Ebola vaccine

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Ebola vaccine
Study Participant Receives NIAID-GSK Candidate Ebola Vaccine (3).jpg
Candidate Ebola Vaccine shot
Specialtyvirology

Ebola vaccine candidates against Ebola have been developed in the decade prior to 2014,[1] but none had been approved for clinical use in humans.[2][3] One, rVSV-ZEBOV, had been used extensively in 2018-19 under a compassionate use protocol,[4] and in September 2019, the FDA accepted a Biologics License Application and granted priority review for the vaccine.[5] Several promising vaccine candidates have been shown to protect nonhuman primates (usually macaques) against lethal infection.[6][7][8]

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 not ethical in this case. For such situations, the Food and Drug Administration (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.[9]

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.[10][11][12] However, the design of this study and the high efficacy of the vaccine were questioned.[13]

In November 2019, the European Commission granted a conditional marketing authorization to Ervebo (Ebola Zaire Vaccine (rVSV∆G-ZEBOV-GP, live))[14] and the World Health Organization (WHO) prequalified an Ebola vaccine for the first time.[15]

Types in development[edit]

Summary table[edit]

Vaccine Associated organisations Status
Chimp adenovirus 3 vectored glycoprotein (cAd3-EBO Z) GSK & NIAID Phase III Feb. 2016[9]
rVSV vectored glycoprotein (VSV-EBOV) Newlink Genetics & Merck in use [16][17]
Human adenovirus 5 vectored 2014 glycoprotein insert (Ad5-EBOV) BIT & CanSino Phase I complete[18]
Adenovirus 26 vectored glycoprotein / MVA-BN (Ad26.ZEBOV/​MVA-BN) Johnson & Johnson Phase I complete April, 2016[19][20]
HPIV-3 vectored glycoprotein Ministry of Health (Russia) Phase I planned[21]
Rabies vectored glycoprotein Thomas Jefferson University & NIAID Non-human primate challenge complete[22]
Purified glycoprotein Protein Sciences NHP challenge initiated[23]
Ebola ∆VP30 H2O2 treated University of Wisconsin Non-human primate challenge complete[24]

rVSV-ZEBOV[edit]

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,[25][26] has been developed by the Public Health Agency of Canada, with development subsequently taken over by Merck Inc.[27] In October 2014, the Wellcome Trust, who was also one of the biggest UK founders,[28] announced the start of multiple trials in healthy volunteers in Europe, Gabon, Kenya, and the US.[29] 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 two 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.[30] The trial was temporarily halted in December 2014 due to possible adverse effects, but subsequently resumed.[31] As of April 2015, a Phase III trial with a single dose of VSV-EBOV began in Liberia after a successful Phase II study in the West African country.[32] On 31 July 2015, preliminary results of a Phase III trial in Guinea indicated that the vaccine appears to be "highly efficacious and safe."[33] 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.[34][35] 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.[36] 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.[10][11][12]

In November 2019, the European Commission granted a conditional marketing authorization to Ervebo.[37] The WHO prequalification came fewer than 48 hours later, making it the fastest vaccine prequalification process ever conducted by WHO.[15]

cAd3-EBO Z[edit]

Ebola virions

In September 2014, two Phase I 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.[38] 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.[39] 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.[40][41] 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.[42][43] The trial which has enrolled a total of 60 volunteers will see 30 volunteers vaccinated with the booster vaccine. As of April 2015, Phase III trial with a single dose of cAd3-EBO Z begins in Sierra Leone after a successful Phase 2 study in West Africa countries.[32][44]

Ad26.ZEBOV/MVA-BN[edit]

Johnson & Johnson 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)[45] 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.[46] This product commenced Phase I clinical trial at the Jenner Institute in Oxford during January 2015.[47][48] The preliminary data indicated the prime-boost vaccine regimen elicited temporary immunologic response in the volunteers as expected from vaccination. The Phase II trial enrolled 612 adult volunteers and commenced in July 2015, in the United Kingdom and France. A second Phase II trial, involving 1,200 volunteers, was initiated in Africa[45] with the first trial commenced in Sierra Leone in October 2015.[49]

In September 2019, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) granted an accelerated assessment to Janssen for Ad26.ZEBOV and MVA-BN,[50] and in November 2019, Janssen submitted a Marketing Authorization Application (MAA) to the EMA for approval of Ad26.ZEBOV and MVA-BN.[50][51]

Ebola GP vaccine[edit]

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[52] of the 2014 Guinea Ebola (Makona) strain that is responsible for the 2014 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 two primate studies on baboons and macaques and had initiated a Phase I clinical trial in Australia. The Lipid nanoparticle (LNP)-encapsulated siRNAs rapidly adapted to target the Makona outbreak strain of EBOV and are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at three days postexposure while animals were viremic and clinically ill.[53] The top line Phase I human trial results showed that the adjuvanted Ebola GP Vaccine was highly immunogenic at all dose levels.[medical citation needed]

Nasal vaccine[edit]

On 5 November 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.[54] 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.[55] As of November 2014, further development by the team appeared unlikely due to lack of funding.[54][56]

Vaxart tablet[edit]

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 I trial.[57]

Novel recombinant adenovirus type-5 vector-based Ebola vaccine[edit]

In late 2014 and early 2015, a double-blind, randomized Phase I 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.[18]

Attenuated Ebola Virus vaccine[edit]

A study published in Science during March 2015, demonstrated 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.[58] The new vaccine relies on a strain of Ebola called EBOVΔVP30, which is unable to replicate.[24]

GamEvac-Combi[edit]

A study published in Human Vaccines & 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.[59]

Ad5-EBOV[edit]

In 2017, the China Food and Drug Administration (CFDA) announced approval of 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.[60] It contains a human adenovirus serotype 5 vector (Ad5) with the glycoprotein gene from ZEBOV.[61] Their findings were consistent with previous tests on rVSV-ZEBOV in Africa and Europe.[62]

Clinical trials in West Africa[edit]

In January 2015, Marie-Paule Kieny, the World Health Organization's (WHO) 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.[63] 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,[32][44] and in Guinea in March 2016.[35]

In addition, a medical anthropologist at Université de Montréal, had 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.[30]

The Russian Foreign Ministry announced in 2016, the intention to conduct field trials of two Russian vaccines involving 2000 people.[64] 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 were slated to continue until 2018.[64][65] As of October 2019, Russia was reportedly ready to ship an Ebola vaccine to Africa following registration of the vaccine.[66]

U.S. national stockpile[edit]

In 2014, Credit Suisse estimated that the U.S. government will provide over $1 billion in contracts to companies to develop medicine and vaccines for Ebola virus disease.[67] Congress passed a law in 2004, that funds a national stockpile of vaccines and medicine for possible outbreaks of disease.[67] A number of companies were expected to develop Ebola vaccines: GlaxoSmithKline, NewLink Genetics, Johnson & Johnson and Bavarian Nordic.[67] Another company, Emergent BioSolutions, was a contestant for manufacturing new doses of ZMapp,[citation needed] a drug for Ebola virus disease treatment originally developed by Mapp Biopharmaceutical.[68] Supplies of ZMapp ran out in August 2014.[69] In September 2014, the Biomedical Advanced Research and Development Authority (BARDA) entered into a multimillion dollar contract with Mapp Biopharmaceutical to accelerate the development of ZMapp.[70] Additional contracts were signed in 2017.[71]

See also[edit]

References[edit]

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Further reading[edit]