Vaccines Safety During Accelerated Research and Development

The 25 August 2020 certification of Africa as wild polio free¹ serves to remind us of the value of vaccination in preventing infection related death and disability within populations. Vaccines are typically administered to healthy persons (including infants), therefore tolerance for adverse effects from vaccination is typically lower than tolerance to risks associated with medicines given to ill persons. Where sustained high coverage with an efficacious vaccine has led to near elimination of the target disease within a population, safety concerns can become even more prominent since fewer and fewer persons have experienced the disease but many persons will still be immunized and may be harmed. Rigorous scientific safety data are needed to optimize a vaccine’s benefit-risk ratio.  In a public health emergency, the urgent need for an effective vaccine must be balanced against potential for vaccine related harms to ensure appropriate use. How can this be achieved when developing a vaccine at ‘warp speed’?

Advantages of using existing approved technologies in a pandemic emergency are multiple: established techniques result in availability of reliable manufacturing centres for rapid scale up; vaccine manufacturing components, including well qualified cell banks used for the initial viral culture (which have been built up since the recognition of vaccine contamination by several adventitious agents in the past²), are likely to be available for immediate exploitation; lastly, a great deal is known about the reliability of immune response to vaccines of this type, supporting extrapolation of existing knowledge to the new virus.  In contrast novel techniques must start de novo and the manufacturing capacity built ‘at risk’^3,4. In addition, performance of vaccines made using these technologies is not widely understood in practice, limiting ability to extrapolate from prolonged experience. Additional safety considerations may arise. For DNA vaccines, concerns include the development of autoimmunity, host cell genome integration and tissue destruction due to cytotoxic responses. There is also a potential concern for release of DNA products into the environment and other considerations linked to use of a genetically modified organism (GMO) in clinical practice⁵. The manufacturing processes for RNA vaccines do not require toxic chemicals or cell cultures that could be contaminated with adventitious viruses and, unless delivered within a viral vector, avoid the common risks associated with other vaccine platforms. The short manufacturing time required reduces the risk of introducing contaminating microorganisms and potential integration of the vector genome into host cell DNA is not a concern⁶. These features suggest RNA vaccines have some advantages relative to other technologies but also a potential risk regarding B cell activation and of exacerbating autoimmune reactions in some cases.

As for any new therapeutic, preclinical assessment must be completed prior to conducting clinical trials. The International Coalition of Medicines Regulatory Authorities (ICMRA) held several workshops to agree a consistent approach to vaccine development for COVID-19. FDA has also published regulatory guidance for this indication ^7,8. Where adequate information to characterize product safety is available, e.g. the COVID-19 vaccine candidate is made using a platform technology utilized to manufacture a licensed vaccine or other previously studied investigational vaccines and is sufficiently characterized, it may be possible to use toxicology data and clinical data accrued with other products using the same platform to support FIH clinical trials with the new vaccine candidate. Local tolerance information with the candidate is required. Biodistribution studies in an animal species are required if the vaccine construct is novel, there is a likelihood of altered infectivity and tissue tropism or a novel route of administration/formulation is to be used. An immune response must be demonstrated in an in vivo animal model. A range of COVID-19 animal models have been investigated, each of which reflects different features of COVID-19 disease in humans. Although murine models are usually preferred (low cost, high reproductive rate and wealth of available reagents) wild type mice are unsuitable due to receptor incompatibility. A transgenic mouse model incorporating the human ACE2 receptor has been developed. Because hamster and transgenic mouse models display clinical symptoms these models have been used to study the early efficacy of various vaccines, while later studies (used to predict doses and safety assessments prior to human trials) have frequently been performed in non-human primates^9-13.

The clinical development of vaccines follows that required for any therapeutic i.e. early studies in healthy volunteers to explore dose response (immunogenicity) and initial adverse effects and local tolerability, extending later to trials in vulnerable populations and large phase III programs to document prevention of infection/disease during a community disease outbreak and to continue vaccine safety assessment.  To date, at least 41 candidate vaccines for SARS-CoV-2 have started clinical trials, of which 10 are in phase III, with 151 in preclinical testing²⁰. Results of early trials have suggested vaccine associated adverse events (VAERs) include injection site reactions and systemic symptoms including fever, myalgia, joint pain, fatigue and headache at doses which result in satisfactory evolution of humoral and T cell immune response^21-23. Safety evaluation of successful phase III candidates will need to continue post marketing. The Coalition for Epidemic Preparedness Innovations (CEPI) has funded the Brighton Collaboration to produce specific templates for standardised collection of COVID-19 vaccine associated adverse effects²⁴ while WHO has enhanced the Global Vaccines Safety Initiative (GVSI)²⁵. In the EU, surveillance will be enhanced by the ADVANCE consortium, which was formed after the late recognition of an increased risk of narcolepsy caused by a licensed pandemic influenza vaccine²⁶. The stage is set: we await arrival of the first SARS-CoV-2 vaccine(s).