Genetic Adjuvants in Replicating Single-Cycle Adenovirus Vectors Amplify Systemic and Mucosal Immune Responses against HIV-1 Envelope

Abstract

Most infections occur at mucosal surfaces. Providing a barrier of protection at these surfaces may be a useful strategy to combat the earliest events in infection when there are relatively few pathogens to address. The majority of vaccines are delivered systemically by the intramuscular (IM) route. While IM vaccination can drive mucosal immune responses, mucosal immunization at intranasal (IN) or oral sites can lead to better immune responses at mucosal sites of viral entry. In macaques, IN immunization with replicating single-cycle adenovirus (SC-Ads) and protein boosts generated favorable mucosal immune responses. However, there was an apparent "distance effect" in generating mucosal immune responses. IN immunization generated antibodies against HIV envelope (env) nearby in the saliva, but weaker responses in samples collected from the distant vaginal samples. To improve on this, we tested here if SC-Ads expressing genetic adjuvants could be used to amplify antibody responses in distant vaginal samples when they are codelivered with SC-Ads expressing clade C HIV env immunogen. SC-Ads env 1157 was coadministered with SC-Ads expressing 4-1BBL, granulocyte macrophage colony-stimulating factor (GMCSF), IL-21, or Clostridoides difficile (C. diff.) toxin fragments by IN or IM routes. These data show that vaginal antibody responses were markedly amplified after a single immunization by the IN or IM routes, with SC-Ad expressing HIV env if this vaccine is complemented with SC-Ads expressing genetic adjuvants. Furthermore, the site and combination of adjuvants appear to "tune" these antibody responses towards an IgA or IgG isotype bias. Boosting these priming SC-Ad responses with another SC-Ad or with SOSIP native-like env proteins markedly amplifies env antibody levels in vaginal washes. Together, this data may be useful in informing the choice of route of delivery adenovirus and peptide vaccines against HIV-1.

Injection site vaccinology of a recombinant vaccinia-based vector reveals diverse innate immune signatures

“…Recent sequencing of ancient Variola viruses from Viking corpses perhaps supports such strategies, as active expression of immune modulating genes may be associated with reduced pathogenicity [ 219 , 220 ]. Co-formulation of SCV with adjuvants [ 221 , 222 ] or encoding genetic adjuvants within SCV [ 223 ] might appear superfluous, given the large number of adjuvant pathways already being activated. Introducing apoptosis inhibitors to improve immunogenicity [ 14 ] may have minimal impact for i.m.…”

Systems vaccinology analysis of a recombinant vaccinia-based vector reveals diverse innate immune signatures at the injection site

“…Recent sequencing of ancient Variola viruses from Viking corpses perhaps supports such strategies, as active expression of immune modulating genes may be associated with reduced pathogenicity (Alcami, 2020; Muhlemann et al ., 2020). Co-formulation of SCV with adjuvants (Barrera et al ., 2018; Magnusson et al ., 2018) or encoding genetic adjuvants within SCV (Matchett et al ., 2020) might appear superfluous, given the large number of adjuvant pathways already being activated. Introducing apoptosis inhibitors to improve immunogenicity (Chea et al ., 2019) may have minimal impact for i.m.…”

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).…”