Alternate aerosol and systemic immunisation with a recombinant viral vector for tuberculosis, MVA85A: A phase I randomised controlled trial.

BackgroundThere 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).Methods and findingsBetween 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 One participant was withdrawn and was replaced.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.ConclusionsTo 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.Trial registrationClinicalTrials.gov NCT01954563

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"La vida sólo puede entenderse mirando hacia atrás, pero ha de vivirse yendo hacia delante" Soren Kierkegaar

A Phase I, Open-Label Trial, Evaluating the Safety and Immunogenicity of Candidate Tuberculosis Vaccines AERAS-402 and MVA85A, Administered by Prime-Boost Regime in BCG-Vaccinated Healthy Adults

<div><p>Background</p><p>MVA85A and AERAS-402 are two clinically advanced viral vectored TB vaccine candidates expressing <i>Mycobacterium tuberculosis</i> antigens designed to boost BCG-induced immunity. Clinical trials with candidate malaria vaccines have demonstrated that adenoviral vector based priming immunisation, followed by MVA vector boost, induced high levels of immunity. We present the safety and immunogenicity results of the first clinical trial to evaluate this immunisation strategy in TB.</p><p>Methods</p><p>In this phase 1, open-label trial, 40 healthy previously BCG-vaccinated participants were enrolled into three treatment groups and vaccinated with 1 or 2 doses of AERAS-402 followed by MVA85A; or 3 doses of AERAS-402.</p><p>Results</p><p>Most related adverse events (AEs) were mild and there were no vaccine related serious AEs. Boosting AERAS-402 with MVA85A significantly increased Ag85A-specific T-cell responses from day of vaccination. Two priming doses of AERAS-402 followed by MVA85A boost, resulted in a significantly higher AUC post-peak Ag85A response compared to three doses of AERAS-402 and historical data with MVA85A vaccination alone. The frequency of CD8+ T-cells producing IFN-γ, TNF-α and IL-2 was highest in the group receiving two priming doses of AERAS-402 followed by MVA85A.</p><p>Conclusions</p><p>Vaccination with AERAS-402 followed by MVA85A was safe and increased the durability of antigen specific T-cell responses and the frequency and polyfunctionality of CD8+ T-cells, which may be important in protection against TB. Further clinical trials with adenoviral prime-MVA85A boost regimens are merited to optimise vaccination intervals, dose and route of immunisation and to evaluate this strategy in the target population in TB high burden countries.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01683773" target="_blank">NCT01683773</a>.</p></div

CONSORT flow diagram.

<p>CONSORT flow diagram showing subject recruitment and follow up. Subjects were allocated to Groups A and B in parallel and once both groups were complete, subjects were enrolled to Group C. *One subject was lost to follow up in Group B post day 14 follow up visit. All AEs post Day 0 vaccination had resolved prior to loss to follow up. **Two subjects withdrew from the study; one subject withdrew from Group B post first vaccination as did not wish to undergo any further venepunctures; one subject withdrew from Group C post second vaccination due to unexpected relocation. Both withdrawals were not considered related to vaccination and all AEs had resolved prior to withdrawal. The subject lost to follow up and the subject who withdrew from Group A was replaced; the subject who withdrew from Group C was not replaced as the study was nearing completion.</p

Serum antibody responses.

<p>Serum antibody responses to Ag85A (A), Ag85B (B) and TB10.4 (C) in the three study groups; Group A (AERAS-402, AERAS-402, MVA85A), Group B (AERAS-402, MVA85A) and Group C (AERAS-402, AERAS-402, AERAS-402). Antibody responses were measured in optical density (OD), data is presented as fold change responses calculated by dividing each time point’s antibody response by its corresponding day 0 response. Box and whisker plots show median, inter-quartile range, minimum and maximum values. Stars denote significant changes in responses after vaccination (Wilcoxon matched pairs) * p = < 0.05, ** p = < 0.01, *** p = < 0.001, ns = not significant.</p

Ex-<i>vivo</i> IFN-γ ELISpot vector responses.

<p>Responses to MVA peptides for CD4+ (A), and CD8+ T-cell epitopes (B) and summed responses to 3 pools of adenovirus peptides (C) in BCG-vaccinated, healthy adults for Group A (AERAS-402, AERAS-402, MVA85A), Group B (AERAS-402, MVA85A) and Group C (AERAS-402, AERAS-402, AERAS-402). Box and whisker plots show median, inter-quartile range, minimum and maximum values. Stars denote significant changes in responses after vaccination (Wilcoxon matched pairs) * p = < 0.05, ** p = < 0.01, *** p = < 0.001, ns = not significant.</p

<i>Ex-vivo</i> IFN-γ ELISpot insert responses.

<p>Responses to Ag85A (A), Ag85B (B) and TB10.4 (C) in BCG-vaccinated, healthy adults for Group A (AERAS-402, AERAS-402, MVA85A), Group B (AERAS-402, MVA85A) and Group C (AERAS-402, AERAS-402, AERAS-402). Responses to Ag85A are also shown from TB022 (MVA85A). Box and whisker plots show median, inter-quartile range, minimum and maximum values. Stars denote significant changes in responses after vaccination (Wilcoxon matched pairs) * p = < 0.05, ** p = < 0.01, *** p = < 0.001, ns = not significant.</p

The numbers of subjects within each group reporting each related adverse event.

<p>Local adverse events that were reported twice by individual subjects (8 adverse events) in the seven day diary card period are included in the summary adverse event <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141687#pone.0141687.t002" target="_blank">Table 2</a>.</p><p>All related adverse events were reported during the seven day diary card period apart from one volunteer who reported axillary tenderness at day 20 post second AERAS-402 vaccination which was deemed possibly related to vaccination. Abbreviations: AEs, adverse events; ALT, alanine transaminase; AST, aspartate aminotransferase.</p><p>The numbers of subjects within each group reporting each related adverse event.</p