Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses

Meyer, Michelle; Garrón, Tania; Lubaki, Ndongala Michel; Mire, Chad E.; Fenton, Karla A.; Klages, Curtis; Olinger, Gene G.; Geisbert, Thomas W.; Collins, Peter L.; Bukreyev, Alexander

doi:10.1172/jci81532

Cited by 69 publications

(59 citation statements)

References 46 publications

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“…Nearly all these vaccines use filovirus glycoprotein (GP) as the protective immunogen. These vaccines completely protected NHPs against lethal disease and are mostly replication-defective or replication-competent viral vectors, including alphavirus replicons 241,242 , human adenoviruses [243][244][245][246][247] , chimpanzee adenoviruses 248 , paramyxoviruses 249,250 , rabies viruses 251,252 and several different strategies with recombinant vesicular stomatitis viruses (rVSVs), including both the prototype rVSV vaccine [253][254][255][256][257] and a newer rVSV vaccine developed for enhanced safety (VesiculoVax) 258 . Virus-like particles [259][260][261] , a biologically contained EBOV lacking viral protein 30 (VP30) 262 , DNA 244 and several combinations of vaccines that include DNA, modified vaccinia Ankara (MVA) and various adenoviruses can also completely protect NHPs from lethal filovirus disease 244,248,263 .…”

Section: Box 2 | Vaccination To Prevent Filovirus Infectionmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

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106

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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Section: Box 2 | Vaccination To Prevent Filovirus Infectionmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

Self Cite

106

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“…In addition to inducing systemic immunity, i.n. vaccines induce a mucosal antibody response and respiratory tract resident CD4 ϩ and CD8 ϩ T cells (10), which would be expected to protect against EBOV infection via aerosol, skin, or mucosal routes. Intranasal vaccination is needle free and thus eliminates the concern for spreading blood-borne pathogens in the areas where EBOV is endemic.…”

Section: Discussionmentioning

confidence: 99%

Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys

Lingemann

Liu

Surman

et al. 2017

J Virol

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The recent 2014-2016 Ebola virus (EBOV) outbreak prompted increased efforts to develop vaccines against EBOV disease. We describe the development and preclinical evaluation of an attenuated recombinant human parainfluenza virus type 1 (rHPIV1) expressing the membrane-anchored form of EBOV glycoprotein GP, as an intranasal (i.n.) EBOV vaccine. GP was codon optimized and expressed either as a full-length protein or as an engineered chimeric form in which its transmembrane and cytoplasmic tail (TMCT) domains were replaced with those of the HPIV1 F protein in an effort to enhance packaging into the vector particle and immunogenicity. GP was inserted either preceding the N gene (pre-N) or between the N and P genes (N-P) of rHPIV1 bearing a stabilized attenuating mutation in the P/C gene (C Δ170 ). The constructs grew to high titers and efficiently and stably expressed GP. Viruses were attenuated, replicating at low titers over several days, in the respiratory tract of African green monkeys (AGMs). Two doses of candidates expressing GP from the pre-N position elicited higher GP neutralizing serum antibody titers than the N-P viruses, and unmodified GP induced higher levels than its TMCT counterpart. Unmodified EBOV GP was packaged into the HPIV1 particle, and the TMCT modification did not increase packaging or immunogenicity but rather reduced the stability of GP expression during in vivo replication. In conclusion, we identified an attenuated and immunogenic i.n. vaccine candidate expressing GP from the pre-N position. It is expected to be well tolerated in humans and is available for clinical evaluation.IMPORTANCE EBOV hemorrhagic fever is one of the most lethal viral infections and lacks a licensed vaccine. Contact of fluids from infected individuals, including droplets or aerosols, with mucosal surfaces is an important route of EBOV spread during a natural outbreak, and aerosols also might be exploited for intentional virus spread. Therefore, vaccines that protect against mucosal as well as systemic inoculation are needed. We evaluated a version of human parainfluenza virus type 1 (HPIV1) bearing a stabilized attenuating mutation in the P/C gene (C Δ170 ) as an intranasal vaccine vector to express the EBOV glycoprotein GP. We evaluated expression from two different genome positions (pre-N and N-P) and investigated the use of vector packaging signals. African green monkeys immunized with two doses of the vector expressing GP from the pre-N position developed high titers of GP neutralizing serum antibodies. The attenuated vaccine candidate is expected to be safe and immunogenic and is available for clinical development.

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“…Currently, into human experimental clinical trials of multivalent DNA vaccine against EVD is ongoing in West Africa and in regions neighbouring EVD-endemic areas including vaccine candidates cAd3-EBOV (cAd3), from GlaxoSmithKline (GSK) and the U. [10][11][12][13]. Both cAd3 and rVSV vaccine candidates at two different doses (1×1010 vp, 2.5×1010 vp, and 5×1010 vp).…”

Section: Chronology and Progress In Ebola Vaccines And Treatmentsmentioning

confidence: 99%

“…Also effective and integrated coordination and community participation of both vulnerable and non as well as travellers in the context of Ebola epidemic response and vaccination is required. A number Ebola candidate vaccines are at preclinical and clinical stages in the development pipeline [10,11,13,14].There is a need for careful multicenter clinical trials documentation and long term pharmacovigilance to ensuring that mass immunization safety and efficacy outcomes. Also, reliable and sustainable surveillance and monitoring systems including vaccines procurement and supply chains management as well as other medical equipment are important at national and global level.…”

Section: Chronology and Progress In Ebola Vaccines And Treatmentsmentioning

confidence: 99%

“…Globally, the importance of winning the fight against Ebola and other emerging infectious diseases is imperative in the 21 st century and beyond [12,13]. There is a need for national commitment and public-private investment in strengthening health systems and Ebola robust population-wide immunization with efficient immunization delivery systems and health advice and other health interventions [11]. This is vital in strengthening the expectations of Ebola vaccines financing and in shaping vaccine markets sustainability over time.…”

Section: Sharing the Potential Benefits Of National Ebola Immunizatiomentioning

confidence: 99%

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Values and Hopes of Ebola Vaccines Mass Immunization Programs and Treatments Adoption and Implementation Benefits in Africa

Tambo¹

2015

IJVV

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Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses

Cited by 69 publications

References 46 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys

Values and Hopes of Ebola Vaccines Mass Immunization Programs and Treatments Adoption and Implementation Benefits in Africa

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