Ebola virus disease in humans is highly lethal, with case fatality rates ranging from 25 to 90%. There is no licensed treatment or vaccine against the virus, underscoring the need for efficacious ...countermeasures. We ascertained that a human survivor of the 1995 Kikwit Ebola virus disease outbreak maintained circulating antibodies against the Ebola virus surface glycoprotein for more than a decade after infection. From this survivor we isolated monoclonal antibodies (mAbs) that neutralize recent and previous outbreak variants of Ebola virus and mediate antibody-dependent cell-mediated cytotoxicity in vitro. Strikingly, monotherapy with mAb114 protected macaques when given as late as 5 days after challenge. Treatment with a single human mAb suggests that a simplified therapeutic strategy for human Ebola infection may be possible.
Ebolavirus disease causes high mortality, and the current outbreak has spread unabated through West Africa. Human adenovirus type 5 vectors (rAd5) encoding ebolavirus glycoprotein (GP) generate ...protective immunity against acute lethal Zaire ebolavirus (EBOV) challenge in macaques, but fail to protect animals immune to Ad5, suggesting natural Ad5 exposure may limit vaccine efficacy in humans. Here we show that a chimpanzee-derived replication-defective adenovirus (ChAd) vaccine also rapidly induced uniform protection against acute lethal EBOV challenge in macaques. Because protection waned over several months, we boosted ChAd3 with modified vaccinia Ankara (MVA) and generated, for the first time, durable protection against lethal EBOV challenge.
Chimpanzee Adenovirus Vector Ebola Vaccine Ledgerwood, Julie E; DeZure, Adam D; Stanley, Daphne A ...
New England journal of medicine/The New England journal of medicine,
03/2017, Letnik:
376, Številka:
10
Journal Article
Recenzirano
Odprti dostop
This update of a preliminary report from November 2014 presents safety, immunogenicity, and long-term durability data from a trial of an Ebola vaccine in humans that is based on a chimpanzee ...adenovirus type 3 construct with the Ebola Zaire and Sudan glycoprotein inserts.
In August 2014, the World Health Organization declared the epidemic of Ebola virus disease (EVD) in West Africa to be a public health emergency of international concern. This was the first time in more than 20 outbreaks since EVD was identified in 1976 that such a declaration had been made.
1
The epidemic accounted for more cases of EVD than all previous EVD outbreaks combined, with 28,616 cases and 11,310 deaths reported.
2
,
3
The majority of cases occurred in Guinea, Liberia, and Sierra Leone, with a small number of cases in other West African countries,
4
Europe, and the United States.
5
Whereas . . .
We recently identified a single potently neutralizing monoclonal antibody (mAb), mAb114, isolated from a human survivor of natural Zaire ebolavirus (EBOV) infection, which fully protects nonhuman ...primates (NHPs) against lethal EBOV challenge. To evaluate the ability of vaccination to generate mAbs such as mAb114, we cloned antibodies from NHPs vaccinated with vectors encoding the EBOV glycoprotein (GP). We identified 14 unique mAbs with potent binding to GP, 4 of which were neutralized and had the functional characteristics of mAb114. These vaccine-induced macaque mAbs share many sequence similarities with mAb114 and use the same mAb114 VH gene (ie, IGHV3-13) when classified using the macaque IMGT database. The antigen-specific VH-gene repertoire present after each immunization indicated that IGHV3-13 mAbs populate an EBOV-specific B-cell repertoire that appears to become more prominent with subsequent boosting. These findings will support structure-based vaccine design aimed at enhanced induction of antibodies such as mAb114.
Summary Background The 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine ...expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo). Methods In the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18–65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18–50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six Malian or four US; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 1010 viral particle units (pu), 2·5 × 1010 pu, 5 × 1010 pu, or 1 × 1011 pu; US participants received 1 × 1010 pu or 1 × 1011 pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 108 plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured with occurrence of adverse events for 7 days after vaccination. Both trials are registered with ClinicalTrials.gov , numbers NCT02231866 (US) and NCT02267109 (Malian). Findings Between Oct 8, 2014, and Feb 16, 2015, we randomly allocated 91 participants in Mali (ten 11% to 1 × 1010 pu, 35 38% to 2·5 × 1010 pu, 35 38% to 5 × 1010 pu, and 11 12% to 1 × 1011 pu) and 20 in the USA (ten 50% to 1 × 1010 pu and ten 50% to 1 × 1011 pu), and boosted 52 Malians with MVA-BN-Filo (27 52%) or saline (25 48%). We identified no safety concerns with either vaccine: seven (8%) of 91 participants in Mali (five 5% received 5 × 1010 and two 2% received 1 × 1011 pu) and four (20%) of 20 in the USA (all received 1 × 1011 pu) given ChAd3-EBO-Z had fever lasting for less than 24 h, and 15 (56%) of 27 Malians boosted with MVA-BN-Filo had injection-site pain or tenderness. Interpretation 1 × 1011 pu single-dose ChAd3-EBO-Z could suffice for phase 3 efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission. MVA-BN-Filo boosting, although a complex regimen, could confer long-lived protection if needed (eg, for health-care workers). Funding Wellcome Trust, Medical Research Council UK, Department for International Development UK, National Cancer Institute, Frederick National Laboratory for Cancer Research, Federal Funds from National Institute of Allergy and Infectious Diseases.
Marburg virus (MARV) causes a severe hemorrhagic fever disease in primates with mortality rates in humans of up to 90%. MARV has been identified as a category A bioterrorism agent by the Centers for ...Disease Control and Prevention (CDC) and priority pathogen A by the National Institute of Allergy and Infectious Diseases (NIAID), needing urgent research and development of countermeasures because of the high public health risk it poses. The recent cases of MARV in West Africa underscore the substantial outbreak potential of this virus. The potential for cross-border spread, as had occurred during the 2014-2016 Ebola virus outbreak, illustrates the critical need for MARV vaccines. To support regulatory approval of the chimpanzee adenovirus 3 (ChAd3)-MARV vaccine that has completed phase 1 trials, we showed that the nonreplicating ChAd3 vector, which has a demonstrated safety profile in humans, protected against a uniformly lethal challenge with MARV/Ang. Protective immunity was achieved within 7 days of vaccination and was maintained through 1 year after vaccination. Antigen-specific antibodies were an immune correlate of protection in the acute challenge model, and their concentration was predictive of protection. These results demonstrate that a single-shot ChAd3-MARV vaccine generated a protective immune response that was both rapid and durable with an immune correlate of protection that will support advanced clinical development.
Heterologous prime-boost immunization regimens are a common strategy for many vaccines. DNA prime rAd5-GP boost immunization has been demonstrated to protect non-human primates against a lethal ...challenge of Ebola virus, a pathogen that causes fatal hemorrhagic disease in humans. This protection correlates with antibody responses and is also associated with IFNγ
TNFα
double positive CD8
T-cells. In this study, we compared single DNA vs. multiple DNA prime immunizations, and short vs. long time intervals between the DNA prime and the rAd5 boost to evaluate the impact of these different prime-boost strategies on vaccine-induced humoral and cellular responses in non-human primates. We demonstrated that DNA/rAd5 prime-boost strategies can be tailored to induce either CD4
T-cell or CD8
T-cell dominant responses while maintaining a high magnitude antibody response. Additionally, a single DNA prime immunization generated a stable memory response that could be boosted by rAd5 3 years later. These results suggest DNA/rAd5 prime-boost provides a flexible platform that can be fine-tuned to generate desirable T-cell memory responses.
In this phase 1 study involving 76 healthy volunteers in England, a single dose of a monovalent chimpanzee adenovirus vaccine elicited immune responses to Ebola virus. The immune response was ...superior after a booster dose of a modified vaccinia Ankara strain.
The recent outbreak of Ebola virus disease (EVD) in West Africa has led to more than 11,000 deaths, with a peak in mortality from August through December of 2014 and a subsequent decline in the number of new cases. The development of a durable and effective Ebola vaccine is a priority both to eliminate the remnants of the outbreak and to prevent and control future epidemics. Several candidate vaccines have shown promising results in phase 1 trials,
1
–
6
and a recombinant vesicular stomatitis virus–based vaccine expressing the surface glycoprotein of
Zaire ebolavirus
(rVSV-ZEBOV) showed efficacy in an interim analysis of . . .
WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human ...clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy adults.
We did a first-in-human, phase 1, open-label, dose-escalation trial of the cAd3-Marburg vaccine at the Walter Reed Army Institute of Research Clinical Trials Center in the USA. Healthy adults aged 18–50 years were assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 1010 or 1 × 1011 particle units (pu). Primary safety endpoints included reactogenicity assessed for the first 7 days and all adverse events assessed for 28 days after vaccination. Secondary immunogenicity endpoints were assessment of binding antibody responses and T-cell responses against the Marburg virus glycoprotein insert, and assessment of neutralising antibody responses against the cAd3 vector 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT03475056.
Between Oct 9, 2018, and Jan 31, 2019, 40 healthy adults were enrolled and assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 1010 pu (n=20) or 1 × 1011 pu (n=20). The cAd3-Marburg vaccine was safe, well tolerated, and immunogenic. All enrolled participants received cAd3-Marburg vaccine, with 37 (93%) participants completing follow-up visits; two (5%) participants moved from the area and one (3%) was lost to follow-up. No serious adverse events related to vaccination occurred. Mild to moderate reactogenicity was observed after vaccination, with symptoms of injection site pain and tenderness (27 68% of 40 participants), malaise (18 45% of 40 participants), headache (17 43% of 40 participants), and myalgia (14 35% of 40 participants) most commonly reported. Glycoprotein-specific antibodies were induced in 38 (95%) of 40 participants 4 weeks after vaccination, with geometric mean titres of 421 95% CI 209–846 in the 1 × 1010 pu group and 545 276–1078 in the 1 × 1011 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 95% CI 13–119 in the 1 ×1010 pu group and 27 95–156 in the 1 ×1011 pu group; both p<0·0001). T-cell responses to the glycoprotein insert and neutralising responses against the cAd3 vector were also increased at 4 weeks after vaccination.
This first-in-human trial of this cAd3-Marburg vaccine showed the agent is safe and immunogenic, with a safety profile similar to previously tested cAd3-vectored filovirus vaccines. 95% of participants produced a glycoprotein-specific antibody response at 4 weeks after a single vaccination, which remained in 70% of participants at 48 weeks. These findings represent a crucial step in the development of a vaccine for emergency deployment against a re-emerging pathogen that has recently expanded its reach to new regions.
National Institutes of Health.
PDF
