SARS-CoV-2 Doggybone DNA Vaccine Produces Cross-Variant Neutralizing Antibodies and Is Protective in a COVID-19 Animal Model

To combat the COVID-19 pandemic, an assortment of vaccines has been developed. Nucleic acid vaccines have the advantage of rapid production, as they only require a viral antigen sequence and can readily be modified to detected viral mutations. Doggybone™ DNA vaccines targeting the spike protein of SARS-CoV-2 have been generated and compared with a traditionally manufactured, bacterially derived plasmid DNA vaccine that utilizes the same spike sequence. Administered to Syrian hamsters by jet injection at two dose levels, the immunogenicity of both DNA vaccines was compared following two vaccinations. Immunized hamsters were then immunosuppressed and exposed to SARS-CoV-2. Significant differences in body weight were observed during acute infection, and lungs collected at the time of euthanasia had significantly reduced viral RNA, infectious virus, and pathology compared with irrelevant DNA-vaccinated controls. Moreover, immune serum from vaccinated animals was capable of neutralizing SARS-CoV-2 variants of interest and importance in vitro. These data demonstrate the efficacy of a synthetic DNA vaccine approach to protect hamsters from SARS-CoV-2

Nonhuman Primates Are Protected from Smallpox Virus or Monkeypox Virus Challenges by the Antiviral Drug ST-246▿

ST-246, a potent orthopoxvirus egress inhibitor, is safe and effective at preventing disease and death in studies of small-animal models involving challenge by several different pathogenic poxviruses. In this report, the antiviral efficacy of ST-246 in treatment of nonhuman primates infected with variola virus or monkeypox virus was assessed. The data indicate that oral dosing once per day with ST-246 protects animals from poxvirus disease, as measured by reductions in viral load and numbers of lesions and enhancement of survival

Transmission electron micrographs of VARV infected, tecovirimat-treated NHP haired skin.

Panels A and B from surviving NHPs reveal more organized epidermis and dermis skin layers in two end-of-study VARV infected, tecovirimat-treated non-human primates. Panels A’ and B’, are slightly higher magnifications of the epidermis and dermis layers, respectively. No variola virus is evident.</p

Gross findings by tecovirimat treatment group.

Smallpox was the most rampant infectious disease killer of the 20th century, yet much remains unknown about the pathogenesis of the variola virus. Using archived tissue from a study conducted at the Centers for Disease Control and Prevention we characterized pathology in 18 cynomolgus macaques intravenously infected with the Harper strain of variola virus. Six macaques were placebo-treated controls, six were tecovirimat-treated beginning at 2 days post-infection, and six were tecovirimat-treated beginning at 4 days post-infection. All macaques were treated daily until day 17. Archived tissues were interrogated using immunohistochemistry, in situ hybridization, immunofluorescence, and electron microscopy. Gross lesions in three placebo-treated animals that succumbed to infection primarily consisted of cutaneous vesicles, pustules, or crusts with lymphadenopathy. The only gross lesions noted at the conclusion of the study in the three surviving placebo-treated and the Day 4 treated animals consisted of resolving cutaneous pox lesions. No gross lesions attributable to poxviral infection were present in the Day 2 treated macaques. Histologic lesions in three placebo-treated macaques that succumbed to infection consisted of proliferative and necrotizing dermatitis with intracytoplasmic inclusion bodies and lymphoid depletion. The only notable histologic lesion in the Day 4 treated macaques was resolving dermatitis; no notable lesions were seen in the Day 2 treated macaques. Variola virus was detected in all three placebo-treated animals that succumbed to infection prior to the study’s conclusion by all utilized methods (IHC, ISH, IFA, EM). None of the three placebo-treated animals that survived to the end of the study nor the animals in the two tecovirimat treatment groups showed evidence of variola virus by these methods. Our findings further characterize variola lesions in the macaque model and describe new molecular methods for variola detection.</div

Skin lesions observed, maximum viremia, time to maximum viremia, and survival by tecovirimat treatment day.

Skin lesions observed, maximum viremia, time to maximum viremia, and survival by tecovirimat treatment day.</p

Summary of histologic findings for placebo and tecovirimat treated NHPs that survived to end of study by tecovirimat treatment group.

Summary of histologic findings for placebo and tecovirimat treated NHPs that survived to end of study by tecovirimat treatment group.</p

Variola-infected, placebo treated NHPs. Multifocal proliferative and necrotizing dermatitis (pox lesions).

A) Facial skin (13 days post infection); B) Abdominal skin, left inner thigh, and scrotum (7 days post infection); C) Glabrous skin, left palm: multifocal proliferative dermatitis (7 days post infection); D) Glabrous skin, left palm: multifocal healed lesions with depigmentation (29 days post infection).</p

Immunohistochemistry and in situ hybridization findings: Placebo-treated NHPs.

Immunohistochemistry and in situ hybridization findings: Placebo-treated NHPs.</p