Ebola Vaccine Research Articles

Lot-to-lot consistency, immunogenicity, and safety of the Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccine regimen: A phase 3, randomized, double-blind, placebo-controlled trial

ABSTRACT This phase-3, double-blind, placebo-controlled study (NCT04228783) evaluated lot-to-lot consistency of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen. Participants were randomized (6:6:6:1) to receive the two-dose regimen from three consecutively manufactured lots of Ad26.ZEBOV on Day 1 paired with three consecutively manufactured lots of MVA-BN-Filo on Day 57 (Groups 1–3) or two doses of placebo (Group 4). An additional cohort also received an Ad26.ZEBOV booster or placebo 4 months post-dose 2. Equivalence of the immunogenicity at 21 days post-dose 2 between any two groups was demonstrated if the 95% confidence interval (CI) of the Ebola virus glycoprotein (EBOV GP)–binding antibody geometric mean concentration (GMC) ratio was entirely within the prespecified margin of 0.5–2.0. Lot-to-lot consistency (i.e., consecutive lots can be consistently manufactured) was accomplished if equivalence was shown for all three pairwise comparisons. Results showed that the primary objective in the per-protocol immunogenicity subset (n = 549) was established for each pairwise comparison (Group 1 vs 2: GMC ratio = 0.9 [95% CI: 0.8, 1.1], Group 1 vs 3: 0.9 [0.8, 1.1], Group 2 vs 3: 1.0 [0.9, 1.2]). Equivalence of the three groups for the Ad26.ZEBOV component only was also demonstrated at 56 days post-dose 1. EBOV GP–binding antibody responses (post-vaccination concentrations >2.5-fold from baseline) were observed in 419/421 (99.5%) vaccine recipients at 21 days post-dose 2 and 445/460 (96.7%) at 56 days post-dose 1. In the booster cohort (n = 39), GMCs increased 9.0- and 11.8-fold at 7 and 21 days post-booster, respectively, versus pre-booster. Ad26.ZEBOV, MVA-BN-Filo was well tolerated, and no safety issues were identified.

Shielding Africa, Protecting the World: Unleashing the Power of Preventative Use of Ebola Vaccines

Africa CDC recently conducted a comprehensive risk ranking assessment of epidemic-prone diseases across the continent, identifying Ebola as one of the top 19 infectious diseases with the highest scores in disease severity risk and epidemic potential. The Ebolaviruses first described in the Democratic Republic of the Congo (DRC) in 1976 have left a harrowing trail across sub-Saharan Africa, triggering no less than 34 Ebola outbreaks in 11 sub-Saharan Africa countries, a statistic further compounded by the recent outbreak in Uganda in 2022. At present, the World Health Organization (WHO) has approved two Ebola vaccines, including Ervebo and two-component Zabdeno and Mvabea boost vaccines, for use by individuals above the age of 1 year, including pregnant women as per the Strategic Advisory Group of Experts on Immunization (SAGE) recommendations. The use of these vaccines has demonstrated noteworthy efficacy in safeguarding against Ebola in most African communities and frontline health workers in Ebola-endemic countries such as Sierra Leone, Guinea, and Liberia, among others. Unfortunately, the uptake of these vaccines in Ebola-endemic countries remains dishearteningly constrained despite their availability due to, among other things, the unpredictable timing of outbreaks, sub-optimal surveillance, vaccine demand volatility, palpable vaccine hesitancy, and fragile health infrastructure. Addressing these challenges requires a multifaceted approach that includes a synergy of partnerships between governments, communities, development partners, and private sector partners, such as pharmaceuticals. Recognizing that outbreaks originate and seize at the community level, the imperative of confronting hesitancy through sustained proactive community engagement and utilizing promising vaccination strategies such as ring vaccination must be encouraged. Governments must increase investments to strengthen the regulatory environment for timely access to vaccine stockpiles, robust and cost-effective Ebola vaccination programs for at-risk populations, and preventative use for the health workforce. The International Coordinating Group (ICG) on Vaccine Provision also recommends that national and international health authorities initiate vaccine access by submitting a request to the ICG. This opportunity is at no cost for GAVI-eligible countries and on a reimbursement basis for non-eligible countries. In parallel, Africa CDC is also working closely with Member States on the continent to increase availability and access to medical countermeasures, which include therapeutics, vaccines, and diagnostics, making it critical that Africa CDC is included in the ICG. This will promote timely issue profiling and resolution for increased demand for vaccine stockpiles across the continent where they are needed most as the continent moves towards enhanced health security.

A causal multiomics study discriminates the early immune features of Ad5-vectored Ebola vaccine recipients

The vaccine-induced innate immune response is essential for the generation of an antibody response. To date, how Ad5-vectored vaccines are influenced by preexisting anti-Ad5 antibodies during activation of the early immune response remains unclear. Here, we investigated the specific alterations in GP1,2-specific IgG-related elements of the early immune response at the genetic, molecular, and cellular levels on days 0, 1, 3, and 7 after Ad5-EBOV vaccination. In a causal multiomics analysis, distinct early immune responses associated with GP1,2-specific IgG were observed in Ad5-EBOV recipients with a low level of preexisting anti-Ad5 antibodies. This study revealed the correlates of the Ad5-EBOV-induced IgG response and provided mechanistic evidence for overcoming preexisting Ad5 immunity during the administration of Ad5-vectored vaccines.

Long-Term Clinical Safety of the Ad26.ZEBOV and MVA-BN-Filo Ebola Vaccines: A Prospective, Multi-Country, Observational Study.

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.

Translational success of fundamental virology: a VSV-vectored Ebola vaccine.

Ebola virus disease (EVD) caused by Ebola virus (EBOV) is a severe, often fatal, hemorrhagic disease. A critical component of the public health response to curb EVD epidemics is the use of a replication-competent, recombinant vesicular stomatitis virus (rVSV)-vectored Ebola vaccine, rVSVΔG-ZEBOV-GP (ERVEBO). In this Gem, we will discuss the past and ongoing development of rVSVΔG-ZEBOV-GP, highlighting the importance of basic science and the strength of public-private partnerships to translate fundamental virology into a licensed VSV-vectored Ebola vaccine.

Perceptions toward Ebola vaccination and correlates of vaccine uptake among high-risk community members in North Kivu, Democratic Republic of the Congo.

The tenth Ebola Virus Disease (EVD) outbreak (2018-2020, North Kivu, Ituri, South Kivu) in the Democratic Republic of the Congo (DRC) was the second-largest EVD outbreak in history. During this outbreak, Ebola vaccination was an integral part of the EVD response. We evaluated community perceptions toward Ebola vaccination and identified correlates of Ebola vaccine uptake among high-risk community members in North Kivu, DRC. In March 2021, a cross-sectional survey among adults was implemented in three health zones. We employed a sampling approach mimicking ring vaccination, targeting EVD survivors, their household members, and their neighbors. Outbreak experiences and perceptions toward the Ebola vaccine were assessed, and modified Poisson regression was used to identify correlates of Ebola vaccine uptake among those offered vaccination. Among the 631 individuals surveyed, most (90.2%) reported a high perceived risk of EVD and 71.6% believed that the vaccine could reduce EVD severity; however, 63.7% believed the vaccine had serious side effects. Among the 474 individuals who had been offered vaccination, 397 (83.8%) received the vaccine, 180 (45.3%) of those vaccinated received the vaccine after two or more offers. Correlates positively associated with vaccine uptake included having heard positive information about the vaccine (RR 1.30, 95% CI 1.06-1.60), the belief that the vaccine could prevent EVD (RR 1.23, 95% CI 1.09-1.39), and reporting that religion influenced all decisions (RR 1.13, 95% CI 1.02-1.25). Ebola vaccine uptake was high in this population, although mixed attitudes and vaccine delays were common. Communicating positive vaccine information, emphasizing the efficacy of the Ebola vaccine, and engaging religious leaders to promote vaccination may aid in increasing Ebola vaccine uptake during future outbreaks.

Piloting delivery of PfSPZ vaccines for malaria through a cryogenic vaccine cold chain to travel and military medicine clinics.

PfSPZ vaccines comprising Plasmodium falciparum (Pf) sporozoites (SPZ) have demonstrated > 90% protection against variant Pf malaria infections for at least 12weeks; they are the only vaccines with the level of efficacy necessary to protect travellers. PfSPZ are eukaryotic cells stabilized by cryopreservation and distributed using a cryogenic (below -150°C) cold chain. The Ebola vaccine and mRNA vaccines against SARS-CoV-2 pioneered uptake of vaccines requiring non-standard ultra-low temperature cold chains. The cryogenic cold chain using liquid nitrogen (LN2) vapour phase (LNVP) cryoshippers, is simpler, more efficient than -80, -20 or 2-8°C cold chains, and does not use electricity. This study was conducted to evaluate implementation and integration of a cryogenically distributed vaccine at travel and military immunization clinics. We conducted sequential 28-day studies evaluating vaccine shipping, storage, maintenance and accession at two US military and two civilian travel health/immunization clinics. In each clinic, personnel were trained in equipment use, procurement and handling of LN2, temperature monitoring and inventory record keeping by in-person or video instruction. Sites required 2-4h/person for two persons to assimilate and develop the expertise to manage vaccine storage and LNVP operations. LN2 for recharging cryoshippers was delivered every 1-2weeks. Vaccine ordering, receipt, storage and inventory control was conducted effectively. Simulated single dose vaccine cryovial retrieval and thawing were performed successfully in different travel clinic settings. Continuous temperature monitoring at each site was maintained with only one short excursion above -150°C (-145°C) through shipping, use and reverse logistics. Staff, during and at study conclusion, provided feedback that has been incorporated into our models for cold chain logistics. These studies demonstrated that the training in delivery, storage, administration and integration of PfSPZ vaccines can be successfully managed in different immunization clinic settings for travellers and military personnel.

Refined innate plasma signature after rVSVΔG-ZEBOV-GP immunization is shared among adult cohorts in Europe and North America.

During the last decade Ebola virus has caused several outbreaks in Africa. The recombinant vesicular stomatitis virus-vectored Zaire Ebola (rVSVΔG-ZEBOV-GP) vaccine has proved safe and immunogenic but is reactogenic. We previously identified the first innate plasma signature response after vaccination in Geneva as composed of five monocyte-related biomarkers peaking at day 1 post-immunization that correlates with adverse events, biological outcomes (haematological changes and viremia) and antibody titers. In this follow-up study, we sought to identify additional biomarkers in the same Geneva cohort and validate those identified markers in a US cohort. Additional biomarkers were identified using multiplexed protein biomarker platform O-link and confirmed by Luminex. Principal component analysis (PCA) evaluated if these markers could explain a higher variability of the vaccine response (and thereby refined the initial signature). Multivariable and linear regression models evaluated the correlations of the main components with adverse events, biological outcomes, and antibody titers. External validation of the refined signature was conducted in a second cohort of US vaccinees (n=142). Eleven additional biomarkers peaked at day 1 post-immunization: MCP2, MCP3, MCP4, CXCL10, OSM, CX3CL1, MCSF, CXCL11, TRAIL, RANKL and IL15. PCA analysis retained three principal components (PC) that accounted for 79% of the vaccine response variability. PC1 and PC2 were very robust and had different biomarkers that contributed to their variability. PC1 better discriminated different doses, better defined the risk of fever and myalgia, while PC2 better defined the risk of headache. We also found new biomarkers that correlated with reactogenicity, including transient arthritis (MCP-2, CXCL10, CXCL11, CX3CL1, MCSF, IL-15, OSM). Several innate biomarkers are associated with antibody levels one and six months after vaccination. Refined PC1 correlated strongly in both data sets (Geneva: r = 0.97, P < 0.001; US: r = 0.99, P< 0.001). Eleven additional biomarkers refined the previously found 5-biomarker Geneva signature. The refined signature better discriminated between different doses, was strongly associated with the risk of adverse events and with antibody responses and was validated in a separate cohort.

Solusi Eksak Sistem Imun Terhadap Virus Ebola

The Ebola virus is a deadly disease that causes blood clots in the body's organs and is spread through direct contact with the blood or body fluids of sufferers. Based on this, the immune system in the body will continue to decrease and cause Ebola Hemorrhagic Fever. The 2014-2016 Ebola outbreak in West Africa has accelerated the development of several preventive vaccines against the Ebola virus. The goal of the vaccination is to induce immunity against infectious diseases. And also to stimulate the immune system and its ability to store and remember information about specific pathogens, leading to long-term protective immunity. The model equation for the Ebola virus vaccine in this study involves the concentration of the antigen which is a variable , by means of which the vaccine is inserted into the patient's body where it will attach to B memory cells which are variable , which will then be stimulated by the cells short-lived antibodies are denoted by variables or long-lived cells are denoted by variables , while antibodies will prove efficacy denoted by variables on the patient's immune response. The simulation of the exact solution for the Ebola vaccine uses the integration factor method which will later be compared with numerical simulations according to the parameter values from the research of Irene Balelli et al (2020). The simulation obtained has a very small calculation error value for each variable, which means that the exact value of the Ebola virus vaccination model shows that there is no significant difference to the numerical solution using the order 45 Rungge Kutta method, the largest resulting numerical error is 2.29640283510782×〖10〗^9.

Longitudinal assessment of an Ebola vaccine trial understanding among healthcare providers in the Democratic Republic of the Congo

BackgroundThe long-term retention of information disclosed during the informed consent in clinical trials lasting over a year cannot be guaranteed for all volunteers. This study aimed to assess the level of participants’ retention and understanding of the trial information after two years of participation in a vaccine trial. MethodsIn total, 699 health care providers (HCPs) and frontline workers were enrolled in the EBL2007 vaccine trial conducted between February 2019 and September 2022 in the Health District of Boende, Democratic Republic of the Congo (DRC). Individual scores obtained from a questionnaire (test of understanding, TOU), specifically designed to assess the understanding of the consent at baseline, were collected before the clinical trial started and at one-year and two-year intervals. ResultsTOU scores were high in the beginning of the trial (median TOU = 10/10), but significantly decreased in both the first and second years following (median TOU = 8/10 in year 1 and median TOU = 9/10 in year 2, p-value < 0.0001). The decrease in scores was significantly higher among individuals with occupations requiring shorter education such as midwives (median TOU = 7/10 in year 1 and 8/10 in year 2, pvalue = 0.025). Furthermore, older participants exhibited poorer retention of information compared to younger individuals (median TOU = 8/10 vs 9/10, p-value = 0.007). ConclusionWe observed a significant decline in the informational knowledge of informed consent, specifically in terms of basic knowledge on the study vaccine and trial procedures. As participant safety and understanding is a paramount ethical concern for researchers, it is crucial for participants to fully comprehend the study's objectives and potential risks. Therefore, our findings suggest the need for clinical researchers to re-explain participants to optimize the protection of their rights and wellbeing during the research.

Public perceptions of Ebola vaccines and confidence in health services to treat Ebola, malaria, and tuberculosis: Findings from a cross-sectional household survey in Uganda, 2020.

Uganda used Ebola vaccines as part of its preparedness and response during the 2018-2020 10th Ebola virus disease (EVD) outbreak in neighboring Democratic Republic of the Congo (DRC). We evaluated the public's perceptions of Ebola vaccines and compared their confidence in health services to treat Ebola versus malaria and tuberculosis as part of a survey on Ebola knowledge, attitudes, and practices (KAP) conducted in March 2020. A cross-sectional household survey was implemented in six districts in Uganda using multi-stage cluster sampling to randomly select participants. The districts were purposively selected from districts classified by the government as at high- or low-risk for an EVD outbreak. We describe perceptions of Ebola vaccines and confidence in health services to treat Ebola, tuberculosis, and malaria. Modified Poisson regression modeling was used to identify the demographic correlates of these outcomes. Among 3,485 respondents, 18% were aware of Ebola vaccines. Of those, 92% agreed that the vaccines were needed to prevent Ebola. Participants aged 15-24 years were 4% more likely to perceive such need compared to those 60 years and older (adjusted prevalence ratio [aPR] 1.04, 95% confidence interval [CI] 1.0-1.08). The perceived need was 5% lower among participants with at least some secondary education compared to uneducated participants (aPR 0.95; 0.92-0.99). Overall, 81% of those aware of the vaccines believed that everyone or most people in their community would get vaccinated if offered, and 94% said they would likely get vaccinated if offered. Confidence in health services to treat Ebola was lower compared to treating malaria or tuberculosis (55% versus 93% and 77%, respectively). However, participants from the EVD high-risk districts were 22% more likely to be confident in health services to treat Ebola compared to those in low-risk districts (aPR: 1.22; 95% CI: 1.08, 1.38). Our findings suggest that intent to take an Ebola vaccine during an outbreak was strong, but more work needs to be done to increase public awareness of these vaccines. The public's high confidence in health services to treat other health threats, such as malaria and tuberculosis, offer building blocks for strengthening their confidence in health services to treat EVD in the event of an outbreak.

Bayesian inference for prediction of survival probability inprime-boost vaccination regimes.

We focus on Bayesian inference for survival probabilities in a prime-boost vaccination regime in the development of an Ebola vaccine. We are interested in the heterologous prime-boost regimen (unmatched vaccine deliverys using the same antigen) due to its demonstrated durable immunity, well-tolerated safety profile, and suitability as a population vaccination strategy. Our research is motivated by the need to estimate the survival probability given the administered dosage. To do so, we establish two key relationships. Firstly, we model the connection between the designed dose concentration and the induced antibody count using a Bayesian response surface model. Secondly, we model the association between the antibody count and the probability of survival when experimental subjects are exposed to the Ebola virus in a controlled setting using a Bayesian probability of survival model. Finally, we employ a combination of the two models with dose concentration as the predictor of the survival probability for a future vaccinated population. We implement our two-level Bayesian model in Stan, and illustrate its use with simulated and real-world data. Performance of this model is evaluated via simulation. Our work offers a new application of drug synergy models to examine prime-boost vaccine efficacy, and does so using a hierarchical Bayesian framework that allows us to use dose concentration to predict survival probability.

Conducting an Ebola vaccine trial in a remote area of the Democratic Republic of the Congo: Challenges, mitigations, and lessons learned

Conducting a vaccine trial in a low- and middle-income country (LMIC) can present unique challenges and lessons learned. This Ebola vaccine trial, enrolling 699 healthcare providers and frontliners and jointly set up by the University of Antwerp (Sponsor) and the University of Kinshasa (Principal Investigator (PI)), was conducted in Boende, a remote city in the Democratic Republic of the Congo (DRC), between December 2019 and October 2022 (ClinicalTrials.gov: NCT04186000). While being bound by strict ICH-GCP and international funder regulations, this trial, exemplary for being a public–private partnership, required collaboration between several international stakeholders (e.g., two universities, a pharmaceutical company, and a clinical research organization), local communities and government agencies. Here we address several logistical and administrative challenges, cultural differences, language barriers and regulatory, political, and ethical considerations over the trial’s 2.5-year duration, while tailoring and adapting the study to the specific local context.Lessons learned include the importance of clear communication with participants in all phases of the study, but also within the study team and among different stakeholders. Challenges, mitigations, and lessons learned are presented in nine categories (e.g., safety management; trial documentation, tools, and materials; communication, staff training and community engagement/sensitization; financial and administrative hurdles; and more). Ultimately, to reach the successful end of the vaccine trial in this remote Ebola endemic area in the DRC, careful planning, collaboration, and great flexibility and adaptability was often required from all involved partners. Despite the encountered challenges, the vaccine trial discussed in this paper was able to obtain high participant retention rates (i.e., 92% of participants completed the study). We hope that other international teams aspiring to conduct similar trials in remote areas of LMICs can learn from the way our challenges were addressed, mitigations developed, and lessons were learned.

Safety and immunogenicity of an Ad26.ZEBOV booster vaccine in Human Immunodeficiency Virus positive (HIV+) adults previously vaccinated with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against Ebola: A single-arm, open-label Phase II clinical trial in Kenya and Uganda

BackgroundPeople living with HIV constitute an important part of the population in regions at risk of Ebola virus disease outbreaks. The two-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen induces strong immune responses in HIV-positive (HIV+) adults but the durability of this response is unknown. It is also unclear whether this regimen can establish immune memory to enable an anamnestic response upon re-exposure to antigen. MethodsThis paper describes an open-label, phase 2 trial, conducted in Kenya and Uganda, of Ad26.ZEBOV booster vaccination in HIV+ participants who had previously received the Ad26.ZEBOV, MVA-BN-Filo primary regimen. HIV+ adults with well-controlled infection and on highly active antiretroviral therapy were enrolled, vaccinated with booster, and followed for 28 days. The primary objectives were to assess Ad26.ZEBOV booster safety and antibody responses against the Ebola virus glycoprotein using the Filovirus Animal Non-Clinical Group ELISA. ResultsThe Ad26.ZEBOV booster was well-tolerated in HIV+ adults with mostly mild to moderate symptoms. No major safety concerns or serious adverse events were reported. Four and a half years after the primary regimen, 24/26 (92 %) participants were still classified as responders, with a pre-booster antibody geometric mean concentration (GMC) of 726 ELISA units (EU)/mL (95 %CI 447–1179). Seven days after the booster, the GMC increased 54-fold to 38,965 EU/mL (95 %CI 23532–64522). Twenty-one days after the booster, the GMC increased 176-fold to 127,959 EU/mL (95 %CI 93872–174422). The responder rate at both post-booster time points was 100 %. ConclusionsThe Ad26.ZEBOV booster is safe and highly immunogenic in HIV+ adults with well-controlled infection. The Ad26.ZEBOV, MVA-BN-Filo regimen can generate long-term immune memory persisting for at least 4·5 years, resulting in a robust anamnestic response.Trial Registration: Pan African Clinical Trial Registry (PACTR202102747294430). Clinicaltrials.gov (NCT05064956).

Baseline gene signatures of reactogenicity to Ebola vaccination: a machine learning approach across multiple cohorts.

The rVSVDG-ZEBOV-GP (Ervebo®) vaccine is both immunogenic and protective against Ebola. However, the vaccine can cause a broad range of transient adverse reactions, from headache to arthritis. Identifying baseline reactogenicity signatures can advance personalized vaccinology and increase our understanding of the molecular factors associated with such adverse events. In this study, we developed a machine learning approach to integrate prevaccination gene expression data with adverse events that occurred within 14 days post-vaccination. We analyzed the expression of 144 genes across 343 blood samples collected from participants of 4 phase I clinical trial cohorts: Switzerland, USA, Gabon, and Kenya. Our machine learning approach revealed 22 key genes associated with adverse events such as local reactions, fatigue, headache, myalgia, fever, chills, arthralgia, nausea, and arthritis, providing insights into potential biological mechanisms linked to vaccine reactogenicity.

In Silico Analyses, Experimental Verification and Application in DNA Vaccines of Ebolavirus GP-Derived pan-MHC-II-Restricted Epitopes.

(1) Background and Purpose: Ebola virus (EBOV) is the causative agent of Ebola virus disease (EVD), which causes extremely high mortality and widespread epidemics. The only glycoprotein (GP) on the surface of EBOV particles is the key to mediating viral invasion into host cells. DNA vaccines for EBOV are in development, but their effectiveness is unclear. The lack of immune characteristics resides in antigenic MHC class II reactivity. (2) Methods: We selected MHC-II molecules from four human leukocyte antigen II (HLA-II) superfamilies with 98% population coverage and eight mouse H2-I alleles. IEDB, NetMHCIIpan, SYFPEITHI, and Rankpep were used to screen MHC-II-restricted epitopes with high affinity for EBOV GP. Further immunogenicity and conservation analyses were performed using VaxiJen and BLASTp, respectively. EpiDock was used to simulate molecular docking. Cluster analysis and binding affinity analysis of EBOV GP epitopes and selected MHC-II molecules were performed using data from NetMHCIIpan. The selective GP epitopes were verified by the enzyme-linked immunospot (ELISpot) assay using splenocytes of BALB/c (H2d), C3H, and C57 mice after DNA vaccine pVAX-GPEBO immunization. Subsequently, BALB/c mice were immunized with Protein-GPEBO, plasmid pVAX-GPEBO, and pVAX-LAMP/GPEBO, which encoded EBOV GP. The dominant epitopes of BALB/c (H-2-I-AdEd genotype) mice were verified by the enzyme-linked immunospot (ELISpot) assay. It is also used to evaluate and explore the advantages of pVAX-LAMP/GPEBO and the reasons behind them. (3) Results: Thirty-one HLA-II-restricted and 68 H2-I-restricted selective epitopes were confirmed to have high affinity, immunogenicity, and conservation. Nineteen selective epitopes have cross-species reactivity with good performance in MHC-II molecular docking. The ELISpot results showed that pVAX-GPEBO could induce a cellular immune response to the synthesized selective peptides. The better immunoprotection of the DNA vaccines pVAX-LAMP/GPEBO coincides with the enhancement of the MHC class II response. (4) Conclusions: Promising MHC-II-restricted candidate epitopes of EBOV GP were identified in humans and mice, which is of great significance for the development and evaluation of Ebola vaccines.

Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in infants: a phase 2, randomised, double-blind, active-controlled trial in Guinea and Sierra Leone

This study assessed the safety and immunogenicity of the Ad26.ZEBOV and MVA-BN-Filo Ebola virus (EBOV) vaccine regimen in infants aged 4-11 months in Guinea and Sierra Leone. In this phase 2, randomised, double-blind, active-controlled trial, we randomly assigned healthy infants (1:1 in a sentinel cohort, 5:2 for the remaining infants via an interactive web response system) to receive Ad26.ZEBOV followed by MVA-BN-Filo (Ebola vaccine group) or two doses of meningococcal quadrivalent conjugate vaccine (control group) administered 56 days apart. Infants were recruited at two sites in west Africa: Conakry, Guinea, and Kambia, Sierra Leone. All infants received the meningococcal vaccine 8 months after being randomly assigned. The primary objective was safety. The secondary objective was immunogenicity, measured as EBOV glycoprotein-binding antibody concentration 21 days post-dose 2, using the Filovirus Animal Non-Clinical Group ELISA. This study is registered with ClinicalTrials.gov (NCT03929757) and the Pan African Clinical Trials Registry (PACTR201905827924069). From Aug 20 to Nov 29, 2019, 142 infants were screened and 108 were randomly assigned (Ebola vaccine n=75; control n=33). The most common solicited local adverse event was injection-site pain (Ebola vaccine 15 [20%] of 75; control four [12%] of 33). The most common solicited systemic adverse events with the Ebola vaccine were irritability (26 [35%] of 75), decreased appetite (18 [24%] of 75), pyrexia (16 [21%] of 75), and decreased activity (15 [20%] of 75). In the control group, ten (30%) of 33 had irritability, seven (21%) of 33 had decreased appetite, three (9%) of 33 had pyrexia, and five (15%) of 33 had decreased activity. The frequency of unsolicited adverse events was 83% (62 of 75 infants) in the Ebola vaccine group and 85% (28 of 33 infants) in the control group. No serious adverse events were vaccine-related. In the Ebola vaccine group, EBOV glycoprotein-binding antibody geometric mean concentrations (GMCs) at 21 days post-dose 2 were 27 700 ELISA units (EU)/mL (95% CI 20 477-37 470) in infants aged 4-8 months and 20 481 EU/mL (15 325-27 372) in infants aged 9-11 months. The responder rate was 100% (74 of 74 responded). In the control group, GMCs for both age groups were less than the lower limit of quantification and the responder rate was 3% (one of 33 responded). Ad26.ZEBOV and MVA-BN-Filo was well tolerated and induced strong humoral responses in infants younger than 1 year. There were no safety concerns related to vaccination. Janssen Vaccines & Prevention and Innovative Medicines Initiative 2 Joint Undertaking. For the French translation of the abstract see Supplementary Materials section.

Infants can access Ebola vaccines during outbreaks

Infants can access Ebola vaccines during outbreaks

Adaptation of an rVSV Ebola vaccine purification process for rapid development of a viral vaccine candidate for SARS-CoV-2.

During the COVID-19 pandemic, long development timelines typically associated with vaccines were challenged. The urgent need for a vaccine provided a strong driver to reevaluate existing vaccine development approaches. Innovative approaches to regulatory approval were realized, including the use of platform-based technology. In collaboration with the International AIDS Vaccine Initiative, Inc. (IAVI), Merck & Co., Inc., Rahway, NJ, USA rapidly advanced an investigational SARS-CoV-2 vaccine based on the recombinant vesicular stomatitis virus (rVSV) platform used for the Ebola vaccine ERVEBO (rVSV∆G-ZEBOV-GP). An rVSV∆G-SARS-CoV-2 vaccine candidate was generated using the SARS-CoV-2 spike protein to replace the VSV G protein. The purification process development for this vaccine candidate was detailed in this paper. Areas were highlighted where the ERVEBO platform process was successfully adopted and where additional measures were needed for the SARS-CoV-2 vaccine candidate. These included: (i) endonuclease addition directly into the bioreactor prior to harvest, (ii) inclusion of a core-shell chromatography step for improved purification, and (iii) incorporation of a terminal, sterile filtration step to eliminate the need for aseptic, closed processing. High infectious virus titers were achieved in Phase 3 clinical drug substance (>108 PFUmL-1 ), and process consistency was demonstrated across four large scale batches that were completed in 6 months from clone selection.

Best practices and lessons learned from implementing a massive Ebola vaccination program: Summarizing UMURINZI team experience.

The unified Rwandan initiative for national ZEBOVAC immunization (UMURINZI) program's community engagement component was enacted to mobilize and vaccinate high-risk community members. This article describes best practices and lessons learned from the implementation of UMURINZI, a large-scale Ebola vaccination program. The population deemed to be at risk for EVD consisted of people who frequently cross Rwanda and the Democratic Republic of Congo (DRC) borders including those coming from Kigali City, potential first responders who have not previously been vaccinated against EVD, as well as people who reside in high-risk border-proximate areas of the Rubavu and Rusizi districts in the Western Province of Rwanda. These districts were selected because of their proximity to high-traffic borders linking Rwanda to DRC's cities near an active Ebola outbreak. Volunteers of this program were adults, adolescents, and children aged 2 years or above who resided in the selected communities. Recruitment at the sites was conducted in close collaboration with each health area's Community Health Workers (CHWs). Volunteers were informed that the program involved being fully vaccinated (two doses of Ebola vaccines) within 2 months apart in the allocated vaccination sites. Lessons learned were categorized into four pillars: infrastructure, leadership, myths, and partnership with respect. The best practices that were used during the implementation of the UMURINZI program were the results of a collaboration among CHWs, the involvement of national and local leaders, the use of a comprehensive engagement plan, and training. The study also had limitations. We described best practices and lessons learned during the implementation of the UMURINZI program in Rwanda. These practices and lessons learned represent promising options that could contribute to better community members' participation in mass vaccination programs. Hence, we demonstrated that rigorously designed community awareness and sensitization programs are effective for the implementation of similar programs in resource-limited settings.