Oral Vaccination with Replication-Competent Adenovirus in Mice Reveals Dissemination of the Viral Vaccine beyond the Gastrointestinal Tract

Abstract

Since the 1970s, replication-competent human adenoviruses 4 and 7 have been used as oral vaccines to protect U.S. soldiers against the severe respiratory diseases caused by these viruses. These vaccines are thought to establish a digestive tract infection conferring protection against respiratory challenge through antibodies. The success of these vaccines makes replication-competent adenoviruses attractive candidates for use as oral vaccine vectors. However, the inability of human adenoviruses to replicate efficiently in laboratory animals has hampered the study of such vectors. Here, we used mouse adenovirus type 1 (MAV-1) in mice to study oral replication-competent adenovirus-based vaccines. We show that MAV-1 oral administration provides protection that recapitulates the protection against homologous respiratory challenge observed with adenovirus 4 and 7 vaccines. Moreover, live oral MAV-1 vaccine better protected against a respiratory challenge than inactivated vaccines. This protection was linked not only with the presence of MAV-1-specific antibodies but also with a better recruitment of effector CD8 T cells. However, unexpectedly, we found that such oral replication-competent vaccine systemically spread all over the body. Our results therefore support the use of MAV-1 to study replication-competent oral adenovirus-based vaccines but also highlight the fact that those vaccines can disseminate widely in the body. IMPORTANCE Replication-competent adenoviruses appear to be promising vectors for the development of oral vaccines in humans. However, the study and development of these vaccines suffer from the lack of any reliable animal model. In this study, mouse adenovirus type 1 was used to develop a small-animal model for oral replication-competent adenovirus vaccines. While this model reproduced in mice what is observed with human adenovirus oral vaccines, it also highlighted that oral immunization with such a replication-competent vaccine is associated with the systemic spread of the virus. This study is therefore of major importance for the future development of such vaccine platforms and their use in large human populations.

Circulating Adaptive Immune Cells Expressing the Gut Homing Marker α4β7 Integrin Are Decreased in COVID-19

“…It has previously been shown for adenovirus subtypes and influenza that oral vaccines can also protect from pulmonary infections (43)(44)(45). Moreover, mucosal administration has been proposed to be more effective in inducing protective mucosal immunity (including the lung) than systemic application (46). It would then have to be doubted that this is similarly the case in COVID-19 in view of reduced gut-imprinted immunity in the circulation during active infection with the virus.…”

Murine adenoviruses: tools for studying adenovirus pathogenesis in a natural host

“…Oral replication‐competent vaccines against HAdV‐4 and ‐7 have long been used to immunize the US military against severe respiratory infection caused by these viruses . MAdV‐1 has recently been examined as a model to study oral replication‐competent AdV vaccines in vivo in a natural host . Intranasal, intraperitoneal, and natural MAdV‐1 infection generate neutralizing antibodies .…”

“…Oral infection of C57BL/6 mice, which have intermediate susceptibility to MAdV‐1 , leads to a systemic infection with moderate bowel pathogenesis and antiviral neutralizing antibody responses . In the MAdV‐1 vaccine study, when BALB/c mice, which are more resistant to MAdV‐1 infection , were inoculated orally, there was only a subclinical infection that also generated a virus‐specific neutralizing antibody response . Although clinical signs of disease were not seen after oral infection of the BALB/c mice, sporadic shedding of virus in feces occurred, as measured by qPCR.…”

A single oral immunization with a replication-competent adenovirus-vectored vaccine protects mice from influenza respiratory infection

“…The use of mouse AdV type 1 (MAV-1) in the mouse, its natural host, permits to study AdVs infection in replicative conditions (18). We recently showed that MAV-1 oral administration in mice reproduces the homologous protection observed in humans with AdV-4 and AdV-7 based oral vaccines (19). In the present study, we exploited this mouse model to investigate the potential of replication-competent AdVs as vectors for oral vaccination against influenza.…”