Safety and immunogenicity of a thermostable ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults.

Adjuvant-containing subunit vaccines represent a promising approach for protection against tuberculosis (TB), but current candidates require refrigerated storage. Here we present results from a randomized, double-blinded Phase 1 clinical trial (NCT03722472) evaluating the safety, tolerability, and immunogenicity of a thermostable lyophilized single-vial presentation of the ID93 + GLA-SE vaccine candidate compared to the non-thermostable two-vial vaccine presentation in healthy adults. Participants were monitored for primary, secondary, and exploratory endpoints following intramuscular administration of two vaccine doses 56 days apart. Primary endpoints included local and systemic reactogenicity and adverse events. Secondary endpoints included antigen-specific antibody (IgG) and cellular immune responses (cytokine-producing peripheral blood mononuclear cells and T cells). Both vaccine presentations are safe and well tolerated and elicit robust antigen-specific serum antibody and Th1-type cellular immune responses. Compared to the non-thermostable presentation, the thermostable vaccine formulation generates greater serum antibody responses (p < 0.05) and more antibody-secreting cells (p < 0.05). In this work, we show the thermostable ID93 + GLA-SE vaccine candidate is safe and immunogenic in healthy adults.

Safety and immunogenicity of the adjunct therapeutic vaccine ID93 + GLA-SE in adults who have completed treatment for tuberculosis: a randomised, double-blind, placebo-controlled, phase 2a trial.

BACKGROUND: A therapeutic vaccine that prevents recurrent tuberculosis would be a major advance in the development of shorter treatment regimens. We aimed to assess the safety and immunogenicity of the ID93 + GLA-SE vaccine at various doses and injection schedules in patients with previously treated tuberculosis. METHODS: This randomised, double-blind, placebo-controlled, phase 2a trial was conducted at three clinical sites near Cape Town, South Africa. Patients were recruited at local clinics after receiving 4 months of tuberculosis treatment, and screened for eligibility after providing written informed consent. Participants were aged 18-60 years, BCG-vaccinated, HIV-uninfected, and diagnosed with drug-sensitive pulmonary tuberculosis. Eligible patients had completed standard treatment for pulmonary tuberculosis in the past 28 days. Participants were enrolled after completing standard treatment and randomly assigned sequentially to receive vaccine or placebo in three cohorts: 2 µg intramuscular ID93 + 2 µg GLA-SE on days 0 and 56 (cohort 1); 10 µg ID93 + 2 µg GLA-SE on days 0 and 56 (cohort 2); 2 µg ID93 + 5 µg GLA-SE on days 0 and 56 and placebo on day 28 (cohort 3); 2 µg ID93 + 5 µg GLA-SE on days 0, 28, and 56 (cohort 3); or placebo on days 0 and 56 (cohorts 1 and 2), with the placebo group for cohort 3 receiving an additional injection on day 28. Randomisation was in a ratio of 3:1 for ID93 + GLA-SE and saline placebo in cohorts 1 and 2, and in a ratio of 3:3:1 for (2 ×) ID93 + GLA-SE, (3 ×) ID93 + GLA-SE, and placebo in cohort 3. The primary outcomes were safety and immunogenicity (vaccine-specific antibody response and T-cell response). For the safety outcome, participants were observed for 30 min after each injection, injection site reactions and systemic adverse events were monitored until day 84, and serious adverse events and adverse events of special interest were monitored for 6 months after the last injection. Vaccine-specific antibody responses were measured by serum ELISA, and T-cell responses after stimulation with vaccine antigens were measured in cryopreserved peripheral blood mononuclear cells specimens using intracellular cytokine staining followed by flow cytometry. This study is registered with ClinicalTrials.gov, number NCT02465216. FINDINGS: Between June 17, 2015, and May 30, 2016, we assessed 177 patients for inclusion. 61 eligible patients were randomly assigned to receive: saline placebo (n=5) or (2 ×) 2 µg ID93 + 2 µg GLA-SE (n=15) on days 0 and 56 (cohort 1); saline placebo (n=2) or (2 ×) 10 µg ID93 + 2 µg GLA-SE (n=5) on days 0 and 56 (cohort 2); saline placebo (n=5) on days 0, 28 and 56, or 2 µg ID93 + 5 µg GLA-SE (n=15) on days 0 and 56 and placebo injection on day 28, or (3 ×) 2 µg ID93 + 5 µg GLA-SE (n=14) on days 0, 28, and 56 (cohort 3). ID93 + GLA-SE induced robust and durable antibody responses and specific, polyfunctional CD4 T-cell responses to vaccine antigens. Two injections of the 2 µg ID93 + 5 µg GLA-SE dose induced antigen-specific IgG and CD4 T-cell responses that were significantly higher than those with placebo and persisted for the 6-month study duration. Mild to moderate injection site pain was reported after vaccination across all dose combinations, and induration and erythema in patients given 2 µg ID93 + 5 µg GLA-SE in two or three doses. One participant had grade 3 erythema and induration at the injection site. No vaccine-related serious adverse events were observed. INTERPRETATION: Vaccination with ID93 + GLA-SE was safe and immunogenic for all tested regimens. These data support further evaluation of ID93 + GLA-SE in therapeutic vaccination strategies to improve tuberculosis treatment outcomes. FUNDING: Wellcome Trust (102028/Z/13/Z).

The Systematic Review and Meta-Analysis on the Immunogenicity and Safety of the Tuberculosis Subunit Vaccines M72/AS01E and MVA85A.

Background: Tuberculosis (TB) is a severe infectious disease with devastating effects on global public health. No TB vaccine has yet been approved for use on latent TB infections and healthy adults. In this study, we performed a systematic review and meta-analysis to evaluate the immunogenicity and safety of the M72/AS01E and MVA85A subunit vaccines. The M72/AS01E is a novel peptide-based vaccine currently in progress, which may increase the protection level against TB infection. The MVA85A was a viral vector-based TB subunit vaccine being used in the clinical trials. The vaccines mentioned above have been studied in various phase I/II clinical trials. Immunogenicity and safety is the first consideration for TB vaccine development. Methods: The PubMed, Embase, and Cochrane Library databases were searched for published studies (until October 2019) to find out information on the M72/AS01E and MVA85A candidate vaccines. The meta-analysis was conducted by applying the standard methods and processes established by the Cochrane Collaboration. Results: Five eligible randomized clinical trials (RCTs) were selected for the meta-analysis of M72/AS01E candidate vaccines. The analysis revealed that the M72/AS01E subunit vaccine had an abundance of polyfunctional M72-specific CD4+ T cells [standardized mean difference (SMD) = 2.37] in the vaccine group versus the control group, the highest seropositivity rate [relative risk (RR) = 5.09]. The M72/AS01E vaccinated group were found to be at high risk of local injection site redness (RR = 2.64), headache (RR = 1.59), malaise (RR = 3.55), myalgia (RR = 2.27), fatigue (RR = 2.16), pain (RR = 3.99), swelling (RR = 5.09), and fever (RR = 2.04) compared to the control groups. The incidences of common adverse events of M72/AS01E were local injection site redness, headache, malaise, myalgia, fatigue, pain, swelling, fever, etc. Six eligible RCTs were selected for the meta-analysis on MVA85A candidate vaccines. The analysis revealed that the subunit vaccine MVA85A had a higher abundance of overall pooled proportion polyfunctional MVA85A-specific CD4+ T cells SMD = 2.41 in the vaccine group vs. the control group, with the highest seropositivity rate [estimation rate (ER) = 0.55]. The MVA85A vaccinated group were found to be at high risk of local injection site redness (ER = 0.55), headache (ER = 0.40), malaise (ER = 0.29), pain (ER = 0.54), myalgia (ER = 0.31), and fever (ER = 0.20). The incidences of common adverse events of MVA85A were local injection site redness, headache, malaise, pain, myalgia, fever, etc. Conclusion: The M72/AS01E and MVA85A vaccines against TB are safe and had immunogenicity in diverse clinical trials. The M72/AS01E and MVA85A vaccines are associated with a mild adverse reaction. The meta-analysis on immunogenicity and safety of M72/AS01E and MVA85A vaccines provides useful information for the evaluation of available subunit vaccines in the clinic.

A phase I trial evaluating the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime - MVA85A boost in healthy UK adults.

BACKGROUND: This phase I trial evaluated the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime-MVA85A boost, previously demonstrated to be protective in animal studies, in healthy UK adults. METHODS: We enrolled 42 healthy, BCG-vaccinated adults into 4 groups: low dose Starter Group (n = 6; ChAdOx1 85A alone), high dose groups; Group A (n = 12; ChAdOx1 85A), Group B (n = 12; ChAdOx1 85A prime - MVA85A boost) or Group C (n = 12; ChAdOx1 85A - ChAdOx1 85A prime - MVA85A boost). Safety was determined by collection of solicited and unsolicited vaccine-related adverse events (AEs). Immunogenicity was measured by antigen-specific ex-vivo IFN-γ ELISpot, IgG serum ELISA, and antigen-specific intracellular IFN-γ, TNF-α, IL-2 and IL-17. RESULTS: AEs were mostly mild/moderate, with no Serious Adverse Events. ChAdOx1 85A induced Ag85A-specific ELISpot and intracellular cytokine CD4+ and CD8+ T cell responses, which were not boosted by a second dose, but were boosted with MVA85A. Polyfunctional CD4+ T cells (IFN-γ, TNF-α and IL-2) and IFN-γ+, TNF-α+ CD8+ T cells were induced by ChAdOx1 85A and boosted by MVA85A. ChAdOx1 85A induced serum Ag85A IgG responses which were boosted by MVA85A. CONCLUSION: A ChAdOx1 85A prime - MVA85A boost is well tolerated and immunogenic in healthy UK adults.

Construction and Characterization of the Mycobacterium tuberculosis sigE fadD26 Unmarked Double Mutant as a Vaccine Candidate.

Despite the great increase in the understanding of the biology and pathogenesis of Mycobacterium tuberculosis achieved by the scientific community in recent decades, tuberculosis (TB) still represents one of the major threats to global human health. The only available vaccine (Mycobacterium bovis BCG) protects children from disseminated forms of TB but does not effectively protect adults from the respiratory form of the disease, making the development of new and more-efficacious vaccines against the pulmonary forms of TB a major goal for the improvement of global health. Among the different strategies being developed to reach this goal is the construction of attenuated strains more efficacious and safer than BCG. We recently showed that a sigE mutant of M. tuberculosis was more attenuated and more efficacious than BCG in a mouse model of infection. In this paper, we describe the construction and characterization of an M. tuberculosissigE fadD26 unmarked double mutant fulfilling the criteria of the Geneva Consensus for entering human clinical trials. The data presented suggest that this mutant is even more attenuated and slightly more efficacious than the previous sigE mutant in different mouse models of infection and is equivalent to BCG in a guinea pig model of infection.

Immunogenicity and Safety of the M72/AS01E Candidate Vaccine Against Tuberculosis: A Meta-Analysis.

Background: Currently, there is no tuberculosis (TB) vaccine recommended for use in latent TB infections and healthy adults. M72/AS01E is a new peptide vaccine currently under development, which may improve protection against TB disease. This vaccine has been investigated in several phase I/II clinical trials. We conducted a meta-analysis to clarify the immunogenicity and safety of the M72/AS01E peptide vaccine. Methods: We searched the PubMed, Embase, and Cochrane Library databases for published studies (until December 2018) investigating this candidate vaccine. A meta-analysis was performed using the standard methods and procedures established by the Cochrane Collaboration. Results: Seven eligible studies-involving 4,590 participants-were selected. The analysis revealed a vaccine efficacy was 57.0%, significantly higher abundance of polyfunctional M72-specific CD4+ T cells [standardized mean difference (SMD) = 2.58] in the vaccine group vs. the control group, the highest seropositivity rate [relative risk (RR) = 74.87] at 1 month after the second dose of vaccination (Day 60), and sustained elevated anti-M72 IgG geometric mean concentration at study end (Day 210) (SWD = 4.94). Compared with the control, participants who received vaccination were at increased risk of local injection site redness [relative risk (RR) = 5.99], local swelling (RR = 7.57), malaise (RR = 3.01), and fatigue (RR = 3.17). However, they were not at increased risk of headache (RR = 1.57), myalgia (RR = 0.97), and pain (RR = 3.02). Conclusion: The M72/AS01E vaccine against TB is safe and effective. Although the vaccine is associated with a mild adverse reaction, it is promising for the prevention of TB in healthy adults.

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

BACKGROUND: 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). METHODS AND FINDINGS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01954563.

Beyond memory T cells: mechanisms of protective immunity to tuberculosis infection.

Tuberculosis (TB) is a serious infectious disease caused by infection with Mycobacterium tuberculosis, and kills more people annually than any other single infectious agent. Although a vaccine is available, it is only moderately effective and an improved vaccine is urgently needed. The ability to develop a more effective vaccine has been thwarted by a lack of understanding of the mechanism of vaccine-induced immune protection. Over recent decades, many novel TB vaccines have been developed and almost all have aimed to generate memory CD4 T cells. In this review, we critically evaluate evidence in the literature that supports the contention that memory CD4 T cells are the prime mediators of vaccine-induced protection against TB. Because of the lack of robust evidence supporting memory CD4 T cells in this role, the potential for B-cell antibody and "trained" innate cells as alternative mediators of protective immunity is explored.

Designing tuberculosis vaccine efficacy trials - lessons from recent studies.

INTRODUCTION: Tuberculosis (TB) is the leading infectious killer globally and new TB vaccines will be crucial to ending the epidemic. Since the introduction in 1921 of the only currently licensed TB vaccine, BCG, very few novel vaccine candidates or strategies have advanced into clinical efficacy trials. Areas covered: Recently, however, two TB vaccine efficacy trials with novel designs have reported positive results and are now driving new momentum in the field. They are the first Prevention of Infection trial, evaluating the H4:IC31 candidate or BCG revaccination in high-risk adolescents and a Prevention of Disease trial evaluating the M72/AS01E candidate in M.tuberculosis-infected, healthy adults. These trials are briefly reviewed, and lessons learned are proposed to help inform the design of future efficacy trials. The references cited were chosen by the author based on PubMed searches to provide context for the opinions expressed in this Perspective article. Expert opinion: The opportunities created by these two trials for gaining critically important knowledge are game-changing for TB vaccine development. Their results clearly establish feasibility in the relatively near term of developing novel, effective vaccines that could be crucial to ending the TB epidemic.

Meeting report: 5th Global Forum on TB Vaccines, 20-23 February 2018, New Delhi India.

The 5th Global Forum on TB Vaccines was held in New Delhi, India from 20 to 23 February 2018. This was the largest Global Forum on TB Vaccines to date with nearly 350 participants from more than 30 countries. The program included over 60 speakers in 12 special, plenary and breakout sessions and 72 posters. This Global Forum brought a great sense of momentum and excitement to the field. New vaccines are in clinical trials, new routes of delivery are being tested, novel assays and biomarker signatures are being developed, and the results from the first prevention of infection clinical trial with the H4:IC31 vaccine candidate and BCG revaccination were presented. Speakers and participants acknowledged the significant challenges that the TB vaccine R&D field continues to face - including limited funding, and the need for novel effective vaccine candidates and tools such as improved diagnostics and biomarkers to accurately predict protective efficacy. New solutions and approaches to address these challenges were discussed. The following report presents highlights from talks presented at this Global Forum. A full program, abstract book and presentations (where publicly available) from the Forum may be found at tbvaccinesforum.org.

Long-term safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in HIV-positive and -negative Indian adults: Results from a phase II randomized controlled trial.

OBJECTIVES: To assess the long-term safety and immunogenicity of the M72/ Adjuvant System (AS01E) candidate tuberculosis (TB) vaccine up to 3 years post-dose 2 (Y3) in human immunodeficiency virus (HIV)-positive (HIV+) and HIV-negative (HIV-) Indian adults. METHODS: This phase II, double-blind, randomised, controlled clinical trial (NCT01262976) was conducted at YRG CARE Medical Centre, in Chennai, India, between January 2011 and June 2015.Three cohorts (HIV+ participants stable on antiretroviral therapy [ART; HIV+ART+], HIV+ ART-naïve [HIV+ART-], and HIV- participants) were randomised (1:1) to receive 2 doses of M72/AS01E (M72/AS01E groups) or saline (control groups) 1 month apart and were followed up toY3. Latent TB infection was assessed at screening using an interferon-gamma (IFN-γ) release assay (IGRA). Safety and immunogenicity results up to Y1 post-vaccination were reported elsewhere. Here, we report serious adverse events (SAEs), humoral and cell-mediated immune (CMI) responses to M72 recorded at Y2 and Y3. RESULTS: Of 240 enrolled and vaccinated participants, 214 completed the long-term follow-up part of the study.In addition to SAEs previously described, between Y1 and Y2 1 M72/AS01E recipient in the HIV+ART+ cohort reported 2 SAEs (sinus cavernous thrombosis and gastroenteritis) that were not considered as causally related to the study vaccine.Vaccination elicited persistent humoral immune responses against M72. At Y3, seropositivity rates were 97.1%, 66.7%, and 97.3% and geometric mean concentrations (GMCs) were 22.0  ELISA units (EU)/mL, 4.9 EU/mL, and 24.3 EU/mL in the HIV+ART+, HIV+ART-, and HIV- cohorts, respectively. Humoral immune response was lowest in the HIV+ART- cohort.In M72/AS01E recipients, no notable decrease in the frequency of M72-specific CD4 T-cells expressing ≥2 immune markers among interleukin-2 (IL-2), IFN-γ, tumour necrosis factor alpha (TNF-α) and CD40 ligand (CD40L) was observed at Y3 post-vaccination. Median values (interquartile range) of 0.35% (0.13-0.49), 0.05% (0.01-0.10), and 0.15% (0.09-0.22) were recorded in the HIV+ART+, HIV+ART- and HIV- cohorts, respectively. CD4 T-cell response was lowest in the HIV+ART- cohort.No CD8 T-cell response was observed. CONCLUSION: The cellular and humoral immune responses induced by M72/AS01E in HIV+ and HIV- adults persisted up to Y3 post-vaccination. No safety concerns were raised regarding administration of M72/AS01E to HIV+ adults. CLINICAL TRIAL REGISTRATION: NCT01262976 (www.clinicaltrials.gov).

Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

BACKGROUND: A vaccine to interrupt the transmission of tuberculosis is needed. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both. RESULTS: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: M72/AS01E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).

Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination.

BACKGROUND: Recent Mycobacterium tuberculosis infection confers a predisposition to the development of tuberculosis disease, the leading killer among global infectious diseases. H4:IC31, a candidate subunit vaccine, has shown protection against tuberculosis disease in preclinical models, and observational studies have indicated that primary bacille Calmette-Guérin (BCG) vaccination may offer partial protection against infection. METHODS: In this phase 2 trial, we randomly assigned 990 adolescents in a high-risk setting who had undergone neonatal BCG vaccination to receive the H4:IC31 vaccine, BCG revaccination, or placebo. All the participants had negative results on testing for M. tuberculosis infection on the QuantiFERON-TB Gold In-tube assay (QFT) and for the human immunodeficiency virus. The primary outcomes were safety and acquisition of M. tuberculosis infection, as defined by initial conversion on QFT that was performed every 6 months during a 2-year period. Secondary outcomes were immunogenicity and sustained QFT conversion to a positive test without reversion to negative status at 3 months and 6 months after conversion. Estimates of vaccine efficacy are based on hazard ratios from Cox regression models and compare each vaccine with placebo. RESULTS: Both the BCG and H4:IC31 vaccines were immunogenic. QFT conversion occurred in 44 of 308 participants (14.3%) in the H4:IC31 group and in 41 of 312 participants (13.1%) in the BCG group, as compared with 49 of 310 participants (15.8%) in the placebo group; the rate of sustained conversion was 8.1% in the H4:IC31 group and 6.7% in the BCG group, as compared with 11.6% in the placebo group. Neither the H4:IC31 vaccine nor the BCG vaccine prevented initial QFT conversion, with efficacy point estimates of 9.4% (P=0.63) and 20.1% (P=0.29), respectively. However, the BCG vaccine reduced the rate of sustained QFT conversion, with an efficacy of 45.4% (P=0.03); the efficacy of the H4:IC31 vaccine was 30.5% (P=0.16). There were no clinically significant between-group differences in the rates of serious adverse events, although mild-to-moderate injection-site reactions were more common with BCG revaccination. CONCLUSIONS: In this trial, the rate of sustained QFT conversion, which may reflect sustained M. tuberculosis infection, was reduced by vaccination in a high-transmission setting. This finding may inform clinical development of new vaccine candidates. (Funded by Aeras and others; C-040-404 ClinicalTrials.gov number, NCT02075203 .).

Safety and immunogenicity of the novel tuberculosis vaccine ID93 + GLA-SE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial.

BACKGROUND: A vaccine that prevents pulmonary tuberculosis in adults is needed to halt transmission in endemic regions. This trial aimed to assess the safety and immunogenicity of three administrations at varying doses of antigen and adjuvant of an investigational vaccine (ID93 + GLA-SE) compared with placebo in previously BCG-vaccinated healthy adults in a tuberculosis endemic country. METHODS: In this randomised, double-blind, placebo-controlled phase 1 trial, we enrolled HIV-negative, previously BCG-vaccinated adults (aged 18-50 years), with no evidence of previous or current tuberculosis disease, from among community volunteers in the Worcester region of Western Cape, South Africa. Participants were randomly assigned to receive varying doses of ID93 + GLA-SE or saline placebo at day 0, day 28, and day 112. Enrolment into each cohort was sequential. Cohort 1 participants were Mycobacterium tuberculosis uninfected (as defined by negative QuantiFERON [QFT] status), and received 10 µg ID93 plus 2 µg GLA-SE, or placebo; in cohorts 2-4, QFT-negative or positive participants received escalating doses of vaccine or placebo. Cohort 2 received 2 µg ID93 plus 2 µg GLA-SE; cohort 3 received 10 µg ID93 plus 2 µg GLA-SE; and cohort 4 received 10 µg ID93 plus 5 µg GLA-SE. Dose cohort allocation was sequential; randomisation within a cohort was according to a randomly-generated sequence (3 to 1 in cohort 1, 5 to 1 in cohorts 2-4). The primary endpoint was safety of ID93 + GLA-SE as defined by solicited and unsolicited adverse events up to 28 days after each study injection and serious adverse events for the duration of the study. Specific immune responses were measured by intracellular cytokine staining, flow cytometry, and ELISA. All analyses were done according to intention to treat, with additional per-protocol analyses for immunogenicity outcomes. This trial is registered with ClinicalTrials.gov, number NCT01927159. FINDINGS: Between Aug 30, 2013, and Sept 4, 2014, 227 individuals consented to participate; 213 were screened (three participants were not included as study number was already met and 11 withdrew consent before screening occurred, mostly due to relocation or demands of employment). 66 healthy, HIV-negative adults were randomly allocated to receive the vaccine (n=54) or placebo (n=12). All study participants received day 0 and day 28 study injections; five participants did not receive an injection on day 112. ID93 + GLA-SE was well tolerated; no severe or serious vaccine-related adverse events were recorded. Vaccine dose did not affect frequency or severity of adverse events, but mild injection site adverse events and flu-like symptoms were common in M tuberculosis-infected participants compared with uninfected participants. Vaccination induced durable antigen-specific IgG and Th1 cellular responses, which peaked after two administrations. Vaccine dose did not affect magnitude, kinetics, or profile of antibody and cellular responses. Earlier boosting and greater T-cell differentiation and effector-like profiles were seen in M tuberculosis-infected than in uninfected vaccinees. INTERPRETATION: Escalating doses of ID93 + GLA-SE induced similar antigen-specific CD4-positive T cell and humoral responses, with an acceptable safety profile in BCG-immunised, M tuberculosis-infected individuals. The T-cell differentiation profiles in M tuberculosis-infected vaccinees suggest priming through natural infection. While cohort sample sizes in this phase 1 trial were small and results should be interpreted in context, these data support efficacy testing of two administrations of the lowest (2 µg) ID93 vaccine dose in tuberculosis endemic populations. FUNDING: Aeras and the Paul G Allen Family Foundation.

A phase I, open-label trial on the safety and immunogenicity of the adjuvanted tuberculosis subunit vaccine H1/IC31® in people living in a TB-endemic area.

BACKGROUND: H1/IC31® is a tuberculosis (TB) subunit vaccine candidate consisting of the fusion protein of Ag85B and ESAT-6 (H1) formulated with the IC31® adjuvant. Previous trials have reported on the H1/IC31® vaccine in M. tuberculosis (Mtb)-naïve, BCG-vaccinated and previously Mtb-infected individuals. In this trial, conducted between December 2008 and April 2010, the safety and immunogenicity of H1/IC31® was assessed in participants living in Ethiopia - a highly TB-endemic area. METHODS: Healthy male participants aged 18-25 years were recruited into four groups. Participants in group 1 (N = 12) and group 2 (N = 12) were Tuberculin Skin Test (TST) negative and QuantiFERON-TB Gold in-tube test (QFT) negative (Mtb-naïve groups), participants in group 3 (N = 3) were TST positive and QFT negative (BCG group), and participants in group 4 (N = 12) were both TST and QFT positive (Mtb-infected group). H1 vaccine alone (group 1) or H1 formulated with the adjuvant IC31® (groups 2, 3 and 4) was administered intramuscularly on day 0 and day 56. Safety and immunogenicity parameters were evaluated for up to 32 weeks after day 0. RESULTS: The H1/IC31®vaccine was safe and generally well tolerated. There was little difference among the four groups, with a tendency towards a higher incidence of adverse events in Mtb-infected compared to Mtb-naïve participants. Two serious adverse events were reported in the Mtb-infected group where a relationship to the vaccine could not be excluded. In both cases the participants recovered without sequelae within 72 h. Immunogenicity assays, evaluated in the 29 participants who received both vaccinations, showed a stronger response to TB antigens in the Mtb-naïve group vaccinated with the adjuvant. CONCLUSION: The trial confirmed the need for an adjuvant for the vaccine to be immunogenic and highlighted the importance of early phase testing of a novel TB vaccine candidate in TB-endemic areas. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT01049282. Retrospectively registered on 14 January 2010.

Safety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette-Guerin for Infants of Human Immunodeficiency Virus-Infected Mothers: A Phase 2 Randomized, Controlled Trial.

Background: Vaccination of human immunodeficiency virus (HIV)-infected infants with bacille Calmette-Guérin (BCG) is contraindicated. HIV-exposed newborns need a new tuberculosis vaccination strategy that protects against tuberculosis early in life and avoids the potential risk of BCG disease until after HIV infection has been excluded. Methods: This double-blind, randomized, controlled trial compared newborn MVA85A prime vaccination (1 × 108 PFU) vs Candin® control, followed by selective, deferred BCG vaccination at age 8 weeks for HIV-uninfected infants and 12 months follow-up for safety and immunogenicity. Results: A total of 248 HIV-exposed infants were enrolled. More frequent mild-moderate reactogenicity events were seen after newborn MVA85A vaccination. However, no significant difference was observed in the rate of severe or serious adverse events, HIV acquisition (n = 1 per arm), or incident tuberculosis disease (n = 5 MVA85A; n = 3 control) compared to the control arm. MVA85A vaccination induced modest but significantly higher Ag85A-specific interferon gamma (IFNγ)+ CD4+ T cells compared to control at weeks 4 and 8 (P < .0001). BCG did not further boost this response in MVA85A vaccinees. The BCG-induced Ag85A-specific IFNγ+ CD4+ T-cell response at weeks 16 and 52 was of similar magnitude in the control arm compared to the MVA85A arm at all time points. Proliferative capacity, functional profiles, and memory phenotype of BCG-specific CD4 responses were similar across study arms. Conclusions: MVA85A prime vaccination of HIV-exposed newborns was safe and induced an early modest antigen-specific immune response that did not interfere with, or enhance, immunogenicity of subsequent BCG vaccination. New protein-subunit and viral-vectored tuberculosis vaccine candidates should be tested in HIV-exposed newborns. Clinical Trials Registration: NCT01650389.

Efficacy and Safety of Mycobacterium indicus pranii as an adjunct therapy in Category II pulmonary tuberculosis in a randomized trial.

Prolonged treatment of tuberculosis (TB) often leads to poor compliance, default and relapse, converting primary TB patients into category II TB (Cat IITB) cases, many of whom may convert to multi-drug resistant TB (MDR-TB). We have evaluated the immunotherapeutic potential of Mycobacterium indicus pranii (MIP) as an adjunct to Anti-Tubercular Treatment (ATT) in Cat II pulmonary TB (PTB) patients in a prospective, randomized, double blind, placebo controlled, multicentric clinical trial. 890 sputum smear positive Cat II PTB patients were randomized to receive either six intra-dermal injections (2 + 4) of heat-killed MIP at a dose of 5 × 108 bacilli or placebo once in 2 weeks for 2 months. Sputum smear and culture examinations were performed at different time points. MIP was safe with no adverse effects. While sputum smear conversion did not show any statistically significant difference, significantly higher number of patients (67.1%) in the MIP group achieved sputum culture conversion at fourth week compared to the placebo (57%) group (p = 0.0002), suggesting a role of MIP in clearance of the bacilli. Since live bacteria are the major contributors for sustained incidence of TB, the potential of MIP in clearance of the bacilli has far reaching implications in controlling the spread of the disease.

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries.

INTRODUCTION: BCG remains the only vaccine against tuberculosis (TB) in use today and despite its impressive global coverage, the nature of BCG protection against the pulmonary forms of TB remains subject to ongoing debate. Because of the limitations of BCG, novel TB vaccine candidates have been developed and several have reached the clinical pipeline. One of these candidates is MTBVAC, the first and only TB vaccine in the clinical pipeline to date based on live-attenuated Mycobacterium tuberculosis that has successfully entered clinical evaluation, a historic milestone in human vaccinology. Areas covered: This review describes development of MTBVAC from discovery to clinical development in high burden TB-endemic countries. The preclinical experiments where MTBVAC has shown to confer improved safety and efficacy over BCG are presented and the clinical development plans for MTBVAC are revealed. The search of all supportive literature in this manuscript was carried out via Pubmed. Expert commentary: Small experimental medicine trials in humans and preclinical efficacy studies with a strong immunological component mimicking clinical trial design are considered essential by the scientific community to help identify reliable vaccine-specific correlates of protection in order to support and accelerate community-wide efficacy trials of new TB vaccines.

Safety and immunogenicity of the novel H4:IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: Two phase I dose escalation trials.

BACKGROUND: Novel vaccine strategies are required to provide protective immunity in tuberculosis (TB) and prevent development of active disease. We investigated the safety and immunogenicity of a novel TB vaccine candidate, H4:IC31 (AERAS-404) that is composed of a fusion protein of M. tuberculosis antigens Ag85B and TB10.4 combined with an IC31® adjuvant. METHODS: BCG-vaccinated healthy subjects were immunized with various antigen (5, 15, 50, 150µg) and adjuvant (0, 100, 500nmol) doses of the H4:IC31 vaccine (n=106) or placebo (n=18) in two randomized, double-blind, placebo-controlled phase I studies conducted in a low TB endemic setting in Sweden and Finland. The subjects were followed for adverse events and CD4+ T cell responses. RESULTS: H4:IC31 vaccination was well tolerated with a safety profile consisting of mostly mild to moderate self-limited injection site pain, myalgia, arthralgia, fever and post-vaccination inflammatory reaction at the screening tuberculin skin test injection site. The H4:IC31 vaccine elicited antigen-specific CD4+ T cell proliferation and cytokine production that persisted 18weeks after the last vaccination. CD4+ T cell expansion, IFN-γ production and multifunctional CD4+ Th1 responses were most prominent after two doses of H4:IC31 containing 5, 15, or 50µg of H4 in combination with the 500nmol IC31 adjuvant dose. CONCLUSIONS: The novel TB vaccine candidate, H4:IC31, demonstrated an acceptable safety profile and was immunogenic, capable of triggering multifunctional CD4+ T cell responses in previously BCG-vaccinated healthy individuals. These dose-escalation trials provided evidence that the optimal antigen-adjuvant dose combinations are 5, 15, or 50µg of H4 and 500nmol of IC31. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02066428 and NCT02074956.

Tuberculosis Detection in Paratuberculosis Vaccinated Calves: New Alternatives against Interference.

Paratuberculosis vaccination in cattle has been restricted due to its possible interference with the official diagnostic methods used in tuberculosis eradication programs. To overcome this drawback, new possibilities to detect Mycobacterium bovis infected cattle in paratuberculosis vaccinated animals were studied under experimental conditions. Three groups of 5 calves each were included in the experiment: one paratuberculosis vaccinated group, one paratuberculosis vaccinated and M. bovis infected group and one M. bovis infected group. The performance of the IFN-gamma release assay (IGRA) and the skin test using conventional avian and bovine tuberculins (A- and B-PPD) but also other more specific antigens (ESAT-6/CFP10 and Rv3615c) was studied under official and new diagnostic criteria. Regarding the IGRA of vaccinated groups, when A- and B-PPD were used the sensitivity reached 100% at the first post-challenge sampling, dropping down to 40-80% in subsequent samplings. The sensitivity for the specific antigens was 80-100% and the specificity was also improved. After adapting the diagnostic criteria for the conventional antigens in the skin test, the ability to differentiate between M. bovis infected and non-infected animals included in paratuberculosis vaccinated groups was enhanced. Taking for positive a relative skin thickness increase of at least 100%, the single intradermal test specificity and sensitivity yielded 100%. The comparative intradermal test was equally accurate considering a B-PPD relative skin increase of at least 100% and greater than or equal to that produced by A-PPD. Using the specific antigens as a proteic cocktail, the specificity and sensitivity reached 100% considering the new relative and absolute cut-offs in all experimental groups (Δ≥30% and Δmm ≥ 2, respectively). Results suggest that the interference caused by paratuberculosis vaccination in cattle could be completely overcome by applying new approaches to the official tuberculosis diagnostic tests.