A Replicating Single-Cycle Adenovirus Vaccine Against Ebola Virus

Anguiano-Zarate, Stephanie S.; Matchett, William E.; Nehete, Pramod N.; Sastry, Jagannadha; Marzi, Andrea; Barry, Michael A.

doi:10.1093/infdis/jiy411

Cited by 15 publications

(27 citation statements)

References 31 publications

(50 reference statements)

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“…This immunogenicity study examined how different routes of gene-based vaccination influence the production of systemic and mucosal immune responses against HIV-1 using new replicating single-cycle Ad (SC-Ad) vaccines (22)(23)(24)(25). Most Ads in clinical vaccine testing are E1 deletion replication-defective Ads (RD-Ads).…”

Section: Discussionmentioning

confidence: 99%

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

Matchett

Anguiano-Zarate

Nehete

et al. 2019

J Virol

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Most human immunodeficiency virus type 1 (HIV-1) infections begin at mucosal surfaces. Providing a barrier of protection at these may assist in combating the earliest events in infection. Systemic immunization by intramuscular (i.m.) injection can drive mucosal immune responses, but there are data suggesting that mucosal immunization can better educate these mucosal immune responses. To test this, rhesus macaques were immunized with replicating single-cycle adenovirus (SC-Ad) vaccines expressing clade B HIV-1 gp160 by the intranasal (i.n.) and i.m. routes to compare mucosal and systemic routes of vaccination. SC-Ad vaccines generated significant circulating antibody titers against Env after a single i.m. immunization. Switching the route of second immunization with the same SC-Ad serotype allowed a significant boost in these antibody levels. When these animals were boosted with envelope protein, envelope-binding antibodies were amplified 100-fold, but qualitatively different immune responses were generated. Animals immunized by only the i.m. route had high peripheral T follicular helper (pTfh) cell counts in blood but low Tfh cell counts in lymph nodes. Conversely, animals immunized by the i.n. route had high Tfh cell counts in lymph nodes but low pTfh cell counts in the blood. Animals immunized by only the i.m. route had lower antibody-dependent cellular cytotoxicity (ADCC) antibody activity, whereas animals immunized by the mucosal i.n. route had higher ADCC antibody activity. When these Env-immunized animals were challenged rectally with simian-human immunodeficiency virus (SHIV) strain SF162P3 (SHIVSF162P3), they all became infected. However, mucosally SC-Ad-immunized animals had lower viral loads in their gastrointestinal tracts. These data suggest that there may be benefits in educating the immune system at mucosal sites during HIV vaccination. IMPORTANCE HIV-1 infections usually start at a mucosal surface after sexual contact. Creating a barrier of protection at these mucosal sites may be a good strategy for to protect against HIV-1 infections. While HIV-1 enters at mucosa, most vaccines are not delivered here. Most are instead injected into the muscle, a site well distant and functionally different than mucosal tissues. This study tested if delivering HIV vaccines at mucosa or in the muscle makes a difference in the quality, quantity, and location of immune responses against the virus. These data suggest that there are indeed advantages to educating the immune system at mucosal sites with an HIV-1 vaccine.

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Section: Discussionmentioning

confidence: 99%

“…To take advantage of transgene DNA replication but avoid the risk of adenovirus infections, we developed single-cycle Ad (SC-Ad) vectors (22)(23)(24)(25). SC-Ads retain their E1 genes to allow the virus to replicate its genome but have deletions of their pIIIa gene to block the production of infectious progeny viruses.…”

mentioning

confidence: 99%

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

Matchett

Anguiano-Zarate

Nehete

et al. 2019

J Virol

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“…SC-Ads generate antibodies and T cells responses that increase over 12 months after single immunization vs. HIV, influenza, Ebola, Zika, or C. difficile antigens [38,[41][42][43][44][45][46][47][48]. SC-Ad carrying influenza hemagglutinin (HA) produced markedly more antigen than RD-Ad in vitro, requiring 33- While RC-Ads are documented to be more potent than RD-Ad vectors, replication-competent Ads pose a real risk of causing adenovirus infections as a side-effect of vaccination.…”

Section: Introductionmentioning

confidence: 99%

“…In vivo, SC-Ad produced significantly higher anti-influenza hemagglutination inhibition (HAI) antibodies than RD-Ad and provided better protection against intranasal influenza challenge in cotton rats after single immunization [41]. An SC-Ad vaccine expressing Ebola glycoprotein (gp) protected against pseudo-challenge with vesicular stomatitis virus (VSV) pseudotyped with Ebola gp a year and a half after single immunization in hamsters [47]. This SC-Ad generated anti-Ebola antibody responses with similar kinetics and levels as were generated by replication-competent VSV-EBOV-Luciferase vector [47].…”

Section: Introductionmentioning

confidence: 99%

“…An SC-Ad vaccine expressing Ebola glycoprotein (gp) protected against pseudo-challenge with vesicular stomatitis virus (VSV) pseudotyped with Ebola gp a year and a half after single immunization in hamsters [47]. This SC-Ad generated anti-Ebola antibody responses with similar kinetics and levels as were generated by replication-competent VSV-EBOV-Luciferase vector [47]. This is notable, since SC-Ad does not replicate in mice, whereas VSV-EBOV is replication-competent.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Retargeting adenoviruses for therapeutic applications and vaccines

Barry

Rubin

2020

FEBS Letters

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Adenoviruses (Ads) are robust vectors for therapeutic applications and vaccines, but their use can be limited by differences in their in vitro and in vivo pharmacologies. This review emphasizes that there is not just one Ad, but a whole virome of diverse viruses that can be used as therapeutics. It discusses that true vector targeting involves not only retargeting viruses, but importantly also detargeting the viruses from off-target cells.

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A Replicating Single-Cycle Adenovirus Vaccine Against Ebola Virus

Cited by 15 publications

References 31 publications

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

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

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

Retargeting adenoviruses for therapeutic applications and vaccines

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