Alternate aerosol and systemic immunisation with a recombinant viral vector for tuberculosis, MVA85A: A phase I randomised controlled trial
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
ID 4514688
Author(s) Manjaly Thomas, Zita-Rose; Satti, Iman; Marshall, Julia L.; Harris, Stephanie A.; Lopez Ramon, Raquel; Hamidi, Ali; Minhinnick, Alice; Riste, Michael; Stockdale, Lisa; Lawrie, Alison M.; Vermaak, Samantha; Wilkie, Morven; Bettinson, Henry; McShane, Helen
Author(s) at UniBasel Manjaly Thomas, Zita-Rose
Year 2019
Title Alternate aerosol and systemic immunisation with a recombinant viral vector for tuberculosis, MVA85A: A phase I randomised controlled trial
Journal PLoS Medicine
Volume 16
Number 4
Pages / Article-Number e1002790
Mesh terms Acyltransferases, immunology; Administration, Inhalation; Adult; Aerosols; Antigens, Bacterial, immunology; Drug Administration Schedule; Female; Genetic Vectors, adverse effects; Humans; Immunization, Secondary; Immunogenicity, Vaccine; Injections, Intradermal; Male; Mycobacterium tuberculosis, immunology; Single-Blind Method; Tuberculosis, prevention & control; Tuberculosis Vaccines, immunology; Vaccination, adverse effects; Vaccines, Synthetic, immunology; Young Adult
Abstract There is an urgent need for an effective tuberculosis (TB) vaccine. Heterologous prime-boost regimens induce potent cellular immunity. MVA85A is a candidate TB vaccine. This phase I clinical trial was designed to evaluate whether alternating aerosol and intradermal vaccination routes would boost cellular immunity to the Mycobacterium tuberculosis antigen 85A (Ag85A).; Between December 2013 and January 2016, 36 bacille Calmette-Guérin-vaccinated, healthy UK adults were randomised equally between 3 groups to receive 2 MVA85A vaccinations 1 month apart using either heterologous (Group 1, aerosol-intradermal; Group 2, intradermal-aerosol) or homologous (Group 3, intradermal-intradermal) immunisation. Bronchoscopy and bronchoalveolar lavage (BAL) were performed 7 days post-vaccination. Adverse events (AEs) and peripheral blood were collected for 6 months post-vaccination. The laboratory and bronchoscopy teams were blinded to treatment allocation. One participant was withdrawn and was replaced. Participants were aged 21-42 years, and 28/37 were female. In a per protocol analysis, aerosol delivery of MVA85A as a priming immunisation was well tolerated and highly immunogenic. Most AEs were mild local injection site reactions following intradermal vaccination. Transient systemic AEs occurred following vaccination by both routes and were most frequently mild. All respiratory AEs following primary aerosol MVA85A (Group 1) were mild. Boosting an intradermal MVA85A prime with an aerosolised MVA85A boost 1 month later (Group 2) resulted in transient moderate/severe respiratory and systemic AEs. There were no serious adverse events and no bronchoscopy-related complications. Only the intradermal-aerosol vaccination regimen (Group 2) resulted in modest, significant boosting of the cell-mediated immune response to Ag85A (p = 0.027; 95% CI: 28 to 630 spot forming cells per 1 × 106 peripheral blood mononuclear cells). All 3 regimens induced systemic cellular immune responses to the modified vaccinia virus Ankara (MVA) vector. Serum antibodies to Ag85A and MVA were only induced after intradermal vaccination. Aerosolised MVA85A induced significantly higher levels of Ag85A lung mucosal CD4+ and CD8+ T cell cytokines compared to intradermal vaccination. Boosting with aerosol-inhaled MVA85A enhanced the intradermal primed responses in Group 2. The magnitude of BAL MVA-specific CD4+ T cell responses was lower than the Ag85A-specific responses. A limitation of the study is that while the intradermal-aerosol regimen induced the most potent cellular Ag85A immune responses, we did not boost the last 3 participants in this group because of the AE profile. Timing of bronchoscopies aimed to capture peak mucosal response; however, peak responses may have occurred outside of this time frame.; To our knowledge, this is the first human randomised clinical trial to explore heterologous prime-boost regimes using aerosol and systemic routes of administration of a virally vectored vaccine. In this trial, the aerosol prime-intradermal boost regime was well tolerated, but intradermal prime-aerosol boost resulted in transient but significant respiratory AEs. Aerosol vaccination induced potent cellular Ag85A-specific mucosal and systemic immune responses. Whilst the implications of inducing potent mucosal and systemic immunity for protection are unclear, these findings are of relevance for the development of aerosolised vaccines for TB and other respiratory and mucosal pathogens.; NCT01954563.
Publisher Public Library of Science
ISSN/ISBN 1549-1277 ; 1549-1676
Full Text on edoc No
Digital Object Identifier DOI 10.1371/journal.pmed.1002790
PubMed ID
ISI-Number WOS:000466741500016
Document type (ISI) Journal Article, Randomized Controlled Trial

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