A Replicating Single-Cycle Adenovirus Vaccine Effective against Clostridium difficile

Matchett, William E.; Anguiano-Zarate, Stephanie S.; Malewana, Goda Baddage Rakitha; Mudrick, Haley; Weldy, Melissa; Evert, Clayton; Khoruts, Alexander; Sadowsky, Michael J.; Barry, Michael A.

doi:10.3390/vaccines8030470

Cited by 6 publications

(6 citation statements)

References 57 publications

(73 reference statements)

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“…This is true for RD-and SC-Ad vaccines but is also true for mRNA or other platforms that deliver antigens into host cells. Despite the biology that will drive direct cell death through the Ad life cycle and antiviral or antivaccine T cell responses, SC-Ad vaccines appear to be relatively safe as demonstrated in hamsters given IN or IM doses of 10 11 vp of SC-Ad expressing Clostridium difficile vaccine (19) and by the fact that SC-Ad-Spike passed sufficient safety tests to enter phase 1 clinical trials (NCT04839042).…”

Section: Discussionmentioning

confidence: 99%

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Comparison of replicating and nonreplicating vaccines against SARS-CoV-2

et al. 2022

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Most gene-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are nonreplicating vectors. They deliver the gene or messenger RNA to the cell to express the spike protein but do not replicate to amplify antigen production. This study tested the utility of replication in a vaccine by comparing replication-defective adenovirus (RD-Ad) and replicating single-cycle adenovirus (SC-Ad) vaccines that express the SARS-CoV-2 spike protein. SC-Ad produced 100 times more spike protein than RD-Ad and generated significantly higher antibodies against the spike protein than RD-Ad after single immunization of Ad-permissive hamsters. SC-Ad–generated antibodies climbed over 14 weeks after single immunization and persisted for more than 10 months. When the hamsters were challenged 10.5 months after single immunization, a single intranasal or intramuscular immunization with SC-Ad-Spike reduced SARS-CoV-2 viral loads and damage in the lungs and preserved body weight better than vaccination with RD-Ad-Spike. This demonstrates the utility of harnessing replication in vaccines to amplify protection against infectious diseases.

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Section: Discussionmentioning

confidence: 99%

“…mRNA vaccines advanced most quickly in the United States with approval from the Food and Drug Administration. While these advanced vaccines show promise in the fight against coronavirus disease 2019 (COVID- 19), they overlook two opportunities to improve protection.…”

Section: Introductionmentioning

confidence: 99%

Comparison of replicating and nonreplicating vaccines against SARS-CoV-2

et al. 2022

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“…The hamster is profoundly more susceptible to CDI than mice and develops many of the clinical symptoms observed in humans [ 22 , 23 , 24 ]. As such, this lethality model has been invaluable for the testing of vaccines and therapeutics [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. C. difficile is a Gram-positive, spore-forming anaerobe that resides in the intestinal tract of humans and animals and in the environment.…”

Section: Introductionmentioning

confidence: 99%

Fasting before Intra-Gastric Dosing with Antigen Improves Intestinal Humoral Responses in Syrian Hamsters

Wood,

Hughes,

Trussell

et al. 2024

Vaccines

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Oral vaccines, unlike injected, induce intestinal secretory immunoglobulin A (sIgA) mimicking our natural defense against gut pathogens. We previously observed sIgA responses after administering the Clostridioides difficile colonisation factor CD0873 orally in enteric capsules to hamsters. Enteric-coated capsules are designed to resist dissolution in the stomach and disintegrate only at the higher pH of the small intestine. However, the variable responses between animals led us to speculate suboptimal transit of antigens to the small intestine. The rate of gastric emptying is a controlling factor in the passage of oral drugs for subsequent availability in the small intestine for absorption. Whilst in humans, food delays gastric emptying, in rats, capsules can empty quicker from fed stomachs than from fasted. To test in hamsters if fasting improves the delivery of antigens to the small intestine, as inferred from the immune responses generated, 24 animals were dosed intragastrically with enteric capsules containing recombinant CD0873. Twelve hamsters were fasted for 12 h prior to each dose and the other 12 fed. Significantly higher sIgA titres, with significantly greater bacterial-adherence-blocking activity, were detected in small intestinal lavages in the fasted group. We conclude that fasting in hamsters improves intestinal delivery leading to more robust responses.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Barry

Mudrick

McGlinch

et al. 2021

Preprint

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SARS-CoV-2 enters the body at mucosal surfaces, such as the nose and lungs. These events involve a small number of virions at these mucosal barriers and are therefore a strategic point to stop a COVID-19 infection before it starts. Despite this, most vaccines against COVID-19 are being injected into the muscle where they will not generate the highest levels of mucosal protection. The vaccines that are approved for use in humans are all replication-defective (RD) mRNA, DNA, or adenovirus (Ad) vaccines that do not amplify antigen transgenes. We developed single cycle adenovirus (SC-Ad) vectors that replicate antigen genes up to 10,000-fold in human cells, but that are disabled from producing infectious Ad particles. We show here that SC-Ad expressing the full-length SARS-CoV-2 spike protein produces 100-fold more spike protein than a matched RD-Ad-Spike vector. When Ad-permissive hamsters were immunized with these vaccines by intranasal (IN) or intramuscular (IM) routes, SC-Ad produced significantly stronger antibody responses as compared to RD-Ad against the spike protein that rose over 14 weeks after one immunization. Single IN or IM immunizations generated significant antibody responses in serum and in bronchoalveolar lavages (BALs). IN priming, but not IM priming, generated HLA-restricted CD8 T cell responses in BALs. SC-Ad-Spike generated antibodies that retain binding to spike receptor binding domains (RBDs) with mutations from new viral variants. These data suggest empowering the genomes of gene-based vaccines with the ability to amplify antigen genes can increase potency. This may be particularly advantageous when applying mucosal vaccines to combat mucosal pathogens like SARS-CoV-2.

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A Replicating Single-Cycle Adenovirus Vaccine Effective against Clostridium difficile

Cited by 6 publications

References 57 publications

Comparison of replicating and nonreplicating vaccines against SARS-CoV-2

Comparison of replicating and nonreplicating vaccines against SARS-CoV-2

Fasting before Intra-Gastric Dosing with Antigen Improves Intestinal Humoral Responses in Syrian Hamsters

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

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