rVSV-ZEBOV vaccine

Recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV), also known as Ebola Zaire vaccine live and sold under the brand name Ervebo, is an Ebola vaccine for adults that prevents Ebola caused by the Zaire ebolavirus.[4][5][6][7] When used in ring vaccination, rVSV-ZEBOV has shown a high level of protection.[8][9][10] Around half the people given the vaccine have mild to moderate adverse effects that include headache, fatigue, and muscle pain.[8]

rVSV-ZEBOV is a recombinant, replication-competent viral vector vaccine.[11] It consists of rice-derived recombinant human serum albumin and live attenuated recombinant vesicular stomatitis virus (VSV), which has been genetically engineered to express the main glycoprotein from the Zaire ebolavirus so as to provoke a neutralizing immune response to the Ebola virus.[4][12]

The vaccine was approved for medical use in the European Union and the United States in 2019.[5][13][12][14] It was created by scientists at the National Microbiology Laboratory in Winnipeg, Manitoba, Canada, which is part of the Public Health Agency of Canada (PHAC).[15][16] PHAC licensed it to a small company, Newlink Genetics, which started developing the vaccine; Newlink in turn licensed it to Merck in 2014.[17] It was used in the DR Congo in a 2018 outbreak in Équateur province,[18] and has since been used extensively in the 2018–20 Kivu Ebola outbreak, with over 90,000 people vaccinated.[10]

Medical use[edit]

Nearly 800 people were ring vaccinated on an emergency basis with VSV-EBOV when another Ebola outbreak occurred in Guinea in March 2016.[19] In 2017, in the face of a new outbreak of Ebola in the Democratic Republic of the Congo, the Ministry of Health approved the vaccine's emergency use,[20][21] but it was not immediately deployed.[22]

Effectiveness[edit]

In April 2019, following a large-scale ring-vaccination scheme in the DRC outbreak, the WHO published the preliminary results of its research, in association with the DRC's Institut National pour la Recherche Biomedicale, into the effectiveness of the ring vaccination program, stating that the rVSV-ZEBOV-GP vaccine had been 97.5% effective at stopping Ebola transmission, relative to no vaccination.[9][10]

Side effects[edit]

Systemic side effects include headache, feverishness, fatigue, joint and muscle pain, nausea, arthritis, rash, and abnormal sweating.[8][23][24][4] Injection-site side events include injection-site pain, swelling, and redness.[4]

Biochemistry[edit]

rVSV-ZEBOV is a live, attenuated recombinant vesicular stomatitis virus (VSV) in which the gene for the native envelope glycoprotein (P03522) is replaced with that from the Ebola virus (P87666), Kikwit 1995 Zaire strain.[23][25][26] Manufacturing of the vaccine for the Phase I trial was done by IDT Biologika.[27][28] Manufacturing of vaccine for the Phase III trial was done by Merck, using the Vero cell line, which Merck already used to make its RotaTeq vaccine against rotavirus.[29][30]

History[edit]

Area where the West African Ebola virus started and affected nearby countries, in the end causing more than 28,000 cases with about 45% of the total number ending in fatality

Scientists working for the Public Health Agency of Canada (PHAC) created the vaccine, and PHAC applied for a patent in 2003.[15][16][31] From 2005, to 2009, three animal trials on the virus were published, all of them funded by the Canadian and U.S. governments.[28] In 2005, a single intramuscular injection of the EBOV or MARV vaccine was found to induce completely protective immune responses in nonhuman primates (crab-eating macaques) against corresponding infections with the otherwise typically lethal EBOV or MARV.[32][16]

In 2010, PHAC licensed the intellectual property on the vaccine to a small U.S. company called Bioprotection Systems, which was a subsidiary of Newlink Genetics, for US $205,000 and "low single-digit percentage" royalties.[33] Newlink had funding from the U.S. Defense Threat Reduction Agency to develop vaccines.[15][34][35]

In December 2013, the largest-ever Ebola epidemic started in West Africa, specifically, in Guinea.[36] On August 12, the WHO ruled that offering people infected with Ebola the RVSV-ZEBOV vaccine (which at the time was untested on humans) was ethical, and the Canadian government donated 500 doses of the vaccine to the WHO.[37][38] In October 2014, Newlink had no vaccine in production and no human trials underway, and there were calls for the Canadian government to cancel the contract.[33] In September or October 2014, Newlink formed a steering committee among the interested parties, including PHAC, the NIH, and the WHO, to plan the clinical development of the vaccine.[39][40]

In October 2014, Newlink Genetics began a Phase I clinical trial of rVSV-ZEBOV on healthy human subjects to evaluate the immune response, identify any side effects and determine the appropriate dosage.[34][41][42] Phase I trials took place in Gabon, Kenya, Germany, Switzerland, the US, and Canada.[43][44] In November 2014, Newlink exclusively licensed rights to the vaccine to Merck [17] for US $50 million plus royalties.[45]

The Phase I study started with a high dose which caused arthritis and skin reactions in some people, and the vaccine was found replicating in the synovial fluid of the joints of the affected people; the clinical trial was halted because of that, then recommenced with a lower dose.[46]

In March 2015, a Phase II clinical trial and a Phase III started in Guinea at the same time; the Phase II trial focused on frontline health workers, while the Phase III trial was a ring vaccination in which close contacts of people who had contracted Ebola virus were vaccinated with VSV-EBOV.[47][48]

In January 2016, the GAVI Alliance signed an agreement with Merck under which Merck agreed to provide VSV-EBOV vaccine for future outbreaks of Ebola and GAVI paid Merck US$5 million; Merck will use the funds to complete clinical trials and obtain regulatory approval. As of that date, Merck had submitted an application to the World Health Organization (WHO) through their Emergency Use Assessment and Listing (EUAL) program to allow for use of the vaccine in the case of another epidemic.[49] It was used on an emergency basis in Guinea in March 2016.[19]

Results of the Phase III Guinea trial were published in December 2016. It was widely reported in the media that vaccine was safe and appeared to be nearly 100% effective,[50][51] but the vaccine remained unavailable for commercial use as of December 2016.[52]

In April 2017, scientists from the U.S. National Academy of Medicine (NAM) published a review of the response to the Ebola outbreak that included a discussion of how clinical trial candidates were selected, how trials were designed and conducted, and reviewed the data resulting from the trials. The committee found that data from the Phase III Guinea trial were difficult to interpret for several reasons. The trial had no placebo arm; it was omitted for ethical reasons and everyone involved, including the committee, agreed with the decision. This left only a delayed treatment group to serve as a control, but this group was eliminated after an interim analysis showed high levels of protection, which left the trial even more underpowered. The committee found that under an intention-to-treat analysis, the rVSV-ZEBOV vaccine might have had no efficacy, agreed with the authors of the December 2016 report that it probably had some efficacy, but found statements that it had substantial or 100% efficacy to be unsupportable.[50]

In April 2019, following a large-scale ring-vaccination scheme in the DRC outbreak, preliminary results showed that the vaccine had been 97.5% effective at stopping Ebola transmission, relative to no vaccination.[9][10]

In September 2019, the U.S. Food and Drug Administration (FDA) accepted Merck's Biologics License Application and granted priority review for the vaccine.[53]

In October 2019, the European Medicines Agency (EMA) recommended granting conditional marketing authorization for the rVSV-ZEBOV-GP vaccine.[54][55][56]

In November 2019, the European Commission granted a conditional marketing authorization to Ervebo[5][57] and the World Health Organization (WHO) prequalified an Ebola vaccine for the first time, indicating that the vaccine met WHO standards for quality, safety and efficacy, and allowing UN agencies and GAVI to procure vaccine for distributions.[58]

In December 2019, Ervebo was approved for use in the United States.[13]

The approval of Ervebo was supported by a study conducted in Guinea during the 2014-2016 outbreak in individuals 18 years of age and older.[13] The study was a randomized cluster (ring) vaccination study in which 3,537 contacts, and contacts of contacts, of individuals with laboratory-confirmed Ebola virus disease (EVD) received either "immediate" or 21-day "delayed" vaccination with Ervebo.[13] This noteworthy design was intended to capture a social network of individuals and locations that might include dwellings or workplaces where a patient spent time while symptomatic, or the households of individuals who had contact with the patient during that person's illness or death.[13] In a comparison of cases of EVD among 2,108 individuals in the "immediate" vaccination arm and 1,429 individuals in the "delayed" vaccination arm, Ervebo was determined to be 100% effective in preventing Ebola cases with symptom onset greater than ten days after vaccination.[13] No cases of EVD with symptom onset greater than ten days after vaccination were observed in the "immediate" cluster group, compared with ten cases of EVD in the 21-day "delayed" cluster group.[13]

In additional studies, antibody responses to Ervebo were assessed in 477 individuals in Liberia, approximately 500 individuals in Sierra Leone and approximately 900 individuals in Canada, Spain and the U.S.[13] The antibody responses among those in the study conducted in Canada, Spain and the U.S. were similar to those among individuals in the studies conducted in Liberia and Sierra Leone.[13]

The safety of Ervebo was assessed in approximately 15,000 individuals in Africa, Europe and North America.[13] The most commonly reported side effects were pain, swelling and redness at the injection site, as well as headache, fever, joint and muscle aches and fatigue.[13]

The application for Ervebo in the United States was granted priority review, a tropical disease priority review voucher, and breakthrough therapy designation. The U.S. Food and Drug Administration (FDA) granted approval for Ervebo to Merck & Co., Inc.[13]

Merck discontinued development of the related rVSV vaccines for Marburg virus (rVSV-MARV) and Sudan ebolavirus (rVSV-SUDV). Merck returned the rights on these vaccines back to Public Health Agency of Canada. The knowledge on developing rVSV vaccines which Merck gained with GAVI funding remains Merck's, and cannot be used by anyone else wishing to develop a rVSV vaccine.[59]

Ebola 2018[edit]

2018 Kivu Ebola outbreak: Number of rVSV-ZEBOV vaccinated persons in the epidemic area DRC[60]

2018 Democratic Republic of the Congo Ebola virus outbreak[edit]

During an outbreak in the Democratic Republic of the Congo in 2018, the ZEBOV vaccine was used,[61] and what was once contact tracing which numbered 1,706 individuals (ring vaccination which totaled 3,330) was reduced to zero on June 28, 2018.[62] The outbreak completed the required 42-day cycle on July 24.[63][64][65][66][67]

2018 Kivu Ebola outbreak[edit]

On August 1, 2018, an EVD outbreak was declared in North Kivu DRC. After six months the current totals stand at 735 total cases and 371 deaths; violence in the region has helped the spread of the virus.[68][69][70]

Preliminary results show ring vaccination with the vaccine has been highly effective at reducing Ebola transmission.[9][10]

References[edit]

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a b Choi MJ, Cossaboom CM, Whitesell AN, Dyal JW, Joyce A, Morgan RL, et al. (January 2021). "Use of Ebola Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020" (PDF). MMWR Recommendations and Reports. 70 (1): 1–12. doi:10.15585/mmwr.rr7001a1. PMC 7802368. PMID 33417593. This article incorporates text from this source, which is in the public domain.
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a b c Grady, Denise (October 23, 2014). "Ebola Vaccine, Ready for Test, Sat on the Shelf". The New York Times. Retrieved December 21, 2019.
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a b "Merck & Co. Licenses NewLink's Ebola Vaccine Candidate". Genetic Engineering & Biotechnology News. November 24, 2014. Archived from the original on May 18, 2018. Retrieved January 20, 2016.
^ McKenzie, David (May 26, 2018). "Fear and failure: How Ebola sparked a global health revolution". CNN. Retrieved May 26, 2018.
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a b "WHO coordinating vaccination of contacts to contain Ebola flare-up in Guinea". World Health Organization (WHO). March 2016. Retrieved May 14, 2016.
^ "Congo approves use of Ebola vaccination to fight outbreak". Reuters. May 29, 2017. Retrieved May 29, 2017.
^ Maxmen, Amy (2017). "Ebola vaccine approved for use in ongoing outbreak". Nature. doi:10.1038/nature.2017.22024.
^ World Health Organization, Regional Office for Africa, Health Emergencies Programme (June 2017). Ebola Virus Disease Democratic Republic of the Congo: External Situation Report 22 (Report). World Health Organization (WHO) Regional Office for Africa. hdl:10665/255645.
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^ Choi WY (January 2015). "Progress of vaccine and drug development for Ebola preparedness". Clin Exp Vaccine Res. 4 (1): 11–16. doi:10.7774/cevr.2015.4.1.11. PMC 4313103. PMID 25648233.
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^ Hôpitaux Universitaires de Genève FAQs about the context of this clinical trial: Question 22
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a b The strange tale of Canada's ebola vaccine: Walkom. Commercial rights to a vaccine worth $50 million were sold to a U.S. middleman for $205,000. By Thomas Walkom, The Star, November 25, 2014
^ Carly Helfand for FierceVaccine. November 21, 2014 NewLink, Merck sign Ebola vaccine licensing pact
^ Zachary Brennan for BioPharma Reporter. November 25, 2014. Merck to manufacture NewLink Ebola vaccine in-house
^ Published PCT Application WO2004011488: Recombinant vesicular stomatitis virus vaccines for viral hemorrhagic fevers, claiming priority to US provisional patent application serial number 60/398,552 filed on July 26, 2003.
^ Sylvain Baize (2005). "A single shot against Ebola and Marburg virus". Nature Medicine. 11 (7): 720–21. doi:10.1038/nm0705-720. PMID 16015361. S2CID 34226536.
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a b Branswell, Helen (October 20, 2014). "Canada urged to cancel Ebola vaccine licence, transfer rights to bigger company". CTVNews.
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a b "Ebola outbreak: 1st human trials of Canadian vaccine start in U.S." CBC News. Associated Press. October 13, 2014.
^ "Sole Redacted License Agreement for Recombinant Vesicular Stomatitis Virus Vaccines for Viral Hemorrhagic Fevers". Public Health Agency of Canada. October 6, 2014.
^ Origins of the 2014 Ebola epidemic (Report). World Health Organization (WHO). January 2015. Archived from the original on January 20, 2015. Retrieved October 8, 2016.
^ "Exclusive: Canada to donate its own Ebola vaccine to WHO for use in Africa". Reuters. August 12, 2014.
^ Public Health Agency of Canada (August 2, 2013). "Fact Sheet - VSV-EBOV - Canada's vaccine for Ebola".
^ Patricia Van Arnum for DCAT. October 21, 2014 Pharmaceutical companies join the effort to develop and produce vaccines and treatments for the Ebola virus Archived February 4, 2016, at the Wayback Machine
^ Branswell, Helen (October 8, 2014). "Canadian Ebola vaccine safety trials move ahead, NewLink Genetics says". CBC News. Retrieved October 21, 2014.
^ Branswell, Helen (October 8, 2014). "Canadian Ebola vaccine license holder moving ahead with safety trials". Canadian Press. Archived from the original on October 12, 2014. Retrieved October 13, 2014.
^ "A Phase 1 Randomized, Double-Blind, Placebo Controlled, Dose-Escalation Study to Evaluate the Safety and Immunogenicity of Prime-Boost VSV Ebola Vaccine in Healthy Adults". National Institute of Allergy and Infectious Diseases (NIAID). October 9, 2014. Archived from the original on October 17, 2014. Retrieved October 13, 2014.
^ Hôpitaux Universitaires de Genève FAQs about the context of this clinical trial: Question 10
^ Table of vaccine clinical trials. World Health Organization (WHO) (Report). Archived from the original on October 22, 2015. Retrieved October 14, 2016.
^ "Canadian Ebola vaccine development taken over by Merck". Reuters. November 24, 2014.
^ Medaglini, D; Harandi, AM; Ottenhoff, TH; Siegrist, CA; VSV-Ebovac, Consortium. (December 9, 2015). "Ebola vaccine R&D: Filling the knowledge gaps". Science Translational Medicine. 7 (317): 317ps24. doi:10.1126/scitranslmed.aad3106. PMC 6858855. PMID 26659569.
^ "Q&A on trial of Ebola Virus Disease vaccine in Guinea". World Health Organization (WHO). July 17, 2015. Archived from the original on November 15, 2019. Retrieved November 14, 2019.
^ James Gallagher (July 31, 2015). "Ebola vaccine is 'potential game-changer'". BBC News Online. UK. Retrieved July 30, 2015.
^ Hirshler, Ben; Kelland, Kate (January 20, 2016). "Vaccines alliance signs $5 million advance deal for Merck's Ebola shot". Reuters. Retrieved January 20, 2016.
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a b Er, Busta; M, Mancher; Pa, Cuff; K, McAdam; G, Keusch (2017). Keusch, Gerald; McAdam, Keith; Cuff, Patricia; Mancher, Michelle; Busta, Emily R (eds.). Integrating Clinical Research Into Epidemic Response: The Ebola Experience. doi:10.17226/24739. ISBN 978-0-309-45776-7. PMID 28696651.
^ Geisbert, TW (December 22, 2016). "First Ebola virus vaccine to protect human beings?". Lancet. 389 (10068): 479–480. doi:10.1016/S0140-6736(16)32618-6. PMID 28017402.
^ Lisa Schnirring (December 27, 2016). "Ebola vaccine highly effective in final trial results". CIDRAP. Retrieved December 28, 2016.
^ "FDA Accepts Merck's Biologics License Application (BLA) and Grants Priority Review for V920, the Company's Investigational Vaccine for Ebola Zaire Virus" (Press release). September 17, 2019. Retrieved September 17, 2019 – via Business Wire.
^ "Major milestone for WHO-supported Ebola vaccine". World Health Organization (WHO) (Press release). October 18, 2019. Archived from the original on November 11, 2019. Retrieved October 19, 2019.
^ "First vaccine to protect against Ebola". European Medicines Agency (EMA) (Press release). October 18, 2019. Archived from the original on November 11, 2019. Retrieved November 11, 2019.
^ "Ervebo". European Medicines Agency (EMA). October 17, 2019. Archived from the original on November 15, 2019. Retrieved November 15, 2019.
^ "Merck's Ervebo [Ebola Zaire Vaccine (rVSVΔG-ZEBOV-GP) live] Granted Conditional Approval in the European Union" (Press release). Merck. November 11, 2019. Archived from the original on November 11, 2019. Retrieved November 11, 2019 – via Business Wire.
^ "WHO prequalifies Ebola vaccine, paving the way for its use in high-risk countries". World Health Organization (WHO) (Press release). November 12, 2019. Archived from the original on November 15, 2019. Retrieved November 13, 2019.
^ "MSF's response to CEPI's policy regarding equitable access". Médecins Sans Frontières Access Campaign. September 25, 2018. In vaccine development, access to know how is important. Knowledge and expertise including but not limited to purification techniques, cell lines, materials, software codes and their transfer of this to alternative manufacturers in the event the awardee discontinues development of a promising vaccine is critically important. The recent example of Merck abandoning the development of rVSV vaccines for Marburg (rVSV-MARV) and for Sudan-Ebola (rVSV-SUDV) is a case in point. Merck continues to retain vital know-how on the rVSV platform as it developed the rVSV vaccine for Zaire-Ebola (rVSV-ZEBOV) with funding support from GAVI. While it has transferred the rights on these vaccines back to Public Health Agency of Canada, there is no mechanism to share know how on the rVSV platform with other vaccine developers who would like to also use rVSV as a vector against other pathogens.
^ "Ebola RDC – Evolution de la riposte contre l'épidémie d'Ebola dans les provinces du Nord Kivu et de l'Ituri au Lundi 31 décembre 2018". us13.campaign-archive.com. Retrieved December 31, 2018.
^ Berlinger, Joshua. "Congo to begin vaccinating against Ebola". CNN. Retrieved July 2, 2018.
^ "Ebola RDC – Communication spéciale du Ministre de la Santé concernant l'évolution de la neuvième épidémie d'Ebola en RDC". us13.campaign-archive.com. Retrieved July 2, 2018.
^ "Weekly Bulletin on Outbreak and other Emergencies: Week 26: 23–29 June 2018". Weekly Bulletin on Outbreaks and Other Emergencies: 1–23. World Health Organization, Regional Office for Africa. 2018. hdl:10665/272981.
^ "WHO AFRO Outbreaks and Other Emergencies, Week 26: 23 - 29 June 2018 (Data as reported by 17:00; 29 June 2018) - World". ReliefWeb. June 29, 2018. Retrieved January 30, 2022.
^ Schlein, Lisa (July 17, 2018). "Congo Ebola Outbreak Expected to End Next Week". VOA. Retrieved July 17, 2018.
^ "Media Advisory: Expected end of Ebola outbreak". ReliefWeb. July 23, 2018. Retrieved July 23, 2018.
^ "Ebola outbreak in DRC ends: WHO calls for international efforts to stop other deadly outbreaks in the country". World Health Organization (WHO) (Press release). Retrieved July 24, 2018.
^ "Ebola RDC – Evolution de la riposte contre l'épidémie d'Ebola dans les provinces du Nord Kivu et de l'Ituri au Vendredi 4 janvier 2019". us13.campaign-archive.com (in French). Retrieved January 5, 2019.
^ "Statement on disruptions to the Ebola response in the Democratic Republic of the Congo". World Health Organization (WHO). Retrieved January 5, 2019.
^ Mahamba, Fiston (August 1, 2018). "Congo declares new Ebola outbreak in eastern province". Reuters. Retrieved January 5, 2019.

From discovery to delivery: public sector development of the rVSV-ZEBOV Ebola vaccine

Matthew Herder,1,2 Janice E Graham,3 and Richard Gold4

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Abstract

The discovery and development of the Ebola rVSV-ZEBOV vaccine challenge the common assumption that the research and development for innovative therapeutic products and vaccines is best carried out by the private sector. Using internal government documents obtained through an access to information request, we analyze the development of rVSV-ZEBOV by researchers at Canada’s National Microbiology Laboratory beyond its patenting and licensing to a biotech company in the United States in 2010. According to government documentation, the company failed to make any progress toward a phase 1 clinical trial until after the WHO Public Health Emergency of International Concern freed substantial donor and public funds for the vaccine’s further development. The development of rVSV-ZEBOV, from sponsoring early stage research through to carrying out clinical trials during the epidemic, was instead the result of the combined efforts of the Canadian government, its researchers, and other publicly funded institutions. This case study of rVSV-ZEBOV underscores the significant public contribution to the R&D of vaccines even under conditions of precarity, and suggests that an alternative approach to generating knowledge and developing interventions, such as open science, is required in order to fully realize the public sector’s contribution to improved global health.

Keywords: Ebola vaccine, patents, commercialization, open science

It is an open secret that the public sector has long contributed substantially—in terms of scientific labor, know-how, and direct financing—to the development of many important drugs and vaccines1. These contributions often only come to light after the fact, once a publicly developed drug is priced exorbitantly under the control of a private company2. Acting on the theory that only the private sector can successfully commercialize a drug or vaccine, government laboratories and universities risk achieving the opposite: delays, increased prices, and decreased access.

The academic literature contains a substantial critique of this standard approach to commercialization,3 but concrete examples are needed to motivate policy change. In this analysis, we provide an in-depth examination of the development of a promising experimental Ebola vaccine, rVSV-ZEBOV, showing how the private sector was not only unnecessary to its development, but also likely slowed it down. Using over 1600 pages of internal government records obtained through an access to information request,4 we trace the development of rVSV-ZEBOV between the early 2000s to its licensing to a small US-based biotech company in 20105 through to the 2014–2015 Ebola epidemic in West Africa (see Figure 1) and beyond. We reveal how Canadian government scientists drove the development of rVSV-ZEBOV, from laboratory bench to a commercial grade product for use in clinical trials, while private sector partners failed to substantively advance development in the years leading up to the West African epidemic.

Figure 1

Key milestones and events during the development of rVSV-ZEBOV in the lead up to the 2014–2015 Ebola epidemic.

The analysis shows how the standard approach to commercialization also works to reproduce the status quo. Even as it advanced the rVSV-ZEBOV vaccine, reductions in human and financial resources undercut the government laboratory’s capacity to investigate alternative pathways to development, assess the track record of private sector partners, and enforce certain terms of the patent licensing agreement. Despite resolving scientific, technical, and logistical challenges during the research and development process as well as acquiring expertise about manufacturing clinical grade quality vaccine, the government laboratory transferred the knowledge and vaccine supply that it had amassed to a small company that had never brought a product to market.

We conclude that not only does the dominant account of the private sector’s importance to commercialization ignore the facts behind the rVSV-ZEBOV vaccine development, but that sole reliance on the private sector sets a concrete ceiling on how far public sector science can reach, pre-empting experimentation with new approaches to knowledge production. Rather than explore alternative pathways to developing the vaccine, the public sector largely handed over responsibility for development to a private sector unequal to the task. More than 5 years after rVSV-ZEBOV was first deployed in the West African epidemic and trialed in thousands of Ebola patients, the private sector firm controlling the patent finally obtained approval to market the vaccine from European and United States regulators.6 Instead of celebrating this milestone, our analysis raises the question as to whether rVSV-ZEBOV could have been available earlier if public laboratories had taken a different approach to the vaccine’s development.

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Public Financing, Discovery, and Development of VSV-ZEBOV

As with other neglected diseases, public and philanthropic sectors have been at the forefront of funding Ebola research. Public sources contributed over 73% (USD$758.8 million) of the USD$1.035 billion allocated to Ebola and other filovirus research from 1997 to 20157. Much of this public funding followed from political concerns over bioterrorism in the early 2000s8. For its part, Canada created a special stream of biosecurity funding led by Defence Research and Development Canada, later known as the Canadian Safety and Security Program (CSSP)9.

The beginning of the discovery work on the rVSV-ZEBOV vaccine traces back to 1999 when the National Microbiology Laboratory (NML) in Winnipeg, Manitoba recruited Heinz Feldmann from the University of Marburg to become chief of its special pathogens program. With an exceptional background in hemorrhagic fever virus of the Filoviridae family, within three years Feldmann and his colleagues developed an Ebola vaccine candidate: rVSV-ZEBOV10. NML later became part of the Public Health Agency of Canada (PHAC).

As required under Canadian law applicable to government scientists11, Feldmann and colleagues Steven Jones and Ute Stroher disclosed the invention to the NML. The Canadian government filed a provisional US patent application in July 2002 entitled “Recombinant Vesicular Stomatitis Virus Vaccines for Viral Hemorrhagic Fevers”12. Patent offices in Europe, the United States, and Canada eventually granted the rVSV-ZEBOV patent in 2010, 2011, and 2013, respectively.

The theory behind the standard approach to commercialization holds that patents will facilitate follow-on research and development13. Despite the patent application and a series of publications by Feldmann’s team indicating that the rVSV-ZEBOV vaccine was highly effective in mice and nonhuman primates14, there was initially no commercial interest in the vaccine. In 2005, PHAC entered into a material transfer agreement with the US Army Medical Research Institute of Infectious Disease (USAMRIID); however, the agreement was for non-commercial research only.

To develop the vaccine, NML scientists instead secured funding under the government’s CSSP program in 2006 in pursuit of two objectives. The first was to manufacture 1000–2000 doses of “cGMP grade” vaccine for use in clinical trials. Second, the scientists sought to understand the immune correlates of protection for an Ebola virus infection and develop treatment protocols and assays in order to obtain regulatory approval for rVSV-ZEBOV from Health Canada (HC) and the US Food and Drug Administration (FDA) (see Figure 2). A total of Cdn$5.9 million (including in-kind contributions from NML as well as USAMRIID) was budgeted for the project during 2007–2013, which was later extended to March 2014.15

Figure 2

The two main branches of the NML’s rVSV-ZEBOV project. Notes: (1) This figure was included in the NML’s Project Completion Report, dated March 2014.

Within months of securing the CSSP funding, NML began discussions over a possible patent license agreement with BioProtection Systems Inc. (BPS), a small start-up located in Iowa State University’s research park. While the then Canadian Minister of Health stated in Parliament that there had been an open and transparent call for proposals, there is no evidence of this in the record nor any suggestion that any other company submitted or was asked to submit a proposal.

In December 2007, BPS submitted a development plan to PHAC, claiming that it and its “developmental partners have the capability and capacity to manufacture, to bring drugs to the clinic and to follow the development of a drug through to [regulatory] approval”.16 BPS may have been relying on the capacity of its partner, NewLink Genetics, another Iowa State University spin-off company; however, neither BPS nor NewLink, which acquired BPS in 2011, has ever developed a product through to regulatory approval. Nevertheless, BPS proposed a work plan in which it would carry out additional preclinical vaccine testing, perform safety and toxicology studies, assist with the manufacturing of the vaccine, and conduct clinical trials with rVSV-ZEBOV.17

PHAC forwarded patent license terms to BPS in 2008.18 While normal practice for a request for proposals would have required that the terms of the license be agreed to as part of BPS’s proposal, PHAC continued to negotiate the terms of the license over the next two years. During this time, the NML continued its work on the vaccine. In 2008, the NML oversaw the production of plasmids for the reverse genetics system used to generate rVSV-ZEBOV19 and also arranged for the production of cGMP grade rVSV-ZEBOV through a contract with IDT Biologika, a German contract research organization specializing in vaccine manufacturing.

PHAC and BPS formally concluded a license on May 4, 2010. 20 The agreement provided BPS with a “sole” license to the vaccine but with specific carve-outs protecting PHAC’s ability to use the patent rights for non-commercial, educational, and research purposes and rights to use the invention in the context of a humanitarian emergency in Canada or internationally21. BPS was given the power to sub-license the vaccine without prior approval from the Canadian government, but PHAC’s protections would run with any sub-licensing deal.

In conformity with good licensing practices, BPS agreed to make “reasonable efforts” to commercialize the vaccine and deliver “written reports” on its progress. Further, the license clearly provided that shelving the vaccine would be tantamount to a “fundamental breach” of the contract. While the publicly available version of the license blacked out financial terms, NewLink’s regulatory filings show that BPS had agreed to pay for all patent-related fees and costs, pay milestone payments of approximately Cdn$205,000 per regulatory-approved product, and a royalty as a low single-digit percentage of sales to Canada22. Consistent with standard practices of today,23 the agreement was silent with respect to the pricing of any resulting product.

After signing the agreement, PHAC claimed that BPS “had the corporate capabilities to develop the rVSV-ZEBOV vaccine into a fully regulatory-approved product”24 even though the company had no experience of this stage of vaccine development.

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Transferring VSV-ZEBOV to BPS

During the same period as the negotiations, the NML’s internal capacity to drive rVSV-ZEBOV’s development was diminishing. The scientists that had led the basic and preclinical research on rVSV-ZEBOV, notably Feldmann, Jones, and Stroher, had departed the NML by late 2010. Remaining high profile researchers prioritized other Ebola therapeutic leads25 (24). Further, scientists in the civil service were, under the then government, subject to increasing constraints and resource uncertainties26. Midway through the NML’s rVSV-ZEBOV project, for instance, the flexibility to carry over unused CSSP funds to the next fiscal year disappeared.27 With financial and human resources in flux, the NML contemplated canceling the rVSV-ZEBOV project altogether. Judie Alimonti, employed by the NML on a limited term contract, volunteered to take over as project manager.

During 2010–2014, Alimonti worked through myriad challenges and delays with the NML’s partners. A poorly drafted contract with IDT resulted in a “constant stream of negotiations” over who was responsible for each deliverable.28 Early on, IDT struggled to create the Master Seed Virus Bank, an important preliminary step in the manufacturing process.29 Later, Alimonti expressed growing frustrations with various delays on IDT’s end, especially as the CSSP funding was set to end in March 2013.30 After two failed efforts to generate the “clinical trial material,” IDT finally delivered 1350 doses of the vaccine to the NML in June 2013.31 Canada paid IDT Biologika Cdn$877,422.15 for the vaccine’s production32.

BPS’ contributions during the 4 years leading up to the West African epidemic are less clear. Contrary to the terms of license, BPS failed to deliver a single written report of its commercialization progress during 2010–2014. Other documentation betrays a pattern of delay. Originally, BPS had planned to use a 10 L test batch of the vaccine (produced by IDT) for further pre-clinical testing.33 However, BPS elected to wait for PHAC’s order of IDT cGMP grade vaccine for such testing, ostensibly to be more in line with the FDA’s guidance for Phase 1 trials involving experimental vaccines34.

BPS’ lack of alacrity in running pre-clinical experiments was matched by its lack of diligence in meeting with the FDA. In May 2011, IDT suggested that BPS ask the FDA what types of testing would be needed to support an “Investigational New Drug” (IND) application to conduct a Phase 1 trial. 35 It took, however, another year and half for BPS to arrange a “pre-IND” meeting with the FDA to clarify the regulator’s expectations. 36 In terms of experimental contributions, BPS also failed to advance the file. It had planned in 2011 to proceed with both the vaccine pre-exposure and post-exposure protocols for testing the efficacy of the cGMP grade rVSV-ZEBOV once it was in hand. Yet, by the time IDT had delivered the vaccine to NML in June 2013, BPS bowed out, leaving it to the NML to perform efficacy testing September–October 2013.37 In short, BPS did not complete any of the experimental objectives outlined in its vaccine development plan.

With the CSSP funding coming to an end, the NML prepared a final project report just as the government of Guinea reported tens of Ebola deaths in March 201438. Despite BPS’ meager efforts, the NML’s report was optimistic, emphasizing that there was to be “life after the project.” The NML planned to transfer to BPS not only the immunological assays and accompanying treatment protocols, but also the cGMP vaccine that the NML had secured from IDT. BPS would then finally commence Phase 1 and 2 clinical trials, albeit in partnership with the US National Institutes of Health.

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Epidemics as Epilog

The escalation of the Ebola outbreak over the summer of 2014 interrupted the knowledge transfer from NML to BPS. Instead of sending all of the cGMP vaccine to BPS, the Canadian government donated 800 vials of rVSV-ZEBOV to the WHO for use in West Africa39. Questions began to be raised publicly about the delay in development of a vaccine that had been shown to be 100% effective in animal models as early as 200440. In November 2014, BPS sublicensed the patent rights to rVSV-ZEBOV to Merck, Sharp & Dohme41. Meanwhile, using the IDT Biologika-sourced cGMP grade vaccine, the public sector paid for the first Phase 1 clinical trials, which began in the United States in October 2014 (NCT02269423) and in Geneva, Hamburg, and Kilifi in November 201442. The Canadian Center for Vaccinology also began a Phase 1 trial, funded by the Canadian government, in November 2014 in Halifax (NCT02374385)43.

BPS (now owned by NewLink) received USD$50 million from its sublicense to Merck44 as well as an injection of USD$119,355,036 in funding from US government sources (See Table 1). After assuming de jure control of the rVSV-ZEBOV, Merck earned recognition for its in-kind support of the clinical trials that were run during the 2014–2015 epidemic, most notably, the WHO-led consortium “Ebola Ça Suffit!” Phase 3 trial in Guinea involving 11,841 participants45. It was unclear what Merck did during this period other than provide permission to use the Canadian procured and financed rVSV-ZEBOV clinical grade vaccine. What the record does establish is that it was the public sector, not Merck, that provided all of the financing, including for clinical trials, during the West African epidemic (see Table 2)46 in addition to providing the technical expertise, human resources, and infrastructure that was necessary to carry out the trials.

Table 1

Funding received by BioProtection Systems Inc. 2008–2016 in USD$.

Fiscal Year

Dept. of Health & Human Services

Dept. of Defense

Dept. of Agriculture

Total

Pre- & Post-Epidemic Total

2008

462,742

69,990

532,732

$9,688,115

2009

43,062

630,738

4,947,313

(2008–2013)

535,681

29,995

3,707,837

2010

299,975

119,261

419,236

2011

299,920

3,388,914

100,000

3,788,834

2012

2013

2014

1,000,000

2,885,133

$119,355,036

1,885,871

(2014–2016)

(738)

2015

29,967,985

1,025,080

(10,000)

63,969,873

17,883,564

8,168,814

4,467,990

1,504,482

961,958

2016

24,752,733

2,794,840

52,500,031

2,227,245

534,323

593,685

(15,458)

21,681,676

(69,013)

Total

$103,216,258

$25,736,893

$90,000

$129,043,151

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Notes: (1) Financial figures in the table are derived from https://www.usaspending.gov/; (2) Figures that appear in parentheses () reflect a liability; (3) Multiple figures in a given fiscal year are indicative of separate grants or contracts; (4) One figure (USD$29,967,984 in fiscal year 2015 from the Dept. of Health & Human Services is actually dated Dec. 19, 2014; however, the website lists this contract under fiscal year 2015; and (5) Not all figures are related to Ebola research. For example, the figures listed under Dept. of Health & Human Services for fiscal years 2010 and 2011 are grants for research into yellow fever and adenoviruses. Other figures, especially prior to the 2014–2015 epidemic, may be unrelated to Ebola research as well but this information was not available.

Table 2

Clinical Trials of rVSV-ZEBOV Initiated During West Africa Ebola Epidemic.

Identifier

Sponsor (s)

Collaborator (s)

Phase

Start date

Completion date

#Participants

NCT02269423

Merck Sharp & Dohme Corp.

BioProtection Systems Corporation

Oct. 2014

Aug. 2015

United States Department of Defense

NCT02280408

Merck Sharp & Dohme Corp.

National Institute of Allergy and Infectious Diseases (NIAID)

Oct. 2014

Dec. 2015

BioProtection Systems Corporation

NCT02374385

Dalhousie University

Canadian Institutes of Health Research (CIHR)

Nov. 2014

Jun. 2015

NewLink Genetics Corporation

NCT02283099

Universitätsklinikum Hamburg- Eppendorf

German Center for Infection Research

Nov. 2014

Nov. 2015

Philipps University Marburg Medical Center World Health Organization

Clinical Trial Center North University Hospital, Geneva Albert Schweitzer Hospital

Institute of Tropical Medicine, University of Tuebingen Wellcome Trust

KEMRI-Wellcome Trust Collaborative Research Program

NCT02287480

University Hospital, Geneva

World Health Organization

Nov. 2014

Jan. 2016

115

Wellcome Trust

Universitätsklinikum Hamburg-Eppendorf Philipps University Marburg Medical Center Albert Schweitzer Hospital

Institute of Tropical Medicine, University of Tuebingen KEMRI-Wellcome Trust Collaborative Research Program

NCT02296983

University of Oxford

World Health Organization

Dec. 2014

Sep. 2016

40*

Wellcome Trust

Institute of Tropical Medicine, University of Tuebingen Albert Schweitzer Hospital

Philipps University Marburg Medical Center Universitätsklinikum Hamburg-Eppendorf University Hospital, Geneva

NCT02314923

Merck Sharp & Dohme Corp.

BioProtection Systems Corporation

Dec. 2014

Jun. 2016

512

US Department of Health and Human Services

NCT02344407 “PREVAIL”

National Institute of Allergy and Infectious Diseases (NIAID)

None

Jan. 20, 2015

Jun. 1, 2020*

1500*

PACTR201503001057193

“Ebola ca suffit!”

World Health Organization

Ministry of Health Guinea

Mar. 3, 2015

Jan. 20, 2016

8851

Medecins Sans Frontieres Epicentre

Norwegian Institute of Public Health

Institute of Social and Preventive Medicine and Centre for clinical trials University of Bern

London School of Hygiene and Tropical Medicine University of Florida

Centre for Vaccine Development, Mali/Maryland Public Health England

Public Health Agency of Canada

NewLink/Merck

NCT02378753 “STRIVE”

Centers for Disease Control and

University of Sierra Leone

2/3

Apr. 2015

Dec. 5, 2016

8651

Prevention

Ministry of Health and Sanitation, Sierra Leone

Department of Health and Human Services eHealth Africa

NCT02503202

Merck Sharp & Dohme Corp.

None

Aug. 17, 2015

Sep. 29, 2017*

1198

NCT02933931

University Hospital, Geneva

None

Nov. 2016

Apr. 2020*

100*

NCT02876328

National Institute of Allergy and

The Liberia-US Clinical Trials Partnership Program, Partnership

Mar. 31, 2017

Mar. 2019*

5500*

Infectious Diseases (NIAID)

for Research on Ebola Virus in Liberia Project (PREVAIL)

Institut National de la Santé Et de la Recherche Médicale, France

London School of Hygiene and Tropical Medicine

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Notes: (1) All data in this table are derived from https://clinicaltrials.gov; (2) Entries in bold indicate that a private sector entity was involved, either as a sponsor or collaborator, in a given clinical trial; (3) Despite being named a sponsor in four trials, the publications that have resulted from these trials do not state that Merck, Sharp & Dohme provided financing for those trials; (4) Figures with an asterisk (*) reflect estimated figures at the time of data extraction from clinicaltrials.gov; (5) Although the final trial in the table was initiated in March 2017, after the epidemic had subsided, it is included here because it builds upon a previous trial known as the “PREVAIL” trial (NCT02344407) that was initiated during the epidemic.

Through 2016–2017 multilateral (Gavi, the Vaccine Alliance USD$5 million47) and government (US Department of Health and Human Services, USD$39.2 million48) sources continued to fund Merck’s late stage development of the vaccine. The funding from Gavi reportedly came with an obligation to create stockpile doses of rVSV-ZEBOV and ensure the vaccine was priced affordably in developing countries,49 but the precise terms of the Gavi-Merck agreement are not publicly available.

Merck missed the 2017 target specified in the Gavi agreement for the vaccine’s submission to the FDA50. But by November 2018, when over 42,000 frontline health workers and Ebola contacts had (at that time) been vaccinated through a ring vaccination strategy in the outbreak that was continuing to unfold in the Democratic Republic of the Congo,51 and the data from 12 rVSV-ZEBOV trials now in hand, Merck finally initiated a “rolling submission” to the FDA.52 Importantly, though, according to some sources, Merck’s supply of clinical grade rVSV-ZEBOV has not kept pace with public health needs to address the outbreak in the Congo as the company has thus far not been able to produce the vaccine at its industrial scale facility.53

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The Security to Experiment with New Modes of Knowledge Production

Our analysis of rVSV-ZEBOV illustrates that the conventional wisdom of licensing out patents to the private sector for the purpose of commercialization permeates the furthest corners of public sector science. Even in the global health research context where there is little market incentive to develop a pharmaceutical intervention54, control over a promising and now-approved vaccine is transferred to a company on the strength of the assumption that the company will be better positioned to bring it to market. Yet, the development of rVSV-ZEBOV suggests otherwise: the NML performed the bulk of the experimental work and problem-solved various technical challenges encountered by IDT in the manufacturing process, from quality assurance to characterizing the vaccine’s toxicity, potency, and immunogenicity, and producing cGMP-grade lots of the vaccine. Beyond advising NML scientists about the FDA’s standards, BPS did little to advance rVSV-ZEBOV prior to the 2014–2015 epidemic.

At the same time, the public sector’s invaluable contributions to rVSV-ZEBOV’s development occurred under precarious conditions. The CSSP funding for the project took years to secure only to be later undercut by a change in federal government support for civil servant scientists. The inventors of rVSV-ZEBOV all departed the NML by 2010, leaving Alimonti—herself precariously employed—to run the project with minimal institutional support.

These two aspects of rVSV-ZEBOV’s development are mutually constitutive. Public sector institutions such as the NML struggle to identify private sector partners with the capacity to further the development of promising products. The licensing agreement was struck with BPS, which had no track record of bringing a product to market. And when the partners (BPS and IDT Biologika) failed to perform as promised, the public sector lacked the capacity to enforce the terms of the contract. The NML’s decisions were, in other words, clouded by the conventional logic of commercialization. And, just as that logic inspires licensing patent rights out to the private sector, it renders precarious funding and labor in public sector science while simultaneously obscuring the actual contributions of publicly funded research to therapeutic interventions such as rVSV-ZEBOV. This is how commercialization practice works to entrench the status quo.

To disrupt this pattern, alternative approaches to knowledge production and diffusion, particularly in the context of global health where market interest is often lacking, are needed; so too must the state better support publicly funded institutions and scientists to pursue translational research. That is, rather than assume that the only way to advance vaccines and other products is by patenting and licensing to the private sector, government laboratories, funding agencies, and universities ought to consider a broader range of options.

One option, which is gaining interest, is to create a “public option,” that is, a public sector led supply of essential, affordably priced medicines from discovery all the way through manufacturing and regulatory approval.55 Indeed, the case of rVSV-ZEBOV shows that such a public option is not simply theoretical; rather, as demonstrated by the NML, the public sector has the capacity to do much more than pure discovery research. Armed with sufficient resources, public sector labs can conduct phase 1, 2, and 3 clinical trials as well as solve many of the technical challenges that manufacturing a clinical grade vaccine will entail.

Pursuing such an alternative approach to research and development can begin with changing how the work of science is done. Here, open science collaborations, where publications and data are widely shared without restrictions imposed by intellectual property, appear promising. Rather than supplying an additional market reward, open science collaborations change the way that science is practiced and knowledge is generated56. The global influenza research network, which succeeded in producing the information needed to generate seasonal influenza vaccines for decades, stands as a powerful example of high-cost, high-risk open science.57 Other innovative research models exist in the neglected disease realm as well58. Given the modest outcomes from relying on incentives to industry as observed in the case of rVSV-ZEBOV, secure funding and employment for public sector scientists to experiment with these new modes of knowledge production may prove a far better investment.

While the high prices of many publicly funded and developed drugs and vaccines continue to command policy attention, it is critical that we attend to the ways in which the standard logic of commercialization and the division of scientific labor that it commands as between the public and private sectors tends to reproduce the status quo. Unless the norms and practices of knowledge generation begin to change, the contributions and capacity of public sector science to the development of important health interventions like rVSV-ZEBOV will continue to be under-realized and, if and when interventions result, subject to pricing abuse.

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Supplementary Material

JLB_Ebola_submission_Supp_File_FINAL_lsz019

Click here for additional data file.(7.8M, pdf)

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ACKNOWLEDGEMENTS

The research for this paper was funded by the Canadian Institutes of Health Research (CIHR EOG 123678, CIHR PJT 156256, and CIHR PJT 148908), the PACEOMICS project funded by Genome Canada, Genome Alberta, Genome Quebec, the Canadian Institutes for Health Research, Alberta Innovates—Health Solutions, and the Social Sciences and Humanities Research Council. The authors would also like to acknowledge the contributions of several research assistants, including Heather Webster, Marcus McLeod, Michael Gardener and Alexandra Ghelerter.

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CONFLICTS OF INTEREST

We have the following interests to declare: MH is a member of Canada’s Patented Medicine Prices Review Board (PMPRB). He receives honoraria for his work as a PMPRB member. MH has no other financial relationships with government agencies, non-governmental organizations, or private corporations. RG has no conflict of interests to declare. JG has no conflict of interests to declare.

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Footnotes

1Ashley J. Stevens et al., The Role of Public-Sector Research in the Discovery of Drugs and Vaccines, 364 N.E.J.M. 535 (2011); Ekaterina G. Cleary et al., Contribution of NIH Funding to New Drug Approvals 2010–2016, 115 P.N.A.S., 2329 (2018); Aaron S. Kesselheim et al., The Roles of Academia., Rare Diseases, and Repurposing in the Development of the Most Transformative Drugs, 34 HEALTH AFFAIRS 286 (2015).

2Christopher Rowland, An HIV Treatment Costs Taxpayers Millions. The Government Patented It. But A Pharma Giant Is Making Millions, WASHINGTON POST (March 26, 2019), https://www.washingtonpost.com/business/economy/pharma-giant-profits-from-hiv-treatment-funded-by-taxpayers-and-patented-by-the-government/2019/03/26/cee5afb4-40fc-11e9-9361-301ffb5bd5e6_story.html (accessed Sep. 9, 2019).

3Mariana Mazzucato, THE ENTREPENURIAL STATE (New York: Anthem Press, 2014); Mark A. Lemley, Ex Ante Versus Ex Post Justifications for Intellectual Property, 71 U. CHI. L. REV. 129 (2004); Janice E. Graham, Ebola Vaccine Innovation: A Case Study of Pseudoscapes in Global Health, 29 CRITICAL PUB. HEALTH 401 (2019).

4See Supplementary File—Methods.

5See Supplementary File—BPS Agreement.

6Ewen Callaway, ‘Make Ebola a thing of the past’: first vaccine against deadly virus approved, Nature (Nov. 12, 2019), https://www.nature.com/articles/d41586-019-03490-8 (accessed Nov. 25, 2019). The vaccine was also submitted by Merck to the US Food and Drug Administration and subsequently approved. See Merck, Merck Begins Rolling Submission of Licensure Application for V920 (rVSV∆G-ZEBOV-GP) to U.S. Food and Drug Administration (Nov. 13, 2018), https://investors.merck.com/news/press-release-details/2018/Merck-Begins-Rolling-Submission-of-Licensure-Application-for-V920-rVSVG-ZEBOV-GP-to-US-Food-and-Drug-Administration/default.aspx (accessed Sep. 9, 2019); Shelby Lin Erdman, ‘FDA approves first-ever vaccine for prevention of Ebola virus’, CNN health (Dec. 20, 2019), https://www.cnn.com/2019/12/20/health/fda-approves-first-ever-vaccine-ebola-virus/index.html (accessed Dec. 29, 2019).

7Joseph R. A. Fitchett et al., Ebola Research Funding: A Systematic Analysis, 1997–2015, 6 J. GLOB. HEALTH, 020703 (2016).

8MELANIE ARMSTRONG, GERM WARS: THE POLITICS OF MICROBES AND AMERICA’S LANDSCAPE OF FEAR (Oakland, California: University of California Press, 2017).

9Government of Canada, Defence Research and Development Canada, Foresight Helped Make Canada a World Leader in Ebola Research (Sep. 10, 2014), http://www.drdc-rddc.gc.ca/en/dynamic-article.page?doc=foresight-helped-make-canada-a-world-leader-in-ebola-research/hzvlqma8 (accessed Sep. 9, 2019).

10Heinz Feldmann et al., Ebola Virus: From Discovery to Vaccine, 3 NAT. REV. IMMUN. 677 (2003).

11Public Servants Inventions Act, RSC 1985, c P-32.

12U.S. Patent No. 8,012,489. Recombinant Vesicular Stomatitis Virus Vaccines for Viral Hemorrhagic Fevers (published February 5, 2004).

13STAFF OF S. COMM. ON THE JUDICIARY, 85TH CONG., SUBCOMM. ON PATENTS, TRADEMARKS, & COPYRIGHTS, STUDY 15: An Economic Review of the Patent System (Comm. Print 1958 prepared by Fritz Machlup); Edmund W. Kitch, The Nature and Function of the Patent System, 20 J.L. & ECON. 265 (1977).

14Michael Garbutt et al., Properties of Replication-Competent Vesicular Stomatitis Virus Vectors Expressing Glycoproteins of Filoviruses and Arenaviruses, 78 J. VIROL. 5458 (2004); Steven M. Jones et al, Live Attenuated Recombinant Vaccine Protects Nonhuman Primates against Ebola and Marburg Viruses, 11 NATURE MED. 786 (2005); Heinz Feldmann et al, Effective Post-Exposure Treatment of Ebola Infection, 3 P.L.O.S. PATHOGENS e2 (2007).

15See Supplementary File—Project Completion Report.

16See Supplementary File—BPS Development Plan.

17See Supplementary File—BPS Development Plan.

18See Supplementary File—PHAC License Negotiation Term Sheet.

19See Supplementary File—BPS Project Updates A.

20See Supplementary File—BPS Agreement.

21NewLink Genetics Corp., Sole License Agreement for Recombinant Stomatitis Virus Vaccines for Viral Hemorrhagic Fevers (2010), https://www.sec.gov/Archives/edgar/data/1126234/000104746911009169/a2206169zex-10_67.htm (accessed Sep. 9, 2019).

22NewLink Genetics Corp., Form 10-K (Dec. 31, 2011), https://www.sec.gov/Archives/edgar/data/1126234/000112623412000014/nlnk-20111231x10k.htm (accessed Sep. 9, 2019).

23It is worth noting that there are important historical exceptions to today’s practice of not stipulating a commitment to ‘reasonable pricing’ in patent licensing agreements. See, for e.g., Maurice Cassier & Christiane Sinding, ‘Patenting in the Public Interest:’ Administration of Insulin Patents by the University of Toronto, 24 Hist. & Tech. 153 (2008).

24Pursuant to Standing Order 32(2), Mr. Van Loan (Leader of the Government in the House of Commons) laid upon the Table,—Answer to question Q-1155 on the Order Paper.—Sessional Paper No. 8530–412-25.

25Qiu Xiangguo et al., Sustained Protection against Ebola Virus Infection Following Treatment of Infected Nonhuman Primates with ZMAb, 3 SCIENTIFIC REPORTS 3365 (2013).

26Allain J. Barnett & Melanie G. Wiber, What Scientists Say about the Changing Risk Calculation in the Marine Environment under the Harper Government of Canada (2006–2015), 44 S.T. & H.V. 29 (2018). See also Supplementary File—Project Completion Report.

27See Supplementary File—Project Completion Report.

28See Supplementary File—Project Completion Report.

29See Supplementary File—Key Emails A, Project Updates B.

30See Supplementary File—Key Emails B.

31See Supplementary File—Key Emails C.

32 Sessional Paper, supra note 24.

33See Supplementary File—Project Completion Report.

34U.S. Dep’t of Health and Human Servs. et al., Guidance for Industry: CGMP for Phase 1 Investigational Drugs (July 2008), https://www.fda.gov/downloads/drugs/guidances/ucm070273.pdf (accessed Sep. 9, 2019). See also Supplementary File—Project Completion Report.

35See Supplementary File—Project Updates C.

36See Supplementary File—Key Emails D, Project Updates C.

37See Supplementary File—Key Emails E, Project Updates D.

38World Health Org., Origins of the 2014 Ebola Epidemic (Jan. 2015), https://www.who.int/csr/disease/ebola/one-year-report/virus-origin/en (accessed Sep. 9, 2019).

39Thomas Walkom, The Strange Tale of Canada’s Ebola Vaccine, TORONTO STAR (Nov. 25, 2014), https://www.thestar.com/news/canada/2014/11/25/the_strange_tale_of_canadas_ebola_vaccine_walkom.html (accessed Sep. 9, 2019).

40Denise Grady, Ebola Vaccine, Ready for Test, Sat on the Shelf, N.Y.T. (Oct. 23, 2014), https://www.nytimes.com/2014/10/24/health/without-lucrative-market-potential-ebola-vaccine-was-shelved-for-years.html (accessed Sep. 9, 2019); Amir Attaran & Jason W. Nickerson, Is Canada Patent Deal Obstructing Ebola Vaccine Development? 384 THE LANCET e61 (2014).

41NewLink Genetics Corp., Exhibit 10.105, License and Collaboration Agreement (2014), https://www.sec.gov/Archives/edgar/data/1126234/000112623415000054/nlnk-20141231xex10105.htm (accessed Sep. 9, 2019).

42The National Academies of Sciences, Engineering, Medicine, Integrating Clinical Research into Epidemic Response: The Ebola Experience (Apr. 12, 2017), (http://nationalacademies.org/hmd/Reports/2017/integrating-clinical-research-into-epidemic-response-the-ebola-experience.aspx (accessed Sep. 9, 2019).

43May S. ElSherif et al., Assessing the Safety and Immunogenicity of Recombining Vesicular Stomatitis Virus Ebola Vaccine in Heatlhy Adults: A Randomized Clinical Trial, 189 CAN. MED. ASSOC. J. e819 (2017).

44 Exhibit 10.105, supra note 22.

45Ana Maria Henao-Restrepoet 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!), 389 THE LANCET 505 (2016). It is important to note that the number of participants reported here (11,841) encompasses all the individuals whom the WHO-led consortium recruited for potential enrollment in the trial. As explained in the published version of the trial, the total number of participants that were found eligible to enroll (8334) or actually gave consent to take part in the trial (6367) was substantially lower. Further, these numbers also differ from the number of participants reported in Table 2 below for the same Ebola Ça Suffit! trial. However, inconsistencies between published clinical studies and data reported in Clinicaltrials.gov (the source for all of the data in Table 2) are common, and the number of participants eligible to enroll (8334) is relatively close to the number of participants reported on Clinicaltrials.gov (8851).

46Merck has received funding from multiple government agencies in the US and Europe. See for e.g., Innovative medicines initiative, Europe’s partnership for health. VSV-EBOPLUS: Vaccine safety and immunogenicity signatures of human responses to VSV-ZEBOV, https://www.imi.europa.eu/projects-results/project-factsheets/vsv-eboplus (accessed Sep. 16, 2019).

47Gavi, Ebola Vaccine Purchasing Commitment from Gavi to Prepare for Future Outbreaks (Jan. 2016), https://www.gavi.org/library/news/press-releases/2016/ebola-vaccine-purchasing-commitment-from-gavi-to-prepare-for-future-outbreaks/ (accessed Sep. 9, 2019).

48Department of Health and Human Services, HHS Accelerates Development of First Ebola Vaccines and Drugs (Sep. 29, 2017), https://www.hhs.gov/about/news/2017/09/29/hhs-accelerates-development-first-ebola-vaccines-and-drugs.html (accessed Sep. 9, 2019).

49Gavi, supra note 47.

50Eric Sagonowsky, Merck Will Delay Filing Ebola Vaccine for Approval until 2018, Company Confirms, FIERCEPHARMA (Nov. 21, 2017), https://www.fiercepharma.com/vaccines/merck-to-miss-2017-filing-target-for-ebola-vaccine-spokesperson (accessed Sep. 9, 2019).

51John Gever, Still no clarity on Merck’s Ebola vax in Congo, Medpage Today (Oct. 30, 2018), https://www.medpagetoday.com/meetingcoverage/astmh/76018 (accessed Oct. 7, 2019).

52Merck, supra note 6.

53Jenny Lei Ravelo, Merck to make more Ebola vaccine, WHO declines to declare global emergency, devex (Jun. 14, 2019), https://www.devex.com/news/merck-to-make-more-ebola-vaccine-who-declines-to-declare-global-emergency-95114 (accessed Sep. 17, 2019).

54Patrice Trouiller et al., Drugs for Neglected Diseases: A Failure of The Market and A Public Health Failure? 6 TROP. MED. INT. HEALTH 945 (2001).

55Dana Brown, Medicine for All: The Case for a Public Option in the Pharmaceutical Industry, Democracy Collaborative (Sep. 2019), https://docs.google.com/viewerng/viewer?url=https://thenextsystem.org/sites/default/files/2019-09/MedicineforAll_WEB.pdf (accessed Sep. 17, 2019).

56E. Richard Gold, Accelerating Translational Research Through Open Science, 14 P.L.O.S. BIOL. e2001259 (2016).

57Amy Kapczynski, Order Without Intellectual Property Law: Open Science in Influenza, 102 CORNELL L. REV. 1539 (2017).

58Michael P. Pollastri, Finding New Collaboration Models for Enabling Neglected Tropical Disease Drug Discovery, 8 P.L.O.S. e2866 (2014).

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rVSV-ZEBOV vaccine

rVSV-ZEBOV vaccine

Medical use[edit]

Effectiveness[edit]

Side effects[edit]

Biochemistry[edit]

History[edit]

Ebola 2018[edit]

2018 Democratic Republic of the Congo Ebola virus outbreak[edit]

2018 Kivu Ebola outbreak[edit]

References[edit]

Further reading[edit]

From discovery to delivery: public sector development of the rVSV-ZEBOV Ebola vaccine

Associated Data

Abstract

Public Financing, Discovery, and Development of VSV-ZEBOV

Transferring VSV-ZEBOV to BPS

Epidemics as Epilog

Table 1

Table 2

The Security to Experiment with New Modes of Knowledge Production

Supplementary Material

ACKNOWLEDGEMENTS

CONFLICTS OF INTEREST

Footnotes