Persistence of immunological memory as a potential correlate of long-term, vaccine-induced protection against Ebola virus disease in humans

Abstract

Introduction: In the absence of clinical efficacy data, vaccine protective effect can be extrapolated from animals to humans, using an immunological biomarker in humans that correlates with protection in animals, in a statistical approach called immunobridging. Such an immunobridging approach was previously used to infer the likely protective effect of the heterologous two-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen. However, this immunobridging model does not provide information on how the persistence of the vaccine-induced immune response relates to durability of protection in humans.

Methods and results: In both humans and non-human primates, vaccine-induced circulating antibody levels appear to be very stable after an initial phase of contraction and are maintained for at least 3.8 years in humans (and at least 1.3 years in non-human primates). Immunological memory was also maintained over this period, as shown by the kinetics and magnitude of the anamnestic response following re-exposure to the Ebola virus glycoprotein antigen via booster vaccination with Ad26.ZEBOV in humans. In non-human primates, immunological memory was also formed as shown by an anamnestic response after high-dose, intramuscular injection with Ebola virus, but was not sufficient for protection against Ebola virus disease at later timepoints due to a decline in circulating antibodies and the fast kinetics of disease in the non-human primates model. Booster vaccination within three days of subsequent Ebola virus challenge in non-human primates resulted in protection from Ebola virus disease, i.e. before the anamnestic response was fully developed.

Discussion: Humans infected with Ebola virus may benefit from the anamnestic response to prevent disease progression, as the incubation time is longer and progression of Ebola virus disease is slower as compared to non-human primates. Therefore, the persistence of vaccine-induced immune memory could be considered as a potential correlate of long-term protection against Ebola virus disease in humans, without the need for a booster.

Keywords: Ebola; correlate; immunological memory; persistence; protection; vaccine.

Figure 1

Persistence of the primary immune response in adults after vaccination with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen. EBOV GP-binding antibody GMCs in EU/mL at various time points, with accompanying 95% CIs, are depicted. Samples were analyzed following standard operating procedure at Q² Solutions using the FANG ELISA, and a single reportable value for each sample at each time point was uploaded for statistical analysis. The horizontal dashed line indicates the FANG ELISA lower limit of quantification of 36.11 EU/mL. The blue arrowheads below the x-axis indicate the timing of administration of the Ad26.ZEBOV vaccine, and the black arrowheads indicate timing of administration of the MVA-BN-Filo vaccine dose. CI, confidence interval; EBOV GP, Ebola virus glycoprotein; ELISA, enzyme-linked immunosorbent assay; EU, ELISA unit; mL, milliliter; FANG, Filovirus Animal Nonclinical Group; GMC, geometric mean concentration; HIV+, human immunodeficiency virus positive; Ad26, Ad26.ZEBOV; MVA, MVA-BN-Filo; Mos, months; Yr, year; Yrs, years; FRA, France; UK, United Kingdom; BFA, Burkina Faso; CIV, Côte d’Ivoire; KEN, Kenya; UGA, Uganda; GNA, Guinea; LIB, Liberia; MAL, Mali; SL, Sierra Leone; USA, United States of America. N is the total number of participants, from all studies, with data at the indicated time point. Percentages indicate the range of percent responders observed across studies at the indicated time point.

Figure 2

Persistence of the primary immune response in children and adolescents after vaccination with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen. EBOV GP-binding antibody GMCs in EU/mL at various time points, with accompanying 95% CIs, are depicted. Samples were analyzed following standard operating procedure at Q² Solutions using the FANG ELISA, and a single reportable value for each sample at each time point was uploaded for statistical analysis. The horizontal dashed line indicates the FANG ELISA lower limit of quantification of 36.11 EU/mL. The blue arrowheads below the x-axis indicate the timing of administration of the Ad26.ZEBOV vaccine, and the black arrowheads indicate timing of administration of the MVA-BN-Filo vaccine dose. CI, confidence interval; EBOV GP, Ebola virus glycoprotein; ELISA, enzyme-linked immunosorbent assay; EU, ELISA unit; mL, milliliter; FANG, Filovirus Animal Nonclinical Group; GMC, geometric mean concentration; Ad26, Ad26.ZEBOV; MVA, MVA-BN-Filo; Mos, months; Yr, year; Yrs, years; BFA, Burkina Faso; CIV, Côte d’Ivoire; KEN, Kenya; UGA, Uganda; GNA, Guinea; LIB, Liberia; MAL, Mali; SL, Sierra Leone. N is the total number of participants, from all studies, with data at the indicated time point. Percentages indicate the range of percent responders observed across studies at the indicated time point.

Figure 3

Persistence of the primary immune response after vaccination with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen and activation of an immune memory response after administration of an Ad26.ZEBOV booster dose. EBOV GP-binding antibody GMCs in EU/mL at various time points, with accompanying 95% CIs, are depicted. Ad26.ZEBOV booster dose administered between 1 year and 3.8 years post-dose 1 in adults (A, B) and children (C, D). Samples were analyzed following standard operating procedure at Q² Solutions using the FANG ELISA, and a single reportable value for each sample at each time point was uploaded for statistical analysis. The horizontal dashed lines indicate the FANG ELISA lower limit of quantification of 36.11 EU/mL. The blue arrowheads below the x-axis indicate the timing of administration of the Ad26.ZEBOV vaccine doses, the black arrowheads indicate timing of administration of the MVA-BN-Filo vaccine dose, and the green arrowheads indicate timing of administration of the Ad26.ZEBOV booster dose. CI, confidence interval; EBOV GP, Ebola virus glycoprotein; ELISA, enzyme-linked immunosorbent assay; EU, ELISA unit; mL, milliliter; FANG, Filovirus Animal Nonclinical Group; GMC, geometric mean concentration; Ad26, Ad26.ZEBOV; MVA, MVA-BN-Filo; Yrs, years; BFA, Burkina Faso; CIV, Côte d’Ivoire; KEN, Kenya; UGA, Uganda; GNA, Guinea; LIB, Liberia; MAL, Mali; SL, Sierra Leone. N is the number of participants with data at pre-booster baseline.

Figure 4

Anti-EBOV GP responses in serum of NHPs after vaccination and EBOV challenge as a measure of vaccine immunogenicity and the anamnestic response after challenge. EBOV GP-binding antibody levels at various time points in log10 EU/mL at various time points. (A) Comparison of the antibody response over time after vaccination with the clinical regimen with or without Ad26.ZEBOV boost at 0.5 years (day 196). Data are shown as group mean with standard deviation, n = 6/group. (B) Serum antibody concentration after vaccination followed by EBOV challenge 1.6 years (548 days) after the first dose. Individual NHP response profiles are shown. (C) Serum antibody concentrations after vaccination with Ad26.ZEBOV and MVA-BN-Filo, followed by short-term EBOV challenge 84 days after the first dose. Individual NHP response profiles are shown. The x-axis for this panel is reported in days, rather than years, due to the short time course of the experiment. (D) Serum antibody concentrations after vaccination with either Ad26.ZEBOV-MVA-BN-Filo or Ad26.Filo-MVA-BN-Filo, followed by Ad26.ZEBOV booster either 7 days or 3 days prior to EBOV challenge, 1.6 years (592 days) post-first dose. Data are displayed as group mean with standard deviation; group sizes as indicated in the figure legend. C-7, booster administration 7 days prior to EBOV challenge; C-3, booster administration 3 days prior to challenge. In (A–C), the blue arrows below the x-axis indicate the timing of administration of the Ad26.ZEBOV vaccine doses, and the black arrows indicate timing of administration of the MVA-BN-Filo vaccine dose. In all panels, red arrows indicate intramuscular challenge with EBOV. Data points shaded green represent animals surviving EBOV challenge, while data points shaded red represent animals succumbing to the challenge before the study end. Dashed horizontal lines indicate lower limit of detection for each data set. For data in (C) the LOD for post-challenge data was set at the LOD of the pre-challenge data (1.46 vs. 1.56 log10 EU/mL). A continuous x-axis is used for panels (A, C) and an interrupted x-axis is used for (B, D) EU/mL, ELISA units per milliliter; GP, glycoprotein; NHPs, non-human primates; LOD, limit of detection.