Treatment and vaccines for Ebola virus disease
Treatment and vaccines for Ebola virus disease under development
In the absence of a licensed vaccine to protect against Ebola virus disease (EVD) or a specific drug for treatment of infected patients in the large Ebola virus outbreak that started in December 2013 in Guinea, and subsequently spread to Liberia and Sierra Leone, potential new Ebola vaccines and therapies were reviewed by the World Health Organization (WHO). International funding for clinical trials of promising candidates were identified and studies assessing immunogenicity, efficacy and safety of vaccine candidates and efficacy and safety of antiviral candidate drugs, candidate monoclonal antibodies and convalescent whole blood or plasma from EVD survivors were started.
Promising results of several clinical trials have been reported in the scientific literature, but no vaccine, antiviral drug or monoclonal antibody has been authorised so far in Africa, the European Union (EU) or the United States (US) for the prevention or treatment of EVD. However, studies are continuing and WHO has stockpiled investigational vaccines for compassionate use in new Ebola virus outbreaks.
Ebola vaccine candidates are currently being evaluated in phase I–III clinical trials conducted in Africa, the EU and the US. Although preclinical development of candidate vaccines utilise different platforms, including inactivated viral particles, DNA vaccines, recombinant viral vectors, recombinant proteins, subunit proteins and virus-like particles, the most advanced vaccine candidates are based on viral vectors engineered to serve as antigen delivery platforms that encode the full length of the surface glycoprotein of the Ebola virus .
Examples of viral vectors expressing ebolavirus glycoproteins include recombinant human adenovirus (Ad26), recombinant simian adenovirus (chimpanzee Ad3), recombinant vaccinia virus (MVA) and a live vesicular stomatitis virus (rVSV) used alone or in prime-booster regimens .
The genus Ebolavirus, a member of the family of Filoviridae, is comprised of five distinct species: Bundibugyo (BDBV), Ebola virus (EBOV) (formerly designated as Zaire ebolavirus, ZEBOV), Reston (RESTV), Sudan (SUDV) and Taï Forest (TAFV). The EBOV and SUDV species are the predominant causes of most EVD outbreaks [2, 3]. Glycoproteins from the different filoviruses show a high degree of diversity at the nucleotide and amino acid levels (60-65% conservation), implying that vaccines for protection against different filovirus infections would have to express and induce an immune response to several glycoproteins and would optimally be multivalent encoding glycoproteins from different viral species into one vaccine regimen. Single dose or prime-boost regimens are being explored in ongoing clinical trials.
Data from the first human clinical trials are starting to become available for the following three candidate vaccine regimens:
- the rVSV-ZEBOV vaccine candidate (V920) administered in a single dose (Merck)
- the Ad26-ZEBOV/MVA-BN-Filo vaccine candidates administered in a prime-boost regimen (Janssen Vaccines & Prevention B.V. in collaboration with Bavarian Nordic GmbH); and
- the ChAd3-EBO-Z vaccine candidate administered either in a single dose (GlaxoSmithKline) or in combination with a booster dose with the MVA-BN-Filo vaccine candidate (Bavarian Nordic GmbH).
The rVSV-ZEBOV vaccine candidate is based on a recombinant replication-competent vesicular stomatitis virus (rVSV) expressing the surface glycoprotein of ZEBOV as mentioned above. This candidate was shown to be safe and highly protective against Ebola when tested in adults > 18 years of age participating in a phase III clinical trial in Guinea during the large West African outbreak that mainly occurred in 2014 to 2016 . In a planned interim analysis, it was shown that when vaccinating close contacts of Ebola virus-infected cases using cluster-randomised ring vaccination strategy around infected cases, none of the 5 837 volunteers who took part became infected with the virus. In short, 90 clusters were included in a planned interim analysis: 48 were randomly assigned to immediate vaccination with rVSV-ZEBOV and 42 were randomly assigned to delayed vaccination on day 21 from onset of disease in index case. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, while in the delayed vaccination group, there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036).
Following the interim analysis mentioned above, the study data safety monitoring board (DSMB) advised that the trial should be continued to expand evidence on vaccine effectiveness and safety, but that randomisation should be stopped and immediate vaccination should be the choice for new clusters and also include vaccination of children aged 6–17 years old, although no studies in this age group had been undertaken . More recently, long-term immune responses in vaccinated individuals have been shown .
In 2018, investigational rVSV-ZEBOV vaccines maintained in the WHO stockpile have been offered to high-risk populations (contacts of infected individuals 6 years of age and older and healthcare/front-line workers) in affected geographical regions in Democratic Republic of the Congo where an outbreak has occurred . The reason for not offering the vaccine to children under 6 years of age, as well as pregnant and lactating women, is that no clinical trials to assess safety in these populations have been conducted. However, experience from the vaccination trial in Guinea shows that some indirect protection is provided to unvaccinated individuals when employing ring vaccination strategy .
The Ad26-ZEBOV/MVA-BN-Filo prime-boost vaccine candidate regimen containing the viral vector human adenovirus type 26 expressing the ZEBOV glycoprotein (Ad26-ZEBOV) in the priming dose and in the booster dose a recombinant vaccinia virus expressing glycoproteins from a combination of ZEBOV, SUDV, Marburg virus and a nucleoprotein from TAFV Ebola species (MVA-BN-Filo) has been shown to produce sustained immune responses up to one year post vaccination [7-8]. Further, immunogenicity of the ChAd3-EBO-Z Ebola virus vaccine candidate containing the simian adenovirus type 3 expressing Zaire EBOV alone or in combination with the MVA-BN Filo candidate as a booster is also under evaluation [9–11]. Whether the prime-boost regimen induces stronger and more durable immune responses than a single dose of ChAd3 or rVSV vectors express the glycoprotein and dose interval for optimal response will need to be assessed long-term.
Researchers continue to study the immunogenicity and safety of these vaccines in populations not included in the initial trial such as children <6 years of age and individuals infected with HIV [12–14].
Preparations for licensure of the first Ebola vaccines in Africa, the EU and the United States are under way , but the route for approval may vary by regulatory agency.
Two Ebola vaccines have been authorised outside the EU and the United States: in China (Ad5-EBOV vaccine produced by CanSinoBio and authorised in China in 2017) and Russia (GamEvac-Combi, a heterologous VSV- and Ad5-vectored prime-boost Ebola vaccine expressing the same Ebolavirus glycoprotein in the two vectors produced by Gamaleya Federal Research Center of Epidemiology and Microbiology and authorised in Russia in 2017). To date, limited information about immunogenicity and safety of these two vaccines in humans is available in scientific literature [15, 16].
Experimental antiviral therapies include ZMapp, a monoclonal antibody medication composed of three chimeric monoclonal antibodies that target the EBOV glycoprotein (Mapp Biopharmaceutical), and two antiviral drugs, favipiravir and remdesivir (GS-5734), which were given to varying but smaller numbers of patients (<100) during the 2014 to 2016 epidemic in West Africa [17–19] and collected data are not sufficient for authorisation. Although these therapies may be available in experimental settings, further clinical trials to assess their efficacy and safety are needed before any of these therapies can be licensed and available for general treatment of infected patients [1, 20].
Blood transfusions from survivors were also explored in the 2014 to 2016 outbreak in West Africa as possible treatment of infected individuals and WHO interim guidelines were developed [21–24]. The use of whole blood or plasma from EVD survivors does not require an authorisation from a regulatory agency and is rather the responsibility of national competent authorities for blood and blood components.
- Espeland EM, Tsai C-W, Larsen J, Disbrow GL. Safeguarding against Ebola: Vaccines and therapeutics to be stockpiled for future outbreaks. PLoS Negl Trop Dis. 2018 Apr 5;12(4): e0006275
- Sanchez A, Trappier SG, Mahy BW, Peters CJ, Nichol ST. The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3602-7.
- Sanchez A, Ksiazek TG, Rollin PE, Miranda ME, Trappier SG, Khan AS, et al. Detection and molecular characterization of Ebola viruses causing disease in human and nonhuman primates. J Infect Dis. 1999 Feb;179 Suppl 1:S164-9.
- Henao-Restrepo AM, Camacho A, Longini IM, Watson CH, Edmunds WJ, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open label, cluster-randomised trial (Ebola Ça Suffit!). Lancet. 2017 Feb 4;389(10068)505-518.
- Huttner A, Agnandji ST, Combescure C, Fernandes JF, Bache EB, Kabwende L, et al. Determinants of antibody persistence across doses and continents after single-dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study. Lancet Infect Dis. 2018 Jul;18(7): 738-748.
- World Health Organization. Frequently asked questions on compassionate use of investigational vaccine for the Ebola virus disease outbreak in Democratic Republic of the Congo [Internet]. Geneva: WHO; 2018 [accessed 3 Aug 2018]. Available from: http://www.who.int/ebola/drc-2018/faq-vaccine.
- Milligan ID, Gibani MM, Sewell R, Clutterbuck EA, Campbell D, Plested E, et al. Safety and Immunogenicity of Novel Adenovirus Type 26– and Modified Vaccinia Ankara–Vectored Ebola Vaccines A Randomized Clinical Trial. JAMA. 2016 Apr 19;315(15): 1610–1623.
- Winslow RL, Milligan ID, Voysey M, Luhn K, Shukarev G, Douoguih M, Snape MD. Immune Responses to Novel Adenovirus Type 26 and Modified Vaccinia Virus Ankara–Vectored Ebola Vaccines at 1 Year. JAMA. 2017 Mar 14;317(10): 1075–1077.
- De Santis O, Audran R, Pothin E, Warpelin-Decrausaz L, Vallotton L, Wuerzner G, et al. 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. Lancet Infect Dis. 2016 Mar;16(3):311-20.
- Tapia MD, Sow SO, Lyke KE, Haidara FC, Diallo F, Doumbia M, et al. Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2016 Jan;16(1):31-42.
- Kennedy SB, Bolay F, Kieh M et al PREVAIL I Study Group. Phase 2 Placebo-Controlled Trial of Two Vaccines to Prevent Ebola in Liberia. N Engl J Med. 2017 Oct 12;377(15):1438-1447.
- ClinicalTrials.gov. African-Canadian Study of HIV-Infected Adults and a Vaccine for Ebola - ACHIV-Ebola [Internet]. Bethesda: U.S. National Library of Medicine; 2018 [accessed 3 August 2018]. Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT03031912.
- ClinicalTrials.gov. Safety, Tolerability and Immunogenicity Study of 3 Prime-boost Regimens for Ebola Vaccines Ad26.ZEBOV/MVA-BN-Filo in Healthy Adults, Children and Human Immunodeficiency Virus Positive (HIV+) Adults [Internet]. Bethesda: U.S. National Library of Medicine; 2018 [accessed 3 August 2018]. Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT02564523.
- ClinicalTrials.gov. A Study to Evaluate the Safety and Immunogenicity of a Candidate Ebola Vaccine in Children [Internet]. Bethesda: U.S. National Library of Medicine; 2018 [accessed 3 August 2018]. Available from: https://www.clinicaltrials.gov/ct2/show/study/NCT02548078.
- Wu L, Zhang Z, Gao H, Li Y, Hou L, Yao H et al. Open-label phase I clinical trial of Ad5-EBOV in Africans in China. Hum Vaccin Immunother. 2017 Sep 2;13(9):2078-2085.
- Dolzhikova IV, Zubkova OV, Tukhvatulin AI, Dzharullaeva AS, Tukhvatulina NM, Shcheblyakov DV, et al. Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia. Hum Vaccin Immunother. 2017 Mar 4;13(3):613–620.
- Davey RT Jr, Dodd L, Proschan MA , Neaton J, Neuhaus Nordwall J, Koopmeiners JS, et al. A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med. 2016 Oct 13;375(15):1448-1456.
- Carazo Perez S, Folkesson E, Anglaret X, Beavogui AH, Berbain E, Camara AM, et al. Challenges in preparing and implementing a clinical trial at field level in an Ebola emergency: A case study in Guinea, West Africa. PLoS Negl Trop Dis. 2017 Jun 22;11(6):e0005545.
- Dörnemann J, Burzio C, Ronsse A, Sprecher A, De Clerck H, Van Herp M, et al. First Newborn Baby to Receive Experimental Therapies Survives Ebola Virus Disease. J Infect Dis. 2017 Jan 15;215(2):171-174.
- World Health Organization. R&D Blueprint Ebola | Additional documents [Internet]. Geneva: WHO; 2016 [accessed 3 August 2018]. Available from: http://www.who.int/blueprint/priority-diseases/key-action/ebola-additional-documents.
- World Health Organization. Use of Convalescent Whole Blood or Plasma Collected from Patients Recovered from Ebola Virus Disease for Transfusion, as an Empirical Treatment during Outbreaks. Interim Guidance for National Health Authorities and Blood Transfusion Services. Version 1.0 [Internet, PDF]. Geneva: WHO; 2014 [accessed 3 Aug 2018]. Available from: http://apps.who.int/iris/bitstream/handle/10665/135591/WHO_HIS_SDS_2014.8_eng.pdf.
- van Griensven J, Edwards T, Baize S; Ebola-Tx Consortium. Efficacy of Convalescent Plasma in Relation to Dose of Ebola Virus Antibodies. N Engl J Med 2016 Dec 8;375(23):2307–9.
- van Griensven J, Edwards T, de Lamballerie X, Semple MG, Gallian P, Baize S, et al. Ebola-Tx Consortium. Evaluation of Convalescent Plasma for Ebola Virus Disease in Guinea. N Engl J Med. 2016 Jan 7;374(1):33–42.
- Brown JF, Dye JM, Tozay S, Jeh-Mulbah G, Wohl DA, Fischer WA 2nd, et al. Anti–Ebola Virus Antibody Levels in Convalescent Plasma and Viral Load After Plasma Infusion in Patients With Ebola Virus Disease. J Infect Dis. 2018 Jul 13;218(4): 555–562.