Ebola vaccine

Ebola vaccine
Candidate Ebola Vaccine shot
Specialty virology

Ebola vaccine candidates against Ebola have been 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]

In December 2016, a study found the VSV-EBOV vaccine to be 70–100% effective against the Ebola virus, making it the first proven vaccine against the disease.[9][10]

Types in development

Summary table

VaccineAssociated organisationsStatus
Chimp adenovirus 3 vectored glycoprotein (cAd3-EBO Z)GSK & NIAIDPhase III Feb. 2016[11]
rVSV vectored glycoprotein (VSV-EBOV)Newlink Genetics & Merck in use [12][13]
Human adenovirus 5 vectored 2014 glycoprotein insertBIT & CanSinoPhase I complete[14]
Adenovirus 26 vectored glycoprotein / MVA-BN (Ad26.ZEBOV/ MVA-BN)Johnson & JohnsonPhase I complete April, 2016[15][16]
HPIV-3 vectored glycoproteinMinistry of Health (Russia)Phase I planned[17]
Rabies vectored glycoproteinThomas Jefferson University & NIAIDNon-human primate challenge complete[18]
Purified glycoproteinProtein SciencesNHP challenge initiated[19]
Ebola ∆VP30 H2O2 treatedUniversity of WisconsinNon-human primate challenge complete[20]

rVSV-ZEBOV

A vaccine based on the vesicular stomatitis virus which was genetically modified to express a surface glycoprotein of Zaire Ebola virus, known as either VSV-EBOV or rVSV-ZEBOV,[21][22] has been developed by the Public Health Agency of Canada, with development subsequently taken over by Merck Inc.[23] In October 2014, the Wellcome Trust, who was also one of the biggest UK founders,[24] announced the start of multiple trials in healthy volunteers in Europe, Gabon, Kenya, and the US.[25] The vaccine was proven safe at multiple sites in North America, Europe, and Africa, but several volunteers at one trial site in Geneva, Switzerland, developed vaccine-related arthritis after about 2 weeks, and about 20–30% of volunteers at reporting sites developed low-grade post-vaccine fever, which resolved within a day or two. Other common side-effects were pain at the site of injection, myalgia, and fatigue.[26] The trial was temporarily halted in December 2014 due to possible adverse effects, but subsequently resumed.[27] 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.[28] On 31 July 2015, preliminary results of a Phase 3 trial in Guinea indicated that the vaccine appears to be "highly efficacious and safe."[29] 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.[30][31] 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.[32] In December 2016, a study found the VSV-EBOV vaccine to be 95-100% effective against the Ebola virus, making it the first proven vaccine against the disease.[9][10]

cAd3-EBO Z

Ebola virions

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.[33] 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.[34] 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.[35][36] 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.[37][38] 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.[28][39]

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)[40] 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.[41] This product commenced Phase 1 clinical trial at the Jenner Institute in Oxford during January 2015.[42][43] 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[40] with the first trial commenced in Sierra Leone in October 2015.[44]

Ebola GP vaccine

Recombinant formation plasmids

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[45] 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 Lipid nanoparticle (LNP)-encapsulated siRNAs rapidly adapted to target the Makona outbreak strain of EBOV are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days postexposure while animals were viremic and clinically ill.[46] 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.[47] 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.[48] As of early November 2014 further development by the team appeared unlikely due to lack of funding.[47][49]

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.[50]

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.[14]

Attenuated Ebola 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. This study was conducted in accordance with a protocol approved by an Institutional Animal Care and Use Committee of the National Institutes of Health.[51] The new vaccine relies on a strain of Ebola called EBOVΔVP30, which is unable to replicate.[52]

GamEvac-Combi

A study published in Human Vaccines and Immunotherapeutics in March 2017, analyzing data from a clinical trial of the GamEvac-Combi vaccine in Russia, concluded said vaccine to be safe and effective and recommended proceeding to Phase III trials.[53]

Ad5-EBOV

The China Food and Drug Administration (CFDA) said Friday that it has approved an Ebola vaccine, co-developed by the military-backed Bioengineering Institute of the Chinese Academy of Military Medical Sciences and private drugmaker Tianjin CanSino Biotechnology Inc.[54] This finding, the research team said, is consistent with previous tests on rVSV-ZEBOV in Africa and Europe.[55]

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.[56] 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,[28][39] and in Guinea in March 2016.[31]

In addition, a medical anthropologist at Université de Montréal, has been working in Guinea and raised further questions about safety in the ring trial after spending time in April at one of the Ebola treatment units where trial participants are taken if they become ill, the centre in Coyah, about 50 km from the capital of Conakry.[26]

The Russian Foreign Ministry announced in 2016 the intention to conduct field trials of two Russian vaccines involving 2000 people.[57] According to local media reports, the Guinean government authorized the commencement of the trials on 9 August 2017 at the Rusal-built Research and Diagnostic Center of Epidemiology and Microbiology in Kindia. The trials are slated to continue until 2018.[57][58]

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.[59][60]

During the 2018 outbreak in the Democratic Republic of the Congo

The ZMapp cocktail was assessed by the World Health Organization for emergency use under the MEURI ethical protocol. The panel agreed that "the benefits of ZMapp outweigh its risks" while noting that it presented logistical challenges, particularly that of requiring a cold chain for distribution and storage.[61] Four alternative therapies (Remdesivir, REGN3470-3471-3479, Favipiravir, and mAb114) were also considered for use, but they are at earlier stages of development.[61]

See also

References

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Further reading

  • Farooq, Fouzia; Beck, Kevin; Paolino, Kristopher M.; Phillips, Revell; Waters, Norman C.; Regules, Jason A.; Bergmann-Leitner, Elke S. (21 June 2016). "Circulating follicular T helper cells and cytokine profile in humans following vaccination with the rVSV-ZEBOV Ebola vaccine". Scientific Reports. 6: 27944. doi:10.1038/srep27944. ISSN 2045-2322. PMC 4914957. PMID 27323685.
  • Sullivan, Nancy; Yang, Zhi-Yong; Nabel, Gary J. (1 September 2003). "Ebola virus pathogenesis: implications for vaccines and therapies". Journal of Virology. 77 (18): 9733–9737. doi:10.1128/JVI.77.18.9733-9737.2003. ISSN 0022-538X. PMC 224575. PMID 12941881.
  • Diakite, Ibrahim; Mooring, Eric Q.; Velásquez, Gustavo E.; Murray, Megan B. (10 August 2016). "Novel ordered stepped-wedge cluster trial designs for detecting Ebola vaccine efficacy using a spatially structured mathematical model". PLOS Negl Trop Dis. 10 (8): e0004866. doi:10.1371/journal.pntd.0004866. ISSN 1935-2735. Retrieved 22 August 2016.
  • Cazares, Lisa H.; Ward, Michael D.; Brueggemann, Ernst E.; Kenny, Tara; Demond, Paul; Mahone, Christopher R.; Martins, Karen A. O.; Nuss, Jonathan E.; Glaros, Trevor; Bavari, Sina (5 September 2016). "Development of a liquid chromatography high resolution mass spectrometry method for the quantitation of viral envelope glycoprotein in Ebola virus-like particle vaccine preparations". Clinical Proteomics. 13 (1). doi:10.1186/s12014-016-9119-8. ISSN 1559-0275. Retrieved 7 September 2016.
  • Konduru, Krishnamurthy; Shurtleff, Amy C.; Bradfute, Steven B.; Nakamura, Siham; Bavari, Sina; Kaplan, Gerardo; Tsuji, Moriya (13 September 2016). "Ebolavirus glycoprotein Fc fusion protein protects guinea pigs against lethal challenge". PLOS ONE. 11 (9): e0162446. doi:10.1371/journal.pone.0162446. ISSN 1932-6203. PMC 5021345. PMID 27622456. Retrieved 14 September 2016.
  • Cheng, Feixiong; Murray, James L.; Zhao, Junfei; Sheng, Jinsong; Zhao, Zhongming; Rubin, Donald H. (15 September 2016). "Systems biology-based investigation of cellular antiviral drug targets identified by gene-trap insertional mutagenesis". PLoS Comput Biol. 12 (9): e1005074. doi:10.1371/journal.pcbi.1005074. ISSN 1553-7358. Retrieved 18 September 2016.
  • Olowookere, Samuel A.; Abioye-Kuteyi, Emmanuel A.; Adekanle, O. (October 2016). "Willingness to participate in Ebola viral disease vaccine trials and receive vaccination by health workers in a tertiary hospital in Ile-Ife, Southwest Nigeria". Vaccine. 34: 5758–5761. doi:10.1016/j.vaccine.2016.10.004. ISSN 1873-2518. PMID 27751640.
  • Pavot, Vincent (December 2016). "Ebola virus vaccines: Where do we stand?". Clinical Immunology. 173: 44–49. doi:10.1016/j.clim.2016.10.016. ISSN 1521-7035. PMID 27910805.
  • Completing the development of Ebola vaccines (PDF). CIDRAP and Wellcome Trust. 2017. Retrieved 18 January 2017.
  • Rosales-Mendoza, Sergio; Nieto-Gómez, Ricardo; Angulo, Carlos (1 January 2017). "A perspective on the development of plant-made vaccines in the fight against Ebola virus". Frontiers in Immunology. 8. doi:10.3389/fimmu.2017.00252. ISSN 1664-3224. Retrieved 30 March 2017.
  • "DMOZ - Health: Conditions and Diseases: Infectious Diseases: Viral: Hemorrhagic Fevers: Ebola". www.dmoz.org. Retrieved 26 July 2016.
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