The debate and tension over the efficacy of the Covid-19 vaccines is flaring up. Comparative assessments of vaccine-mediated protection from infection, disease, hospitalisation, and death in vaccinated and unvaccinated people are all over the place, with results ranging from convincing evidence of benefit to compelling proof of failure depending on the source of information. Those who’ve become addicted to these comparative statistics seem to forget that gauging the success of human intervention in a pandemic is about measuring success in a dynamic phenomenon, and that snapshots taken under certain conditions/settings do not provide information about the overall evolutionary trend and likely health outcome of a pandemic. The latter can only be monitored by measuring temporal changes of parameters that are relevant to public and individual health.

By March 2021, molecular epidemiologists had already expressed their concern about the emergence of a super-variant that ‘might have any combinations of increased transmissibility, altered virulence and/or increased capacity to escape population immunity’ and would, therefore, enjoy a huge fitness advantage (1). Back then, their concern was based on phylogenetics-based natural selection analysis indicating that immunity-mediated selective pressure is driving convergent evolution of a diversified spectrum of mutations to ensure viral persistence in the face of mounting infectious and vaccine-induced host immune pressure.

Their findings lead one to conclude that mass vaccination in the presence of more infectious variants inevitably involves selection-driven convergence of compensatory adaptive mutations at positively selected genome sites, and hence promotes enhanced expansion in prevalence of more transmissible immune escape variants. This would imply that vaccine efficacy is expected to diminish over time while the infection rate would progressively increase. It is reasonable to assume that the evolutionary convergence of more infectious immune escape variants and the culmination thereof into a ‘super-variant’ will also cause distinct trajectories of the pandemic to increasingly converge in countries/regions that are subject to mass vaccination.

An increase in infectious pressure leads to a higher risk of rapid viral re-exposure in the population. As far as previously asymptomatically infected unvaccinated individuals are concerned, rapid re-exposure to SARS-CoV-2 may lead to viral replication on a background of suboptimal spike (S)-directed immune pressure (due to suboptimal, short-lived anti-S antibodies [Abs] of low affinity) and even to enhanced susceptibility to disease (due to suppression of functional innate Ab capacity by the afore-mentioned suboptimal anti-S Abs). When such suboptimal anti-S immunity occurs in a substantial part of the population it is likely to further increase natural immune selection pressure on viral infectiousness and, therefore, promote further expansion of more infectious variants, thereby giving rise to additional waves of infectious cases and morbidity. As the evolutionary dynamics of the virus in highly vaccinated countries/regions are now placing huge immune selection pressure on the viral fitness landscape, it is fair to postulate that the highly diversified spectrum of evolutionary trajectories of this pandemic seen in different highly vaccinated countries will now rapidly narrow down to a more uniform path characterized by the following, prognostically unfavourable features:

• Waning of vaccine efficacy as mirrored by a relative increase of morbidity and mortality rates in vaccinees over time

• A relative increase of morbidity and mortality rates over time in vaccinees as compared to the unvaccinated

• A relative increase in suboptimal immunity over time in both the vaccinees and unvaccinated individuals (due to diminished vaccine efficacy and suboptimal naturally elicited Abs, respectively), which may translate into a relative increase in cases of ADE (Ab-dependent enhancement of Covid-19 disease pathology)

• A relative increase in the base-line infectivity rate over time

• Continuing waves of increased infection, morbidity, and mortality rates

• A relative increase in frequency of more infectious viral variants with immune-resistant phenotypes over time

Conclusion: All experts and public health authorities seem to agree that the evolutionary dynamics of a pandemic are very complex and shaped by an interplay between infectious pressure exerted by the virus on the host immune system and immune pressure exerted by the host on viral infectiousness, and that a pandemic can only come to an end when sufficient herd immunity is developed to control the virus. It is, therefore, surprising that none of these authorities seem to worry about the impact that massive immune intervention could have on the evolutionary dynamics of a pandemic that is now characterized by widespread dominance of highly infectious variants. The impact of any human intervention on these dynamics can only be assessed and measured by monitoring changes in population-level infection, morbidity, and mortality rates, and comparing these rates between vaccinees and unvaccinated individuals as a function of time. Likewise, phylogenetics-based natural selection studies should be conducted on viral sequences to monitor the evolutionary dynamics of SARS-CoV-2 adaptation to public health interventions.

If mass vaccination eventually enables SARS-CoV-2 to evolve dominant immune-escape variants that are capable of escaping from both the adaptive and innate immune systems, the outcome of this pandemic will resemble that of introducing a pathogenic virus into a naive host species. This is actually likely to enhance viral virulence instead of controlling viral disease.

(1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941658/