A total of 3575 participants underwent randomization; 3573 participants received at least one dose of M72/AS01E or placebo and were included in the total vaccinated cohort, and 3330 of these participants received both planned doses. Demographic characteristics were balanced between the groups (Table S2). The distribution of participants in the cohorts and the reasons for withdrawal from the trial are described in Figure S1. HIV seroconversion occurred in 113 participants during the trial: in 61 of 1462 participants (4.2%; 95% CI, 3.2 to 5.3) in the M72/AS01E group and in 52 of 1456 participants (3.6%; 95% CI, 2.7 to 4.7) in the placebo group.
Shown is the Kaplan Meier estimate of the probability of freedom from tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with HIV infection, diagnosed before the initiation of treatment for tuberculosis). The analysis was conducted in the according-to-protocol efficacy cohort (3289 participants — 1626 in the M72/AS01E group and 1663 in the placebo group). The time shown is the time from the beginning of follow-up (i.e., 30 days after dose 2). The inset shows the same data on an enlarged y axis.
The according-to-protocol efficacy cohort included 3289 participants (1626 in the M72/AS01E group and 1663 in the placebo group). After a mean (±SD) follow-up of 2.7±0.4 years in the M72/AS01E group and 2.7±0.5 years in the placebo group (median, 2.8 years), 13 cases of active pulmonary tuberculosis in the M72/AS01E group and 26 cases in the placebo group met the first case definition (Table 1). The incidence of cases of pulmonary tuberculosis that met the first case definition was unchanged from the previous analysis (0.3 cases per 100 person-years in the M72/AS01E group and 0.6 cases per 100 person-years in the placebo group). The overall vaccine efficacy at month 36 (analyzed with the use of an unadjusted Cox regression model) was 49.7% (90% CI, 12.1 to 71.2; 95% CI, 2.1 to 74.2). Kaplan Meier curves for the first case definition are shown in Figure 1. The vaccine efficacy estimates according to year were 27.4% for year 1 (90% CI, −90.2 to 72.3; 95% CI, −128.8 to 77.0), 55.2% for year 2 (90% CI, −20.2 to 83.3; 95% CI, −45.3 to 86.2), and 60.2% for year 3 (90% CI, −5.4 to 84.9; 95% CI, −27.0 to 87.5).
An analysis of vaccine efficacy at month 36 that used a Cox regression model with adjustment for country (Kenya, South Africa, or Zambia), sex, diabetes status, age (≤25 or >25 years), current smoking status (yes or no), and previous bacille Calmette Guérin vaccination (yes, no, or unknown) yielded nearly identical results to those of the primary analysis (vaccine efficacy, 49.6%; 90% CI, 11.8 to 71.02; 95% CI, 1.8 to 74.1). We performed a prespecified sensitivity analysis, described previously, that was restricted to participants who presented with cases of tuberculosis that met the first case definition and that were confirmed by at least two bacteriologic tests. The analysis included 7 participants in the M72/AS01E group and 22 participants in the placebo group; the vaccine efficacy was 68.0% (90% CI, 34.7 to 84.3; 95% CI, 25.1 to 86.3). The vaccine efficacy among participants who met the criteria for the second case definition was 61.7% (90% CI, 24.1 to 80.6; 95% CI, 13.5 to 83.0). Among participants who met the criteria for the other protocol-specified case definitions, the efficacy ranged from 29.5 to 40.3% (Table 1).
Analyses performed in the total efficacy cohort yielded results that were similar to those in the according-to-protocol efficacy cohort. In the total efficacy cohort, the incidence of pulmonary tuberculosis that met the first case definition was 0.3 cases per 100 person-years in the M72/AS01E group and 0.6 cases per 100 person-years in the placebo group, and the vaccine efficacy was 54.1% (90% CI, 20.3 to 73.6; 95% CI, 11.5 to 76.2) (Table 1).
Shown is a post hoc assessment of the distribution of the 39 cases of tuberculosis that met the first case definition, according to the age of the participant.
Results of prespecified subgroup analyses among participants who met the criteria for the first case definition indicated a higher vaccine efficacy among participants who were 25 years of age or younger than among participants who were older than 25 years of age (vaccine efficacy, 81.1% vs. −0.6%) and showed a significant interaction for the difference between the age groups (P=0.02, unadjusted for multiplicity) (Table 2). However, the age distribution among participants who had tuberculosis cases that met the first case definition was unevenly clustered around the cutoff of 25 years (Figure 2). When we repeated the subgroup analysis with an age cutoff above that cluster (i.e., 30 years), we observed a vaccine efficacy of 50.0% (90% CI, 2.2 to 74.5; 95% CI, −11.3 to 77.5) among participants 30 years of age or younger and 49.0% (90% CI, −39.7 to 81.4; 95% CI, −69.4 to 84.6) among participants older than 30 years of age (Table 2). In addition, a post hoc analysis did not show a significant interaction between age as a continuous variable and group assignment with respect to efficacy. The distribution of QFT levels in positive and negative cases of tuberculosis is provided in Figure S2.
Immunogenicity was assessed in the according-to-protocol immunogenicity cohort (120 participants in the M72/AS01E group and 124 participants in the placebo group) from the time of randomization (before the first dose of M72/AS01E or placebo) until month 36. Polypositive CD4+ T cells were defined as those that expressed at least two immune markers (interferon-γ, interleukin-2, tumor necrosis factor α [TNF-α], or CD40L). Panel A shows the geometric mean concentrations of anti-M72 IgG antibodies in the M72/AS01E group and the placebo group in enzyme-linked immunosorbent assay (ELISA) units per milliliter. The dashed line indicates the assay cutoff to determine seropositivity. For descriptive purposes, all participants who had a value below the assay cutoff were assigned a value of half the cutoff. ? bars indicate 95% confidence intervals. Panel B shows the median frequencies of M72-specific CD4+ T cells in the two groups according to expression of immune markers and month. Panel C shows the median frequencies of M72-specific CD4+ T cells expressing any one or any combination of immune markers among participants in the M72/AS01E group. The ? bars indicate the interquartile range. Panel D shows the median frequencies of polypositive M72-specific CD4+ T cells according to country (post hoc analysis). Panel E shows the median frequencies of M72-specific CD4+ T cells expressing interferon-γ overall and according to country (post hoc analysis). Q1 denotes the first quartile, and Q3 the third quartile.
The according-to-protocol immunogenicity cohort included 244 participants (120 in the M72/AS01E group and 124 in the placebo group) (Table S4). All participants in this cohort were from Kenya or South Africa, and the demographic characteristics were similar to those of the total vaccinated cohort. All participants in the M72/AS01E group were seropositive by month 2 and remained positive until month 36 (Figure 3A). Results of post hoc analyses of the geometric mean concentrations of anti-M72 IgG antibodies (stratified according to sex, baseline QFT level [<4 IU per milliliter or ≥4 IU per milliliter], age [≤25 years or >25 years], and country [Kenya or South Africa]) are shown in Figure S3. All 95% confidence intervals overlap between groups, with the exception of the geometric mean concentration of anti-M72 IgG antibodies among participants in South Africa (670.9 ELISA units per milliliter; 95% CI, 527.9 to 852.5) and Kenya (440.4 ELISA units per milliliter; 95% CI, 375.2 to 516.8) at month 2.
Among participants in the M72/AS01E group, the frequencies of polypositive M72-specific CD4+ T cells increased substantially after administration of the vaccine and persisted through month 36, with no evidence of waning (Figure 3B). Polypositive M72-specific CD4+ T cells predominantly expressed interferon-γ, interleukin-2, or TNF-α, or any combination of the three, and CD40L expression was low at all time points (Figure 3C). The percentage of participants with a response to the vaccine was 23.5% (95% CI, 12.8 to 37.5) at month 2 and 53.7% (95% CI, 39.6 to 67.4) at month 36.
The frequencies of polypositive M72-specific CD4+ T cells were lower at month 2 than at subsequent time points, with a wide interquartile range (Figure 3B) that coincided with a peak of T cells expressing only interferon-γ (Figure 3C). The frequency of polypositive T cells was approximately 5 times as high among participants in Kenya as among those in South Africa (median at month 2, 2636.0 vs. 529.0 per million CD4+ T cells) (Figure 3D), whereas there was little difference between the two countries in the frequencies of T cells that expressed interferon-γ alone or interferon-γ in addition to other immune markers (Figure 3E). The median frequencies of CD4+ T cells at month 2 that expressed interferon-γ alone were 1134.0 and 450.0 per million CD4+ T cells in South Africa and Kenya, respectively. Results of a post hoc analysis of the frequency of M72-specific CD4+ T cells expressing interferon-γ alone or interferon-γ in addition to other immune markers at month 2 — stratified according to sex, QFT level at baseline (<4 IU per milliliter or ≥4 IU per milliliter), and age (≤25 years or >25 years) — showed no obvious differences among these subgroups (Fig. S4).
There was no significant change in polypositive M72-specific CD4+ T-cell frequencies after administration of placebo at any time point. No CD8+ T-cell responses could be detected in either group.
Two serious adverse events were considered by the investigators to be related to the trial regimen: one case of pyrexia in the M72/AS01E group (with onset on the day of dose 2) and one case of hypertensive encephalopathy in the placebo group (with onset on the day of dose 1). There were 47 deaths during the trial period: 19 deaths among 1786 participants (1.1%) in the M72/AS01E group and 28 among 1787 participants (1.6%) in the placebo group (relative risk, 0.68; 95% CI, 0.36 to 1.26; P=0.24). No deaths were determined by the investigators to be related to the trial regimen. The most common cause of death was trauma (in 28 participants). (All serious adverse events reported until month 6 after the second dose are listed in Table S5, all serious adverse events reported throughout the entire trial period in Table S6, and all deaths in Table S7.) Potential immune-mediated diseases were reported in 2 participants in the M72/AS01E group and in 6 in the placebo group and affected a variety of organ classes (Table S8).
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