Protective Properties of Vaccinia Virus-Based Vaccines: Skin Scarification Promotes a Nonspecific Immune Response That Protects against Orthopoxvirus Disease

Rice, Amanda D.; Adams, Mathew M.; Lindsey, Scott F.; Swetnam, Daniele M.; Manning, Brandi R.; Smith, Andrew; Burrage, Andrew M.; Wallace, Greg; MacNeill, Amy L.; Moyer, Richard W.

doi:10.1128/jvi.00185-14

Cited by 17 publications

(14 citation statements)

References 22 publications

(29 reference statements)

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“…In animal models, administrating smallpox vaccination via skin scarification has been demonstrated to increase the immune response and survival compared with other modes of administration 21. Murine studies have shown that intradermal smallpox vaccination induced long-lived non-recirculating CD8+skin resident T-memory cells that resided within the entire skin and protected against reinfection 22.…”

Section: Discussionmentioning

confidence: 99%

Phase-out of smallpox vaccination and the female/male HIV-1 prevalence ratio: an ecological study from Guinea-Bissau

et al. 2019

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ObjectiveIn Guinea-Bissau, West Africa, we observed that having a smallpox vaccination scar was associated with lower HIV-1 prevalence, more strongly for women than men. If this represents a causal effect, the female/male HIV-1 prevalence ratio would increase for birth cohorts no longer receiving smallpox vaccination due to the phase-out of this vaccine.DesignAn ecological design using HIV surveys and information about smallpox vaccination coverage.SettingUrban and rural Guinea-Bissau.ParticipantsParticipants in HIV surveys were grouped into an age group with decreasing smallpox vaccination coverage (15–34 years) and an age group with steady smallpox vaccination coverage (≥35 years).InterventionsThe exposure of interest was the phase-out of the smallpox vaccine in Guinea-Bissau.Primary and secondary outcome measuresHIV-1 prevalence.ResultsAt both sites, the female/male HIV-1 prevalence ratio increased by calendar time for the age group with decreasing smallpox vaccination coverage; the combined female/male HIV-1 prevalence ratio among people aged 15–34 years was 1.00 (95% CI 0.17 to 5.99) in 1987–1990, 1.16 (95% CI 0.69 to 1.93) in 1996–1997, 2.32 (95% CI 1.51 to 3.56) in 2006–2007 (p value for no trend=0.04). There was no increase in the female-to-male HIV-1 prevalence ratio for the age group >35 years with steady smallpox vaccination coverage; 1.93 (95% CI 0.40 to 9.25) in 1987–1990, 1.32 (95% CI 0.83 to 2.10) in 1996–1997, 0.81 (95% CI 0.56 to 1.16) in 2006–2007 (p value for no trend=0.07).ConclusionsThus, data was compatible with the deduction that the phase-out of smallpox vaccination may have increased the susceptibility to HIV-1 relatively more for women than men. Hence, phasing out smallpox vaccination may have contributed to the global increase in the female/male HIV-1 prevalence ratio among young individuals. Due to the potential fallacies of ecological studies, the results should be interpreted carefully, and this hypothesis needs further assessment. If the hypothesis is true, studies of smallpox vaccination could inform HIV-1 vaccine research.

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Section: Discussionmentioning

confidence: 99%

Phase-out of smallpox vaccination and the female/male HIV-1 prevalence ratio: an ecological study from Guinea-Bissau

et al. 2019

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“…Thus replication-competent smallpox vaccines, including those that were used in the successful eradication of smallpox, such as Dryvax, Lister, LIVP, Temple of Heaven, and EM-63, were mostly administered by skin scarification [61]. The current US-licensed secondgeneration smallpox vaccine, ACAM2000, is also administered by skin scarification, a procedure that is believed to be partly responsible for the success of the global eradication of smallpox by provoking robust innate and adaptive immune responses [62]. Due to the severe attenuation of MVA, as epitomized by its inability to replicate productively in many mammalian cells [11,12,13], MVA and MVA-vectored vaccines are usually administered via routes other than percutaneous in preclinical studies.…”

Section: Discussionmentioning

confidence: 99%

Percutaneous Vaccination as an Effective Method of Delivery of MVA and MVA-Vectored Vaccines

et al. 2016

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The robustness of immune responses to an antigen could be dictated by the route of vaccine inoculation. Traditional smallpox vaccines, essentially vaccinia virus strains, that were used in the eradication of smallpox were administered by percutaneous inoculation (skin scarification). The modified vaccinia virus Ankara is licensed as a smallpox vaccine in Europe and Canada and currently undergoing clinical development in the United States. MVA is also being investigated as a vector for the delivery of heterologous genes for prophylactic or therapeutic immunization. Since MVA is replication-deficient, MVA and MVA-vectored vaccines are often inoculated through the intramuscular, intradermal or subcutaneous routes. Vaccine inoculation via the intramuscular, intradermal or subcutaneous routes requires the use of injection needles, and an estimated 10 to 20% of the population of the United States has needle phobia. Following an observation in our laboratory that a replication-deficient recombinant vaccinia virus derived from the New York City Board of Health strain elicited protective immune responses in a mouse model upon inoculation by tail scarification, we investigated whether MVA and MVA recombinants can elicit protective responses following percutaneous administration in mouse models. Our data suggest that MVA administered by percutaneous inoculation, elicited vaccinia-specific antibody responses, and protected mice from lethal vaccinia virus challenge, at levels comparable to or better than subcutaneous or intramuscular inoculation. High titers of specific neutralizing antibodies were elicited in mice inoculated with a recombinant MVA expressing the herpes simplex type 2 glycoprotein D after scarification. Similarly, a recombinant MVA expressing the hemagglutinin of attenuated influenza virus rgA/Viet Nam/1203/2004 (H5N1) elicited protective immune responses when administered at low doses by scarification. Taken together, our data suggest that MVA and MVA-vectored vaccines inoculated by scarification can elicit protective immune responses that are comparable to subcutaneous vaccination, and may allow for antigen sparing when vaccine supply is limited.

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“…Dermal necrosis and inflammation persisted for up to 14 days in treated skin. This study however lacked control groups using the tattooing device and gene upregulation appeared [356]. Importantly, neutrophil and monocyte infiltrations were more prominent in the VE, dermis and in particular in the s.c. tissue in the first 24h post-treatment.…”

Section: Cell Death and Innate Immune Responses To Vaccine Delivery Dmentioning

confidence: 93%

“…These experimental groups would have been important to exclude the possibility that the excision in itself resulted in a highly proinflammatory micro-environment, with significant DAMP release from cells exposed to alum but also necrotic cells due to the incisions. In particular, since s.s. has been described as inducing a proinflammatory immune response that contributes significantly to the subsequent immunisation [356].…”

Section: Aluminium Saltsmentioning

confidence: 99%

“…Later, the skin scarification was found to be the essential component of eliciting higher humoral and cellular responses coupled to protection following lethal challenge studies [356]. Separately, as a result of tissue injury, neutrophils are the first cells recruited from the blood to the site of insult within minutes, predominantly via the P2X7 receptor [404,555].…”

Section: Immunological and Immuno-modulatory Effects Of Danger Signalsmentioning

confidence: 99%

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Investigation of cell death caused by the Nanopatch™ and its role in vaccine delivery as a physical immune enhancer

Depelsenaire¹

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Since the introduction of vaccines, millions of lives have been saved. Yet, infectious diseases continue to contribute to deaths in underdeveloped countries, with over 2 million children dying per year from preventable diseases such as diphtheria, pertussis and tetanus. Despite the advantages of vaccines, there are also some risks and disadvantages associated with vaccines and their delivery such as the need for medical personnel for administration, refrigeration of the vaccine, disease transmission associated with needles and potential adverse side effects due to adjuvants. While intramuscular and subcutaneous injections are most frequently used for vaccine administration, these sites are poor in antigen-presenting cells. The skin, the largest immunological organ, by contrast contains a dense network of antigen-presenting cells, important in the uptake of antigen and presentation to naive T-cells, and has received increased interest as a target site for vaccine delivery. Intradermal immunisations have achieved significant dose-sparing over conventional immunisation routes. However, using existing needle designs, intradermal injections can be difficult to administer into the thin dermal layer due to the proportionally large scale of the needle. This has led to the development of alternative skin-based delivery methods, such as microneedle arrays.Here, the Nanopatch™ is an array containing 3364 microprojections of ~110 µm in length, which was used to deliver the vaccine into the viable epidermis and dermis of the skin. With an unprecedented >100-fold dose-sparing reported by the Nanopatch™ in comparison to conventional immunisation strategies with an influenza split virion vaccine, the mechanisms behind this skin- The extent of cell death after Nanopatch™ application and intradermal injection was investigated, characterised and quantified by Confocal/ Multiphoton microscopy, Western Blot and flow cytometry. A distinct pattern of dead cells was obtained with significantly higher levels (~65-fold) of cell death in murine ear skin following Nanopatch™ treatment than intradermal injection.ii | P a g e Measured skin cell death was tuneable by changing projection density but not shapes, and was associated with modelled stresses of ≥1 MPa.Immunogenicity studies demonstrated consistently and statistically significantly higher anti-IgG endpoint titres (up to 50-fold higher) in Nanopatch™ than intradermally injected groups after delivery of a split virion influenza vaccine, with a 10-fold dose-sparing effect. Importantly, colocalisation of delivered antigen with both, live and dead cells was necessary for immunogenicity enhancement. Overall, higher inflammatory responses and longer-lasting antigen depot formation were associated with Nanopatch™ immunisations but not with intradermal injections. The findings indicated a correlation between co-localisation of antigen cell death caused by the Nanopatch™ and enhanced immunogenicity with split virion influenza vaccine as model antigen.Collectively, the data presented wi...

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Protective Properties of Vaccinia Virus-Based Vaccines: Skin Scarification Promotes a Nonspecific Immune Response That Protects against Orthopoxvirus Disease

Cited by 17 publications

References 22 publications

Phase-out of smallpox vaccination and the female/male HIV-1 prevalence ratio: an ecological study from Guinea-Bissau

Phase-out of smallpox vaccination and the female/male HIV-1 prevalence ratio: an ecological study from Guinea-Bissau

Percutaneous Vaccination as an Effective Method of Delivery of MVA and MVA-Vectored Vaccines

Investigation of cell death caused by the Nanopatch™ and its role in vaccine delivery as a physical immune enhancer

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