Human vs. veterinary clinical trials and phases of research for regulatory approval Although much is still unknown, huge gains have been made in understanding of immunity, genomics, and systems biology that have led to the development of new vaccine technologies (i.e. new platforms) better positioned to address the need for expedited response to changing and emerging pathogens.1-3 In human vaccine research, researchers’ objectives differ by research phase (Figure 1).4–7 Figure 1. Phases of vaccine clinical trials and their phase-specific endpoints within the process of licensing commercial vaccines for human versus veterinary markets22*Correlates of protection (CoP) = indirect measures of vaccine effects (e.g. immunoglobulin titers, cytokine or cell-mediated responses) validated through correlation with direct measures (e.g. infection or clinical disease);†Challenge virus exposure = controlled purposeful exposure of live animals to the pathogen); Natural virus exposure = study units exposed to the pathogen naturally;‡ Same-species challenge = exposing the intended market species to the pathogen (rare in human vaccine research, standard in veterinary vaccine research. Phase 0 is a “proof-of-concept” stage for candidate vaccines. In Phase I and II clinical trials, researchers identify correlates of protection (CoPs) to measure vaccine efficacy, assess safety, and determine the optimal dose and frequency of administration. CoPs are often validated using Phase IIb challenge trials in animal models (optimally, same-species challenge models).8–10 Historically, serologic assays are standard CoPs, but understanding of immune responses is incomplete; therefore, multiple outcomes must be assessed to accurately predict vaccine performance.11,12 Use of live vaccines and newer vaccine technologies means more technically complex cell-mediated CoPs and also direct measures of virus infection are needed to assess protection.13–16 Although rare in human medicine,17,18 same-species challenge trials are frequently reported as a study design and are often pivotal for licensing of veterinary vaccines. Phase III clinical trials are larger, involve natural exposure of the target population, and provide evidence of efficacy and safety. Manufacturers of human and veterinary vaccines must demonstrate efficacy, safety, purity, and potency to obtain licensing and approval for commercial use. Human vaccine manufacturers must additionally conduct Phase IV post-marketing clinical trials to demonstrate that vaccines perform as expected in ‘real life’ populations (i.e. vaccine effectiveness). Autogenous vaccines are tested for safety and purity but not for efficacy. They are a specific class of conditionally approved veterinary vaccines commonly used in livestock species to protect against viral diseases. Their use is restricted to populations under direct veterinary oversight, and they fill voids where otherwise no commercial vaccine is available or sufficient.19,20 In comparison to human vaccines, approval of veterinary vaccines is expedited because: 1) fewer restrictions govern the conduct of same-species challenge trials;18,20,21 2) veterinary vaccines are commonly approved based on Phase IIb trials; 3) post-marketing evaluation of vaccine performance (i.e. Phase IV trials) is not required,21 and 4) a regulatory framework exists for restricted use of non-licensed autogenous vaccines.20 GettyImages/MachineHeadz To vaccinate or not to vaccinate? Is there a difference between guidelines based on science and evidence-based guidelines? There is, and it is nuanced and important. The Oxford Dictionary defines synthesis as the act of bringing together parts or elements to form a complex whole. “Based on science” is a generic term often used without qualifying the methods used for critical appraisal and synthesis of the scientific evidence upon which recommendations are made. However, within the knowledge translation community of practice, the term “evidence-based” specifically implies application of globally established and standardized methods for synthesizing relevant information to produce recommendations that are inclusive, rigorous, transparent, and accessible.23,24 Evidence-based methods for systematic review and meta-analysis were first developed to address contradictory opinions on human medical treatments.25 Methods have been stress-tested and evolved over decades to become standard practice for informing policy and guideline development in human medicine and, more recently, in other disciplines.26 Systematic review is a process to inventory, characterize, and critically appraise the body of available evidence, to identify gaps, trends, or patterns in the evidence, and then finally to pull it all together to help decision-makers understand the overall quality of available evidence and level of certainty of how a treatment is expected to perform when applied in their clinical situation.27 Getting our arms around vaccine research It is challenging to make sense of veterinary vaccine research when developing vaccination guidelines because: There is an abundance, or more often, a dearth of available and relevant research (Figure 2) Vaccine protection is a broad and often poorly defined term28–30 New and sophisticated vaccine platform technologies have entered the commercial marketplace2,3 (Figure 3) No single outcome can convey protection against infection or disease31 Researchers investigate vaccine performance differently depending on the phase of research and purpose of each study (Figure 4)4,21,32 Researchers are not incentivized to conduct post-marketing vaccine effectiveness studies and therefore too few are available.4,21 Too few systematic reviews of vaccine performance are available Figure 2. An evidence-based method called a scoping review was used to search, screen for relevance, and characterize the available science on a given medical intervention. The numbers are based on real data from a scoping review that identified and characterized all influenza vaccine studies conducted from 1990 to 2018 in swine species.33 The online and manual search of six bibliographic databases and conference proceedings netted over 18,000 publications. After screening out duplicates and other ‘noise’ we were left with 376 relevant studies. Figure 3. This is the dispersion of the 379 studies identified in Figure 1.33 Each row of bubbles represents a different vaccine type (experimental or commercially approved) and platform (killed, live, or other next generation). Bubbles with hashed lines are commercial vaccine products; solid-shaded bubbles are experimental vaccines. The size of the bubble indicates the number of studies conducted during the corresponding year (x-axis). There was a big increase in the number of studies following the 2009 influenza pandemic. From Keay et al 2020.33 Figure 4. Essential research elements considered for each phase of vaccine research.Researchers independently make a myriad of decisions when designing their studies to align selected outcomes with the research phase and stated objectives. This independence contributes to methodologic heterogeneity between studies and complicates efforts to synthesize research. Modified from Keay 2022.34 In an ideal world, veterinary vaccination guidelines are evidence-based, regionally specific, and include the full complement of vaccine programs. However, few systematic reviews are available, so pragmatically, vaccine guideline issuers seek other processes for reaching consensus. The authors of the 2024 WSAVA Dog and Cat Vaccination Guidelines succinctly described this situation as follows:35 “These guidelines are based on published, peer-reviewed evidence wherever possible, but also, unavoidably, on unpublished or non-peer-reviewed scientific evidence and on expert opinions. Given the remarkable breadth of material to be covered in a single document, a narrative review format has once again been adopted as the only one suitable to the task.36 The same format has been chosen by all other international companion animal vaccination guidelines authoring teams.37–39 Use of a systematic review format or a formal, structured approach to reach consensus recommendations based on the Delphi process was considered by the VGG (Vaccination Guidelines Group) when planning this update.40 These approaches were quickly deemed inapplicable given the breadth of material intended to be covered in a single document and the size of the authoring team. Nevertheless, these recommendations are based on the strongest scientific evidence that was found.” So where does this leave us? The good news is that awareness and support of evidence-based methods is growing. Systematic reviews are useful not only to inform practice guidelines,41 but just as importantly to highlight where greater harmonization of the elements of vaccine research is warranted to “allow more reliable comparisons between studies and provide clearer guidance for the development of effective and clinically viable vaccines.”42 Recently, the European Cooperation in Science and Technology (COST) funded the European Network for Optimization of Veterinary Antimicrobial Treatment (ENOVAT) to develop the first evidence-based antimicrobial use guidelines for the international veterinary community (anticipated to include six treatment guidelines applicable across five species groups).43–46 The project involved more than 330 persons from 51 countries and was a massive investment to build crucial capacity in the field of guidelines methodology in veterinary medicine, “a field currently dominated by consensus statements.”47 Specifically, a large group of veterinary professionals were trained in conducting systematic and scoping reviews; both are essential components of evidence-based guidelines.47 Further, ENOVAT built expertise in the GRADE48 methodology for assessing the quality and strength of the body of evidence, which is largely unknown in veterinary medicine but has been adopted by many global guideline issuers, including the World Health Organization and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID). Taken together, ENOVAT’s success “helps to ensure capacity for future development of evidence-based guidelines in veterinary medicine, and it constitutes a platform for education of additional experts within this area.”47 The importance of ENOVAT’s contribution to veterinary medicine cannot be understated. They provided a template and built the infrastructure needed for future collaborative development of evidence-based guidelines in veterinary medicine. Sheila Keay, DVM, MBA, MPH, PhD, graduated from the Ontario Veterinary College (OVC), Ontario, Canada, in 1996 and has lived, worked, and studied across four countries, on three continents, and in various capacities. Dr. Keay returned to OVC to complete her PhD in Epidemiology in 2022, with a focus on knowledge translation and influenza A virus vaccine research in swine. 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