RESUMO
Marburg virus (MARV), a filovirus, was first identified in 1967 in Marburg, Germany, and Belgrade, former Yugoslavia. Since then, MARV has caused sporadic outbreaks of human disease with high case fatality rates in parts of Africa, with the largest outbreak occurring in 2004/05 in Angola. From 2021 to 2023, MARV outbreaks occurred in Guinea, Ghana, New Guinea, and Tanzania, emphasizing the expansion of its endemic area into new geographical regions. There are currently no approved vaccines or therapeutics targeting MARV, but several vaccine candidates have shown promise in preclinical studies. We compared three vaccine platforms simultaneously by vaccinating hamsters with either a single dose of an adenovirus-based (ChAdOx-1 MARV) vaccine, an alphavirus replicon-based RNA (LION-MARV) vaccine, or a recombinant vesicular stomatitis virus-based (VSV-MARV) vaccine, all expressing the MARV glycoprotein as the antigen. Lethal challenge with hamster-adapted MARV 4 weeks after vaccination resulted in uniform protection of the VSV-MARV and LION-MARV groups and 83% of the ChAdOx-1 MARV group. Assessment of the antigen-specific humoral response and its functionality revealed vaccine-platform-dependent differences, particularly in the Fc effector functions.
Assuntos
Doença do Vírus de Marburg , Marburgvirus , Vacinas Virais , Animais , Cricetinae , Vacinas Virais/imunologia , Marburgvirus/imunologia , Doença do Vírus de Marburg/prevenção & controle , Doença do Vírus de Marburg/imunologia , Modelos Animais de Doenças , Adenoviridae/genética , Adenoviridae/imunologia , Vesiculovirus/imunologia , Vesiculovirus/genética , Anticorpos Antivirais/imunologia , Vacinação/métodosRESUMO
Marburg virus (MARV) is a highly contagious and virulent agent belonging to Filoviridae family. MARV causes severe hemorrhagic fever in humans and non-human primates. Owing to its highly virulent nature, preventive approaches are promising for its control. There is currently no approved drug or vaccine against MARV, and management mainly involves supportive care to treat symptoms and prevent complications. Our aim was to design a novel multi-epitope vaccine (MEV) against MARV using immunoinformatics studies. In this study, various proteins (VP35, VP40 and glycoprotein precursor) were used and potential epitopes were selected. CTL and HTL epitopes covered 79.44% and 70.55% of the global population, respectively. The designed MEV construct was stable and expressed in Escherichia coli (E. coli) host. The physicochemical properties were also acceptable. MARV MEV candidate could predict comprehensive immune responses such as those of humoral and cellular in silico. Additionally, efficient interaction to toll-like receptor 3 (TLR3) and its agonist (ß-defensin) was predicted. There is a need for validation of these results using further in vitro and in vivo studies.
Assuntos
Biologia Computacional , Doença do Vírus de Marburg , Marburgvirus , Vacinas Virais , Marburgvirus/imunologia , Doença do Vírus de Marburg/prevenção & controle , Doença do Vírus de Marburg/imunologia , Vacinas Virais/imunologia , Biologia Computacional/métodos , Animais , Humanos , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Epitopos/imunologia , Epitopos/genética , Epitopos/química , Escherichia coli/genética , Escherichia coli/metabolismo , ImunoinformáticaRESUMO
Marburg virus infection in humans is associated with case fatality rates that can reach up to 90%, but to date, there are no approved vaccines or monoclonal antibody (mAb) countermeasures. Here, we immunized Rhesus macaques with multivalent combinations of filovirus glycoprotein (GP) antigens belonging to Marburg, Sudan, and Ebola viruses to generate monospecific and cross-reactive antibody responses against them. From the animal that developed the highest titers of Marburg virus GP-specific neutralizing antibodies, we sorted single memory B cells using a heterologous Ravn virus GP probe and cloned and characterized a panel of 34 mAbs belonging to 28 unique lineages. Antibody specificities were assessed by overlapping pepscan and binding competition analyses, revealing that roughly a third of the lineages mapped to the conserved receptor binding region, including potent neutralizing lineages that were confirmed by negative stain electron microscopy to target this region. Additional lineages targeted a protective region on GP2, while others were found to possess cross-filovirus reactivity. Our study advances the understanding of orthomarburgvirus glycoprotein antigenicity and furthers efforts to develop candidate antibody countermeasures against these lethal viruses. IMPORTANCE: Marburg viruses were the first filoviruses characterized to emerge in humans in 1967 and cause severe hemorrhagic fever with average case fatality rates of ~50%. Although mAb countermeasures have been approved for clinical use against the related Ebola viruses, there are currently no approved countermeasures against Marburg viruses. We successfully isolated a panel of orthomarburgvirus GP-specific mAbs from a macaque immunized with a multivalent combination of filovirus antigens. Our analyses revealed that roughly half of the antibodies in the panel mapped to regions on the glycoprotein shown to protect from infection, including the host cell receptor binding domain and a protective region on the membrane-anchoring subunit. Other antibodies in the panel exhibited broad filovirus GP recognition. Our study describes the discovery of a diverse panel of cross-reactive macaque antibodies targeting orthomarburgvirus and other filovirus GPs and provides candidate immunotherapeutics for further study and development.
Assuntos
Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Antivirais , Reações Cruzadas , Macaca mulatta , Doença do Vírus de Marburg , Marburgvirus , Animais , Marburgvirus/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Monoclonais/imunologia , Doença do Vírus de Marburg/imunologia , Doença do Vírus de Marburg/prevenção & controle , Reações Cruzadas/imunologia , Glicoproteínas/imunologia , Proteínas do Envelope Viral/imunologia , Imunização , Humanos , Ebolavirus/imunologia , Antígenos Virais/imunologiaRESUMO
Marburg viral disease (MVD) is a highly infectious disease with a case fatality rate of up to 90%, particularly impacting resource-limited countries where implementing Infection Prevention and Control (IPC) measures is challenging. This paper shares the experience of how Tanzania has improved its capacity to prevent and control highly infectious diseases, and how this capacity was utilized during the outbreak of the MVD disease that occurred for the first time in the country in 2023.In 2016 and the subsequent years, Tanzania conducted self and external assessments that revealed limited IPC capacity in responding to highly infectious diseases. To address these gaps, initiatives were undertaken, including the enhancement of IPC readiness through the development and dissemination of guidelines, assessments of healthcare facilities, supportive supervision and mentorship, procurement of supplies, and the renovation or construction of environments to bolster IPC implementation.The official confirmation and declaration of MVD on March 21, 2023, came after five patients had already died of the disease. MVD primarily spreads through contact and presents with severe symptoms, which make patient care and prevention challenging, especially in resource-limited settings. However, with the use of a trained workforce; IPC rapid needs assessment was conducted, identifying specific gaps. Based on the results; mentorship programs were carried out, specific policies and guidelines were developed, security measures were enhanced, all burial activities in the area were supervised, and both patients and staff were monitored across all facilities. By the end of the outbreak response on June 1, 2023, a total of 212 contacts had been identified, with the addition of only three deaths. Invasive procedures like dialysis and Manual Vacuum Aspiration prevented some deaths in infected patients, procedures previously discouraged.In summary, this experience underscores the critical importance of strict adherence to IPC practices in controlling highly infectious diseases. Recommendations for low-income countries include motivating healthcare providers and improving working conditions to enhance commitment in challenging environments. This report offers valuable insights and practical interventions for preparing for and addressing highly infectious disease outbreaks through implementation of IPC measures.
Assuntos
Surtos de Doenças , Doença do Vírus de Marburg , Tanzânia/epidemiologia , Humanos , Surtos de Doenças/prevenção & controle , Doença do Vírus de Marburg/epidemiologia , Doença do Vírus de Marburg/prevenção & controle , Controle de Infecções/métodos , Animais , Países em DesenvolvimentoRESUMO
Viral haemorrhagic fevers (VHF) pose a significant threat to human health. In recent years, VHF outbreaks caused by Ebola, Marburg and Lassa viruses have caused substantial morbidity and mortality in West and Central Africa. In 2022, an Ebola disease outbreak in Uganda caused by Sudan virus resulted in 164 cases with 55 deaths. In 2023, a Marburg disease outbreak was confirmed in Equatorial Guinea and Tanzania resulting in over 49 confirmed or suspected cases; 41 of which were fatal. There are no clearly defined correlates of protection against these VHF, impeding targeted vaccine development. Any vaccine developed should therefore induce strong and preferably long-lasting humoral and cellular immunity against these viruses. Ideally this immunity should also cross-protect against viral variants, which are known to circulate in animal reservoirs and cause human disease. We have utilized two viral vectored vaccine platforms, an adenovirus (ChAdOx1) and Modified Vaccinia Ankara (MVA), to develop a multi-pathogen vaccine regime against three filoviruses (Ebola virus, Sudan virus, Marburg virus) and an arenavirus (Lassa virus). These platform technologies have consistently demonstrated the capability to induce robust cellular and humoral antigen-specific immunity in humans, most recently in the rollout of the licensed ChAdOx1-nCoV19/AZD1222. Here, we show that our multi-pathogen vaccines elicit strong cellular and humoral immunity, induce a diverse range of chemokines and cytokines, and most importantly, confers protection after lethal Ebola virus, Sudan virus and Marburg virus challenges in a small animal model.
Assuntos
Ebolavirus , Doença pelo Vírus Ebola , Febre Lassa , Vírus Lassa , Doença do Vírus de Marburg , Marburgvirus , Animais , Camundongos , Ebolavirus/imunologia , Vírus Lassa/imunologia , Marburgvirus/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Doença pelo Vírus Ebola/imunologia , Febre Lassa/imunologia , Febre Lassa/prevenção & controle , Doença do Vírus de Marburg/imunologia , Doença do Vírus de Marburg/prevenção & controle , Vacinas Virais/imunologia , Humanos , Vacinação , Feminino , Anticorpos Antivirais/imunologia , Imunogenicidade da Vacina , Vacinas contra Ebola/imunologiaAssuntos
Ebolavirus , Doença pelo Vírus Ebola , Doença do Vírus de Marburg , Animais , Humanos , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/prevenção & controle , Doença do Vírus de Marburg/prevenção & controle , Prática Clínica Baseada em Evidências , Organização Mundial da SaúdeRESUMO
The co-existence of deadly viral pandemics can be considered a nightmare for public health authorities. The surge of a Marburg virus disease (MVD) outbreak in Africa at a time when the coronavirus-19 (COVID-19) pandemic is partially controlled with its limited resources is an urgent call for concern. Over the past decades, several bouts of MVD outbreaks have occurred in Africa with an alarming case fatality rate. Despite this, little has been done to end its recurrence, and affected countries essentially depend on preventative rather than curative measures of management. The recent outbreak of MVD declared by the health officials of Equatorial Guinea, causing several deaths in the context of the COVID-19 pandemic, signals the need for speed in the establishment and the implementation of appropriate health policies and health system strategies to contain, destroy, and prevent the spread of this deadly virus to other neighboring countries.
Assuntos
Infecções por Coronavirus , Doença do Vírus de Marburg , Marburgvirus , Animais , Humanos , Guiné Equatorial , Pandemias/prevenção & controle , Surtos de Doenças/prevenção & controle , Doença do Vírus de Marburg/epidemiologia , Doença do Vírus de Marburg/prevenção & controle , Infecções por Coronavirus/epidemiologiaRESUMO
BACKGROUND: Marburg virus disease is an acute haemorrhagic fever caused by Marburg virus. Marburg virus is zoonotic, maintained in nature in Egyptian fruit bats, with occasional spillover infections into humans and nonhuman primates. Although rare, sporadic cases and outbreaks occur in Africa, usually associated with exposure to bats in mines or caves, and sometimes with secondary human-to-human transmission. Outbreaks outside of Africa have also occurred due to importation of infected monkeys. Although all previous Marburg virus disease outbreaks have been brought under control without vaccination, there is nevertheless the potential for large outbreaks when implementation of public health measures is not possible or breaks down. Vaccines could thus be an important additional tool, and development of several candidate vaccines is under way. METHODS: We developed a branching process model of Marburg virus transmission and investigated the potential effects of several prophylactic and reactive vaccination strategies in settings driven primarily by multiple spillover events as well as human-to-human transmission. Linelist data from the 15 outbreaks up until 2022, as well as an Approximate Bayesian Computational framework, were used to inform the model parameters. RESULTS: Our results show a low basic reproduction number which varied across outbreaks, from 0.5 [95% CI 0.05-1.8] to 1.2 [95% CI 1.0-1.9] but a high case fatality ratio. Of six vaccination strategies explored, the two prophylactic strategies (mass and targeted vaccination of high-risk groups), as well as a combination of ring and targeted vaccination, were generally most effective, with a probability of potential outbreaks being terminated within 1 year of 0.90 (95% CI 0.90-0.91), 0.89 (95% CI 0.88-0.90), and 0.88 (95% CI 0.87-0.89) compared with 0.68 (0.67-0.69) for no vaccination, especially if the outbreak is driven by zoonotic spillovers and the vaccination campaign initiated as soon as possible after onset of the first case. CONCLUSIONS: Our study shows that various vaccination strategies can be effective in helping to control outbreaks of MVD, with the best approach varying with the particular epidemiologic circumstances of each outbreak.
Assuntos
Quirópteros , Doença do Vírus de Marburg , Marburgvirus , Vacinas , Animais , Humanos , Doença do Vírus de Marburg/epidemiologia , Doença do Vírus de Marburg/prevenção & controle , Teorema de Bayes , Surtos de Doenças/prevenção & controle , Vacinação , Modelos TeóricosRESUMO
Infection with Marburg virus (MARV), the causative agent of Marburg virus disease (MVD), results in haemorrhagic disease and high case fatality rates (>40%) in humans. Despite its public health relevance, there are no licensed vaccines or therapeutics to prevent or treat MVD. A vesicular stomatitis virus (VSV)-based vaccine expressing the MARV glycoprotein (VSV-MARV) is currently in clinical development. Previously, a single 10 million PFU dose of VSV-MARV administered 1-5 weeks before lethal MARV challenge conferred uniform protection in nonhuman primates (NHPs), demonstrating fast-acting potential. Additionally, our group recently demonstrated that even a low dose VSV-MARV (1000 PFU) protected NHPs when given 7 days before MARV challenge. In this study, we longitudinally profiled the transcriptional responses of NHPs vaccinated with this low dose of VSV-MARV either 14 or 7 days before lethal MARV challenge. NHPs vaccinated 14 days before challenge presented with transcriptional changes consistent with an antiviral response before challenge. Limited gene expression changes were observed in the group vaccinated 7 days before challenge. After challenge, genes related to lymphocyte-mediated immunity were only observed in the group vaccinated 14 days before challenge, indicating that the length of time between vaccination and challenge influenced gene expression. Our results indicate that a low dose VSV-MARV elicits distinct immune responses that correlate with protection against MVD. A low dose of VSV-MARV should be evaluated in clinical rails as it may be an option to deliver beneficial public health outcomes to more people in the event of future outbreaks.
Assuntos
Doença do Vírus de Marburg , Marburgvirus , Animais , Humanos , Marburgvirus/genética , Vacinação , Surtos de Doenças , Doença do Vírus de Marburg/prevenção & controle , ImunidadeRESUMO
A full grasp of the epidemiological factors promoting transmission is necessary for responding to highly infectious diseases, which involves their control and prevention. With the recent outbreak of Marburg Virus Disease (MVD) in Equatorial Guinea, we saw the need to re-shed some technical light based on our field experiences and published literature. We reviewed 15 previous MVD outbreaks globally. Coupled with core One-Health approaches, we highlighted the SPIN (socio-environmental context, possible transmission routes, informing and guiding public health action, needs in terms of control measures) framework as a guiding tool for response teams to appropriately approach this highly contagious infectious disease outbreak for collective and stronger global health security. The Central African Regional Collaborating Centre (RCC) of the Africa Centres for Disease Control and Prevention (Africa CDC) has a big lead role to play, most especially in coordinating the community engagement and risk communication packages of the response, which is highly needed at this point. We reiterate that this framework remains relevant, if not timely, in rethinking pandemic preparedness and response in resource-limited settings.
Assuntos
Doença do Vírus de Marburg , Animais , Humanos , Doença do Vírus de Marburg/epidemiologia , Doença do Vírus de Marburg/prevenção & controle , Guiné Equatorial , Surtos de Doenças/prevenção & controle , Saúde Pública , África/epidemiologiaRESUMO
In 1967, the very first case of the Marburgvirus disease (MVD) was detected in Germany and Serbia sequentially. Since then, MVD has been considered one of the most serious and deadly infectious diseases in the world with a case-fatality rate between 23% and 90% and a substantial number of recorded deaths. Marburgvirus belongs to the family of Filoviridae (filoviruses), which causes severe viral hemorrhagic fever (VHF). Some major risk factors for human infections are close contact with African fruit bats, MVD-infected non-human primates, and MVD-infected individuals. Currently, there is no vaccine or specific treatment for MVD, which emphasizes the seriousness of this disease. In July 2022, the World Health Organization reported outbreaks of MVD in Ghana after two suspected VHF cases were detected. This was followed in February and March 2023 with the emergence of the virus in two countries new to the virus: Equatorial Guinea and Tanzania, respectively. In this review, we aim to highlight the characteristics, etiology, epidemiology, and clinical symptoms of MVD, along with the current prevention measures and the possible treatments to control this virus.
Assuntos
Quirópteros , Ebolavirus , Doença pelo Vírus Ebola , Doença do Vírus de Marburg , Marburgvirus , Animais , Humanos , Doença do Vírus de Marburg/epidemiologia , Doença do Vírus de Marburg/prevenção & controle , Doença do Vírus de Marburg/diagnóstico , Surtos de Doenças , Fatores de RiscoAssuntos
Doença pelo Vírus Ebola , Doença do Vírus de Marburg , Animais , Humanos , Doença do Vírus de Marburg/epidemiologia , Doença do Vírus de Marburg/prevenção & controle , África Ocidental/epidemiologia , Zoonoses/epidemiologia , Zoonoses/prevenção & controle , Surtos de Doenças/prevenção & controle , Doença pelo Vírus Ebola/epidemiologiaRESUMO
Zaire ebolavirus (EBOV), Sudan ebolavirus (SUDV) and Marburg virus (MARV), are members of the Filoviridae family that can cause severe disease and death in humans and animals. The reemergence of Ebola, Sudan and Marburg virus disease highlight the need for continued availability of safe and effectives vaccines as well as development of new vaccines. While randomized controlled trials using disease endpoints provide the most robust assessment of vaccine effectiveness, challenges to this approach include the unpredictable size, location, occurrence and duration of filovirus disease outbreaks. Thus, other approaches to demonstrating vaccine effectiveness have been considered. These approaches are discussed using examples of preventive vaccines against other infectious diseases. In addition, this article proposes a clinical immunobridging strategy using licensed EBOV vaccines as comparators for demonstrating the effectiveness of filovirus vaccine candidates that are based on the same licensed vaccine platform technology.
Assuntos
COVID-19 , Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Doença do Vírus de Marburg , Animais , Humanos , Doença do Vírus de Marburg/prevenção & controleRESUMO
BACKGROUND: Marburg virus (MARV) is the causative agent of Marburg virus disease (MVD) which has a case fatality rate up to â¼90% in humans. Recently, there were cases reported in Guinea and Ghana highlighting this virus as a high-consequence pathogen potentially threatening global public health. There are no licensed treatments or vaccines available today. We used a vesicular stomatitis virus (VSV)-based vaccine expressing the MARV-Angola glycoprotein (VSV-MARV) as the viral antigen. Previously, a single dose of 1 × 107 plaque-forming units (PFU) administered 7 days before challenge resulted in uniform protection from disease in cynomolgus macaques. METHODS: As we sought to lower the vaccination dose to achieve a higher number of vaccine doses per vial, we administered 1 × 105 or 1 × 103 PFU 14 days or 1 × 103 PFU 7 days before challenge to cohorts of cynomolgus macaques and investigated immunity as well as protective efficacy. RESULTS: Vaccination resulted in uniform protection with no detectable viremia. Antigen-specific IgG responses were induced by both vaccine concentrations and were sustained until the study endpoint. Neutralizing antibody responses and antibody-dependent cellular phagocytosis were observed. The cellular response after vaccination was characterized by an early induction of NK cell activation. Additionally, antigen-specific memory T cell subsets were detected in all vaccination cohorts indicating that while the primary protective mechanism of VSV-MARV is the humoral response, a functional cellular response is also induced. INTERPRETATION: Overall, this data highlights VSV-MARV as a viable and fast-acting MARV vaccine candidate suitable for deployment in emergency outbreak situations and supports its clinical development. FUNDING: This work was funded by the Intramural Research Program NIAID, NIH.
Assuntos
Doença do Vírus de Marburg , Vacinas Virais , Animais , Humanos , Doença do Vírus de Marburg/prevenção & controle , Macaca fascicularis , Vacinação , Anticorpos NeutralizantesAssuntos
Ensaios Clínicos como Assunto , Surtos de Doenças , Doença do Vírus de Marburg , Marburgvirus , Vacinas Virais , Humanos , Surtos de Doenças/prevenção & controle , Surtos de Doenças/estatística & dados numéricos , Doença do Vírus de Marburg/epidemiologia , Doença do Vírus de Marburg/prevenção & controle , Doença do Vírus de Marburg/virologia , Fatores de TempoRESUMO
Marburg virus disease (MVD) is a lethal viral haemorrhagic fever caused by Marburg virus (MARV) with a case fatality rate as high as 88%. There is currently no vaccine or antiviral therapy approved for MVD. Due to high variation among MARV isolates, vaccines developed against one strain fail to protect against other strains. Here we report that three recombinant rabies virus (RABV) vector vaccines encoding two copies of GPs covering both MARV lineages induced pseudovirus neutralizing antibodies in BALB/c mice. Furthermore, high-affinity human neutralizing antibodies were isolated from a humanized mouse model. The three vaccines produced a Th1-biased serological response similar to that of human patients. Adequate sequential immunization enhanced the production of neutralizing antibodies. Virtual docking suggested that neutralizing antibodies induced by the Angola strain seemed to be able to hydrogen bond to the receptor-binding site (RBS) in the GP of the Ravn strain through hypervariable regions 2 (CDR2) and CDR3 of the VH region. These findings demonstrate that three inactivated vaccines are promising candidates against different strains of MARV, and a novel fully humanized neutralizing antibody against MARV was isolated.