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During the 2018-2020 Ebola virus disease (EVD) outbreak, residents in Goma, Democratic Republic of the Congo, were offered a two-dose prophylactic EVD vaccine. This was the first study to evaluate the safety of this vaccine in pregnant women. Adults, including pregnant women, and children aged ≥1 year old were offered the Ad26.ZEBOV (day 0; dose 1), MVA-BN-Filo (day 56; dose 2) EVD vaccine through an open-label clinical trial. In total, 20,408 participants, including 6635 (32.5%) children, received dose 1. Fewer than 1% of non-pregnant participants experienced a serious adverse event (SAE) following dose 1; one SAE was possibly related to the Ad26.ZEBOV vaccine. Of the 1221 pregnant women, 371 (30.4%) experienced an SAE, with caesarean section being the most common event. No SAEs in pregnant women were considered related to vaccination. Of 1169 pregnancies with a known outcome, 55 (4.7%) ended in a miscarriage, and 30 (2.6%) in a stillbirth. Eleven (1.0%) live births ended in early neonatal death, and five (0.4%) had a congenital abnormality. Overall, 188/891 (21.1%) were preterm births and 79/1032 (7.6%) had low birth weight. The uptake of the two-dose regimen was high: 15,328/20,408 (75.1%). The vaccine regimen was well-tolerated among the study participants, including pregnant women, although further data, ideally from controlled trials, are needed in this crucial group.

During the 2018-2020 Ebola virus disease outbreak in Democratic Republic of the Congo, a phase 3 trial of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine (DRC-EB-001) commenced in Goma, with participants being offered the two-dose regimen given 56 days apart. Suspension of trial activities in 2020 due to the COVID-19 pandemic led to some participants receiving a late dose 2 outside the planned interval. Blood samples were collected from adults, adolescents, and children prior to their delayed dose 2 vaccination and 21 days after, and tested for IgG binding antibodies against Ebola virus glycoprotein using the Filovirus Animal Nonclinical Group (FANG) ELISA. Results from 133 participants showed a median two-dose interval of 9.3 months. The pre-dose 2 antibody geometric mean concentration (GMC) was 217 ELISA Units (EU)/mL (95% CI 157; 301) in adults, 378 EU/mL (281; 510) in adolescents, and 558 EU/mL (471; 661) in children. At 21 days post-dose 2, the GMC increased to 22,194 EU/mL (16,726; 29,449) in adults, 37,896 EU/mL (29,985; 47,893) in adolescents, and 34,652 EU/mL (27,906; 43,028) in children. Participants receiving a delayed dose 2 had a higher GMC at 21 days post-dose 2 than those who received a standard 56-day regimen in other African trials, but similar to those who received the regimen with an extended interval.

In this prospective, observational study (ClinicalTrials.gov Identifier: NCT02661464), long-term safety information was collected from participants previously exposed to the Ebola vaccines Ad26.ZEBOV and/or MVA-BN-Filo while enrolled in phase 1, 2, or 3 clinical studies. The study was conducted at 15 sites in seven countries (Burkina Faso, France, Kenya, Tanzania, Uganda, the United Kingdom, and the United States). Adult participants and offspring from vaccinated female participants who became pregnant (estimated conception ≤28 days after vaccination with MVA-BN-Filo or ≤3 months after vaccination with Ad26.ZEBOV) were enrolled. Adults were followed for 60 months after their first vaccination, and children born to female participants were followed for 60 months after birth. In the full analysis set (n = 614 adults; median age [range]: 32.0 [18-65] years), 49 (8.0%) had ≥1 serious adverse event (SAE); the incidence rate of any SAE was 27.4 per 1000 person-years (95% confidence interval: 21.0, 35.2). The unrelated SAEs of malaria were reported in the two infants in the full analysis set, aged 11 and 18 months; both episodes were resolved. No deaths or life-threatening SAEs occurred during the study. Overall, no major safety issues were identified; one related SAE was reported. These findings support the long-term clinical safety of the Ad26.ZEBOV and MVA-BN-Filo vaccines.

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., Competing Interests: CM, KD, AG, BK, MK, MD, CR, LS, DC-C, LD, MP, BC, JS, HS, RZ, KL, JH, and RR are employees of Janssen Vaccines and Prevention, B.V., and may hold shares of Johnson & Johnson. YW and AV are employees of Bavarian Nordic and may hold shares in the company., (Copyright © 2023 McLean, Dijkman, Gaddah, Keshinro, Katwere, Douoguih, Robinson, Solforosi, Czapska-Casey, Dekking, Wollmann, Volkmann, Pau, Callendret, Sadoff, Schuitemaker, Zahn, Luhn, Hendriks and Roozendaal.)

We assessed whether the immunogenicity of the two-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen with a 56-day interval between doses was affected by exposure to malaria before dose 1 vaccination and by clinical episodes of malaria in the period immediately after dose 1 and after dose 2 vaccinations. Previous malaria exposure in participants in an Ebola vaccine trial in Sierra Leone (ClinicalTrials.gov: NCT02509494) was classified as low, intermediate, and high according to their antibody responses to a panel of Plasmodium falciparum antigens detected using a Luminex MAGPIX platform. Clinical malaria episodes after vaccinations were recorded as part of the trial safety monitoring. Binding antibody responses against the Ebola virus (EBOV) glycoprotein (GP) were measured 57 days post dose 1 and 21 days post dose 2 by ELISA and summarized as Geometric Mean Concentrations (GMCs). Geometric Mean Ratios (GMRs) were used to compare groups with different levels of exposure to malaria. Overall, 587 participants, comprising 188 (32%) adults (aged ≥ 18 years) and 399 (68%) children (aged 1-3, 4-11, and 12-17 years), were included in the analysis. There was no evidence that the anti-EBOV-GP antibody GMCs post dose 1 and post dose 2 differed between categories of previous malaria exposure. There was weak evidence that the GMC at 57 days post dose 1 was lower in participants who had had at least one episode of clinical malaria post dose 1 compared to participants with no diagnosed clinical malaria in the same period (GMR = 0.82, 95% CI: 0.69-0.98, p -value = 0.02). However, GMC post dose 2 was not reduced in participants who experienced clinical malaria post-dose 1 and/or post-dose 2 vaccinations. In conclusion, the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen is immunogenic in individuals with previous exposure to malaria and in those who experience clinical malaria after vaccination. This vaccine regimen is suitable for prophylaxis against Ebola virus disease in malaria-endemic regions.

Background: This analysis evaluated the immune response to the two-dose, heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccine regimen, administered 56-days apart, from multiple African sites based on results from one analytic laboratory., Methods: Immunogenicity across three trials (EBL2002, EBL2004/PREVAC, EBL3001) conducted in East and West Africa is summarised. Vaccine-induced Ebola glycoprotein-binding antibody concentrations were analysed by Q 2 Solutions laboratory at baseline, 21 days (EBL2002 and EBL3001) or 28 days (EBL2004) post-dose 2 (regimen completion), and 12 months post-dose 1 using the validated Filovirus Animal Nonclinical Group Ebola glycoprotein enzyme-linked immunosorbent assay (ELISA). Responders were defined as those with a >2.5-fold increase from baseline or the lower limit of quantification (LLOQ) if 

Background: Children account for a substantial proportion of cases and deaths during Ebola virus disease outbreaks. We aimed to evaluate the safety and immunogenicity of a booster dose of the Ad26.ZEBOV vaccine in children who had been vaccinated with a two-dose regimen comprising Ad26.ZEBOV as dose one and MVA-BN-Filo as dose two., Methods: We conducted an open-label, non-randomised, phase 2 trial at one clinic in Kambia Town, Sierra Leone. Healthy children, excluding pregnant or breastfeeding girls, who had received the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen in a previous study, and were aged 1-11 years at the time of their first vaccine dose, received an intramuscular injection of Ad26.ZEBOV (5 × 10 10 viral particles) and were followed up for 28 days. Primary outcomes were safety (measured by adverse events) and immunogenicity (measured by Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration) of the booster vaccine dose. Safety was assessed in all participants who received the booster vaccination; immunogenicity was assessed in all participants who received the booster vaccination, had at least one evaluable sample after the booster, and had no major protocol deviations that could have influenced the immune response. This trial is registered with ClinicalTrials.gov, NCT04711356., Findings: Between July 8 and Aug 18, 2021, 58 children were assessed for eligibility and 50 (27 aged 4-7 years and 23 aged 9-15 years) were enrolled and received an Ad26.ZEBOV booster vaccination, more than 3 years after receiving dose one of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen. The booster was well tolerated. The most common solicited local adverse event during the 7 days after vaccination was injection site pain, reported in 18 (36%, 95% CI 23-51) of 50 participants. The most common solicited systemic adverse event during the 7 days after vaccination was headache, reported in 11 (22%, 12-36) of 50 participants. Malaria was the most common unsolicited adverse event during the 28 days after vaccination, reported in 25 (50%, 36-64) of 50 participants. No serious adverse events were observed during the study period. 7 days after vaccination, the Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration was 28 561 ELISA units per mL (95% CI 20 255-40 272), which was 44 times higher than the geometric mean concentration before the booster dose. 21 days after vaccination, the geometric mean concentration reached 64 690 ELISA units per mL (95% CI 48 356-86 541), which was 101 times higher than the geometric mean concentration before the booster dose., Interpretation: A booster dose of Ad26.ZEBOV in children who had received the two-dose Ad26.ZEBOV and MVA-BN-Filo vaccine regimen more than 3 years earlier was well tolerated and induced a rapid and robust increase in binding antibodies against Ebola virus. These findings could inform Ebola vaccination strategies in paediatric populations., Funding: Innovative Medicines Initiative 2 Joint Undertaking., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests Janssen Vaccines and Prevention was the vaccine manufacturer and donated the vaccine for this study. BKe, AG, CM, KL, and CR were full-time employees of Janssen, Pharmaceutical Companies of Johnson & Johnson, at the time of the study. AG, CM, KL, and CR report ownership of shares in Janssen, Pharmaceutical Companies of Johnson & Johnson. All other authors declare funding from the Innovative Medicines Initiative 2 Joint Undertaking., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We explored the association of Ebola virus antibody seropositivity and concentration with potential risk factors for infection. Among 1,282 adults and children from a community affected by the 2014-2016 Ebola outbreak in Sierra Leone, 8% were seropositive for virus antibodies but never experienced disease symptoms. Antibody concentration increased with age.

Background: Children account for a substantial proportion of cases and deaths from Ebola virus disease. We aimed to assess the safety and immunogenicity of a two-dose heterologous vaccine regimen, comprising the adenovirus type 26 vector-based vaccine encoding the Ebola virus glycoprotein (Ad26.ZEBOV) and the modified vaccinia Ankara vector-based vaccine, encoding glycoproteins from the Ebola virus, Sudan virus, and Marburg virus, and the nucleoprotein from the Tai Forest virus (MVA-BN-Filo), in a paediatric population in Sierra Leone., Methods: This randomised, double-blind, controlled trial was done at three clinics in Kambia district, Sierra Leone. Healthy children and adolescents aged 1-17 years were enrolled in three age cohorts (12-17 years, 4-11 years, and 1-3 years) and randomly assigned (3:1), via computer-generated block randomisation (block size of eight), to receive an intramuscular injection of either Ad26.ZEBOV (5 × 10 10 viral particles; first dose) followed by MVA-BN-Filo (1 × 10 8 infectious units; second dose) on day 57 (Ebola vaccine group), or a single dose of meningococcal quadrivalent (serogroups A, C, W135, and Y) conjugate vaccine (MenACWY; first dose) followed by placebo (second dose) on day 57 (control group). Study team personnel (except for those with primary responsibility for study vaccine preparation), participants, and their parents or guardians were masked to study vaccine allocation. The primary outcome was safety, measured as the occurrence of solicited local and systemic adverse symptoms during 7 days after each vaccination, unsolicited systemic adverse events during 28 days after each vaccination, abnormal laboratory results during the study period, and serious adverse events or immediate reportable events throughout the study period. The secondary outcome was immunogenicity (humoral immune response), measured as the concentration of Ebola virus glycoprotein-specific binding antibodies at 21 days after the second dose. The primary outcome was assessed in all participants who had received at least one dose of study vaccine and had available reactogenicity data, and immunogenicity was assessed in all participants who had received both vaccinations within the protocol-defined time window, had at least one evaluable post-vaccination sample, and had no major protocol deviations that could have influenced the immune response. This study is registered at ClinicalTrials.gov, NCT02509494., Findings: From April 4, 2017, to July 5, 2018, 576 eligible children or adolescents (192 in each of the three age cohorts) were enrolled and randomly assigned. The most common solicited local adverse event during the 7 days after the first and second dose was injection-site pain in all age groups, with frequencies ranging from 0% (none of 48) of children aged 1-3 years after placebo injection to 21% (30 of 144) of children aged 4-11 years after Ad26.ZEBOV vaccination. The most frequently observed solicited systemic adverse event during the 7 days was headache in the 12-17 years and 4-11 years age cohorts after the first and second dose, and pyrexia in the 1-3 years age cohort after the first and second dose. The most frequent unsolicited adverse event after the first and second dose vaccinations was malaria in all age cohorts, irrespective of the vaccine types. Following vaccination with MenACWY, severe thrombocytopaenia was observed in one participant aged 3 years. No other clinically significant laboratory abnormalities were observed in other study participants, and no serious adverse events related to the Ebola vaccine regimen were reported. There were no treatment-related deaths. Ebola virus glycoprotein-specific binding antibody responses at 21 days after the second dose of the Ebola virus vaccine regimen were observed in 131 (98%) of 134 children aged 12-17 years (9929 ELISA units [EU]/mL [95% CI 8172-12 064]), in 119 (99%) of 120 aged 4-11 years (10 212 EU/mL [8419-12 388]), and in 118 (98%) of 121 aged 1-3 years (22 568 EU/mL [18 426-27 642])., Interpretation: The Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen was well tolerated with no safety concerns in children aged 1-17 years, and induced robust humoral immune responses, suggesting suitability of this regimen for Ebola virus disease prophylaxis in children., Funding: Innovative Medicines Initiative 2 Joint Undertaking and Janssen Vaccines & Prevention BV., Competing Interests: Declaration of interests BKe was a full-time employee of Janssen Pharmaceutical Companies of Johnson & Johnson at the time of the study. NG, ML, AG, DH, VB, KL, BC, CR, and MD were full-time employees of Janssen Pharmaceutical Companies of Johnson & Johnson at the time of the study, and declare ownership of shares in Janssen Pharmaceutical Companies of Johnson & Johnson. DW-J reports grants from the Innovative Medicines Initiative and non-financial support from Janssen Vaccines & Prevention BV during the conduct of the study; and grants from the Coalition for Epidemic Preparedness Innovations and non-financial support from Janssen Vaccines & Prevention BV outside the submitted work. HL reports grants from GSK and Merck outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)