key: cord-0724181-xupfh6wd authors: Gurwith, Marc; Condit, Richard C.; Excler, Jean-Louis; Robertson, James S.; Kim, Denny; Fast, Patricia E.; Drew, Stephen; Wood, David; Klug, Bettina; Whelan, Mike; Mallett Moore, Tamala; Khuri-Bulos, Najwa; Smith, Emily R.; Chen, Robert T; Kochhar, Sonali title: Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) standardized template for collection of key information for benefit-risk assessment of live-attenuated viral vaccines date: 2020-10-16 journal: Vaccine DOI: 10.1016/j.vaccine.2020.09.042 sha: d452f6eac230598e4916a35e534da734770a6971 doc_id: 724181 cord_uid: xupfh6wd Several live-attenuated viral vaccine candidates are among the COVID-19 vaccines in development. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) has prepared a standardized template to describe the key considerations for the benefit-risk assessment of live-attenuated viral vaccines. This will help key stakeholders assess potential safety issues and understand the benefit-risk of such vaccines. The standardized and structured assessment provided by the template would also help to contribute to improved communication and support public acceptance of licensed live-attenuated viral vaccines. The Brighton Collaboration (www.brightoncollaboration.org) was launched in 2000 to improve the science of vaccine safety [1] . The Brighton Collaboration formed the Viral Vector Vaccines Safety Working Group (V3SWG) in October 2008 to improve the ability of key stakeholders to anticipate potential safety issues and meaningfully assess or interpret safety data, thereby facilitating broader acceptance when viral vaccines are licensed [2] . One of the tools developed by the V3SWG is a standardized template describing the key considerations for benefit-risk assessment of viral vaccines. Completed by the vaccine developers/sponsors, it will be peer reviewed by the V3SWG and published. The information on the template may facilitate communication of otherwise complex and highly technical data among key stakeholders (some of whom may lack subspecialized training in biotechnology) and increase the transparency, comparability, and comprehension of essential information. A similar template has been used for the standardized risk-assessment of several new viral vector vaccines [3] [4] [5] , including some targeting Ebola. The WHO Global Advisory Committee on Vaccine Safety (GACVS) endorsed the use of the template for other new candidate Ebola vaccines ''as it is a structured approach to vaccine safety" [6] . In 2020, the development of vaccines for COVID-19 is occurring with unprecedented speed [7] . The pace and volume of development make a deliberate and systematic approach that is accessible and understandable to a diversity of stakeholders all the more important. Live-attenuated viral vaccine candidates are among the COVID-19 vaccines in development [8] . The Brighton Collaboration V3SWG has therefore developed a specific template for live-attenuated vaccines that vaccine developers and other key stakeholders can use to evaluate and communicate the benefitrisk of such vaccines. See Supplementary Material for definitions and additional guidance for completing this template. Live-attenuated viral vaccines are among the most successful types of vaccines developed to date. They consist of a modified version of the virus against which protection is sought. The vaccine viruses replicate in the vaccinee; while generally not causing disease nor symptoms, and are able to stimulate a protective immune response [9] . In the development of such a vaccine, attenuation and immunogenicity have to be balanced carefully [10, 11] . Liveattenuated vaccines are usually contraindicated in individuals with impaired immunity. Additionally, some live-attenuated viral vaccines are shed from vaccinees and could present a risk to unvaccinated individuals with impaired immunity. Live-attenuated viral vaccines have been classically developed by multiple passages of a wild type specimen in vitro in a variety of cell lines, in vivo in animals or in ovo, whereas today liveattenuated vaccines are generally created by genetic engineering. For viruses with segmented genomes, live-attenuated vaccine viruses have been generated by directed or engineered reassortment of the genomes of different strains. The success of live-attenuated vaccines is based on the fact that the immune response to the attenuated vaccine virus mimics closely the response resulting from natural infection. Examples of successful live-attenuated viral vaccines include those targeting polio, mumps, measles and rubella; now part of childhood immunisation programmes; and influenza, varicella, yellow fever and, of course, vaccinia, that was used for the eradication of smallpox [10, 11] . Compared with other types of vaccines, attenuated viral vaccines usually require considerably more time to develop and test. This is due to the need to demonstrate not only safety and immunogenicity in the vaccinees; but also to demonstrate safety in immunologically vulnerable populations, such as infants and the immunosuppressed, as well as lack of transmission and/or occurrence of disease particularly in vulnerable contacts of the vaccine; such as immunosuppressed or pregnant contacts. Additionally, while transmission to contacts may even be seen as a benefit in some mass vaccination programs, there are potential concerns about reversion to less attenuated variants if there is ongoing transmission of the vaccine in the community. In some instances there may be a need to demonstrate lack of transmission to non-human animals. The V3SWG intends that this template focuses on key questions related to the essential safety and benefit-risk issues relevant for the intrinsic properties of the vaccine components. Although we recognize that other aspects of manufacturing, quality, and implementation can play an important role in the safety of a vaccine, we have chosen to keep some of those issues out of scope of this template in order to summarize the most useful information for stakeholders. The latest version of the template can be accessed on https:// brightoncollaboration.us/v3swg/. Developers of live-attenuated vaccines are encouraged to complete the template for their vaccine candidate and collaborate with the V3SWG. The draft template will be shared for review by the V3SWG and submitted for publication. Similarly, updates to the template by the vaccine developer should be submitted to the Brighton Collaboration website for V3SWG review. Please read these instructions before you complete the nine sections. Send questions to: bc-coordinator@taskforce.org The first section entitled ''Authorship" should include your name and the latest date completing the form. If you are working with someone else to complete this form, their name should be provided as well. If you are updating the form, please provide the updated date. These co-authors will be included in the final published template in Vaccine once reviewed and approved by the V3SWG and in subsequent Wiki updates on the V3SWG website. Sections 2-8 collect information regarding the basic vaccine information (Section 2), the target pathogen and population (Section 3), characteristics of attenuated vaccine virus (Section 4), delivery and administration (Section 5), toxicology and nonclinical (Section 6), and human efficacy and other important information (Section 7). Depending on the vaccine, some sections may be redundant or not applicable. In cases of redundancies, an answer may simply refer to the answer in a previous section. Answer questions by responding in the column entitled 'Information.' If you have any comments or concerns regarding the question or your answer to the question, note these in the 'Comments/Concerns' column. Finally, please provide references in the 'Reference' column. More than one reference can be used per question. You can simply write the first author's last name, first name initials, and year of publication (e.g., Lewis M. Gurwith, R.C. Condit, Jean-Louis Excler et al. Vaccine xxx (xxxx) xxx MH, 2003) in the ''Reference" column here, but please provide the full citation for the reference at the end of the form. Unpublished data are acceptable, though we do wish for you to include the source and contact information. Sections 8 and 9 have column titles that differ from preceding sections intended to provide a summary assessment of adverse effects and toxicity of the vaccine. Please summarize adverse effects and toxicities as requested and rate the risk in the following fashion: none, minimal, low, moderate, high, or unknown. If there is insufficient data for use of the platform in humans to accurately make these assessments, please state so in response to the questions. When completing information on adverse effects in Section 9, please provide as many details as possible based on the Brighton Collaboration Guidelines for collection, analysis and presentation of vaccine safety data in pre-and post-licensure clinical studies [12] . If a literature search was conducted to complete any of the Sections (strongly encouraged), please add the following information in the Reference(s) column: 1) time period covered (e.g., month/year to month/year); 2) Medical Subject Headings (MeSH) terms used; 3) the number of references found; and 4) the actual references with relevant information used. For prior published templates, please search PubMed for ''Brighton Collaboration V3SWG". The findings, opinions, conclusions, and assertions contained in this consensus document are those of the individual members of the Working Group. They do not necessarily represent the official positions of any participant's organization (e.g., government, university, or corporations) and should not be construed to represent any Agency determination or policy. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The Brighton Collaboration: addressing the need for standardized case definitions of adverse events following immunization (AEFI) The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) Live virus vaccines based on a yellow fever vaccine backbone: standardized template with key considerations for a risk/benefit assessment Live virus vaccines based on a vesicular stomatitis virus (VSV) backbone: Standardized template with key considerations for a risk/benefit assessment rVSVDG-ZEBOV-GP (also designated V920) recombinant vesicular stomatitis virus (continued) Brighton Collaboration Standardized Template for Collection of Key Information for Benefit-Risk Assessment of Live Attenuated Viral Vaccines For regular version Adverse Event (AE) Assessment of the Vaccine Platform (*see Instructions Overall Risk pseudotyped with Ebola Zaire Glycoprotein: Standardized template with key considerations for a risk/benefit assessment Global Advisory Committee on Vaccine Safety The COVID-19 vaccine development landscape Rapid COVID-19 vaccine development Live attenuated vaccines: Historical successes and current challenges Attenuated Vaccines for Augmented Immunity Rationalizing the development of live attenuated virus vaccines Guidelines for collection, analysis and presentation of vaccine safety data in pre-and post-licensure clinical studies Vaccine xxx (xxxx) xxx We thank the following colleagues for their helpful advice: Brighton Collaboration members. We acknowledge the financial support provided by the Coalition for Epidemic Preparedness Innovations (CEPI) for our work under a service order entitled Safety Platform for Emergency vACcines (SPEAC) Project with the Brighton Collaboration, a program of the Task Force for Global Health, Decatur, GA.