ILAR Journal, 2021, Vol. 00, No. 00, 1–16

doi: 10.1093/ilar/ilab004 Review Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 Challenges and Opportunities in the Use of High and Maximum Biocontainment Facilities in Developing and Licensing Risk Group 3 and Risk Group 4 Agent Veterinary Vaccines David A. Brake1,*,JensH.Kuhn 2, Glenn A. Marsh3, Martin Beer4 and Joshua B. Fine5 1BioQuest Associates LLC., Stowe, Vermont, USA, 2National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), Division of Clinical Research (DCR), Integrated Research Facility at Fort Detrick (IRF-Frederick), Fort Detrick, Frederick, Maryland, USA, 3Australian Centre for Disease Preparedness, CSIRO, East Geelong, Victoria, Australia, 4Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Greifswald, Germany, and 5Tunnell Government Services Inc., Bethesda, Maryland, USA

*Corresponding Author: David A. Brake, PhD, BioQuest Associates, P.O. Box 787, Stowe, VT 05672, USA. E-mail: [email protected].

Abstract New solutions are necessary for the singular global health security threat formed by endemic, epidemic, and emerging/re-emerging zoonoses, coupled with epizootic and enzootic transboundary animal diseases (TADs). This One Health issue is related to the daily interactions between wildlife, domesticated and indigenous livestock, and humans primarily associated with global trade, transboundary co-movement of humans and diverse livestock/livestock products, and agriculture production intensification and penetration into previously uninhabited areas. The World Health Organization defines Risk Group 3 (RG-3) and RG-4 pathogens as mainly viruses but also bacteria that serve as the foundation for approximately 60% of emerging infectious diseases that are zoonoses. The World Organisation for Animal Health defines trade-notifiable TADs, and subsets of these are zoonotic. Livestock vaccination policies mainly focus on TADs that are promulgated by the United Nations Food and Agriculture Organization and government agriculture agencies. The development, licensure, and product manufacturing of next-generation molecular-based RG-3 and RG-4 veterinary vaccines largely ignored by the global animal health biopharmaceutical sector can have an important positive impact on food security and One Health. There have been sharp increases in the global demand for livestock meat and milk products, especially in low- and middle-income countries in Africa and Asia. This relatively recent market driver—coupled with scientific advances in human EID and zoonotic disease vaccine platform technologies and increases in the number of high (US biosafety level 3 agriculture) and maximum (US animal biosafety level 4) biocontainment facilities with supporting workforce capabilities—offers new investment opportunities to the animal health biopharmaceutical sector. Moreover, a growing number of One Health public-private partnerships have moved the net present value calculus in favor of the financial feasibility of RG-3 and RG-4 veterinary vaccine product development and licensure. This article highlights the challenges and opportunities in the use of high and maximum biocontainment facilities in developing and licensing RG-3 and RG-4 veterinary vaccines that are safe and effective against epizootic and enzootic TADs and zoonotic diseases. Key words: biohazard containment; livestock; One Health; RG-3; RG-4; transboundary animal diseases; veterinary vaccines; zoonotic

Received: May 18, 2020. Revised: September 15, 2020. Accepted: October 1, 2020 Published by Oxford University Press on behalf of the National Academies of Sciences, Engineering, and Medicine 2021. This work is written by Federal Government employees and contractors and is in the public domain in the US.

1 2 Brake et al.

Introduction wild artiodactyl (even-toed ungulates), perissodactyl (odd-toed In 430 BCE, Greek historian Thucydides recorded the first known ungulates), and carnivore relatives has likely intensified oppor- 14 description of a probable zoonotic disease in the context of tunities for pathogen transmission across animals. Consider- acquired natural immunity.1 From 430 to 426 BCE, the Athenian ing this information together, it is reasonable to postulate that plague killed an estimated 90 000 people (more than one-quarter domesticated and indigenous livestock can serve as an active of the city population of 250 000–300 000). Although scholars source of cross-species zoonotic virus transmission and increase still widely debate the specific etiologic agent responsible for the risk of zoonoses spillover to humans. RG-3/-4 veterinary the epidemic, a subset of zoonotic pathogens has been pro- vaccines for these livestock animals can be a useful tool to help 2 mitigate these risks. posed, including Yersinia pestis (the cause of bubonic plague), Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 Rickettsia prowazekii (epidemic typhus),3 Burkholderia mallei (glan- There is an escalating consumer demand for meat and spe- ders),4 Lassa virus (Lassa fever),5 and Ebola virus (Ebola virus cific meat preferences (eg, higher income switch from poultry disease).6 to pork and subsequently to beef) to meet the needs of a grow- The World Health Organisation (WHO) and the World ing human population with longer projected life expectancies. Organisation for Animal Health (OIE) define Risk Group 3 Livestock production (meat and milk) is critical to providing (RG-3) agents as pathogens that cause serious human or food security for the human population, which is estimated to 15 animal disease, are not commonly transmitted from 1 infected reach 9.7 billion by 2050. A 2018 United Nations (UN) Food individual to another, and cannot be countered effectively with and Agriculture Organization (FAO) report emphasized the cen- available medical countermeasures (MCMs) such as therapeutics tral catalytic role that global livestock production can serve or vaccines.7 RG-4 agents are pathogens that typically cause in strengthening household livelihood, improving the health serious human or animal disease and are readily transmissible of millions of people worldwide, and helping to enhance food 16 between individuals but usually cannot be countered effectively security. with available MCMs. A number of non-zoonotic, OIE-listed Agricultural modernization and intensification practices are transboundary animal diseases (TADs), for example foot-and- driving the creation of new grazing areas for domestic livestock mouth disease virus, require high-level biocontainment facilities and for growing feed crops, thus clearing and disrupting natural for the purposes of research and development (R&D) and whole wildlife habitat. In addition, in some countries, novel farming virus inactivated vaccine manufacturing. A relatively small systems for wild carnivores (eg, mink) and omnivores (eg, fox number of licensed veterinary vaccines exist for RG-3 and RG-4– and raccoon dog) have created ideal reservoirs and amplifying associated zoonotic diseases, most notably rabies and anthrax, hosts for some zoonoses. These largely uncontrolled practices as well as brucellosis, Q fever, and Rift Valley fever (RVF). There have also resulted in the convergence of diverse wildlife (eg, are also several poultry vaccines against highly pathogenic bush meat) and domesticated and indigenous livestock into the avian influenza A virus subtype H5, H7, and H9 infections.8 It same or overlapping ecosystems and/or the same food supply is remarkable that no licensed veterinary vaccine exists against chains. Consequently, some of the large-scale zoonotic disease any of the 5 RG-3/-4 pathogens listed above that may have caused outbreaks during the past 25-year period may have been due the Athenian plague over 2 millennia ago and that still pose in part to an increase in the daily probability of virus exchange 17 athreat. events between wildlife, domesticated animals, and humans. 18 Beginning approximately 1 century ago and rapidly increas- For example, the first reported henipavirus encephalitis and 19 ing over the past 2 decades (perhaps coinciding with agricul- Middle East respiratory syndrome zoonoses may have been due ture intensification into biodiverse habitats), there has been a to these inter-species virus exchanges. Most infectious disease rise in the types and frequencies of RG-3/-4 emerging infec- and public health experts agree with the dire prediction of tious diseases (EIDs) causing epizootic outbreaks in livestock a continuing increase in the frequency, magnitude, and geo- and zoonotic disease in humans.9 Endemic zoonoses—such as graphic locations of zoonotic disease outbreaks, including the brucellosis, RVF, rabies, Q fever, and anthrax—are ubiquitous heightened potential for new global pandemics, such as the throughout many parts of Africa and/or Asia. Epidemic zoonoses current COVID-19 pandemic, which began in late 2019. Food have a wider spatial distribution and are sporadic, whereas security and One Health are more interdependent than ever emerging/re-emerging zoonoses have appeared in new popu- before in human history, particularly in low- and middle-income lations with increased frequency and/or geographical range.10 countries (LMICs), often located in the same anthropogenic- Table 1 lists 11 examples of significant RG-3/-4 zoonotic viral driven “hot-spot” regions historically affected by periodic epi- 20 disease outbreaks that have occurred in the past 100 years. Of zootic, enzootic, and zoonotic outbreaks. Thus, MCMs for high- the 11 viral etiologies listed, 8 also cause disease in susceptible consequence RG-3 and RG-4 TAD and zoonotic agents are critical domesticated livestock. to counter EID epidemics and pandemics. Numerous zoonotic viruses infect domesticated and indige- It is conspicuous that, though over 300 years have passed nous livestock. These animals may also serve as amplifying since the first reported poxvirus-based vaccinations were con- 21 hosts and/or reservoirs for diseases such as Japanese encephali- ducted in humans to control smallpox, there are fewer than 10 tis virus (JEV) in domestic pigs11 and RVF in domestic red sheep veterinary vaccines against diseases caused by RG-3/-4 zoonotic and young calves.12 A 2020 study identified that an average agents (eg, highly pathogenic avian influenza A virus H5, H7, and of 19.3 (min. 5, max. 31) zoonotic viruses are shared between H9 subtypes; West Nile virus [WNV], rabies virus, Coxiella burnetii, domesticated animals and humans, in contrast to an average Brucella abortus, and Hendra virus [HeV]). There are a number of of only 0.23 viruses (min. 0, max. 16) shared between wildlife reasons for the paucity of epizootic/enzootic TAD and zoonotic and humans.13 Moreover, this same study showed that zoonotic RG-3/-4 veterinary vaccines. First is the number of knowledge viruses in domesticated animals are also shared with wild ani- gaps associated with understanding livestock-protective innate mals in the Cetartiodactyla and Carnivora orders. Previously, and adaptive immune responses in the context of specific bacte- it has been speculated that the close phylogenetic relatedness rial or virus disease pathogenesis. Second, despite tremendous between globally distributed domesticated animals and their advances in the biological disciplines and the ability to generate Challenges and Opportunities in the Use of High and Maximum Biocontainment Facilities in Developing 3

Table 1 Notable 10 RG-3 and RG-4 Virus Zoonotic Disease Outbreaks in the Last 100 Years

Zoonotic Virus Risk Virus Family Highly Notable Natural or Vector Susceptible Group Widespread Amplifying Association Domesticated Outbreak Wildlife Host Livestock

Japanese 3 Flaviviridae 1921–24 Wild wading and Mosquitoes Pig, horse, ass encephalitis virus water birds Rift Valley fever 3 Phenuiviridae 1977–78 Bats (Chiroptera) Mosquitoes Red sheep, virus domesticated Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 cattle, horse, one-humped camel, goat, African buffalo West Nile virus 3 Flaviviridae 1996–97 Perching birds Mosquitoes Horse (Passeriformes) Nipah virus 4 Paramyxoviridae 1998–99 Bats (Chiroptera) None Domestic pig, domesticated cattle SARS-CoVa 4 Coronaviridae 2002–03 Masked palm None None identified to civet (Paguma date larvata) Crimean-Congo 3 Nairoviridae 2002–08 European hare Ticks Red sheep, ass, hemorrhagic fever (Lepus horse, virus europaeus), domesticated hedgehogs cattle, (Mesechinus spp.) one-humped camel Hendra virus 4 Paramyxoviridae 2011–12 Bats None Horse (Pteropodidae) Middle East 4 Coronaviridae 2012 Bats None one-humped respiratory (Pteropodidae) camel, pigs, llama syndrome virus Ebola virus 4 Filoviridae 2013–16 Unknown (bats None None identified to suspected as date reservoir host) Zika virus 3 Flaviviridae 2015–16 Bats (Chiroptera) Mosquitoes Red sheep SARS-CoVa-2 3 Coronaviridae 2019–present Unknown (bats None None identified to suspected as dateb reservoir host) aSevere acute respiratory syndrome coronavirus. bExcludes mink that are highly susceptible. Disease susceptibility among livestock of different species is under evaluation. Abbreviation: RG = Risk Group. and analyze extremely large datasets quickly, the time required requiring high biocontainment. This has largely been the case to experimentally expose, test, and evaluate vaccine candidates in Africa, where such companies have developed veterinary in the target host in high/maximum biocontainment facilities vaccines for enzootic TADs such as African horse sickness (AHS), has remained relatively constant. In the Americas, Europe, and bluetongue, lumpy skin disease, and zoonotic diseases (such as Australia, high (United States biosafety level 3 agriculture [BSL-3 RVF and Q fever). Interestingly, some European countries may Ag; BSL-3-like]) and maximum (US ABSL-4; ABSL-4-like) animal need to urgently import some of these LMIC-developed RG-3/-4 biocontainment facilities provide the essential infrastructure in veterinary vaccines in response to an outbreak of an OIE-listed which to conduct basic and applied research, vaccine regulatory disease (ie, bluetongue and Q fever). Thus, it is acutely appar- development, and licensing studies using RG-3/-4 pathogens. ent that traditional veterinary vaccine R&D paradigms used by Challenges in leveraging these high/maximum biocontainment the larger global animal health companies located in OIE-listed facilities exist mainly due to the total number currently avail- disease-free countries regularly encounter significant barriers to able, with most being owned and operated by government agen- market entry. cies and not controlled directly by the biopharmaceutical private sector. Third, and perhaps most critical, most if not all of the net present value (NPV) models fail to proactively (ie, in the absence Current and Future Drivers for Veterinary of a major global epizootic or zoonotic disease outbreak) actuate Vaccine Development for RG-3 and RG-4 these companies to independently invest in RG-3/-4 livestock Agents in High/Maximum Biocontainment vaccine development. Due to the clear and growing market need for such vaccines, smaller regional veterinary companies that Facilities are often government-owned and located in LMICs with enzootic Some mid-size and all of the larger global animal health com- and zoonotic TAD diseases have had the financial benefit of panies have corporate-level social responsibility programs asso- developing and licensing RG-3/-4 veterinary vaccines without ciated with TAD epizootic/enzootic, EIDs, and zoonotic diseases. 4 Brake et al.

Despite these initiatives, the principal drivers for RG-3/-4 vet- understanding that some human EIDs originate from asymp- erinary vaccine development are NPV and return on investment tomatic domestic animal reservoirs. RG-3/-4 veterinary vaccines, (ROI). More recently, many government funding agencies and if adequately used to establish and sustain herd immunity, may non-profit funders are increasingly requiring ROI metrics to potentially disrupt or eliminate such reservoirs in domestic, justify investments in RG-3/-4 veterinary vaccine R&D. semi-domestic, and indigenous livestock. For all veterinary R&D projects, animal health companies calculate NPV based on a vaccine product’s projected net cash Commercial Veterinary Vaccine Host Targets flow over time less the project’s initial cash investment to obtain and Product Markets product licensure. If the project NPV is ≥0, the project might be Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 greenlighted. Rabies veterinary vaccine is a rare example of a Over the past 70 years, veterinary vaccine product licensure in positive value NPV for a RG-3 vaccine. In other special instances, the food and agriculture sector has largely focused on endemic RG-3/-4 vaccine projects may be internally approved. The mar- bacterial and viral diseases. Excluding poultry vaccines (out- kets are created by national or regional vaccine stockpile banks side the scope of this paper), the vast majority of licensed (eg, National Animal Vaccine and Veterinary Countermeasures vaccines are approved for use in a limited subset of domestic Bank) or significant funding subsidies from government agen- livestock (Table 2), with specific product claims for domesti- cies; examples are the US Department of Homeland Security cated cattle (Bos taurus)ordomesticpigs(Sus scrofa domesticus). Science and Technology Directorate for the adenovirus-vectored Importantly, in the context of RG-3 endemic zoonoses, there are FMD vaccine program and the European Union Sixth Framework numerous other indigenous livestock—particularly small rumi- Programme for classical swine fever vaccines. Unfortunately, nants that support owners and farmers in Africa and Asia—for the vast majority of RG-3/-4 veterinary vaccines have an NPV which veterinary vaccines have not been specifically developed <0, especially when vaccine-tiered pricing is applied to LMIC and licensed for use but may be occasionally used “off-label” markets. Thus, in the absence of a globally active pandemic (Table 3). One of the principal factors for the very low penetration or significant external funding, most promising RG-3/-4 vet- rate of veterinary vaccines for small ruminants and indigenous erinary vaccine candidates languish in government and aca- animals found in many parts of Africa and Asia is the rela- demic research laboratory freezers and are never transitioned tively high cost of vaccination that includes the omnipresent to veterinary biopharmaceutical industry partners for product cold chain supply issue. The “vaccine-underserved” indigenous development. livestock listed in Table 3, comprised of more than 35 species However, newly emergent market drivers are an opportunity that belong to various families and subfamilies, can survive in to re-evaluate traditional NPV RG-3/-4 veterinary vaccine devel- harsher conditions and on sparser feed resources compared with opment models. First, veterinary vaccines for some zoonotic domesticated livestock. Due to their strong adaptability, many of diseases offer intrinsic One Health value by functioning as a the animals listed in Table 3 represent a diverse and vital compo- strategic barrier to human infection. Arguably, the most success- nent of food security and One Health, especially in LMICs.27 It is ful, archetypal, and global One Health veterinary immunization relatively apparent that most of these indigenous livestock pose program has been the successful vaccination of domestic, semi- significant challenges with respect to RG-3/-4 veterinary vaccine domestic and indigenous livestock, and wild animals (eg, rac- development in high-level biocontainment facilities, especially coons, coyotes, foxes, skunks) against rabies, which has led to the with respect to unique animal husbandry,handling, and disposal direct positive impacts of reducing human rabies virus infections challenges. One solution may be to conduct safety and efficacy and saving lives.22 The RVF veterinary vaccine is another notable studies in countries with OIE-listed epizootic and enzootic dis- example of the One Health strategic barrier concept, based on eases, thus removing the likely need for costly clinical studies the observation that administration of a killed RVF virus (RVFV) in high-level biocontainment facilities. In addition, it should be vaccine preparation to ruminants reduced RVF outbreak severity noted that in current OIE disease-free countries, a new disease and favorably influenced RVF virus transmission dynamics.23 outbreak might allow a resetting of the BSL designation in which Second, RG-3/-4 veterinary vaccines for Q fever and brucellosis clinical trials are required to be conducted, as was the case for zoonoses provide critical protection to large and small ruminant the cattle bluetongue outbreak in Germany from 2006 to 2008. stocks with high reproductive breeding values based on genetic The global market for veterinary vaccines is usually analyzed traits of interest (eg, milk yield, fat yield, and feed intake) or via geographical regions, namely North America, Europe, Asia to those that possess rare genetic traits. Third, enzootic and Pacific, and the rest of the world.28 North America has a high- epizootic TADs for which no differentiating infected from vacci- income economy and maintains the largest market with the nated animals (DIVA) marker vaccines are currently available for highest profit, followed by the EU, which has a range of upper- use in companion serology diagnostic testing inevitably result in middle- to high-income economies. Thus, the top global animal mass livestock depopulation and disposal campaigns that have health companies have historically focused on new vaccine significant ethical, ecological, and economic impacts.24 Effective, products for North American and European markets for the prophylactic DIVA vaccination against OIE-listed diseases can livestock listed in Table 2. Private regional and smaller veterinary be an important economic tool to help mitigate the need for biopharmaceutical companies, as well as government-owned domestic livestock mass culling and disposal as a result of a companies in Africa, Asia, and Russia, have historically served sudden outbreak in an OIE disease-free country. However, even as the principal R&D engine for RG-3/-4 veterinary vaccines in these cases, challenges remain due to strong non-vaccination in LMIC markets. Unfortunately, these companies do not typi- policies driven by federal government agency decision-makers. cally possess the financial strength to develop RG-3/-4 veteri- Fourth, the One Health concept includes a transcendent, integra- nary vaccines using highly innovative or state-of-the-art vac- tive notion of animal health, human health, and environmental cine methodologies to satisfactorily address the current safety health25 as exemplified by the increased coordination of trans- and efficacy gaps associated with inactivated and older (first national organizations, including FAO, OIE, WHO, and the World generation) live attenuated vaccine technologies. Bank. Finally, a relatively recent market driver is the now well- Over the next decade, the Asia-Pacific region and parts accepted recognition of the economic impact of EIDs26 and the of Africa with growing economies are forecast to have the Challenges and Opportunities in the Use of High and Maximum Biocontainment Facilities in Developing 5

Table 2 Domesticated Livestock for Which Veterinary Vaccines Are Primarily Licensed

Livestock Family Subfamily Common Name (genus and species/subspecies)

Bovidae Bovinae Domesticated cattlea (Bos taurus) Caprinae Goat (Capra hircus) Red sheep (Ovis aries) Suidae N/A Domestic pig (Sus scrofa domesticus) Equidae N/A Domesticated horse (Equus ferus caballus) Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021

aIncludes zebu. Abbreviation: N/A = not applicable.

Table 3 Representative Indigenous Livestock for Which RG-3 and RG-4 Veterinary Licensed Vaccines Are Unavailable or Are Used “Off-Label”a

Livestock Family Subfamily Common name (genus and species/subspecies)

Antilocapridae Antilopinae Pronghorn (Antilocapra americana) Impala (Aepyceros melampus) Dorcas gazelle (Gazella dorcas) Blackbuck (Antilope cervicapra) Indian gazelle (Gazella bennettii) Springbok (Antidorcas marsupialis) Bovidae Alcelaphinae Blue wildebeest (Connochaetes taurinus) Black wildebeest (Connochaetes gnou) Bontebok (Damaliscus pygargus) Bovinae Water buffalo (Bubalus bubalis) African buffalo (Syncerus caffer) American bison (Bison bison) Yak (Bos grunniens) Bali cattle (Bos javanicus javanicus) Gaur (Bos frontalis) Nilgai (Boselaphus tragocamelus) Greater kudu (Tragelaphus strepsiceros) Derby eland (Taurotragus derbianus) Capriane Bighorn red sheep (Ovis canadensis) Nubian ibex (Capra nubiana) Muskox (Ovibos moschatus) Barbary red sheep (Ammotragus lervia) European mouflon (Ovis aries musimon) Hippotraginae Arabian oryx (Oryx leucoryx) Gemsbok (Oryx gazella) Fringe-eared oryx (Oryx beisa callotis) Sable antelope (Hippotragus niger) Camelidae N/A one-humped camel (Camelus dromedarius) Bactrian camel (Camelus bactrianus) Guanaco (Lama glama) Vicuña (Vicugna vicugna) Cervidae Cervinae Reindeer (Rangifer tarandus) Moose (Alces americanus) Fallow deer (Dama dama) Red deer (Cervus elaphus) Chital (Axis axis) Capreolinae White-tailed deer (Odocoileus virginianus) Equidae N/A Ass (Equus asinus)

aD. Brake, personal communication. Abbreviation: N/A = not applicable. highest growth in the livestock vaccine global market, fueled by LMICs, to reduce the use of antibiotics owing to the eco-green increases in meat/milk product demand and consumption. For movement and increased risk of drug-resistant pathogens.31 example, recent FAO figures project that LMIC demand for meat The increasing incidence of TADs, EIDs, and zoonotic diseases in will increase by 80% by 2030 and 200% by 2050.29 LMICs with LMICs is propelling increased demand for RG-3/-4 veterinary RG-3/-4 livestock TADs are actively increasing their livestock vaccines. In addition, it is becoming increasingly clear that populations and densities, resulting in the precipitous loss in the more than 50 million African pastoralists can benefit native biodiversity associated with grasslands, savannas, and from livestock vaccination, not only directly from the positive tropical forests.30 Moreover, there is a global push, including in animal health and productivity benefits, but also from human 6 Brake et al.

development benefits associated with household expenditures, facilities because natural exposure to infected vectors is prefer- such as education, food, and health.32 able for studying disease pathogenesis and vaccine efficacy. To reduce both the incidence and magnitude of likely future epizootic and zoonotic disease outbreaks, development of new, RG-3 and RG-4 Epizootic, Enzootic, safer, and more efficacious licensed RG-3/-4 veterinary vaccines and Zoonotic Pathogens for the diseases listed in Table 7 may be important, including reg- ulatory approval for use in the majority of susceptible animals One method to prioritize RG-3 and RG-4 veterinary livestock listed. vaccine development in high/maximum level biocontainment Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 facilities is to divide the target pathogens into 2 distinct groups. The first group includes RG-3/-4 agents associated with OIE- Hurdles/Barriers to Entry listed (reportable) livestock epizootic and enzootic TADs that Once past the initial NPV hurdle, animal health biologic com- are connected to human well-being (eg, food security and eco- panies (including the largest and most profitable) clearly under- nomic prosperity) (Table 4). The second group includes RG-3/- stand the remaining significant obstacles to develop and license 4 agents with a direct or indirect link to human transmission RG-3/-4 veterinary vaccines, particularly for livestock. High BSL- and zoonotic disease outbreaks (Table 5; Table 6). In 2020 alone, 3Ag and maximum ABSL-4 biocontainment facilities to sup- outbreaks of anthrax, glanders, Q fever, RVF, and WNV have port preclinical and clinical R&D require highly sophisticated, been reported in several countries. Among the zoonotic agents complex infrastructures that are very expensive to operate and listed in Table 5, there are licensed veterinary vaccines for bovine logistically challenging to maintain. Proper high/maximum bio- brucellosis, Q fever, RVF, WNV, Venezuelan equine encephali- containment facilities are required for target host pathogen tis, JEV, and HeV. However, for various reasons, ranging from exposure, evaluation of rationally gene-deleted live attenuated poor vaccine safety (bovine brucellosis, Q fever) and efficacy (Q vaccine candidates for genetic stability/reversion to virulence, fever) to animal husbandry practices (JEV) to sporadic small focal and, in some cases, vaccine manufacturing. A general rule of outbreaks (HeV-caused henipavirus encephalitis), many of these thumb is that the annual operating cost of a US BSL-3 Ag or veterinary vaccines are not widely used. ABSL-4 biocontainment facility is approximately 10% of the It is very difficult to predict with any reasonable certainty construction cost and can account for roughly 75% of the total which RG-3 or RG-4 TAD pathogens are most likely to cause annual facility budget.34,35 It is precisely for this reason that the the next wave of major global epizootic outbreaks over the majority of currently registered US BSL-3 Ag and ABSL-4 facilities next decade and when and where this may happen. The same for livestock vaccine R&D are either government owned and holds true for attempting to forecast with relative accuracy the operated or government subsidized. These BSL-3 Ag and ABSL- next currently known or perhaps completely new RG-3 or RG-4 4 facilities and their personnel are highly regulated from both zoonosis that will spill over into livestock and/or humans and Occupational Safety and Health policy and biosurety (eg, Biolog- cause the next major epidemic or global pandemic. Therefore, ical Select Agent and Toxins) perspectives.36,37 In addition, as an expanding current veterinary vaccine repositories and vaccine example of pathogen-specific regulations, in the EU work with banksneedstobediscussed,ashaslongbeenthecasefor FMDV is highly regulated, and all regulations are summarized in FMD (inactivated antigen storage) and more recently for classical a guidance document.38 These mandated biorisk management swine fever (ready-to-use vaccines). programs are integral components to support the institutional A closer examination of the origins of zoonotic diseases may and laboratory personnel accreditations associated with labora- offer some predictive clues. Of the top 10 mammals associated tory infectious disease R&D performance quality management, with the highest number of zoonotic viruses, 6 are domesti- but they are expensive from operations and oversight perspec- cated: pigs, cattle, and horses (n = 31 each), red sheep (n = 30), tives. Another barrier to investment in the development of TAD goats (n = 22), and one-humped camels (n = 15).13 This is a salient and zoonotic veterinary vaccines is that all licensed high/max- finding with respect to prioritizing future investments in live- imum biocontainment facilities have sophisticated engineering stock immunology, zoonotic disease pathogenesis, and trans- and procedural controls for staff safety and facility security that mission in these specific animals for RG-3/-4 veterinary vaccine require validation and continuous maintenance by a large group development. of highly trained engineers and facility technicians. Table 7 provides a summary of known pathogens and live- High biocontainment facilities for BSL-3 Ag and maximum stock targets that could serve as the basis for epizootic and biocontainment facilities for ABSL-4 require the development of zoonotic disease outbreaks in the coming decade. The common a highly qualified, diverse, sustainable workforce that is prop- denominator is that either no veterinary vaccine currently exists erly and continuously trained.39 RG-3/-4 veterinary vaccine R&D (African swine fever [ASF], Crimean-Congo hemorrhagic fever, requires a large trans-disciplinary cadre of scientists with sub- Menangle infection, norovirus infections) or the available vac- ject matter expertise across a broad spectrum of disciplines, cines have poor efficacy, namely little or no impact on pathogen including but not limited to research veterinarians and (compar- shed and spread from infected to susceptible, naive hosts. ASF, ative) pathologists, molecular biologists, virologists, immunolo- an OIE-listed TAD disease that was largely restricted to Africa gists, microbiologists, entomologists, biochemists, and compu- until 2007, has since spread outside Africa to over 50 countries tational scientists. All of these individuals must work under the in Europe and Asia. In the absence of a licensed vaccine, approx- biosafety demands of strict laboratory environments (including imately 25% of the global domestic pig population was lost in specialized personal protective equipment, possibly mandatory 2019. More recently, in March 2020, an epizootic outbreak of vaccinations, quarantine regulations, or special medical and/or lethal AHS was reported in Thailand, the first time this disease personnel reliability requirements).40 In addition, as it specifi- has been recorded in Asia since 1961.33 What is particularly cally pertains to ABSL-4 vivarium spaces that house large ani- interesting is that both ASF and AHS have arthropod reservoirs. mals in relatively confined areas, challenges include compliance In such cases, this adds to the challenges for RG-3/-4 veteri- with the myriad of regulations and rigid safety measures to nary vaccine development in high/maximum biocontainment minimize risk for physical injury to animal care staff and R&D Challenges and Opportunities in the Use of High and Maximum Biocontainment Facilities in Developing 7

Table 4 High-Priority RG-3 Epizootic and Enzootic TADs in Livestock Connected to Human Well-being

Epizootic Diseasea Agent (Family) Susceptible Livestock Comment Species/Subspecies African horse sickness (AHS) African horse sickness virus (Reoviridae)Horse(Equus caballus ferus), African wild Most economically significant equine ass (Equus asinus africanus), ass (Equus disease worldwide; endemic in asinus) sub-Saharan Africa (serotype 9); epizootic in Western Asia, 2020 outbreak in Vietnam; live-attenuated vaccines available but offer poor Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 efficacy and safety African swine fever (ASF) African swine fever virus (Asfaviridae) Affects most members of Suidae family Top global transboundary animal including domestic pig (Sus domestica, disease threat to swine industry; a.k.a. Sus scrofa scrofa) enzootic in sub-Saharan Africa, epizootic in Caucasus, Eastern Europe, Asia, Southeastern Asia; no licensed vaccines Bluetongue Bluetongue virus (Reoviridae) Multiple animals of Bovinae, Caprinae, >24 major serotypes and several Alcelaphinae subfamilies atypical serotypes; red sheep most severely affected animal; Culicoides midge vector; found globally within tropical and subtropical climates; endemic areas in Africa, Europe, western Asia, North and South America, Asia; serotype 8 responsible for large outbreak in northern Europe in 2006–07; attenuated and killed vaccines are serotype specific Classical swine fever (CSF) Classical swine fever virus (Flaviviridae) Affects most members of Suidae family 3 genotypes and 11 sub-genotypes; including domestic pig (Sus domestica, genotype 2 most prevalent; enzootic in a.k.a. Sus scrofa scrofa) parts of Asia, parts of South and Central America; only 1 licensed vaccine to differentiate vaccinated from infected animals (DIVA) currently available Contagious bovine Mycoplasma mycoides subsp. mycoides Domesticated cattle (Bos taurus)and One of the most important cattle pleuropneumonia (CBPP) (Mycoplasmataceae) African buffalo (Syncerus caffer) infectious diseases in Africa; new primary hosts; also water buffalo recombinant, subunit vaccine to soon (Bubalus bubalis), yak (Bos grunniens), be launched by Kenya Veterinary and bison (Bos bison) Vaccines Production Institute Contagious caprine Mycoplasma capricolum subsp. Goat (Capra hircus), some evidence of Globally one of the most severe, pleuropneumonia (CCPP) capripneumoniae (Mycoplasmataceae) clinical cases in ibex (Capra ibex), contagious infectious diseases in gazelle (Gazella species), and oryx (Oryx goats; enzootic in many parts of Africa species) and Asia; bacterin vaccine available with mixed safety and efficacy results Epizootic haemorrhagic Epizootic hemorrhagic virus (Reoviridae) Numerous wild and domestic ruminants >8 serotypes; white-tailed deer highly disease (EHD) susceptible; Culicoides midge vector; serotypes 1, 2, 6 endemic in Northern America; also seen in South America, Caribbean, Australia, Asia, Africa and western Asia; live attenuated and killed cattle vaccines in Japan only Foot-and-mouth disease (FMD) Foot-and-mouth disease virus Numerous domestic and wild 7 major circulating serotypes; A, O and (Picornaviridae) ruminants; domestic pig (Sus Asia most prevalent; enzootic and domestica, a.k.a. Sus scrofa scrofa) epizootic in parts of Africa, Asia; more efficacious cross-serotype protective vaccines needed Lumpy skin disease (LSD) Lumpy skin disease virus (Poxviridae) Domesticated cattle (B. taurus), water Enzootic in most of Africa, parts of buffalo (Bubalus bubalis), African Western Asia and Turkey; transmitted buffalo (Syncerus caffer) mainly by arthropod vectors; live attenuated vaccines available but generally ineffective in enzootic areas Peste des petits ruminants Peste-des-petits-ruminants virus Red sheep (Ovis aries), goat (Capra hircus), Enzootic in parts of Africa and Asia, and (goat plague; PPR) (Paramyxoviridae) gazelle (Gazella spp.), impala (Aepyceros most of Western Asia; FAO/OIE global melampus), springbok (Antidorcas eradication vaccination program using marsupialis), ibex (Capra ibex), and live, attenuated vaccines is currently other antelopes, camels in progress Swine vesicular disease (SVD) Swine vesicular disease virus Domestic pig (Sus domestica, a.k.a. Sus Recent circulating strains often do not (Picornaviridae) scrofa scrofa) cause clinical signs; no licensed vaccines currently available Sheep pox (SPP) and goat pox Sheeppox virus (SPPV) and goatpox Red sheep (Ovis aries),goat(Capra hircus) SPPV mainly affects red sheep and GTPV (GTP) virus (GTPV) (Poxviridae) primarily affects goats, however some isolates can cause disease in both animals; enzootic in north/central Africa, parts of Western Asia, Turkey and Asia including Indian subcontinent; live, attenuated licensed vaccines available but need improvement aAll are OIE (World Organization for Animal Health)-listed diseases; https://www.oie.int/animal-health-in-the-world/technical-disease-cards/. Abbreviations: RG = Risk Group; FAO = Food and Agriculture Organization; OIE = World Organisation for Animal Health. 8 Brake et al.

Table 5 RG-3 and RG-4 Pathogen-Associated Endemic Zoonoses

Zoonotic Risk Agent (Family) Susceptible Livestock Comment a Disease Group Family

Anthrax 3 Bacillus anthracis Primarily Bovinae, but Adequate killed vaccines (Bacillaceae) also Equidae, Camelidae available Brucellosis 3 Brucella abortus Bovinae Live attenuated vaccines (Brucellaceae) available Brucella suis (Brucellaceae)Suidae,mainly Common in Asia and Latin Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 domesticated pig America; maintained in feral swine; no effective vaccines Brucella melitensis Caprinae (primarily red Most common brucellae in (Brucellaceae) sheep and goats), human illnesses; most Bovinae and Camelidae common in susceptible Southern/Eastern Europe, parts of Asia and South America; live attenuated vaccine has some safety issues Glanders 3 Burkholderia mallei Equidae (horse, mules, Bioterrorist threat; enzootic (Burkholderiaceae) ass), Camelidae in parts of Asia, Africa, and Central/South America; no vaccines available Qfever 3 Coxiella burnetii Caprinae (mainly red Global distribution; killed (Coxiellaceae) sheep and goats), also vaccines reduce but do not Bovinae, Cervidae eliminate shedding Tularemia 3 Francisella tularensis Caprinae Mainly Northern (Francisellaceae) Hemisphere, parts of Europe and western Asia; no vaccines available Rift Valley 3/4 Rift Valley fever virus Bovinae, Caprinae Endemic in sub-Saharan fever (Phenuiviridae) Equinae, Camelidae Africa, epidemics in northern Africa, western Asia; current killed and live attenuated vaccines lack safety and/or efficacy Middle East 4 MERS-CoV (Coronaviridae) Camelidae Western Asia; promising Respiratory human vaccines in Syndrome development West Nile 3 West Nile virus Equidae Rapid global spread since virus (Flaviviridae) 1990s; several vaccines infection available Venezuelan 3 Venezuelan equine Equidae Epizootic and enzootic equine encephalitis virus groups; killed vaccines encephalitis (Togaviridae) available Japanese 4 Japanese encephalitis Suidae, Equidae Currently expanding encephalitis virus (Flaviviridae) geographic range in Asia and western Pacific; vaccines available but not widely used Crimean- 4 Crimean-Congo Bovinae Caprinae, Animals asymptomatic; Congo hemorrhagic fever virus Camelidae widespread in Africa, Asia, hemorrhagic (Nairoviridae) also parts of Southern and fever Eastern Europe; no vaccines available Henipavirus 4 Hendra virus Equidae Emerging disease in encephalitis (Paramyxoviridae) Australia; horses are incidental hosts; recombinant subunit vaccine available Nipah virus Suidae, Caprinae Emerging disease endemic (Paramyxoviridae) in Southeastern Asia, at least 2 major strains; no vaccine available; human vaccine in Phase I aD. Brake, personal communication. Abbreviations: RG = Risk Group. Challenges and Opportunities in the Use of High and Maximum Biocontainment Facilities in Developing 9

Table 6 Additional Emerging Zoonoses for Veterinary Vaccine Development

Zoonotic Virus Virus Family Susceptible Livestock Species/Subspecies Comment 1

Alkhurma hemorrhagic Flaviviridae Redsheep(Ovis aries), goats (Capra hircus), Genetically related to KFDV; tick fever virus one-humped camel (Camelus dromedarius) vector Banna virus Reoviridae Domestic pig (Sus scrofa domesticus)and Mosquito vector cattle (Bos taurus) Bhanja virus Phenuiviridae African buffalo (Syncerus caffer), red sheep Tick vector

(Ovis aries), ass (Equus asinus), horse Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 (Equus ferus caballus), domesticated cattle (Bos taurus), water buffalo (Bubalis bubalis), one-humped camel (Camelus dromedarius) Borna disease viruses 1 Bornaviridae Ass (Equus asinus), redsheep(Ovis aries), Sad horse disease/Borna disease and 2 horse (Equus ferus caballus), alpaca (Vicugna pacos), guanaco (Lama glama)

Variegated squirrel Bornaviridae First reported in variegated squirrel bornavirus 1 breeders Dhori virus Orthomyxoviridae Goat (Capra hircus), red sheep (Ovis aries), Tick and mosquito vector horse (Equus ferus caballus), domesticated cattle (Bos taurus), one-humped camel (Camelus dromedarius) Dugbe virus Nairoviridae Redsheep(Ovis aries), domesticated cattle Tick vector (Bos taurus), water buffalo (Bubalis bubalis), one-humped camel (Camelus dromedarius) Eyach virus Reoviridae Goat (Capra hircus), red sheep (Ovis aries)Tickvector Kokoberra virus Flaviviridae Horse (Equus ferus caballus)Mosquitovector Kyasanur Forest disease Flaviviridae Goats (Capra hircus), redsheep(Ovis aries), Tick vector virus (KFDV) domesticated cattle (Bos taurus) Louping ill virus Flaviviridae Redsheep(Ovis aries), goats (Capra hircus), Tick vector; related to tick borne domestic pig (Sus scrofa domesticus), horse encephalitis virus (Equus ferus caballus), domesticated cattle (Bos taurus), red deer (Cervus elaphus), guanaco (Lama glama) Menangle virus Paramyxoviridae Domestic pig (Sus scrofa domesticus) Found in Australia; related to Tioman virus; fruit bats likely reservoir Murray Valley encephalitis Flaviviridae Horse (Equus ferus caballus) Found in Australia, South Pacific; virus mosquito vector Noroviruses Caliciviridae Domestic pig (Sus scrofa domesticus)and Possibility of domestic pig/human cattle (Bos taurus) isolate recombination O’nyong-nyong virus Togaviridae Goats (Capra hircus), redsheep(Ovis aries), Mosquito vector domesticated cattle (Bos taurus), one-humped cattle (Camelus dromedarius) Orf virus Poxviridae Goats (Capra hircus), redsheep(Ovis aries), Contagious ecthyma; first one-humped cattle (Camelus dromedarius), generation goat vaccines Cervidae spp. ineffective, lack of strain cross-protection Parechovirus B Picornaviridae Domestic pig (Sus scrofa domesticus) Formerly Ljungan virus Picobirnaviruses Picobirnaviridae Domestic pig (Sus scrofa domesticus)and Small double-stranded RNA virus; cattle (Bos taurus) gastroenteric and respiratory infections Sindbis virus Togaviridae Horse (Equus ferus caballus)Mosquitovector Tick-borne encephalitis Flaviviridae Goats (Capra hircus), redsheep(Ovis aries), Tick-borne; related to Omsk virus horse (Equus ferus caballus), domesticated hemorrhagic fever, Kyasanur cattle (Bos taurus) Forest disease, and Alkhurma viruses Tioman virus Paramyxoviridae Domestic pig (Sus scrofa domesticus) Antigenically related to Menangle virus Wesselsbron virus Flaviviridae Goats (Capra hircus), redsheep(Ovis aries), Mosquito vector domestic pig (Sus scrofa domesticus)and cattle (Bos taurus), horse (Equus ferus caballus), one-humped camel (Camelus dromedarius)

1J. H. Kuhn, personal communication. Abbreviations: RG = Risk Group; N/A = not applicable. 10 Brake et al.

Table 7 Livestock RG-3 and RG-4 Pathogens That May Serve as the Basis for Epizootic and Zoonotic Outbreaks From 2021–2030

Disease/Agent Zoonotic Family Susceptible Livestock Family a

African swine fever virus No Asfarviridae Suidae Foot-and-mouth disease virus No Picornaviridae Bovidae, Suidae, Caprinae Bluetongue virus (exotic serotypes) No Reoviridae Bovinae, Caprinae, Alcelaphinae Coxiella burnetii Yes Coxiellaceae Caprinae (mainly red sheep and goats), also Bovinae, Cervidae Rift Valley Fever Yes Phenuiviridae Bovinae, Caprinae, Camelidae, Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 Equidae Japanese encephalitis virus Yes Flaviviridae Suidae, Equidae Crimean-Congo hemorrhagic fever virus Yes Nairoviridae Bovinae, Caprinae, Camelidae Menangle virus Yes Paramyxoviridae Suidae Noroviruses Yes Caliciviridae Suidae, Bovidae aThe Center for Food Safety and Public Health (CFSPH); http://www.cfsph.iastate.edu.

scientists as well as the logistics of performing basic proce- candidates in veterinary animals, such as pigs, in parallel with dures (eg, animal handling, sedation, vaccine administration, the regulatory requirement of preclinical testing in nonhuman sample collection, and necropsy). Livestock studies in ABSL-4 primates. maximum biocontainment facilities pose significant challenges Finally, despite significant progress through ongoing efforts with respect to animal welfare compliance, physical space (eg, of the Veterinary International Conference on Harmonization extra-wide hallways and doors and additional protective gating), to closely coordinate the technical requirements for registering wet animal husbandry conditions associated with daily room veterinary vaccines (United States, Europe, and Japan),44 much cleaning, special necropsy rooms (large carcass movement and work is still needed. In the absence of full alignment between cold storage), and large carcass disposal (eg, alkaline hydrolysis the leading global regulatory agencies, significant delays in vet- digesters, specially designed incinerators, environmental per- erinary vaccine product licensure will continue for registrations mits). Specifically,FMDV poses challenges due to the time-bound in the emerging markets of Asia-Pacific and Africa, adding signif- physical distancing requirements from farms, livestock shows, icant global development costs to any RG-3/-4 veterinary vaccine etc. that staff need to follow outside of the work environment. program. Another major limitation is the general absence of veterinary species-specific immune reagents and assays to close knowl- Current Knowledge and Operational Gaps edge gaps in disease pathogenesis and host protective immune responses. A further challenge is the indispensable requirement There are currently more than 15 BSL-3 Ag high biocontainment for diverse livestock target hosts for disease model development and/or ABSL-4-like maximum biocontainment facilities located to enable vaccine safety and efficacy clinical studies. This need throughout the world that are capable of housing livestock in is particularly problematic for many of the indigenous animals support of RG-3/-4 veterinary vaccine development. A represen- listed in Table 3, many of which are difficult to obtain due to the tative facility list is summarized in Table 8. federal permit requirements to house in captivity for vaccine The only ABSL-4 facility with large-animal capabilities in R&D. In some instances, this hurdle has been overcome, as Europe is located at the Friedrich-Loeffler-Institut (FLI), Greif- evidenced by the use of bison, wild boars, warthogs, captive swald, Germany. Two independent large animal units, a necropsy deer, and camels in some large animal biocontainment facilities. room, a thermal tissue digester system for carcass treatment, Additionally, supporting model development in the intermedi- and the direct connection to a large BSL-4 laboratory allow exper- ate (amplifying) host and/or natural reservoir—which ideally iments with RG-4 zoonotic pathogens, such as Crimean-Congo includes bats, passeriform birds, and rodents—is possible but hemorrhagic fever virus or Ebola virus. Major challenges of the can be complicated, time consuming, and very expensive to work with livestock at the FLI include (1) animal handling in establish and perform in high/maximum biocontainment. More- general, (2) thorough cleaning and disinfection of animal hous- over, high/maximum biocontainment facility use of arthropod ing spaces, (3) the need for specially trained personnel, and (4) vectors (eg, mosquitoes, ticks, and various types of flies) must overall workload and time investment per animal experiment. meet defined guidelines.41 The Australian Centre for Disease Preparedness, formerly Due to the One Health concept and approach to human and known as the Australian Animal Health Laboratory, operated by animal vaccine development, another contemporary challenge the Commonwealth Scientific and Industrial Research Organi- is the competing practical and moral priorities of human/public sation (CSIRO) in Geelong, Australia, is an animal health facility health vs veterinary health. In addition, from a funding priority built with capabilities to handle livestock and other animals at perspective, government and private sector funding for human the highest biocontainment level. This facility has first-hand vaccine development for RG-3/-4 zoonoses far outweighs fund- experience in dealing with RG-4 pathogens in large animals, ing for veterinary vaccine TAD development. Thus, utilization including the seminal work on HeV discovery that led to product of high/maximum biocontainment facility space is prone to licensure of a HeV-targeted equine vaccine (see below). The the same disparity. The One Health approach emphasizes the unique set of challenges of working with animals as large as integration of animal and human health but does not provide horses in BSL-4 at Australian Centre for Disease Preparedness guidance on best implementation.42,43 However, the multitude of include space requirements, husbandry, and handling issues, zoonotic vaccines currently in human MCM development offers and the need for a highly skilled workforce that must be main- an excellent opportunity to test and evaluate these vaccine tained and available when needed. Challenges and Opportunities in the Use of High and Maximum Biocontainment Facilities in Developing 11

Table 8 Global Locations and Description of BSL-3 Ag- and ABSL-4-like Biocontainment Facilities With Capabilities to Support Large Livestock RG-3 and RG-4 Veterinary Vaccine R&Da

Facility Owner Location USA Equivalent Containment Levels

Plum Island Animal Disease Center US Department of Homeland New York, USA BSL-3Ag (livestock) (PIADC) Security National Biodefense Analysis and Maryland, USA ABSL-4 (includes CDC registration Countermeasure Center (NBACC) for small ruminants, calves, pigs) National Centers for Animal Health US Department of Agriculture Iowa, USA BSL-3Ag (livestock, wildlife) Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 (NCAH) United States Army Medical US Department of Defense Maryland, USA BSL-3Ag (small ruminants) Research Institute for Infectious Diseases (USAMRIID) Biosecurity Research Institute Kansas State University Kansas, USA BSL-3Ag (livestock, wildlife) Infectious Disease Research Center Colorado State University Colorado, USA BSL-3Ag (livestock, wildlife) Regional Biocontainment Lab Global Health Research Complex Texas A&M University Texas, USA BSL-3Ag (livestock, wildlife) Battelle Biomedical Research Battelle Memorial Institute Ohio, USA ABSL-3 Center (BRC) National Centre for Foreign Animal Canadian Government Manitoba, Canada BSL-3Agb(livestock) Disease (NCFAD) VIDO-Intervac University of Saskatchewan Saskatchewan, Canada BSL-3Agb(livestock) The Pirbright Institute Publicly funded (BBSRC) private Surrey, UK BSL-3Agb(livestock) company Wageningen BioVeterinary Wageningen University and Lelystad, the Netherlands BSL-3Agb(livestock) Research (WBR) Wageningen Research Foundation Institute of Virology and Swiss Federal Veterinary Office Bern, Switzerland BSL-3Agb(livestock) Immunoprophylaxis (IVI) Friedrich-Loeffler Institut (FLI) Federal Ministry for Food and Insel Riems, Germany BSL-3Agb(livestock) ABSL-4 Agriculture (livestock) National Institute of High Security Indian Council of Agricultural Madhya Pradesh, India BSL-3+c Animal Diseases (NIHSAD) Research Australian Centre for Disease Commonwealth Scientific and Victoria, Australia ABSL-4d (livestock) Preparedness (ACDP) Industrial Research Organization (CRISO) Harbin Veterinary Research Chinese Academy of Agricultural Harbin, China BSL-3Ag (livestock) ABSL-4 Institute (HVRI) Sciences (livestock) National Bio and Agro-Defense US Department of Agriculture Kansas, USA BSL-3Ag (livestock) ABSL-4 Facility (NBAF)e (livestock)

aD. Brake, personal communication; representative versus exhaustive list. bContainment Level 4 Agriculture (CL-4Ag) equivalent. cContainment Animal Wing. BSL3 containment with appropriate enhancements (eg, BSL-3 with respiratory protection, HEPA filtration, shower out); http://www.nihsad.nic.in/cont-ani-wing.html. dPhysical Containment Level 4 (PC 4) equivalent. eUSDA expects facility to be operational in 2023; https://www.usda.gov/nbaf. Abbreviations: RG = Risk Group; BSL = biosafety level; ABSL = animal biosafety level.

Beginning in 2023, the new National Bio and Agro-Defense strategic goals associated with international disease response, Facility in the United States45 will deliver ABSL-4 large-animal knowledge sharing and institutional cooperation, training, capabilities for the first time and replace the BSL-3 Ag facility at and scientific excellence. BSL4ZNet will continue to play an the Plum Island Animal Disease Center. important future role in strengthening operational capabilities BSL4ZNet, an international consortium established in 2016 at the One Health and science-biosafety interfaces. This will and funded by the Canadian Safety and Security Program,46 is allow international partnerships to drive One Health vaccine actively addressing knowledge and operational gaps in RG-3/-4 development and enable a new generation of RG-3/-4 veterinary zoonotic disease preparedness and response. BSL4ZNET is com- and human licensed vaccines through efficient global utilization prised of working groups of laboratory-based experts associated of high or maximum biocontainment facilities. with 11 high and/or maximum biocontainment animal and pub- Some knowledge gaps remain on how to effectively design, lic health laboratories, spanning 5 countries: Australia (CSIRO); implement, and execute successful RG-3/-4 veterinary vaccine Canada (Canadian Food Inspection Agency, Public Health Agency regulatory development plans in high/maximum containment, of Canada, Department of National Defence, and Global Affairs particularly for newer, next-generation, first-in-class vaccines. Canada); Germany (FLI); United Kingdom (Animal and Plant This is due in part to the relatively small number of RG-3/-4 Health Agency, The Pirbright Institute, and Public Health Eng- veterinary vaccines licensed, the majority of which are based on land); and the United States (Department of Agriculture [USDA], older, first-generation vaccine technology. This gap is especially Department of Homeland Security, Centers for Disease Control true for vaccine projects that use nonreplicating molecular- and Prevention). BSL4ZNET has 4 working groups encompassing based (eg, recombinant, protein subunit) or replication-deficient 12 Brake et al.

(eg, viral-vectored) vaccine platform approaches. Improvements have changed the investment calculus for private-sector vaccine are needed in the identification of pathogen-agnostic, rapid companies by removing the NPV paradigm that incorporates response vaccine platforms for target pathogens within each private-sector commercial sales. These PPPs have provided major epizootic, enzootic, and zoonotic virus family and within a guaranteed sales market and thus a sustainable incentive most species of a livestock family or subfamily. There also is a for biopharmaceutical companies to pull vaccine candidates need for a more robust decision-tree analysis flow to determine through development to product licensure. GALVmed is whether high or maximum biocontainment is more appropriate currently the largest PPP exclusively dedicated to RG-3 livestock for certain pathogens and disease models. (Note: globally, risk vaccines for numerous TADs (ASF, contagious bovine pleurop- group pathogen classification does not translate 1-to-1 to bio- neumonia [CBPP], contagious caprine pleuropneumonia, FMD, Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 containment level requirements.) In addition, there are numer- and lumpy skin disease) and zoonotic pathogens (brucellosis, ous operational gaps in understanding the types of nontradi- Q fever, and RVF).57 GALVmed collaborated with another PPP, tional indigenous livestock (Table 3) that can be studied safely AgResults,58 to launch the Brucellosis Vaccine Initiative59 in high/maximum biocontainment environments. Finally, from and incentivize animal health vaccine companies and other a One Health perspective, significant knowledge gaps remain in institutions to develop improved brucellosis small ruminant TAD and zoonotic disease pathogenesis in each affected animal vaccines for developing countries. Another active PPP is the and how to best prioritize R&D for the relatively long list of Livestock Vaccine Innovation Fund (LVIF), a tripartite entity current RG-3 and RG-4 veterinary vaccine targets. comprised of the BMG Foundation, Global Affairs Canada, and the International Development Research Centre.60 LVIF supports Current Veterinary Biologics Companies innovative vaccine development and production to improve livestock health and small farmer livelihood in sub-Saharan in the Field Africa. There are also several additional PPP livestock consortia All 5 of the leading global veterinary vaccine companies have comprised of government laboratories, nonprofit government active TAD, EID, and One Health programs. These efforts will con- organizations, and industry partners—such as Defend,61 the tinue to have a meaningful impact on One Health and food secu- Global African Swine Fever Research Alliance,62 and the Global rity.47,48 Zoetis features a Center for Transboundary and Emerg- Foot-and-Mouth Disease Research Alliance.63 ing Diseases and focuses on specific RG-3 TAD and zoonotic virus 49 agents. Zoetis was the first company to develop and license RG-3/-4 Livestock Vaccine Case History an RG-4 veterinary vaccine (Equivac HeV against HeV-caused equine disease).50 Boehringer Ingelheim Animal Health runs The current landscape of RG-3/-4 large animal licensed vaccines an active veterinary public health business unit that engages is relatively limited with respect to both pathogen type and governments, nonprofit government organizations, and private animal host. A few notable examples are detailed below. partners to fund TAD prevention and control programs that impact public health.51 Merck Animal Health has teamed with WNV (RG-3) the Washington State University Paul G. Allen School for Global Several WNV equine vaccines have been successfully developed Animal Health and other international partners on a Rabies in the United States over the past 15 years. The first inactivated Free Africa program that has provided over a million doses of WNV vaccine received a USDA license in 2003.64 A recombinant rabies vaccine.52 Elanco supports a Healthy Purpose program,53 live canarypox-vectored vaccine received USDA approval a year and Ceva Sante Animale has important RG-3 veterinary vaccine later and confers protection following a single dose.65 A plasmid programs focusing on Q fever and brucellosis.54 DNA vaccine was licensed by the USDA in 2005 but was with- There is rarely significant financial incentive for any single drawn from the market.66 A live chimeric vaccine, based on a animal health biopharmaceutical company to bring a new yellow fever virus backbone, was also developed and licensed in RG-3/-4 veterinary vaccine to the market. The involvement 2006.67 In the United States, the WNV fraction is often included of public-private partnerships (PPPs) in the TAD and zoonotic as part of a larger multivalent equine vaccine that includes other disease health sectors is more than 5 years old and was zoonotic viruses, such as eastern equine encephalitis virus and primarily started based on the recognition that the myriad of western equine encephalitis virus. These WNV vaccines illus- RG-3 and RG-4 human disease threats could not be tackled trate that RG-3 innovative veterinary vaccines can be developed by government agencies alone. PPPs promote sustainable under the One Health banner. business models that allow for innovation in bringing new products to the market. The 2013–2016 Ebola virus disease Coxiella burnetii (RG-3) outbreak in Western Africa is the first clear example of a PPP successfully delivering a human vaccine solution to an First-generation inactivated licensed vaccines for Q fever to emerging zoonotic disease. The Global Alliance for Vaccines reduce the incidence of abortion in cattle, red sheep, and goats and Immunization (GAVI),55 with sustainable funding provided are marketed in Africa, Asia, Australia, and parts of Europe. Many by multiple partners, including the Bill & Melinda Gates (BMG) of these vaccines have a marginal safety profile and fail to pre- Foundation, World Bank, and Merck Sharp & Dohme, worked to vent bacterial shedding through vaginal discharge, placenta (a develop and produce an investigational vaccine that was used major route in zoonotic transmission), and milk. Safer and more in the Democratic Republic of the Congo. Similarly, launched efficacious second-generation vaccines for Q fever are urgently in 2017, the Coalition for Epidemic Preparedness Innovations needed. A consortium named Q-VaxCelerate was established to (CEPI)56 supports the development of human vaccines to prevent develop and produce a new vaccine68 along with a One Health Lassa fever, henipavirus encephalitis, Middle East respiratory approach for control of Q fever.69 During the 2007–2009 human syndrome, and most recently COVID-19. CEPI is a global PPP outbreak of Q fever in the Netherlands, a policy decision was leader in zoonotic disease vaccine programs, with support from made to use a livestock vaccination with the goal of reducing 2 national governments, the Wellcome Trust, BMG Foundation, the number of human cases.70 These authors concluded that and the World Economic Forum. These and numerous other PPPs vaccination under field conditions contributed to a reduction in Challenges and Opportunities in the Use of High and Maximum Biocontainment Facilities in Developing 13

C. burnetii shedding in dairy goat and red sheep and a reduction need for commercial product sales in the private sector to gener- risk of human exposure. ate ROI. There is a clear opportunity to weigh investments in RG- 3/-4 veterinary vaccine candidate development as part of a coor- dinated One Health benefit in which each component—humans, Mycoplasma mycoides subsp. mycoides (RG-3) domesticated and indigenous (semi-domesticated/tame in- CBPP is one of the most devastating livestock diseases in captivity animals) livestock, and wildlife—all benefit within the Africa and Asia. Along with high morbidity and mortality, same ecosystem. Overlay the heretofore untapped opportunity CBPP, together with contagious caprine pleuropneumonia, its to apply the relatively well-established safety and efficacy sister disease in goats, has adverse livelihood and well-being properties of virus family-specific vectored vaccine platforms Downloaded from https://academic.oup.com/ilarjournal/advance-article/doi/10.1093/ilar/ilab004/6169308 by guest on 27 September 2021 impacts on small farm holders in many LMICs. A notable recent that have been recently developed to target human diseases, achievement among the RG-3 TAD diseases listed in Table 4 and there is now significantly less technical risk associated with is the development of a recombinant subunit CBPP vaccine RG-3/-4 veterinary vaccine development and product licensure through a highly successful PPP. The Canadian International compared with a decade ago. Food Security Research Fund, Kenya Veterinary Vaccines There is also an opportunity to directly test and evaluate Production Institute, Kenya Agricultural and Livestock Research EID and zoonotic human vaccine candidates for safety and Organization, the International Livestock Research Institute, and efficacy in veterinary livestock disease models. This presents a the University of Saskatchewan’s Vaccine and Infectious Disease favorable circumstance for the high/maximum biocontainment Organization—International Vaccine Centre all collaborated on global facilities to forge international collaborations for RG-3 and this program.71 RG-4 agent prioritization and establishment of high/maximum biocontainment facility-specific One Health vaccine develop- HeV (RG-4) ment programs for a specific subset of pathogens. Moreover, new opportunities exist to coordinate the parallel development ® The relatively rapid development and launch of the Equivac of veterinary and human vaccine candidates, assuming that the HeV vaccine in late 2012 was a remarkable achievement, pro- investment supports the target outcome. Although the strategic pelled by initial positive results from the US Uniformed Services implementation of this concept among public health and animal University of the Health Sciences. The subsequent formation health government agencies has yet to be achieved, the syner- of a PPP comprised of US Uniformed Services University of gies of co-parallel human and veterinary vaccine development the Health Sciences, the Henry M. Jackson Foundation for the for TADs and zoonotic diseases are numerous. Advancement of Military Medicine, CSIRO’s Australian Centre for Disease Preparedness, and Zoetis accelerated the program through regulatory approval by the Australian Pesticides and Conclusions 50 Veterinary Medicines Authority. Additional funding was pro- There is an unmet commercial need for highly effective and vided by the National Hendra Research Program to implement safe RG-3 and RG-4 veterinary vaccines for numerous epizootic the One Health concept of horse vaccination to break the HeV and enzootic TADs and zoonotic diseases currently present in transmission chain from flying foxes through horses to humans. livestock populations throughout sub-Saharan Africa, Asia, and Southeastern Asia. These regions represent the fastest-growing markets for new Opportunities livestock vaccines for small ruminants and indigenous live- Over the past few years, there has been a coalescence of new stock—animals that serve as the engine for human economic market drivers for RG-3 and RG-4 veterinary vaccines for TADs prosperity and well-being in most LMICs. RG-3 and RG-4 veteri- and zoonotic diseases, including (1) emerging rapidly growing nary vaccine R&D in high and maximum biocontainment facil- product markets, specifically in Southeastern Asia and sub- ities has historically been challenging, particularly for livestock Saharan Africa; (2) an increased frequency and magnitude of vaccines. Traditional vaccine development based on inactivated EIDs and human zoonoses; and (3) favorable changes in NPV whole virus is problematic due to the inherent need for BSL-3 paradigms, principally due to One Health and PPP supported or BSL-4 manufacturing facilities and the associated expense for programs. The net result has created new entrepreneurial oppor- their safe operation. RG-3 and RG-4 veterinary vaccine R&D in tunities to creatively rethink why, how, and where RG-3/-4 vet- thenextdecadeshouldpreferablybebasedonmodernconcepts erinary vaccine development and product licensure should be like recombinant protein or molecular vectored subunit vaccine expanded and accelerated. platforms that have been shown safe and effective for human Global population growth and urbanization is linked to agri- EID and zoonotic vaccine development. However, individual ani- cultural transitions in food animal production. Food animal mal biopharmaceutical companies do not have the sufficient industrialization has supported the rural to urban population bandwidth or funding for sustained investments in RG-3 and migration in high-income countries over the past 30 years, and RG-4 veterinary vaccine development and product licensure. this same trend is now increasing in LMICs. LMICs in South- PPPs with a One Health mission can serve as the catalyst eastern Asia and sub-Saharan Africa have the dual problem of of change by significantly reducing the traditional hurdles high-density human and animals populations sharing confined and market barriers to entry for individual companies. PPP- conditions in larger vertical integration settings (such as in the incentivized direct engagement with high/maximum biocon- swine industry), along with intensive agriculture-led deforesta- tainment facilities can actualize vaccine testing and evaluation tion practices, reducing and isolating wildlife habitats. Collec- in livestock. This can enable early “go/no go” decision points tively, these practices have been linked in certain geographic for the further vaccine development with reduced technical settings to increases in epizootic and enzootic TADs as well as risk. Aided by PPP investments, transfer of RG-3 and RG-4 zoonotic disease outbreaks in humans. veterinary vaccine manufacturing technologies to regional There has been a disruption in NPV paradigms for RG-3/-4 veterinary vaccine companies in Africa and Asia can further vaccine development traditionally associated with the driving increase vaccine manufacturing capacity. Licensed vaccine 14 Brake et al.

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