AI Insight
This study investigated the use of recombinant human adenovirus serotype 4 (Ad4) as a vaccine vector in mouse models, examining transgene expression, viral replication, and immune response generation. Researchers found that BALB/c mice are semi-permissive to Ad4 infection, with detectable luciferase activity lasting up to 20 days after intranasal inoculation and evidence of low-level viral replication confirmed by cidofovir antiviral treatment. When Ad4 was engineered to express HSV-2 glycoprotein D and administered intranasally to mice, it induced neutralizing antibodies and provided measurable protection against vaginal HSV-2 challenge, including reduced disease severity, improved survival, and lower viral shedding.
Why it matters
These findings support the use of the well-established BALB/c mouse model for evaluating Ad4-based mucosal vaccine candidates, which could accelerate preclinical development of vaccines against HSV-2 and potentially other mucosal pathogens. Ad4 is already approved as a safe oral vaccine in humans, making it a clinically relevant vector platform with a realistic path toward broader vaccine applications.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Human adenovirus serotype 4 (Ad4) is used as a replication-competent oral vaccine that safely and effectively prevents Ad4 respiratory illness in US military personnel. Recombinant Ad4 vaccine candidates elicit mucosal and systemic immune responses against respiratory viruses in hamsters, nonhuman primates, and humans. Although evaluation of Ad4 vaccine candidates in mice would be extremely useful given the large number of immunologic tools available, this has been limited by concerns about a lack of viral replication in these animals. Here we generated recombinant Ad4 vectors that express either luciferase (Ad4-Luc) or herpes simplex virus type 2 (HSV-2) glycoprotein D (Ad4-gD2) to identify transgene expression kinetics, the presence of Ad4 vector replication, and HSV-2 immune responses and protection against HSV-2 infection. Local luciferase activity was observed from 7 hours to 20 days after intranasal inoculation of BALB/c and humanized mice. Subsequent inoculations with Ad4-Luc showed reduced luciferase expression in BALB/c mice, but robust expression in humanized mice, suggesting an immune response to the vector in wild-type mice. Ad4 DNA, but not luciferase activity, was reduced in the lungs of BALB/c mice treated with cidofovir before inoculation with Ad4, implying that Ad4 replicated, albeit at a low level, in the lungs. Intranasal vaccination of mice with Ad4-gD2 resulted in HSV-2 neutralizing antibody in the serum, and after HSV-2 intravaginal challenge reduced disease scores, increased survival, and reduced shedding. Overall, the BALB/c mouse model is semi-permissive to Ad4 mucosal infection, but transgene expression is sufficient for the study of Ad4-based vaccine candidates.