Preliminary concerns with vaccine vectors

Many aspects of vaccine development, efficacy and safety deserve the utmost of attention as unparalleled progress in this regard occurs at breakneck speed for COVID-19. Aspects of vaccine safety that proportionately lack discussion even publicly in the scientific arena, whether inadvertently or purposely, are the issues of mutagenesis or oncogenesis. As Ball suggests, anti-vaccine postures will arise and potentially gain momentum in the context of a general hesitation for vaccination among some in the populace (1). Any damage done in the SARS-CoV-2 vaccine movement will undoubtedly be seen by some as collateral damage to the general concept of vaccination, especially if it is understood that corners will be cut for expediency. It is imperative, therefore, to ensure that a more comprehensive view of vaccine safety is well discussed, if not acted on, at least initially in scientific fora. As generally known, there are many approaches currently being investigated for SARS-CoV-2 vaccine development. Some of these, although not necessarily new, will be brought to clinical application and may include such new products as mRNA vaccines, plasmid or similar DNA constructs, and different virus-based carrier systems in the least. Safety will undoubtedly be analysed for short- or intermediate-term adverse effects. Will any such study, whether Phases 1, 2, or 3, be of sufficient number and timing to understand any opportunity for cellular transformation? For example only, adenovirus vectors for vaccination (and cancer and gene therapy) are forefront (2). The classic study from Graham and colleagues demonstrated that sheared adenovirus 5 (Ad5) DNA could transform what was believed to be human embryonic kidney cells (3). The latter research was only a progression, however, from much previous work, which found that adenoviruses could transform non-human cell lines. Thereafter, hamster tumours induced by adenovirus 12 (Ad12) appeared to lose Ad12 DNA but remained transformed (4). This outcome raised the question as to what part of the viral genome would have been essential to such oncogenic transition. In other studies, adenovirus 9 induced mammary tumours in a rodent model (5). Cooperation between cytomegalovirus and adenovirus E1A gene was found to be an instigator for the transformation of newborn rat kidney cells, but CMV DNA appeared to disappear in these cells, thus raising the prospect of a ‘hit-and-run’ mechanism for causation (6). Subsequent studies with Ad12 transformed cells were able to take advantage of more sophisticated viral DNA detection methods and showed that very small fragments of Ad12 were yet persistent in many transformations (7). Nevertheless, some tumour passages apparently lacked Ad12 DNA completely, and the ‘hit-an-run’ concept re-emerged. Adenovirus E1A was associated with the induction of a human fusion transcript (EWS-FLI1) that is characteristic of Ewing’s sarcoma (8). The efficiency of adenovirus E1A transformation was considerably enhanced by the co-expression of Ad E1B (9). The Ad E4 region also has a potential oncogenic role, but eukaryotic cells absent of both E4 and E1A (and any Ad viral DNA) could nevertheless maintain transformation characteristics, once again raising a ‘hit-and-run’ hypothesis (10). More recently, a similar transformation was achieved for primary human mesenchymal stromal cells (11). The latter is consistent with the Ad5 transformation of putative embryonic kidney cells, which eventually proved to have a relationship to neuronal cells rather than to kidney cells (3,12). Ornelles and colleagues remind us that Species C Adenoviruses commonly establish latent non-lytic lymphocyte infections (13). Their research, however, also proposed that Ad-specific changes in B cells are similar to those changes which are found in childhood leukemia cell lines. With such malignant B cells being absent of Ad DNA, it once again raised the spectre of ‘hit-and-run’ oncogenesis. Ad vector-based vaccines commonly are constructed with E1 deletions and some variably have deletions in at least E3 and E4 transcription units. Conceivably, such modifications may yield a measure of safety when Ad-vectored vaccines are used in humans. Are the current array of platforms for vaccines (whether mRNA, DNA or virus-vectored or any other) vetted for mutagenic or transformational potential? The speed at which the SARS-CoV-2 moves ahead will not be slowed down by any means, nor should it. The topic of such safety is not new and was aptly raised again only recently (14). Similar to those who have very cleverly engineered emerging coronavirus vaccines, we have an incredible worldwide collective of scientific experts in the area of oncogenic transformations. With their current capabilities, it is quite likely that at least some in vitro or animal model studies of such safety could be accomplished sooner than it would take to make a coronavirus vaccine broadly available. To give any such research impact and to give society some provisional assurances, this work could be independent of and simultaneous to those creating and producing the vaccines. Whereas there are obvious implications for COVID-19 vaccine safety, such research will also potentially benefit other similar or related clinical applications as they emerge (15). Funding was not sought for this publication. There is no third party support including that from the pharmaceutical industry. Conflict of interest statement: None declared.

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