{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T01:12:30Z","timestamp":1766711550880,"version":"3.48.0"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Vaxxas Pty Ltd., Brisbane, Queensland 4007, Australia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objective: Despite available SARS-CoV-2 vaccines, coverage gaps persist due to unequal distribution and limited access. Microarray patches offer a promising solution to address these challenges, providing a safer and easier-to-use alternative. We present a randomised, double-blind Phase I clinical trial evaluating the SARS-CoV-2 spike protein subunit vaccine, HexaPro, delivered via a high-density microarray patch (HD-MAP). Methods: Forty-four healthy adults aged 18\u201350 years were assigned to receive either 0 \u00b5g, 15 \u00b5g, or 45 \u00b5g of HexaPro via the HD-MAP, with the primary objective of assessing safety and tolerability. Results: The HD-MAP HexaPro vaccine was found to be safe and well tolerated, with only mild adverse events reported. Following vaccination significant increases in spike-specific IgG titers were observed by 7 days and remained stable through day 90. This IgG response effectively neutralised multiple SARS-CoV-2 variants. Additionally, the HexaPro HD-MAP was stable for up to 12 months at 40 \u00b0C. Conclusions: These findings support the continued clinical development of HD-MAPs as an alternative vaccination strategy.<\/jats:p>","DOI":"10.3390\/vaccines14010028","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:50:21Z","timestamp":1766710221000},"page":"28","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Booster Immunisation with Skin-Patch-Delivered Unadjuvanted SARS-CoV-2 Spike Protein Vaccine Is Safe and Immunogenic in Healthy Adults"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5316-0986","authenticated-orcid":false,"given":"Christopher L. D.","family":"McMillan","sequence":"first","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia"},{"name":"Australian Infectious Diseases Research Centre, Brisbane, QLD 4072, Australia"},{"name":"Global Virus Network Centre of Excellence, Brisbane, QLD 4029, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4375-7890","authenticated-orcid":false,"given":"David A.","family":"Muller","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia"},{"name":"Australian Infectious Diseases Research Centre, Brisbane, QLD 4072, Australia"},{"name":"Global Virus Network Centre of Excellence, Brisbane, QLD 4029, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3260-0548","authenticated-orcid":false,"given":"Germain J. P.","family":"Fernando","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia"},{"name":"Vaxxas PTY Ltd., Hamilton, QLD 4007, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6743-0097","authenticated-orcid":false,"given":"Alexandra C. I.","family":"Depelsenaire","sequence":"additional","affiliation":[{"name":"School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia"},{"name":"Vaxxas PTY Ltd., Hamilton, QLD 4007, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cesar","family":"Jayashi-Flores","sequence":"additional","affiliation":[{"name":"Vaxxas PTY Ltd., Hamilton, QLD 4007, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly-Anne","family":"Masterman","sequence":"additional","affiliation":[{"name":"Vaxxas PTY Ltd., Hamilton, QLD 4007, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarika","family":"Namjoshi","sequence":"additional","affiliation":[{"name":"Vaxxas PTY Ltd., Hamilton, QLD 4007, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kartik","family":"Vyas","sequence":"additional","affiliation":[{"name":"Vaxxas PTY Ltd., Hamilton, QLD 4007, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7726-2946","authenticated-orcid":false,"given":"Deborah","family":"Pascoe","sequence":"additional","affiliation":[{"name":"Vaxxas PTY Ltd., Hamilton, QLD 4007, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6178-1953","authenticated-orcid":false,"given":"Julian","family":"Hickling","sequence":"additional","affiliation":[{"name":"Working in Tandem Ltd., 23 Rathmore Road, Cambridge CB1 7AB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Wallace","sequence":"additional","affiliation":[{"name":"University of the Sunshine Coast Clinical Trials Centre, Sippy Downs, QLD 4556, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Duijsings","sequence":"additional","affiliation":[{"name":"Cerba Research, Marconistraat 16, 3029 AK Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joelle","family":"Vink","sequence":"additional","affiliation":[{"name":"Cerba Research, Marconistraat 16, 3029 AK Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam K.","family":"Wheatley","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9072-1017","authenticated-orcid":false,"given":"Jennifer","family":"Juno","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Greg","family":"Siller","sequence":"additional","affiliation":[{"name":"Siller Medical, The University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5363-2015","authenticated-orcid":false,"given":"Angus H.","family":"Forster","sequence":"additional","affiliation":[{"name":"Vaxxas PTY Ltd., Hamilton, QLD 4007, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"ref_1","first-page":"127","article-title":"SARS-CoV-2 variants offer a second chance to fix vaccine inequities","volume":"21","author":"Hotez","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_2","unstructured":"Johns Hopkins University of Medicine (2024, June 11). Coronavirus Resource Center. Available online: https:\/\/coronavirus.jhu.edu\/region\/papua-new-guinea."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2359","DOI":"10.1002\/rmv.2359","article-title":"Recent developments in SARS-CoV-2 vaccines: A systematic review of the current studies","volume":"33","author":"Sadeghalvad","year":"2023","journal-title":"Rev. Med. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Forster, A.H., Witham, K., Depelsenaire, A.C.I., Veitch, M., Wells, J.W., Wheatley, A., Pryor, M., Lickliter, J.D., Francis, B., and Rockman, S. (2020). Safety, tolerability, and immunogenicity of influenza vaccination with a high-density microarray patch: Results from a randomized, controlled phase I clinical trial. PLoS Med., 17.","DOI":"10.1371\/journal.pmed.1003024"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Garg, N., Tellier, G., Vale, N., Kluge, J., Portman, J.L., Markowska, A., and Tussey, L. (2024). Phase 1, randomized, rater and participant blinded placebo-controlled study of the safety, reactogenicity, tolerability and immunogenicity of H1N1 influenza vaccine delivered by VX-103 (a MIMIX microneedle patch [MAP] system) in healthy adults. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0303450"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.biomaterials.2015.04.007","article-title":"Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch","volume":"57","author":"Hirobe","year":"2015","journal-title":"Biomaterials"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0140-6736(17)30575-5","article-title":"The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): A randomised, partly blinded, placebo-controlled, phase 1 trial","volume":"390","author":"Rouphael","year":"2017","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1016\/S0140-6736(24)00532-4","article-title":"A measles and rubella vaccine microneedle patch in The Gambia: A phase 1\/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial","volume":"403","author":"Adigweme","year":"2024","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Baker, B., Bermingham, I.M., Leelasena, I., Hickling, J., Young, P.R., Muller, D.A., and Forster, A.H. (2023). Safety, Tolerability, and Immunogenicity of Measles and Rubella Vaccine Delivered with a High-Density Microarray Patch: Results from a Randomized, Partially Double-Blinded, Placebo-Controlled Phase I Clinical Trial. Vaccines, 11.","DOI":"10.20944\/preprints202308.0501.v1"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1016\/S2666-5247(21)00269-X","article-title":"Safety and dose-sparing effect of Japanese encephalitis vaccine administered by microneedle patch in uninfected, healthy adults (MNA-J): A randomised, partly blinded, active-controlled, phase 1 trial","volume":"3","author":"Iwata","year":"2022","journal-title":"Lancet Microbe"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1080\/14760584.2023.2270598","article-title":"Microarray patches: Scratching the surface of vaccine delivery","volume":"22","author":"Choo","year":"2023","journal-title":"Expert. Rev. Vaccines"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jconrel.2015.11.019","article-title":"Microneedle patches for vaccination in developing countries","volume":"240","author":"Arya","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Menon, I., Bagwe, P., Gomes, K.B., Bajaj, L., Gala, R., Uddin, M.N., D\u2019Souza, M.J., and Zughaier, S.M. (2021). Microneedles: A New Generation Vaccine Delivery System. Micromachines, 12.","DOI":"10.3390\/mi12040435"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nguyen, H.X. (2025). Beyond the Needle: Innovative Microneedle-Based Transdermal Vaccination. Medicines, 12.","DOI":"10.3390\/medicines12010004"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1038\/jid.2014.174","article-title":"Colocalization of cell death with antigen deposition in skin enhances vaccine immunogenicity","volume":"134","author":"Depelsenaire","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e2102595118","DOI":"10.1073\/pnas.2102595118","article-title":"Transdermal vaccination via 3D-printed microneedles induces potent humoral and cellular immunity","volume":"118","author":"Caudill","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2100095","DOI":"10.1002\/adtp.202100095","article-title":"Thermostability of Measles and Rubella Vaccines in a Microneedle Patch","volume":"4","author":"Joyce","year":"2021","journal-title":"Adv. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1002\/jps.24283","article-title":"Development of a thermostable microneedle patch for influenza vaccination","volume":"104","author":"Mistilis","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s13346-016-0282-2","article-title":"Long-term stability of influenza vaccine in a dissolving microneedle patch","volume":"7","author":"Mistilis","year":"2017","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12189","DOI":"10.1038\/s41598-022-16365-2","article-title":"Development of the H3N2 influenza microneedle vaccine for cross-protection against antigenic variants","volume":"12","author":"Shin","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/s41587-023-01774-z","article-title":"A microneedle vaccine printer for thermostable COVID-19 mRNA vaccines","volume":"42","author":"Sarmadi","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhao, B., Jin, Z., Yu, Y., Li, Y., Wang, J., Wan, W., Hu, C., Li, X., Li, Y., and Xin, W. (2022). A Thermostable Dissolving Microneedle Vaccine with Recombinant Protein of Botulinum Neurotoxin Serotype A. Toxins, 14.","DOI":"10.3390\/toxins14120881"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"126996","DOI":"10.1016\/j.vaccine.2025.126996","article-title":"Identification of potential vaccines for use with microarray patches in low- and middle-income countries: An assessment from the Vaccine Innovation Prioritisation Strategy Alliance","volume":"55","author":"Frivold","year":"2025","journal-title":"Vaccine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4435","DOI":"10.1016\/j.vaccine.2019.02.079","article-title":"End-user acceptability study of the nanopatch; a microarray patch (MAP) for child immunization in low and middle-income countries","volume":"37","author":"Guillermet","year":"2019","journal-title":"Vaccine"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"O\u2019Shea, J., Prausnitz, M.R., and Rouphael, N. (2021). Dissolvable Microneedle Patches to Enable Increased Access to Vaccines against SARS-CoV-2 and Future Pandemic Outbreaks. Vaccines, 9.","DOI":"10.3390\/vaccines9040320"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4427","DOI":"10.1016\/j.vaccine.2019.03.035","article-title":"Potential use of microarray patches for vaccine delivery in low- and middle- income countries","volume":"37","author":"Peyraud","year":"2019","journal-title":"Vaccine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"379","DOI":"10.2147\/MDER.S198220","article-title":"Technology update: Dissolvable microneedle patches for vaccine delivery","volume":"12","author":"Rodgers","year":"2019","journal-title":"Med. Devices"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/17425247.2023.2168641","article-title":"Accelerating the development of vaccine microarray patches for epidemic response and equitable immunization coverage requires investment in microarray patch manufacturing facilities","volume":"20","author":"Scarna","year":"2023","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Seaman, C.P., Mvundura, M., Frivold, C., Morgan, C., Jarrahian, C., Howell, J., Hellard, M., and Scott, N. (2022). Evaluating the potential cost-effectiveness of microarray patches to expand access to hepatitis B birth dose vaccination in low-and middle-income countries: A modelling study. PLoS Glob. Public Health, 2.","DOI":"10.1371\/journal.pgph.0000394"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1016\/j.vaccine.2023.12.047","article-title":"A review of potential use cases for measles-rubella, measles-mumps-rubella, and typhoid-conjugate vaccines presented on microarray patches","volume":"42","author":"Soble","year":"2024","journal-title":"Vaccine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"eabj8065","DOI":"10.1126\/sciadv.abj8065","article-title":"Complete protection by a single-dose skin patch-delivered SARS-CoV-2 spike vaccine","volume":"7","author":"McMillan","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1126\/science.abd0826","article-title":"Structure-based design of prefusion-stabilized SARS-CoV-2 spikes","volume":"369","author":"Hsieh","year":"2020","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6197","DOI":"10.1038\/s41467-021-26499-y","article-title":"A Newcastle disease virus expressing a stabilized spike protein of SARS-CoV-2 induces protective immune responses","volume":"12","author":"Sun","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1038\/s41467-022-30222-w","article-title":"Quadrivalent mosaic HexaPro-bearing nanoparticle vaccine protects against infection of SARS-CoV-2 variants","volume":"13","author":"Kang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3621","DOI":"10.1016\/j.vaccine.2022.04.078","article-title":"Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomized, placebo-controlled, phase 1\/2 trial in Vietnam","volume":"40","author":"Lawpoolsri","year":"2022","journal-title":"Vaccine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101323","DOI":"10.1016\/j.eclinm.2022.101323","article-title":"Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial","volume":"45","author":"Pitisuttithum","year":"2022","journal-title":"EClinicalMedicine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1208\/s12249-019-1509-6","article-title":"Human Serum Albumin, a Suitable Candidate to Stabilize Freeze-Dried IgG in Combination with Trehalose: Central Composite Design","volume":"20","author":"Nouraei","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/1743-422X-2-84","article-title":"Development of an improved microneutralization assay for respiratory syncytial virus by automated plaque counting using imaging analysis","volume":"2","author":"Zielinska","year":"2005","journal-title":"Virol. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"104878","DOI":"10.1016\/j.ebiom.2023.104878","article-title":"Interim results from a phase I randomized, placebo-controlled trial of novel SARS-CoV-2 beta variant receptor-binding domain recombinant protein and mRNA vaccines as a 4th dose booster","volume":"98","author":"Nolan","year":"2023","journal-title":"EBioMedicine"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Depelsenaire, A.C.I., Witham, K., Veitch, M., Wells, J.W., Anderson, C.D., Lickliter, J.D., Rockman, S., Bodle, J., Treasure, P., and Hickling, J. (2021). Cellular responses at the application site of a high-density microarray patch delivering an influenza vaccine in a randomized, controlled phase I clinical trial. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0255282"},{"key":"ref_41","unstructured":"U.S. Food and Drug Administration (2024, November 18). Fact Sheet for Healthcare Providers Administering Vaccine: Emergency Use Authorization of Novavax COVID-19 Vaccine, Adjuvanted (2024\u20132025 Formula), for Individuals 12 Years of Age and Older, Available online: https:\/\/novavax.widen.net\/s\/9tkdmzh9z6\/us-eua-fact-sheet-hcp."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"001947","DOI":"10.1099\/jgv.0.001947","article-title":"Enhancement of cellular immunity following needle-free vaccination of mice with SARS-CoV-2 spike protein","volume":"105","author":"McMillan","year":"2024","journal-title":"J. Gen. Virol."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/1\/28\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T01:08:39Z","timestamp":1766711319000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/1\/28"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,25]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["vaccines14010028"],"URL":"https:\/\/doi.org\/10.3390\/vaccines14010028","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,25]]}}}