Recombinant adeno-associated virus serotype 9 AAV-RABVG expressing a Rabies Virus G protein confers long-lasting immune responses in mice and non-human primates

Abstract

Three or four intramuscular doses of the inactivated human rabies virus vaccines are needed for pre- or post-exposure prophylaxis in humans. This procedure has made a great contribution to prevent human rabies deaths, which bring huge economic burdens in developing countries. Herein, a recombinant adeno-associated virus serotype 9, AAV9-RABVG, harbouring a RABV G gene, was generated to serve as a single dose rabies vaccine candidate. The RABV G protein was stably expressed in the 293T cells infected with AAV9-RABVG. A single dose of 2 × 10 11 v.p. of AAV9-RABVG induced robust and long-term positive seroconversions in BALB/c mice with a 100% survival from a lethal RABV challenge. In Cynomolgus Macaques vaccinated with a single dose of 1 × 10 13 v.p. of AAV9-RABVG, the titres of rabies VNAs increased remarkably from 2 weeks after immunity, and maintained over 31.525 IU/ml at 52 weeks. More DCs were activated significantly for efficient antigen presentations of RABV G protein, and more B cells were activated to be responsible for antibody responses. Significantly more RABV G specific IFN-γ-secreting CD4+ and CD8+ T cells, and IL-4-secreting CD4+ T cells were activated, and significantly higher levels of IL-2, IFN-γ, IL-4, and IL-10 were secreted to aid immune responses. Overall, the AAV9-RABVG was a single dose rabies vaccine candidate with great promising by inducing robust, long-term humoral responses and both Th1 and Th2 cell-mediated immune responses in mice and non-human primates.

A modified recombinant adenovirus vector containing dual rabies virus G expression cassettes confers robust and long-lasting humoral immunity in mice, cats, and dogs

“…In our study, significantly more mature cDCs were detected in inguinal lymph nodes in Adv-RVDG than Adv-RVG vaccinated mice, which may be attributed to the increased level of RVG expression. Similar results were observed in AAV9-RABVG vaccinated mice [ 56 ]. Logically, more robust germinal centre responses were produced the inguinal lymph nodes of Adv-RVDG immunized mice including Tfh cells differentiation, GC B cells proliferation, and more antibody-secreting cells production.…”

A single vaccination of nucleoside-modified Rabies mRNA vaccine induces prolonged highly protective immune responses in mice

“…Current commercial inactivated vaccines have relatively poor immunogenicity and require repeated injections. In recent years, numerous studies have been carried out to develop novel, safe, and effective rabies vaccines, such as recombinant virus-vector vaccines (33)(34)(35)(36)(37)(38), DNA and RNA-based vaccines (15,16,27,28), live attenuated rabies vaccines (39), and protein vaccines (40). In this study, we mainly demonstrated that a single immunization of nucleoside-modified RABV-G mRNA vaccine induced a more potent immunogenic response than commercial inactivated rabies vaccines, providing complete protection against lethal rabies virus challenge, and induced durable NAb responses in BALB/c mice.…”