Vaccines based on the replication-deficient simian adenoviral vector ChAdOx1: Standardized template with key considerations for a risk/benefit assessment.

Replication-deficient adenoviral vectors have been under investigation as a platform technology for vaccine development for several years and have recently been successfully deployed as an effective COVID-19 counter measure. A replication-deficient adenoviral vector based on the simian adenovirus type Y25 and named ChAdOx1 has been evaluated in several clinical trials since 2012. The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) was formed to evaluate the safety and other key features of new platform technology vaccines. This manuscript reviews key features of the ChAdOx1-vectored vaccines. The simian adenovirus Y25 was chosen as a strategy to circumvent pre-existing immunity to common human adenovirus serotypes which could impair immune responses induced by adenoviral vectored vaccines. Deletion of the E1 gene renders the ChAdOx1 vector replication incompetent and further genetic engineering of the E3 and E4 genes allows for increased insertional capability and optimizes vaccine manufacturing processes. ChAdOx1 vectored vaccines can be manufactured in E1 complementing cell lines at scale and are thermostable. The first ChAdOx1 vectored vaccines approved for human use, against SARS-CoV-2, received emergency use authorization in the UK on 30th December 2020, and is now approved in more than 180 countries. Safety data were compiled from phase I-III clinical trials of ChAdOx1 vectored vaccines expressing different antigens (influenza, tuberculosis, malaria, meningococcal B, prostate cancer, MERS-CoV, Chikungunya, Zika and SARS-CoV-2), conducted by the University of Oxford, as well as post marketing surveillance data for the COVID-19 Oxford-AstraZeneca vaccine. Overall, ChAdOx1 vectored vaccines have been well tolerated. Very rarely, thrombosis with thrombocytopenia syndrome (TTS), capillary leak syndrome (CLS), immune thrombocytopenia (ITP), and Guillain-Barre syndrome (GBS) have been reported following mass administration of the COVID-19 Oxford-AstraZeneca vaccine. The benefits of this COVID-19 vaccination have outweighed the risks of serious adverse events in most settings, especially with mitigation of risks when possible. Extensive immunogenicity clinical evaluation of ChAdOx1 vectored vaccines reveal strong, durable humoral and cellular immune responses to date; studies to refine the COVID-19 protection (e.g., via homologous/heterologous booster, fractional dose) are also underway. New prophylactic and therapeutic vaccines based on the ChAdOx1 vector are currently undergoing pre-clinical and clinical assessment, including vaccines against viral hemorrhagic fevers, Nipah virus, HIV, Hepatitis B, amongst others.

International Nonproprietary Names (INN) for novel vaccine substances: A matter of safety.

International Nonproprietary Names (INN) are assigned by the World Health Organization (WHO) to pharmaceutical substances to ensure global recognition by a unique name. INN facilitate safe prescribing through naming consistency, efficient communication and exchange of information, transnational access and pharmacovigilance of medicinal products. Traditional vaccines such as inactivated or live-attenuated vaccines have not been assigned INN and provision of a general name falls within the scope of the WHO Expert Committee on Biological Standardization (ECBS). However, novel vaccines that contain well-defined active ingredients such as nucleic acids or recombinant proteins fulfil the criteria to be assigned INN. In the current environment where multiple SARS-CoV-2 vaccines are being developed to combat the COVID-19 pandemic and with virus variants emerging, assigning INN to well-defined vaccine substances will strengthen pharmacovigilance and ultimately enhance the safety of vaccine recipients. This article examines the background to INN for vaccines and explains the applicability and value of assigning INN to novel well-defined vaccines.

The harmonization of World Health Organization International Nonproprietary Names definitions for cell and cell-based gene therapy substances: when a name is not enough.

The World Health Organization (WHO) assigns International Nonproprietary Names (INN) to pharmaceutical substances, including advanced therapy medicinal products, to ensure that each substance is globally recognized by a unique name. The majority of INN are published in the WHO Drug Information in accordance with the nomenclature rules of the International Union of Pure and Applied Chemistry. However, advanced therapy medicinal products, and in particular cell therapy and cell-based gene therapy substances, cannot be defined by such chemical nomenclature. Instead, they are published together with a textual definition paragraph to unambiguously describe their characteristics. These definitions are an integral part of the INN nomenclature system, and their presence contributes to pharmacovigilance and patient safety, as they help to distinguish regulated substances from cell-based interventions that have no INN and are marketed without regulatory oversight. Particular attention is therefore allocated to these descriptive paragraphs, as they form the basis for defining the uniqueness of a particular cell substance. This review describes the INN nomenclature system for cell-based substances and focuses on the progress made by the WHO INN Programme to develop and harmonize these definition paragraphs, which is reflected in a newly revised INN application form for cell therapy substances.

The Brighton Collaboration standardized template for collection of key information for risk/benefit assessment of a Modified Vaccinia Ankara (MVA) vaccine platform.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and characteristics of live, recombinant viral vector vaccines. The Modified Vaccinia Ankara (MVA) vector system is being explored as a platform for development of multiple vaccines. This paper reviews the molecular and biological features specifically of the MVA-BN vector system, followed by a template with details on the safety and characteristics of an MVA-BN based vaccine against Zaire ebolavirus and other filovirus strains. The MVA-BN-Filo vaccine is based on a live, highly attenuated poxviral vector incapable of replicating in human cells and encodes glycoproteins of Ebola virus Zaire, Sudan virus and Marburg virus and the nucleoprotein of the Thai Forest virus. This vaccine has been approved in the European Union in July 2020 as part of a heterologous Ebola vaccination regimen. The MVA-BN vector is attenuated following over 500 serial passages in eggs, showing restricted host tropism and incompetence to replicate in human cells. MVA has six major deletions and other mutations of genes outside these deletions, which all contribute to the replication deficiency in human and other mammalian cells. Attenuation of MVA-BN was demonstrated by safe administration in immunocompromised mice and non-human primates. In multiple clinical trials with the MVA-BN backbone, more than 7800 participants have been vaccinated, demonstrating a safety profile consistent with other licensed, modern vaccines. MVA-BN has been approved as smallpox vaccine in Europe and Canada in 2013, and as smallpox and monkeypox vaccine in the US in 2019. No signal for inflammatory cardiac disorders was identified throughout the MVA-BN development program. This is in sharp contrast to the older, replicating vaccinia smallpox vaccines, which have a known risk for myocarditis and/or pericarditis in up to 1 in 200 vaccinees. MVA-BN-Filo as part of a heterologous Ebola vaccination regimen (Ad26.ZEBOV/MVA-BN-Filo) has undergone clinical testing including Phase III in West Africa and is currently in use in large scale vaccination studies in Central African countries. This paper provides a comprehensive picture of the MVA-BN vector, which has reached regulatory approvals, both as MVA-BN backbone for smallpox/monkeypox, as well as for the MVA-BN-Filo construct as part of an Ebola vaccination regimen, and therefore aims to provide solutions to prevent disease from high-consequence human pathogens.

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.

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 standardized template for collection of key information for benefit-risk assessment of viral vector vaccines.

Many of the vaccines under development for COVID-19 involve the use of viral vectors. The Brighton Collaboration Benefit-Risk Assessment of Vaccines by Technology (BRAVATO, formerly the Viral Vector Vaccine Safety Working Group, V3SWG) working group has prepared a standardized template to describe the key considerations for the benefit-risk assessment of viral vector vaccines. This will facilitate key stakeholders to anticipate potential safety issues and interpret or assess safety data. This would also help improve communication and public acceptance of licensed viral vector vaccines.

The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of inactivated viral vaccines.

Inactivated viral vaccines have long been used in humans for diseases of global health threat and are now among the vaccines for COVID-19 under 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 inactivated viral vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of the vaccine platform. The standardized and structured assessment provided by the template would also help to contribute to improved communication and support public acceptance of licensed inactivated viral vaccines.

The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of protein vaccines.

Several protein 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 protein vaccines. This will help key stakeholders to assess potential safety issues and understand the benefit-risk of such a vaccine platform. The structured and standardized assessment provided by the template would also help contribute to improved public acceptance and communication of licensed protein vaccines.

The Brighton Collaboration standardized template for collection of key information for benefit-risk assessment of nucleic acid (RNA and DNA) vaccines.

Nucleic acid (DNA and RNA) vaccines are among the most advanced vaccines for COVID-19 under 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 nucleic acid vaccines. This will facilitate the assessment by key stakeholders of potential safety issues and understanding of overall benefit-risk. The structured assessment provided by the template can also help improve communication and public acceptance of licensed nucleic acid vaccines.

rVSVΔG-ZEBOV-GP (also designated V920) recombinant vesicular stomatitis virus pseudotyped with Ebola Zaire Glycoprotein: Standardized template with key considerations for a risk/benefit assessment.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to evaluate the safety and characteristics of live, recombinant viral vector vaccines. A recent publication by the V3SWG described live, attenuated, recombinant vesicular stomatitis virus (rVSV) as a chimeric virus vaccine for HIV-1 (Clarke et al., 2016). The rVSV vector system is being explored as a platform for development of multiple vaccines. This paper reviews the molecular and biological features of the rVSV vector system, followed by a template with details on the safety and characteristics of a rVSV vaccine against Zaire ebolavirus (ZEBOV). The rVSV-ZEBOV vaccine is a live, replication competent vector in which the VSV glycoprotein (G) gene is replaced with the glycoprotein (GP) gene of ZEBOV. Multiple copies of GP are expressed and assembled into the viral envelope responsible for inducing protective immunity. The vaccine (designated V920) was originally constructed by the National Microbiology Laboratory, Public Health Agency of Canada, further developed by NewLink Genetics Corp. and Merck & Co., and is now in final stages of registration by Merck. The vaccine is attenuated by deletion of the principal virulence factor of VSV (the G protein), which also removes the primary target for anti-vector immunity. The V920 vaccine caused no toxicities after intramuscular (IM) or intracranial injection of nonhuman primates and no reproductive or developmental toxicity in a rat model. In multiple studies, cynomolgus macaques immunized IM with a wide range of virus doses rapidly developed ZEBOV-specific antibodies measured in IgG ELISA and neutralization assays and were fully protected against lethal challenge with ZEBOV virus. Over 20,000 people have received the vaccine in clinical trials; the vaccine has proven to be safe and well tolerated. During the first few days after vaccination, many vaccinees experience a mild acute-phase reaction with fever, headache, myalgia, and arthralgia of short duration; this period is associated with a low-level viremia, activation of anti-viral genes, and increased levels of chemokines and cytokines. Oligoarthritis and rash appearing in the second week occur at a low incidence, and are typically mild-moderate in severity and self-limited. V920 vaccine was used in a Phase III efficacy trial during the West African Ebola epidemic in 2015, showing 100% protection against Ebola Virus Disease, and it has subsequently been deployed for emergency control of Ebola outbreaks in central Africa. The template provided here provides a comprehensive picture of the first rVSV vector to reach the final stage of development and to provide a solution to control of an alarming human disease.

The INN global nomenclature of biological medicines: A continuous challenge.

Medicines are assigned International Nonproprietary Names (INN) by the World Health Organization (WHO), pursuing the aim to increase patient safety. Following scientific developments in drug discovery and biotechnology, the number of biological medicines is constantly growing and a surge in INN applications for them has been observed. Pharmacologically active biological substances have a complex structure and mechanism of action posing new challenges in selecting names that appropriately reflect such properties. As a consequence, existing nomenclature naming schemes may need to be revised and new ones developed. This review reports on the recently implemented policies for naming fusion proteins, monoclonal antibodies, advanced therapy substances that cover gene and cell therapy, virus-based therapies as well as vaccines and vaccine-like substances. Different approaches, based on the use of a one-word versus a two-word naming scheme, have been developed for different categories of biological substances highlighting a major and still not completely resolved issue, i.e. how to assign a name that is both informative, short and euphonic.

Defining the interval for monitoring potential adverse events following immunization (AEFIs) after receipt of live viral vectored vaccines.

Live viral vectors that express heterologous antigens of the target pathogen are being investigated in the development of novel vaccines against serious infectious agents like HIV and Ebola. As some live recombinant vectored vaccines may be replication-competent, a key challenge is defining the length of time for monitoring potential adverse events following immunization (AEFI) in clinical trials and epidemiologic studies. This time period must be chosen with care and based on considerations of pre-clinical and clinical trials data, biological plausibility and practical feasibility. The available options include: (1) adapting from the current relevant regulatory guidelines; (2) convening a panel of experts to review the evidence from a systematic literature search to narrow down a list of likely potential or known AEFI and establish the optimal risk window(s); and (3) conducting "near real-time" prospective monitoring for unknown clustering's of AEFI in validated large linked vaccine safety databases using Rapid Cycle Analysis for pre-specified adverse events of special interest (AESI) and Treescan to identify previously unsuspected outcomes. The risk window established by any of these options could be used along with (4) establishing a registry of clinically validated pre-specified AESI to include in case-control studies. Depending on the infrastructure, human resources and databases available in different countries, the appropriate option or combination of options can be determined by regulatory agencies and investigators.

The Ability of a Non-Egg Adapted (Cell-Like) A(H1N1)pdm09 Virus to Egg-Adapt at HA Loci Other than 222 and 223 and Its Effect on the Yield of Viral Protein.

Previous studies on influenza A(H1N1)pdm09 candidate vaccine viruses (CVVs) that had adapted to growth in embryonated chicken eggs by the acquisition of amino acid substitutions at HA positions 222 or 223 showed that improved protein yield could be conferred by additional amino acid substitutions in the haemagglutinin (HA) that arose naturally during passaging of the virus in eggs. In this study we investigated, by means of reverse genetics, the ability of a non-egg adapted (cell-like) A(H1N1)pdm09 virus to egg-adapt at HA loci other than 222/223, introducing amino acid substitutions previously identified as egg adaptations in pre-H1N1pdm09 H1N1 viruses and assessing their effect on protein yield and antigenicity. We also investigated the effect on the protein yield of these substitutions in viruses that had A(H1N1)pdm09 internal genes rather than the traditional PR8 internal genes of a CVV. The data show that a cell-like A/Christchurch/16/2010 can be egg-adapted via amino acid substitutions in at least three alternative HA loci (187, 190 and 216), in viruses with either PR8 or A/California/7/2009 internal genes, but that the effects on protein yield vary depending on the amino acid substitution and the internal genes of the virus. Since CVVs need to produce high protein yields to be suitable for vaccine manufacture, the findings of this study will assist in the future characterisation of both wild type viruses and lab-derived CVVs for vaccine use.

Unique safety issues associated with virus-vectored vaccines: Potential for and theoretical consequences of recombination with wild type virus strains.

In 2003 and 2013, the World Health Organization convened informal consultations on characterization and quality aspects of vaccines based on live virus vectors. In the resulting reports, one of several issues raised for future study was the potential for recombination of virus-vectored vaccines with wild type pathogenic virus strains. This paper presents an assessment of this issue formulated by the Brighton Collaboration. To provide an appropriate context for understanding the potential for recombination of virus-vectored vaccines, we review briefly the current status of virus-vectored vaccines, mechanisms of recombination between viruses, experience with recombination involving live attenuated vaccines in the field, and concerns raised previously in the literature regarding recombination of virus-vectored vaccines with wild type virus strains. We then present a discussion of the major variables that could influence recombination between a virus-vectored vaccine and circulating wild type virus and the consequences of such recombination, including intrinsic recombination properties of the parent virus used as a vector; sequence relatedness of vector and wild virus; virus host range, pathogenesis and transmission; replication competency of vector in target host; mechanism of vector attenuation; additional factors potentially affecting virulence; and circulation of multiple recombinant vectors in the same target population. Finally, we present some guiding principles for vector design and testing intended to anticipate and mitigate the potential for and consequences of recombination of virus-vectored vaccines with wild type pathogenic virus strains.

Adventitious agents and live viral vectored vaccines: Considerations for archiving samples of biological materials for retrospective analysis.

Vaccines are one of the most effective public health medicinal products with an excellent safety record. As vaccines are produced using biological materials, there is a need to safeguard against potential contamination with adventitious agents. Adventitious agents could be inadvertently introduced into a vaccine through starting materials used for production. Therefore, extensive testing has been recommended at specific stages of vaccine manufacture to demonstrate the absence of adventitious agents. Additionally, the incorporation of viral clearance steps in the manufacturing process can aid in reducing the risk of adventitious agent contamination. However, for live viral vaccines, aside from possible purification of the virus or vector, extensive adventitious agent clearance may not be feasible. In the event that an adventitious agent is detected in a vaccine, it is important to determine its origin, evaluate its potential for human infection and pathology, and discern which batches of vaccine may have been affected in order to take risk mitigation action. To achieve this, it is necessary to have archived samples of the vaccine and ancillary components, ideally from developmental through to current batches, as well as samples of the biological materials used in the manufacture of the vaccine, since these are the most likely sources of an adventitious agent. The need for formal guidance on such vaccine sample archiving has been recognized but not fulfilled. We summarize in this paper several prior major cases of vaccine contamination with adventitious agents and provide points for consideration on sample archiving of live recombinant viral vector vaccines for use in humans.

Introduction of a simple guideline to improve neurological assessment in paediatric patients presenting with upper limb fractures.

BACKGROUND: Neurological examination in children presenting with upper limb fractures is often poorly performed in the Emergency Department (ED). We aimed to assess the improvement in documented neurological examination for children presenting with upper limb fractures following introduction of a simple guideline. METHODS: We developed and introduced a simple guideline for upper limb neurological assessment in children ('rock, paper, scissors, OK'). We compared documentation of neurological examination and nerve injury detection at our hospital before and after introduction of this guideline, as well as for children admitted from external hospitals (where the guideline had not been introduced). RESULTS: In the period following guideline introduction, 97 children with upper limb fractures were admitted (46% presenting directly to our ED and 54% admitted from external hospitals). This cohort was similar in number and distribution to the cohort reviewed prior to the guideline. Documentation of neurological examination in our ED increased from 92% to 98% after guideline introduction. Documented information on nerves examined also increased from 2% to 68% (p<0.01). Prior to the guideline, there were six nerve injuries, all of which were missed in our ED. After guideline introduction, there were four nerve injuries, all of which were detected in our ED. Documentation and nerve injury detection at external hospitals over the same time period showed no improvement. CONCLUSIONS: A simple guideline to assist neurological examination in children with upper limb fractures can significantly improve the quality of documented neurological assessment and nerve injury detection.

Report on the second WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses: Geneva, Switzerland, 5-7 May 2014.

On 5-7 May 2014, the World Health Organization (WHO) convened the second integrated meeting on "influenza vaccines that induce broadly protective and long-lasting immune responses". Around 100 invited experts from academia, the vaccine industry, research and development funders, and regulatory and public health agencies attended the meeting. Areas covered included mechanisms of protection in natural influenza-virus infection and vaccine-induced immunity, new approaches to influenza-vaccine design and production, and novel routes of vaccine administration. A timely focus was on how this knowledge could be applied to both seasonal influenza and emerging viruses with pandemic potential such as influenza A (H7N9), currently circulating in China. Special attention was given to the development of possible universal influenza vaccines, given that the Global Vaccine Action Plan calls for at least one licensed universal influenza vaccine by 2020. This report highlights some of the topics discussed and provides an update on studies published since the report of the previous meeting.

TRANSVAC research infrastructure - Results and lessons learned from the European network of vaccine research and development.

TRANSVAC was a collaborative infrastructure project aimed at enhancing European translational vaccine research and training. The objective of this four year project (2009-2013), funded under the European Commission's (EC) seventh framework programme (FP7), was to support European collaboration in the vaccine field, principally through the provision of transnational access (TNA) to critical vaccine research and development (R&D) infrastructures, as well as by improving and harmonising the services provided by these infrastructures through joint research activities (JRA). The project successfully provided all available services to advance 29 projects and, through engaging all vaccine stakeholders, successfully laid down the blueprint for the implementation of a permanent research infrastructure for early vaccine R&D in Europe.

The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG).

Recombinant viral vectors provide an effective means for heterologous antigen expression in vivo and thus represent promising platforms for developing novel vaccines against human pathogens from Ebola to tuberculosis. An increasing number of candidate viral vector vaccines are entering human clinical trials. The Brighton Collaboration Viral Vector Vaccines Safety Working Group (V3SWG) was formed to improve our ability to anticipate potential safety issues and meaningfully assess or interpret safety data, thereby facilitating greater public acceptance when licensed.