Randomized clinical trials of COVID-19 vaccines: Do adenovirus-vector vaccines have beneficial non-specific effects?

May, 2023

Abstract

We examined the possible non-specific effects of novel mRNA- and adenovirusvector COVID-19 vaccines by reviewing the randomized control trials (RCTs) of mRNA and adenovirus-vector COVID-19 vaccines. We calculated mortality risk ratios (RRs) for mRNA COVID-19 vaccines vs. placebo recipients and compared them with the RR for adenovirus-vector COVID-19 vaccine recipients vs. controls. The RR for overall mortality of mRNA vaccines vs. placebo was 1.03 (95% confidence interval [CI]: 0.63–1.71). In the adenovirus-vector vaccine RCTs, the RR for overall mortality was 0.37 (0.19–0.70). The two vaccine types differed significantly with respect to impact on overall mortality (p = 0.015). The RCTs of COVID-19 vaccines were unblinded rapidly, and controls were vaccinated. The results may therefore not be representative of the long-term effects. However, the data argue for performing RCTs of mRNA and adenovirus-vector vaccines head-to-head comparing long-term effects on overall mortality.

Conclusions

The differences in the effects of adenovirus-vector and mRNA vaccines on overall mortality, if true, would have a major impact on global health. If validated in additional studies, the protective non-specific effects of adenovirus-based vaccines on non-COVID-19 mortality, in addition to their effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may represent an important advantage in vulnerable populations in which cardiovascular mortality is high. Ironically, the rich countries in Europe and the USA have emphasized the more expensive mRNA vaccines because of slightly better short-term vaccine efficacy against COVID-19 compared to the relatively inexpensive adenovirus-vector vaccines and the detection of a rare blood clotting disorder associated with the adenovirus-vector vaccines, mainly AstraZeneca. While this decision is understandable in the short term during a situation with high COVID-19-related mortality, in the endemic situation in which COVID-19- related deaths have decreased, this decision may need to be reassessed. Otherwise, if the protective effects of adenovirus-vector vaccines on overall mortality in the RCTs reflect the reality, this could turn out to be a very costly decision, both economically and health wise.

Limitations of the study

The number of deaths in these RCTs was limited, and chance could therefore have played a role in these findings. However, the internally consistent effects and the large difference in effect sizes between the two vaccine types speak against ‘‘chance’’ as the main explanation. Since there are well-established sex and age differences in the immune system, it is important to report and analyze data by sex and age group.37 This was unfortunately not possible for the present study since the RCTs only reported deaths by randomization allocation, not by sex and age.