Ebola vaccine

Many Ebola vaccine candidates against Ebola were developed in the decade prior to 2014,[1] but none have yet been approved for clinical use in humans.[2][3][4] Several promising vaccine candidates have been shown to protect nonhuman primates (usually macaques) against lethal infection.[5][6][7] These include replication-deficient adenovirus vectors, replication-competent vesicular stomatitis (VSV) and human parainfluenza (HPIV-3) vectors, and virus-like nanoparticle preparations. Conventional trials to study efficacy by exposure of humans to the pathogen after immunization are obviously not feasible in this case. For such situations, the FDA has established the “Animal Efficacy Rule” allowing licensure to be approved on the basis of animal model studies that replicate human disease, combined with evidence of safety and a potentially potent immune response (antibodies in the blood) from humans given the vaccine. Clinical trials involve the administration of the vaccine to healthy human subjects to evaluate the immune response, identify any side effects and determine the appropriate dosage.[8]

Vaccines under development

Summary table

Vaccine Associated organisations Status (as of October 2015)
Chimp adenovirus 3 vectored glycoprotein (cAd3-EBO Z) GSK & NIAID Phase III in progress [9]
rVSV vectored glycoprotein (VSV-EBOV) Newlink Genetics & Merck Interim Phase III results published [10]
Human adenovirus 5 vectored 2014 glycoprotein insert BIT & CanSino Phase I complete [11]
Adenovirus 26 vectored glycoprotein / MVA-BN (Ad26.ZEBOV/ MVA-BN) Johnson & Johnson Phase II in progress [12][13]
MVA vectored glycoprotein Emergent Biosolutions Phase I planned [14]
Glycoprotein nanoparticle + MatrixM (Ebola GP vaccine) Novavax Phase I complete
Oral human adenovirus 5 + TLR3 ligand Vaxart Phase I planned [15]
HPIV-3 vectored glycoprotein Ministry of Health (Russia) Phase I planned [16]
rVSVN4CT1 VesiculoVax Profectus Biosciences Phase I planned [17]
Rabies vectored glycoprotein Thomas Jefferson University & NIAID Non-human primate challenge complete[18]
DNA vaccine Inovio Phase I planned [19]
Purified glycoprotein Protein Sciences NHP challenge initiated [20]
Ebola ∆VP30 H2O2 treated University of Wisconsin Non-human primate challenge complete [21]

cAd3-EBO Z

In September 2014, two Phase 1 clinical trials began for the vaccine cAd3-EBO Z, which is based on an attenuated version of a chimpanzee adenovirus (cAd3) that has been genetically altered so that it is unable to replicate in humans.[22] The cAd3 vector has a DNA fragment insert that encodes the Ebola virus glycoprotein, which is expressed on the virion surface and is critical for attachment to host cells and catalysis of membrane fusion.[9] It was developed by NIAID in collaboration with Okairos, now a division of GlaxoSmithKline. For the trial designated VRC 20, 20 volunteers were recruited by the NIAID in Bethesda, Maryland, while three dose-specific groups of 20 volunteers each were recruited for trial EBL01 by University of Oxford, U.K. Initial results were released in November 2014; all 20 volunteers developed antibodies against Ebola and there were no significant concerns raised about safety.[23][24] In December 2014, University of Oxford expanded the trial to include a booster vaccine based on MVA-BN, a strain of Modified vaccinia Ankara, developed by Bavarian Nordic, to investigate whether it can help increase immune responses further.[25][26] The trial which has enrolled a total of 60 volunteers will see 30 volunteers vaccinated with the booster vaccine. As of April 2015, Phase 3 trial with a single dose of cAd3-EBO Z begins in Sierra Leone after a successful Phase 2 study in West Africa countries.[27][28]

VSV-EBOV

For more details on this topic, see VSV-EBOV.

A vaccine based on the vesicular stomatitis virus which was genetically modified to express a surface glycoprotein of Zaire Ebola virus, called VSV-EBOV, has been developed by the Public Health Agency of Canada, with development subsequently taken over by Merck Inc.[29] In October 2014, the Wellcome Trust announced the start of multiple trials in healthy volunteers in Europe, Gabon, Kenya, and the USA.[30] The trial was temporarily halted in December 2014 due to possible adverse effects, but subsequently resumed.[31] As of April 2015, a Phase 3 trial with a single dose of VSV-EBOV began in Liberia after a successful Phase 2 study in the West Africa country.[27] On 31 July 2015, preliminary results of a Phase 3 trial in Guinea indicated that the vaccine appears to be "highly efficacious and safe."[32] The trial used a ring vaccination protocol that first vaccinated all the closest contacts of new cases of Ebola infection either immediately or after 21 days. Because of the demonstrated efficacy of immediate vaccination, all recipients will now be immunized immediately.[33] Ring vaccination is the method used in the program to eradicate smallpox in the 1970s. The trial will continue to assess whether the vaccine is effective in creating herd immunity to Ebola virus infection.[34]

Ad26.ZEBOV/ MVA-BN

Johnson & Johnson has developed an Ebola vaccine at its Janssen Pharmaceutica Company. The regimen consists of two vaccine components (first vaccine as prime, followed by a second vaccine as boost)[35] that are based on AdVac technology from Crucell Holland B.V., which is part of Janssen, and the MVA-BN technology from Bavarian Nordic. The Ad26.ZEBOV is derived from human adenovirus serotype 26 (Ad26) expressing the Ebola virus Mayinga variant glycoprotein while the second component MVA-BN is the Modified Vaccinia Virus Ankara - Bavarian Nordic (MVA-BN) Filo-vector.[12] This product commenced Phase 1 clinical trial at the Jenner Institute in Oxford during January 2015.[36][37] The preliminary data indicated the prime-boost vaccine regimen elicited temporary immunologic response in the volunteers as expected from vaccination. The Phase 2 trial enrolled 612 adult volunteers and commenced in July 2015 in United Kingdom and France. A second Phase 2 trial, involving 1,200 volunteers, has been initiated in Africa [35] with the first trial commenced in Sierra Leone in October 2015.[13]

Ebola GP vaccine

At the 8th Vaccine and ISV Conference in Philadelphia on 27−28 October 2014, Novavax Inc. reported the development in a "few weeks" of a glycoprotein (GP) nanoparticle Ebola virus (EBOV GP) vaccine using their proprietary recombinant technology. A recombinant protein is a protein whose code is carried by recombinant DNA. The vaccine is based on the newly published genetic sequence[38] of the 2014 Guinea Ebola (Makona) strain that is responsible for the current Ebola disease epidemic in West Africa. In animal studies, a useful immune response was induced, and was found to be enhanced ten to a hundred-fold by the company's "Matrix-M" immunologic adjuvant. A study of the response of non-human primate to the vaccine had been initiated. As of February 2015, Novavax had completed 2 primate studies on baboons and macaques and had initiated a Phase 1 clinical trial in Australia. The top line Phase 1 human trial results showed that the adjuvanted Ebola GP Vaccine was highly immunogenic at all dose levels.

Nasal vaccine

On November 5, 2014, the Houston Chronicle reported that a research team at the University of Texas-Austin was developing a nasal spray Ebola vaccine, which the team had been working on for seven years.[39] The team reported in 2014 that in the nonhuman primate studies it conducted, the vaccine had more efficacy when delivered via nasal spray than by injection.[40] As of early November 2014 further development by the team appeared unlikely due to lack of funding.[39][41]

Vaxart tablet

Vaxart Inc. is developing a vaccine technology in the form of a temperature-stable tablet which may offer advantages such as reduced cold chain requirement, and rapid and scalable manufacturing. In January 2015, Vaxart announced that it had secured funding to develop its Ebola vaccine to Phase 1 trial.[42]

Novel recombinant adenovirus type-5 vector-based Ebola vaccine

In late 2014 and early 2015, a double-blind, randomized Phase 1 trial was conducted in the Jiangsu Province of China; the trial examined a vaccine that contains glycoproteins of the 2014 strain, rather than those of the 1976 strain. The trial found signals of efficacy and raised no significant safety concerns.[43]

Whole virus vaccine

A study published in Science during March 2015 demonstrates that vaccination with a weakened form of the Ebola virus provides some measure of protection to non-human primates. The new vaccine relies on a strain of Ebola called EBOVΔVP30, which is unable to replicate.[44]

Clinical trials in West Africa

In January 2015, Marie-Paule Kieny, the WHO’s assistant director-general of health systems and innovation, announced that the vaccines cAd3-EBO Z and VSV-EBOV had demonstrated acceptable safety profiles during early testing and would soon progress to large-scale trials in Liberia, Sierra Leone and Guinea. The trials would involve up to 27,000 people and comprise 3 groups - members of the first two groups would receive the two candidate vaccines, while the third group will receive a placebo.[45] Both vaccines have since successfully completed the Phase 2 studies. The large scale Phase 3 studies have begun as of April 2015 in Liberia and Sierra Leone.[27][28]

U.S. national stockpile

Credit Suisse has estimated that the U.S. government will eventually provide over $1 billion in contracts to companies to develop medicine and vaccines for Ebola virus disease. Congress passed a law in 2004 that funds a national stockpile of vaccines and medicine for possible outbreaks of disease. A number of companies are developing Ebola vaccines: GlaxoSmithKline, NewLink Genetics, Johnson & Johnson and Bavarian Nordic. Another company, Emergent BioSolutions, is a contestant for manufacturing new doses of ZMapp, a drug for Ebola virus disease treatment originally developed by Mapp Biopharmaceutical. Supplies of ZMapp ran out in October 2014.[46][47]

See also

References

  1. ↑ Richardson JS, Dekker JD, Croyle MA, Kobinger GP (June 2010). "Recent advances in Ebolavirus vaccine development". Human Vaccines (open access) 6 (6): 439–49. doi:10.4161/hv.6.6.11097. PMID 20671437.
  2. ↑ "Statement on the WHO Consultation on potential Ebola therapies and vaccines". WHO. 5 September 2014. Retrieved 1 October 2014.
  3. ↑ "2014 Ebola Outbreak in West Africa". U.S. Food and Drug Administration. Retrieved Oct 2014.
  4. ↑ Alison P. Galvani with three others (21 August 2014). "Ebola Vaccination: If Not Now, When?". Annals of Internal Medicine 161 (10): 749–50. doi:10.7326/M14-1904. PMC 4316820. PMID 25141813.
  5. ↑ Hoenen T, Groseth A, Feldmann H (July 2012). "Current Ebola vaccines". Expert Opin Biol Ther 12 (7): 859–72. doi:10.1517/14712598.2012.685152. PMC 3422127. PMID 22559078.
  6. ↑ Peterson AT, Bauer JT, Mills JN (2004). "Ecologic and Geographic Distribution of Filovirus Disease". Emerging Infectious Diseases 10 (1): 40–47. doi:10.3201/eid1001.030125. PMC 3322747. PMID 15078595.
  7. ↑ Fausther-Bovendo H, Mulangu S, Sullivan NJ (June 2012). "Ebolavirus vaccines for humans and apes". Curr Opin Virol 2 (3): 324–29. doi:10.1016/j.coviro.2012.04.003. PMC 3397659. PMID 22560007.
  8. ↑ Pavot, Vincent (February 17, 2016). "Leading Ebola Vaccine Candidates" (PDF). Vaccination Research Open Journal 1 (1): 1–6.
  9. 1 2 "Partnership for Research on Ebola Vaccines in Liberia (PREVAIL)". 24 June 2015. Retrieved 10 September 2015.
  10. ↑ Henao-Restrepo, Ana Maria; Longini, Ira M; Egger, Matthias; Dean, Natalie E; Edmunds, W John; Camacho, Anton; Carroll, Miles W; Doumbia, Moussa; Draguez, Bertrand; Duraffour, Sophie; Enwere, Godwin; Grais, Rebecca; Gunther, Stephan; Hossmann, Stefanie; Kondé, Mandy Kader; Kone, Souleymane; Kuisma, Eeva; Levine, Myron M; Mandal, Sema; Norheim, Gunnstein; Riveros, Ximena; Soumah, Aboubacar; Trelle, Sven; Vicari, Andrea S; Watson, Conall H; Kéïta, Sakoba; Kieny, Marie Paule; Røttingen, John-Arne (31 July 2015). "Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial". The Lancet 386 (9996): 857–866. doi:10.1016/S0140-6736(15)61117-5.
  11. ↑ Zhu, Feng-Cai; Hou, Li-Hua; Li, Jing-Xin; Wu, Shi-Po; Liu, Pei; Zhang, Gui-Rong; Hu, Yue-Mei; Meng, Fan-Yue; Xu, Jun-Jie; Tang, Rong; Zhang, Jin-Long; Wang, Wen-Juan; Duan, Lei; Chu, Kai; Liang, Qi; Hu, Jia-Lei; Luo, Li; Zhu, Tao; Wang, Jun-Zhi; Chen, Wei (6 June 2015). "Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial". The Lancet 385 (9984): 2272. doi:10.1016/S0140-6736(15)60553-0.
  12. 1 2 "A Safety and Immunogenicity Study of Heterologous Prime-Boost Ebola Vaccine Regimens in Healthy Participants". 23 July 2015. Retrieved 15 October 2015.
  13. 1 2 Hirschler, Ben (9 October 2015). "J&J starts vaccine trial in Sierra Leone, even as Ebola fades". Reuters. Retrieved 15 October 2015.
  14. ↑ "Emergent BioSolutions Signs Agreements With Oxford University, GlaxoSmithKline, and NIAID for the Production of an MVA Ebola Zaire Vaccine Candidate". 16 March 2015. Retrieved 10 September 2015.
  15. ↑ "Vaxart Accelerates Development of Ebola Tablet Vaccine" (PDF). 23 October 2014. Retrieved 10 September 2015.
  16. ↑ "Ebola vaccines, therapies, and diagnostics". 6 July 2015. Retrieved 10 September 2015.
  17. ↑ "Profectus BioSciences Receives $9.5 Million Department of Defense Funding to Manufacture Trivalent VesiculoVaxTM-Vectored Vaccine to Protect Against all Ebola and Marburg Viruses" (PDF). 31 October 2014. Retrieved 10 September 2015.
  18. ↑ Blaney, Joseph E.; Marzi, Andrea; Willet, Mallory; Papaneri, Amy B.; Wirblich, Christoph; Feldmann, Friederike; Holbrook, Michael; Jahrling, Peter; Feldmann, Heinz; Schnell, Matthias J. (30 May 2015). "Antibody Quality and Protection from Lethal Ebola Virus Challenge in Nonhuman Primates Immunized with Rabies Virus Based Bivalent Vaccine". PLoS Pathogens 9 (5): e1003389. doi:10.1371/journal.ppat.1003389. PMID 23737747.
  19. ↑ "Inovio Pharmaceuticals Ebola Vaccine Moving into Human Trial with GeneOne Life Science". 24 September 2014. Retrieved 10 September 2015.
  20. ↑ "CT lab hopes to stop spread of Ebola". 3 March 2015. Retrieved 10 September 2015.
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  22. ↑ Vaccine Research Center, NIAID (29 September 2014). "Ebola Vaccine Clinical Development Overview (presentation)" (PDF). Retrieved 21 October 2014.
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  26. ↑ University of Oxfod (4 December 2014). "Booster Ebola vaccine enters first trials at Oxford University". Retrieved 7 December 2014.
  27. 1 2 3 NIH Press Release (26 March 2015). "Ebola test vaccines appear safe in Phase 2 Liberian clinical trial".
  28. 1 2 CDC Press Release (14 April 2015). "Ebola vaccine trial begins in Sierra Leone".
  29. ↑ "Canadian Ebola vaccine development taken over by Merck". CBC. 24 November 2014. Retrieved 25 November 2014.
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  35. 1 2 Press Release (15 July 2015). "Bavarian Nordic announces that the Oxford Vaccines Group has initiated a Phase 2 study of the Ebola prime-boost vaccine regimen combining MVA-BN Filo and Janssen's Advac technology". Bavarian Nordic. Retrieved 16 July 2015.
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  39. 1 2 Ackerman, Todd (5 November 2014). "UT nasal spray vaccine for Ebola effective in monkeys". Houston Chronicle. Retrieved 13 November 2014.
  40. ↑ Choi, Jin Huk; Jonsson-Schmunk, Kristina; Qiu, Xiangguo; Shedlock, Devon J.; Strong, Jim; Xu, Jason X.; Michie, Kelly L.; Audet, Jonathan; Fernando, Lisa; Myers, Mark J.; Weiner, David; Bajrovic, Irnela; Tran, Lilian Q.; Wong, Gary; Bello, Alexander; Kobinger, Gary P.; Schafer, Stephen C.; Croyle, Maria A. (14 November 2014). "A Single Dose Respiratory Recombinant Adenovirus-Based Vaccine Provides Long-Term Protection for Non-Human Primates from Lethal Ebola Infection". Molecular Pharmaceutics 12 (8): 141114080030002. doi:10.1021/mp500646d.
  41. ↑ Stanton, Dan (12 November 2014). "Ebola nasal vaccine under threat as funding runs dry". in-PharmaTechnologist (Crawley, Sussex, United Kingdom: William Reed Business Media). Retrieved 13 November 2014.
  42. ↑ "Vaxart Completes Financing to Fund Expanding Development Portfolio". Vaxart.
  43. ↑ Zhu, Feng-Cai; et al. (24 March 2015). "Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, Phase 1 trial". The Lancet 385 (9984): 2272. doi:10.1016/S0140-6736(15)60553-0.
  44. ↑ Marzi, A.; Halfmann, P.; Hill-Batorski, L.; Feldmann, F.; Shupert, W. L.; Neumann, G.; Feldmann, H.; Kawaoka, Y. (24 March 2015). "An Ebola whole-virus vaccine is protective in nonhuman primates". Science 348 (6233): 439. doi:10.1126/science.aaa4919. PMID 25814063.
  45. ↑ "UK leads promising Ebola vaccine trial Pharmaceutical company looking into largescale manufacturing if trials are successful.". Ars Technica. Retrieved 10 January 2015.
  46. ↑ Rooney, Ben (28 October 2014). "Ebola: The making of a $1 billion drug". CNN Money. Retrieved 19 November 2014.
  47. ↑ Gantz, Sarah (20 October 2014). "Emergent BioSolutions among three under consideration for Ebola drug manufacturing". Baltimore Business Journal. Retrieved 13 November 2014.
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