery of 2 mg per vaccination with the PharmaJet Stratis device and intradermal delivery of 0.4 mg per vaccination with the PharmaJet Tropis device. We hypothesized that the nCOV-S(JET) vaccine would mount detectable neutralizing antibody responses when delivered by needle-free jet injection by either the intradermal or intramuscular route. When delivered intramuscularly, the vaccines elicited neutralizing and variant (Beta, Gamma, and Delta) cross-neutralizing antibodies against SARS-CoV-2 in all six animals after three vaccinations. The neutralizing response to Omicron was lower with only 4 of 6 animals responding. When delivered at a lower dose by the intradermal route, strong neutralizing antibody responses were only detected in two of six animals. This study confirms that a vaccine previously shown to protect in a hamster model can elicit neutralizing and cross-neutralizing antibodies against SARS-CoV-2 in nonhuman primates. We posit that nCOV-S(JET) has the potential for use as booster vaccine in heterologous vaccination strategies against COVID-19.

Concerns regarding outbreaks of human monkeypox or the potential reintroduction of smallpox into an immunological naïve population have prompted the development of animal models and countermeasures. Here we present a marmoset model of monkeypox and smallpox disease utilizing a relevant poxvirus via a natural exposure route. We found that 1000 plaque forming units (PFU) of Monkeypox virus was sufficient to recapitulate smallpox disease, to include an incubation period of approximately 13 days, followed by the onset of rash, and death between 15 and 17 days. Temporally accurate manifestation of viremia and oral shedding were also features. The number of lesions ranged from no lesions to 299, the most reported in a marmoset exposed to a poxvirus. To both evaluate the efficacy of our antibodies and the applicability of the model system, marmosets were prophylactically treated with two monoclonal antibodies, c7D11 and c8A. Of three marmosets, two were completely free of disease and a single marmoset died 8 days after the mock (n = 1) or PBS control(s) (n = 2). Evaluation of the serum levels of the three animals provided a possible explanation to the animal succumbing to disease. Interestingly, more females had lesions (and a greater number of lesions) and lower viral burden (viremia and oral shedding) than males in our studies, suggesting a possible gender effect.

The search for a universal filovirus vaccine that provides protection against multiple filovirus species has been prompted by sporadic but highly lethal outbreaks of Ebolavirus and Marburgvirus infections. A good prophylactic vaccine should be able to provide protection to all known filovirus species and as an upside potentially protect from newly emerging virus strains. We investigated the immunogenicity and protection elicited by multivalent vaccines expressing glycoproteins (GP) from Ebola virus (EBOV), Sudan virus (SUDV), Taï Forest virus (TAFV) and Marburg virus (MARV). Immune responses against filovirus GP have been associated with protection from disease. The GP antigens were expressed by adenovirus serotypes 26 and 35 (Ad26 and Ad35) and modified Vaccinia virus Ankara (MVA) vectors, all selected for their strong immunogenicity and good safety profile. Using fully lethal NHP intramuscular challenge models, we assessed different vaccination regimens for immunogenicity and protection from filovirus disease. Heterologous multivalent Ad26-Ad35 prime-boost vaccination regimens could give full protection against MARV (range 75%-100% protection) and EBOV (range 50% to 100%) challenge, and partial protection (75%) against SUDV challenge. Heterologous multivalent Ad26-MVA prime-boost immunization gave full protection against EBOV challenge in a small cohort study. The use of such multivalent vaccines did not show overt immune interference in comparison with monovalent vaccines. Multivalent vaccines induced GP-specific antibody responses and cellular IFNγ responses to each GP expressed by the vaccine, and cross-reactivity to TAFV GP was detected in a trivalent vaccine expressing GP from EBOV, SUDV and MARV. In the EBOV challenge studies, higher humoral EBOV GP-specific immune responses (p = 0.0004) were associated with survival from EBOV challenge and less so for cellular immune responses (p = 0.0320). These results demonstrate that it is feasible to generate a multivalent filovirus vaccine that can protect against lethal infection by multiple members of the filovirus family.

DNA vaccines have inherent advantages compared to other vaccine types, including safety, rapid design and construction, ease and speed to manufacture, and thermostability. However, a major drawback of candidate DNA vaccines delivered by needle and syringe is the poor immunogenicity associated with inefficient cellular uptake of the DNA. This uptake is essential because the target vaccine antigen is produced within cells and then presented to the immune system. Multiple techniques have been employed to boost the immunogenicity and protective efficacy of DNA vaccines, including physical delivery methods, molecular and traditional adjuvants, and genetic sequence enhancements. Needle-free injection systems (NFIS) are an attractive alternative due to the induction of potent immunogenicity, enhanced protective efficacy, and elimination of needles. These advantages led to a milestone achievement in the field with the approval for Restricted Use in Emergency Situation of a DNA vaccine against COVID-19, delivered exclusively with NFIS. In this review, we discuss physical delivery methods for DNA vaccines with an emphasis on commercially available NFIS and their resulting safety, immunogenic effectiveness, and protective efficacy. As is discussed, prophylactic DNA vaccines delivered by NFIS tend to induce non-inferior immunogenicity to electroporation and enhanced responses compared to needle and syringe.

A SARS-CoV-2 DNA vaccine targeting the spike protein and delivered by jet injection, nCOV-S(JET), previously shown to protect wild-type and immunosuppressed Syrian hamsters (Mesocricetus auratus), was evaluated via two needle-free delivery methods in rhesus macaques (Macaca mulatta). The methods included intramuscular delivery of 2 mg per vaccination with the PharmaJet Stratis device and intradermal delivery of 0.4 mg per vaccination with the PharmaJet Tropis device. We hypothesized that the nCOV-S(JET) vaccine would mount detectable neutralizing antibody responses when delivered by needle-free jet injection by either the intradermal or intramuscular route. When delivered intramuscularly, the vaccines elicited neutralizing and variant (Beta, Gamma, and Delta) cross-neutralizing antibodies against SARS-CoV-2 in all six animals after three vaccinations. The neutralizing response to Omicron was lower with only 4 of 6 animals responding. When delivered at a lower dose by the intradermal route, strong neutralizing antibody responses were only detected in two of six animals. This study confirms that a vaccine previously shown to protect in a hamster model can elicit neutralizing and cross-neutralizing antibodies against SARS-CoV-2 in nonhuman primates. We posit that nCOV-S(JET) has the potential for use as booster vaccine in heterologous vaccination strategies against COVID-19.

Hantaan virus (HTNV) and Puumala virus (PUUV) are rodent-borne hantaviruses that are the primary causes of hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia. The development of well characterized animal models of HTNV and PUUV infection is critical for the evaluation and the potential licensure of HFRS vaccines and therapeutics. In this study we present three animal models of HTNV infection (hamster, ferret and marmoset), and two animal models of PUUV infection (hamster, ferret). Infection of hamsters with a ~3 times the infectious dose 99% (ID99) of HTNV by the intramuscular and ~1 ID99 of HTNV by the intranasal route leads to a persistent asymptomatic infection, characterized by sporadic viremia and high levels of viral genome in the lung, brain and kidney. In contrast, infection of hamsters with ~2 ID99 of PUUV by the intramuscular or ~1 ID99 of PUUV by the intranasal route leads to seroconversion with no detectable viremia, and a transient detection of viral genome. Infection of ferrets with a high dose of either HTNV or PUUV by the intramuscular route leads to seroconversion and gradual weight loss, though kidney function remained unimpaired and serum viremia and viral dissemination to organs was not detected. In marmosets a 1,000 PFU HTNV intramuscular challenge led to robust seroconversion and neutralizing antibody production. Similarly to the ferret model of HTNV infection, no renal impairment, serum viremia or viral dissemination to organs was detected in marmosets. This is the first report of hantavirus infection in ferrets and marmosets.

The emergence of SARS-CoV-2 has created an international health crisis, and small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection owing to low-affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here, we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promoter (K18). In contrast to nontransgenic mice, intranasal exposure of K18-hACE2 animals to 2 different doses of SARS-CoV-2 resulted in acute disease, including weight loss, lung injury, brain infection, and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals showed increases in transcripts involved in lung injury and inflammatory cytokines. In the low-dose challenge groups, there was a survival advantage in the female mice, with 60% surviving infection, whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared with female mice. To our knowledge, this is the first highly lethal murine infection model for SARS-CoV-2 and should be valuable for the study of SARS-CoV-2 pathogenesis and for the assessment of MCMs.

•Development of a SNV M gene-based DNA vaccine to prevent HPS.•SNV DNA vaccine elicits high-titer neutralizing antibodies in a rabbit model.•SNV DNA vaccine is combined with other hantavirus DNA vaccines to elicit neutralizing antibodies.•SNV DNA vaccine protects hamsters from SNV infection. Sin Nombre virus (SNV; family Bunyaviridae, genus Hantavirus) causes a hemorrhagic fever known as hantavirus pulmonary syndrome (HPS) in North America. There have been approximately 200 fatal cases of HPS in the United States since 1993, predominantly in healthy working-age males (case fatality rate 35%). There are no FDA-approved vaccines or drugs to prevent or treat HPS. Previously, we reported that hantavirus vaccines based on the full-length M gene segment of Andes virus (ANDV) for HPS in South America, and Hantaan virus (HTNV) and Puumala virus (PUUV) for hemorrhagic fever with renal syndrome (HFRS) in Eurasia, all elicited high-titer neutralizing antibodies in animal models. HFRS is more prevalent than HPS (>20,000 cases per year) but less pathogenic (case fatality rate 1–15%). Here, we report the construction and testing of a SNV full-length M gene-based DNA vaccine to prevent HPS. Rabbits vaccinated with the SNV DNA vaccine by muscle electroporation (mEP) developed high titers of neutralizing antibodies. Furthermore, hamsters vaccinated three times with the SNV DNA vaccine using a gene gun were completely protected against SNV infection. This is the first vaccine of any kind that specifically elicits high-titer neutralizing antibodies against SNV. To test the possibility of producing a pan-hantavirus vaccine, rabbits were vaccinated by mEP with an HPS mix (ANDV and SNV plasmids), or HFRS mix (HTNV and PUUV plasmids), or HPS/HFRS mix (all four plasmids). The HPS mix and HFRS mix elicited neutralizing antibodies predominantly against ANDV/SNV and HTNV/PUUV, respectively. Furthermore, the HPS/HFRS mix elicited neutralizing antibodies against all four viruses. These findings demonstrate a pan-hantavirus vaccine using a mixed-plasmid DNA vaccine approach is feasible and warrants further development.

Andes virus (ANDV) is the predominant cause of hantavirus pulmonary syndrome (HPS) in South America and the only hantavirus known to be transmitted person-to-person. There are no vaccines, prophylactics, or therapeutics to prevent or treat this highly pathogenic disease (case-fatality 35-40%). Infection of Syrian hamsters with ANDV results in a disease that closely mimics human HPS in incubation time, symptoms of respiratory distress, and disease pathology. Here, we evaluated the feasibility of two postexposure prophylaxis strategies in the ANDV/hamster lethal disease model. First, we evaluated a natural product, human polyclonal antibody, obtained as fresh frozen plasma (FFP) from a HPS survivor. Second, we used DNA vaccine technology to manufacture a polyclonal immunoglobulin-based product that could be purified from the eggs of vaccinated ducks (Anas platyrhynchos). The natural \"despeciation\" of the duck IgY (i.e., Fc removed) results in an immunoglobulin predicted to be minimally reactogenic in humans. Administration of ≥ 5,000 neutralizing antibody units (NAU)/kg of FFP-protected hamsters from lethal disease when given up to 8 days after intranasal ANDV challenge. IgY/IgYΔFc antibodies purified from the eggs of DNA-vaccinated ducks effectively neutralized ANDV in vitro as measured by plaque reduction neutralization tests (PRNT). Administration of 12,000 NAU/kg of duck egg-derived IgY/IgYΔFc protected hamsters when administered up to 8 days after intranasal challenge and 5 days after intramuscular challenge. These experiments demonstrate that convalescent FFP shows promise as a postexposure HPS prophylactic. Moreover, these data demonstrate the feasibility of using DNA vaccine technology coupled with the duck/egg system to manufacture a product that could supplement or replace FFP. The DNA vaccine-duck/egg system can be scaled as needed and obviates the necessity of using limited blood products obtained from a small number of HPS survivors. This is the first report demonstrating the in vivo efficacy of any antiviral product produced using DNA vaccine-duck/egg system.