Comparison of systemic and mucosal immunization with replicating Single cycle Adenoviruses

Abstract

HIV-1 infections occur during sexual contact at mucosal surfaces. Vaccines need to provide mucosal barrier protection and stimulate systemic immune responses to control HIV spread. Most vaccines are delivered by systemic immunization via intramuscular (IM) injection route. While this can drive systemic and mucosal immune responses, there are data show that mucosal immunization may be superior at driving responses at mucosal barriers. To explore this question, we immunized mice with replicating single-cycle adenovirus (SC Ad) vaccines expressing clade B HIV-1 envelope (Env) by intramuscular (IM), intranasal (IN), or intravaginal (IVAG) routes to compare vaccine responses. SC-Ads generated significant antibodies against Env after only a single immunization by the IN route, but not the other routes. These animals were boosted by the same route or by the mucosal IVAG routes. IM and IN primed animals generated strong antibody responses regardless of the boosting route. In contrast, IVAG primed animals failed to generate robust antibodies whether they were boosted by the IVAG or IM routes. These data suggest there may be benefits in first educating the immune system at mucosal sites during HIV vaccination. IN and IM prime-boost were then compared in Syrian hamsters which support SC-Ad DNA replication. In this case, IN immunization again was the only route that generated significant Env antibodies after a single immunization. Following a boost by IN or IM routes, IN primed animals had significantly higher antibody responses than the IM primed animals. Env antibodies could still be detected one year after immunization, but only in animals that received at least one mucosal IN immunization. These data suggest that there is merit in vaccination by mucosal routes.

Divergent HIV-1-Directed Immune Responses Generated by Systemic and Mucosal Immunization with Replicating Single-Cycle Adenoviruses in Rhesus Macaques

“…Testing of SC-Ad-G4 in small animals revealed that IVAG priming generated weak antibody levels, whereas i.n. priming generated strong responses (29). Given this, the i.n.…”

Adenoviral vector‐based platforms for developing effective vaccines to combat respiratory viral infections

“… 57 , 58 Antigen presentation is aided by alveolar macrophages presenting the antigenic epitopes to naïve T cells in draining lymph nodes or through inflammatory cytokine‐mediated recruitment of circulating T cells for mounting a balanced humoral and cell‐mediated immune (CMI) responses to the Ad vector‐expressed antigen. 59 , 60 , 61 …”

Comparison of Mucosal and Intramuscular Immunization against SARS-CoV-2 with Replication-Defective and Replicating Single-cycle Adenovirus Vaccines

“…The copyright holder for this preprint (which this version posted April 20, 2021. ; https://doi.org/10.1101/2021.04.20.440651 doi: bioRxiv preprint 5 (21,24) and have shown promise as vaccines against influenza (24), Ebola virus, HIV-1 (25)(26)(27), and against Clostridium difficile after single immunization (22,28).…”

“…SC-Ads retain E1 genes and replicate their DNA just as well as RC-Ads, but are deleted for the gene for Ad's pIIIa capsid cement protein, so that they produce empty defective particles (20). SC-Ads appear able to generate more robust and persistent immune responses than RD-Ads (21,24) and have shown promise as vaccines against influenza (24), Ebola virus, HIV-1 (25)(26)(27), and against Clostridium difficile after single immunization (22,28).…”