In response to the SARS-CoV-2 outbreak, and the resulting COVID-19 pandemic, a global competition to develop an anti-COVID-19 vaccine has ensued. The targeted time frame for initial vaccine deployment is late 2020. The present article examines whether short-term, mid-term, and long-term vaccine safety can be achieved under such an accelerated schedule, given the myriad vaccine-induced mechanisms that have demonstrated adverse effects based on previous clinical trials and laboratory research. It presents scientific evidence of potential pitfalls associated with eliminating critical phase II and III clinical trials, and concludes that there is no substitute currently available for long-term human clinical trials to ensure long-term human safety.
The new outbreak of SARS-CoV-2 from December 2019 precipitated a world-wide crisis. Globally, lockdowns of different severity levels were imposed (
The methods used to contain the spread of the virus have been the traditional social distancing, quarantine, use of disinfectant substances, and wearing of protective face masks (
In parallel with the imposed restrictions to prevent viral spread and the testing of (mainly) repurposed anti-viral treatments is the accelerated development of vaccines to prevent/restrict potential viral damage. Questions have been raised as to whether an accelerated vaccine development can be accomplished safely, preventing potential adverse vaccine effects not only in the short-term, but also in the mid- and long-term(
Currently (mid-September, 2020), there is avid competition regarding the development and commercialization of a vaccine by early 2021 (
There are three ways of testing for vaccine safety, in order of increasing credibility: Computer simulations, animal experiments and human trials.
While the growth of statistical software packages and chemical descriptors allows the development of new models, safeguards that account for deficiencies of the underlying models may be lacking. This could impact the credibility of any conclusions on safety or toxicity (
There are several examples where whole animal experiments have been poor predictors of human responses to environmental exposures or drugs. Isotretinoin (acutane), for example, has been demonstrated to cause birth defects in rabbits, monkeys and humans, but not in mice or rats. As another example, corticosteroids are teratogenic in experimental animals, but not in humans. In addition, there is the well-known example of Thalidomide, 'a teratogen in humans, but not in many experimental animal species' (
Why are some animal experiments poor predictors of human outcomes and responses? The studies may be designed poorly and may be inadequate methodologically; the studies may not be replicated or subject to meta-analyses; the metabolic pathways or drug metabolism of humans differ from those of the tested species or strains and 'disease manifestations in the animals are distinct from those encountered in humans' (
Laboratory animal experiments allow for the selection of test animals with short lifetimes, and can identify adverse health effects over the animals' lifetimes (the analog of long-term human effects), and perhaps one or two generations beyond. As previously stated (
Additionally, laboratory animals are typically exposed to one toxic stressor (vaccines, in the present case), whereas human beings are exposed to myriad toxic stressors daily and over their lifetimes (
Human trials have at least two advantages over laboratory animal experiments. First, there are no concerns regarding species differences that occur when extrapolating from laboratory animal testing results to potential human impacts. Second, humans are exposed to myriad toxic stressors before, during and after the trial period, providing results that mirror the real-life experience. In all cases, human trials will be most relevant if the characteristics of the trial population reflect those of the target/user population.
The disadvantages of human clinical trials are as follows: i) The exposures to toxic stimuli are either not known, or, if they are known, have not been estimated accurately; and ii) the identification of the long-term effects requires long periods of time (
An overlooked issue associated with the vaccine discussions is potential transgenerational effects. Transgenerational studies of adverse substance effects tend to be focused on environmental causes; however, there are some examples of such studies for drugs. A previous study on chemotherapy-induced late transgenerational effects (
Due to the inadequate safety testing of several toxic stimuli in the past (including vaccines), it remains uncertain as to whether a number of diseases currently affecting humanity may be due in part to the actions of our predecessors passed on to us through transgenerational effects. It is uncertain as to whether any of the drugs, vaccines, foods or radiation exposures of our predecessors, which were not tested for transgenerational effects, are adversely affecting human life at present. Of note, the question remains whether humanity is currently willing to pass on potential devastating diseases to future generations due to the present need for the speedy development of a vaccine, bypassing adequate long-term and transgenerational safety testing.
There are also ethical issues of concern associated with accelerated vaccine development, particularly with the drastic reduction in time devoted to clinical trial phases II and III (
For any new product, the decision to implement (whether for commercial or non-commercial purposes) typically involves a tradeoff between costs and benefits. In the ideal case, the projected benefits would far outweigh the projected costs. The potential costs and/or benefits may be known to high, modest, or low degrees of certainty. Thus, a risk factor must be applied to the costs and benefits, reflecting the level of uncertainty about the projections.
The vaccine costs in this discussion are the potential adverse health effects from a COVID-19 vaccine, particularly for the mid- and long-term. For a vaccine with high levels of uncertainty as to the projected costs, a high risk factor is required. For the tradeoff to justify moving forward, a very high level of benefits would be required.
The cost-benefit tradeoff for a COVID-19 vaccine would be different for groups with different vulnerabilities to the disease. For simplicity, the target population for vaccination could be divided into 2 groups: The highly vulnerable, and the remainder of the population. The demographic population most vulnerable to the more severe consequences of COVID-19 tends to be the elderly with high comorbidities and others with compromised immune systems (
The vaccine tradeoff analysis will differ for each of these two groups. For the most vulnerable, the main consideration is to survive the season. The mid- and long-term effects may be of lesser importance (although for the few younger members of this demographic population with highly compromised immune systems, the mid- and long-term adverse effects would not be negligible). For the least vulnerable (the vast majority of the population), the need for a vaccine is unclear, since the adverse effects of the virus appear to be minimal for most. This least vulnerable demographic population would have to bear the brunt of any potential mid- and long-term adverse health impacts that may result from a vaccine inadequately tested for these effects.
Thus, a vaccine that proved efficacious for the very short-term for all demographics may potentially be justifiable (albeit high-risk) for the most vulnerable demographic population. However, it is difficult to ascertain how such a vaccine could be justified for the remaining demographics.
Furthermore, the question remains of what are the present prospects for a vaccine efficacious even in the short-term. Trial results for a highly-promoted COVID-19 vaccine reported publicly have exhibited adverse effects of varying severity, where the test group was relatively young and very healthy (
In the present political environment, there is the potential that the majority of the population could be required to be vaccinated, even those demographics that were not vulnerable to the severe effects of COVID-19, and particularly those in the youngest demographic. The potential adverse consequences of such a mass inoculation with a vaccine not adequately tested for mid- and long-term adverse effects could be substantial.
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All authors substantially contributed to the conception, writing and revision of the work and approved the final content of the manuscript.
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DAS is the Editor-in-Chief for the journal, but had no personal involvement in the reviewing process, or any influence in terms of adjudicating on the final decision, for this article. The other authors declare that they have no competing interests.
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