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Clinical Trial
. 2018 Jul 12;379(2):138-149.
doi: 10.1056/NEJMoa1714021.

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

Elisa Nemes  1 , Hennie Geldenhuys  1 , Virginie Rozot  1 , Kathryn T Rutkowski  1 , Frances Ratangee  1 , Nicole Bilek  1 , Simbarashe Mabwe  1 , Lebohang Makhethe  1 , Mzwandile Erasmus  1 , Asma Toefy  1 , Humphrey Mulenga  1 , Willem A Hanekom  1 , Steven G Self  1 , Linda-Gail Bekker  1 , Robert Ryall  1 , Sanjay Gurunathan  1 , Carlos A DiazGranados  1 , Peter Andersen  1 , Ingrid Kromann  1 , Thomas Evans  1 , Ruth D Ellis  1 , Bernard Landry  1 , David A Hokey  1 , Robert Hopkins  1 , Ann M Ginsberg  1 , Thomas J Scriba  1 , Mark Hatherill  1 ; C-040-404 Study Team
Collaborators, Affiliations
Clinical Trial

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

Elisa Nemes et al. N Engl J Med. .

Abstract

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 .).

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Conflict of interest statement

TJS and MH report grants from Aeras. RR was a Sanofi Pasteur employee. SG and CADG are employees and share-holders at Sanofi Pasteur.

PA and IK report annual fees and milestone payments from Sanofi Pasteur and collaboration with Aeras and SATVI in other TB vaccine trials. PA has a patent WO2010/006607 "Vaccines comprising TB10.4" with royalties paid from Sanofi Pasteur to SSI.

TE, BL, DAH were employed by Aeras during the trial. KTR, RH and AMG report grants from Bill and Melinda Gates Foundation, grants from UK DFID, trial co-funding and in-kind support from Sanofi Pasteur, grants from DGIS (Dutch Government), during the conduct of the study; trial co-funding and in-kind support from GSK, outside the submitted work.

EN, HG, VR, FR, NB, SM, LM, ME, AT, HM, LGB, WAH, SGS, RDE have nothing to disclose.

Figures

Figure 1: Study design and CONSORT diagram
Figure 1: Study design and CONSORT diagram
(A) Study design. Each participant followed a schedule of evaluations according to study arm and QFT test results. An 84-day wash-out period was implemented to account for participants who may already have been M.tb-infected at enrollment but had not yet QFT converted. After the primary analysis, the IDMC recommended that participants who converted at Month 6 or 12 should return for an additional end-of-study visit to evaluate sustained QFT conversion. Safety outcomes were assessed at each study visit, including evaluation of symptoms of TB disease. QFT, QuantiFERON-TB Gold In-tube; EoS, end of study. CONSORT diagram. Amongst screened individuals (n=2976), 1986 were excluded for one or more reasons. The most common reason for ineligibility was a positive QFT test (n=1405, 71%); other common reasons for exclusion were: abnormal blood results (n=244, 12%), body mass index out of range (n=122, 6%), previous TB or household TB contact (n=55, 3%). ITT, intent-to-treat; mITT, modified ITT; PP, per protocol.
Figure 2: Immunogenicity
Figure 2: Immunogenicity
Vaccine immunogenicity measured by PBMC intracellular cytokine staining (ICS) and flow cytometry following stimulation with Ag85B or TB10.4 peptide pools (summed response is shown) or BCG. Paired responses of CD4 T cells expressing IFNγ and/or IL2 for each individual (between 23 and 28 participants were included at each time point) at D0 (circles) and D70 (diamonds) randomized to placebo (blue), H4:IC31® (red) or BCG (green). Changes in response between D0 and D70 were compared by Wilcoxon Signed-Rank Test.
Figure 3: Vaccine efficacy
Figure 3: Vaccine efficacy
(A) Longitudinal quantitative IFNγ values measured by QFT by study arm, aligned to initial QFT conversion time point (month 0). Each line represents one individual; those who never converted and those with missing QFT results after initial conversion are not shown. Solid lines denote participants who met the secondary efficacy endpoint (sustained QFT conversion, top row) and dashed lines denote participants with initial QFT conversion who then reverted (bottom row). The solid horizontal line denotes the manufacturer’s recommended threshold (0.35IU/mL); the shaded horizontal area denotes the uncertainty zone (0.2-0.7IU/mL); the horizontal line at 4.0IU/mL denotes an alternative QFT threshold applied in exploratory analyses. Values <0.01IU/mL were set to 0.01 to enable plotting on the log scale. (B) Kaplan-Meier curves representing time to initial QFT conversion (primary efficacy endpoint) after first vaccination by study arm in the mITT population. Statistics are reported in Table 2. (C) Kaplan-Meier curves representing time after first vaccination to initial QFT conversion in participants with sustained conversion (secondary efficacy endpoint) by study arm in the mITT population. Inset depicts time to QFT reversion within 6 months of initial conversion in participants with QFT values at three and six months post-conversion. Statistics for conversion endpoints are reported in Table 2.
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