Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study

Santis, Olga De; Audran, R; Pothin, Emilie; Warpelin-Decrausaz, Loane; Vallotton, Laurent; Wuerzner, Grégoire; Cochet, Camille; Estoppey, Daniel; Steiner-Monard, Viviane; Lonchampt, Sophie; Thierry, Anne Christine; Mayor, Claire; Bailer, Robert T.; Mbaya, Olivier Tshiani; Zhou, Yan; Ploquin, Aurélie; Sullivan, Nancy J.; Graham, Barney S.; Roman, François; Ryck, Iris De; Ballou, W. Ripley; Kiény, Marie Paule; Moorthy, Vasee; Spertini, François; Genton, Blaise

doi:10.1016/s1473-3099(15)00486-7

Cited by 141 publications

(106 citation statements)

References 15 publications

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“…Vaccines that were assessed in phase I and/or II studies during the 2013-2016 EBOV epidemic include rVSV-EBOV [268][269][270][271][272] , Ad5-EBOV [273][274][275] , rVSV-EBOV combined with rAd5-EBOV 276 , ChAd3-EBOV with or without MVA-EBOV [277][278][279][280] , Ad26-EBOV combined with MVA-EBOV 281 , and DNA encoding multiple filovirus GPs 282,283 . These EBOV vaccines generally elicited good immunogenicity against EBOV GP, and no serious adverse events were described.…”

Section: Vaccination Of Humansmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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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: Vaccination Of Humansmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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“…Clinical experiences with Ad vectors have shown them to be well tolerated at doses needed to induce transgene product-specific immune responses. 7,9,24 We developed AdC vectors to circumvent preexisting neutralizing antibodies, which are commonly found in humans to human Ad serotypes. 38,39 Ad-neutralizing antibodies reduce uptake of the corresponding Ad vectors and hence their ability to induce transgene product-specific immune responses.…”

mentioning

confidence: 99%

A PartialE3Deletion in Replication-Defective Adenoviral Vectors Allows for Stable Expression of Potentially Toxic Transgene Products

Haut

Gill

Kurupati

et al. 2016

Human Gene Therapy Methods

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Adenovirus (Ad) is used extensively for construction of viral vectors, most commonly with deletion in its E1 and/or E3 genomic regions. Previously, our attempts to insert envelope proteins (Env) of HIV-1 into such vectors based on chimpanzee-derived Ad (AdC) viruses were thwarted. Here, we describe that genetic instability of an E1-and E3-deleted AdC vector of serotype C6 expressing Env of HIV-1 can be overcome by reinsertion of E3 sequences with anti-apoptotic activities. This partial E3 deletion presumably delays premature death of HEK-293 packaging cell lines due to Env-induced cell apoptosis. The same partial E3 deletion also allows for the generation of stable glycoprotein 140 (gp140)-and gp160-expressing Ad vectors based on AdC7, a distinct AdC serotype. Env-expressing AdC vectors containing the partial E3 deletion are genetically stable upon serial cell culture passaging, produce yields comparable to those of other AdC vectors, and induce transgene product-specific antibody responses in mice. A partial E3 deletion thereby allows expansion of the repertoire of transgenes that can be expressed by Ad vectors.Keywords: HIV-1, vaccine, genetic stability, immune responses INTRODUCTION REPLICATION-DEFECTIVE ADENOVIRUS (Ad) vectors efficiently deliver transgenes to multiple cell types. 1,2 They trigger a potent inflammatory response, 3,4 which initiates adaptive immune responses to the transgene product and the antigens of the Ad vector. 5 This has led to the development of different Ad serotypes as vaccine carriers for a plethora of antigens derived from viruses, 6-10 bacteria, 11,12 parasites, 13,14 or tumor cells, [15][16][17] which have consistently induced potent and sustained B and T cell responses to the transgene products.In most Ad vaccine vectors, the E1 and E3 domains are deleted from the genome. The E1 deletion renders Ad vectors replication defective and reduces synthesis of other Ad antigens. E3 encodes a number of polypeptides that have anti-apoptotic activity or allow the virus to escape immune surveillance. 18,19 The E3 domain, a region that is nonessential for viral replication, is generally deleted to allow for the insertion of lengthy transgene expression cassettes without exceeding the genome size of wild-type virus, as this could potentially result in genetic instability of Ad vectors. 20 Ad vectors have been explored extensively as vaccine carriers for antigens of human immunodeficiency virus (HIV)-1, 21-25 the causative agent of the acquired immunodeficiency syndrome (AIDS). While initial efforts focused on expression of internal antigens for the induction of CD8 + T cell responses against HIV-1, efforts have since shifted toward expression of the envelope protein (Env). The heavily glycosylated and highly variable Env of HIV-1 forms trimers composed of glycoprotein (gp) 120 and gp41 on the surface of the virion. These complexes allow HIV-1 to attach to its receptors and coreceptors and are thereby essential for CD4 + cell infection by HIV-1. Env is not only the sole target of HIV-1-specif...

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“…При этом еди-ничная доза вакцины вызывает образование длительного гуморального иммунного ответа (до 6 месяцев). Стоит отметить, что в группах, получивших разные дозы вакцины, не наблю-далось значительных различий в безопасности и иммуно генности [6].…”

Section: вакцины на основе ад-векторовunclassified

Development of Vaccines Based on Adenoviral Vectors: A Review of Foreign Clinical Studies (Part 2)

Черенова¹,

Каштиго²,

Саядян³

et al. 2017

Med. immunol.

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Адрес для переписки:Черенова Любовь Викторовна ФГБУ «Федеральный научно-исследовательский центр эпидемиологии и микробиологии им. почетного академика Н.Ф. Гамалеи» Министерства здравоохранения РФ 123098, Россия, г. Москва, ул. Гамалеи, 18. Тел.: 8 (916) 329-92-78. Факс: 8 (499) 193-61-35. E-mail: cherenova@yandex.ru Address for correspondence : Cherenova Liubov V. N. Gamaleya Research Institute of Epidemiology and Microbiology 123098, Russian Federation, Moscow, Gamaleya str., 18. Phone: 7 (916) // Медицинская иммунология, 2017. Т. 19, № 4. С. 329-358. doi: 10.15789/1563-0625-2017-4-329-358 © Черенова Л.В. и соавт., 2017 /Meditsinskaya Immunologiya, 2017, Vol. 19, no. 4, pp. 329-358. doi: 10.15789/1563-0625-2017 Резюме. В настоящее время для многих инфекционных заболеваний человека не разработаны эффективные способы лечения и профилактики. Одним из последних достижений биотехнологии является использование аденовирусных векторов, несущих иммунодоминантные антигены различ-ных патогенов, в качестве генно-инженерных вакцин как профилактических, так и терапевтических. Использование генно-инженерных технологий позволяет не применять при производстве вакцин живые вирусы и бактерии, сокращает время разработки и получения новых вакцинных препаратов. Аденовирусные векторы естественным путем проникают в клетки человека, вызывая довольно дли-тельный и значительный как гуморальный, так и клеточный иммунный ответ. Во второй части об-зора мы планируем привести сведения о проводимых в настоящее время за рубежом клинических испытаниях вакцин на основе аденовирусных векторов против таких инфекционных заболеваний, как грипп, малярия, геморрагическая лихорадка Эбола, туберкулез, гепатит и ряда других. Будут рас-смотрены параметры отбора добровольцев, схемы и дозы, используемые при вакцинации, приведены результаты завершенных экспериментов и предварительные результаты незаконченных на данный момент исследований.

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Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study

Abstract: Swiss State Secretariat for Education, Research and Innovation (SERI), through the EU Horizon 2020 Research and Innovation Programme.

Cited by 141 publications

References 15 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

A PartialE3Deletion in Replication-Defective Adenoviral Vectors Allows for Stable Expression of Potentially Toxic Transgene Products

Development of Vaccines Based on Adenoviral Vectors: A Review of Foreign Clinical Studies (Part 2)

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