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

Benn, Christine Stabell; Schaltz‐Buchholzer, Frederik; Nielsen, Sebastian R.; Netea, Mihai G.; Aaby, Péter

doi:10.1016/j.isci.2023.106733

Cited by 16 publications

(17 citation statements)

References 37 publications

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“…10 Similar results and concerns are found in Benn et al, with the authors finding that based 'on the RCTs with the longest possible follow-up, mRNA vaccines had no effect on overall mortality despite protecting against fatal COVID-19', with their data indicating a net mortality deficit (though not statistically significant), and being disappointed that more accurate analyses are 'hampered by the short follow-up in these trials as the individuals from the control groups were offered vaccination after 2-6 months', finally recommending that while 'mass-vaccination programs with COVID-19 vaccines are rolled out, data on their effects on non-COVID-19 mortality should be collected'. 11 Furthermore, the issue of additional, longer term, adverse effects eventually showing up significantly after the vaccines were at least provisionally approved led to a report in the BMJ, wherein the FDA had been 'criticised for taking more than a year to follow up a potential increase in serious adverse events in elderly people receiving Pfizer's COVID-19 vaccine'. 12 It may be that short counting windows, as well as rapid unblinding, are becoming standard practice, not being limited to research on the RNA or DNA vaccines.…”

Section: Potentially Overstating Safety In Vaccine Clinical Trialsmentioning

confidence: 99%

How the adverse effect counting window affected vaccine safety calculations in randomised trials of COVID‐19 vaccines

Lataster

2024

Evaluation Clinical Practice

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Several articles published recently in the Journal of Evaluation in ClinicalPractice raise important questions about how the efficacy and safety of COVID-19 vaccines have been and are being measured. First, Fung, Jones, and Doshi explained that statistical biases, particularly the case counting window bias, can greatly exaggerate the perceived effectiveness of COVID-19 vaccines in observational studies. 1 A follow-up article by myself explained that this effect may be understated, due to the often accompanied definitional bias, and also that these biases could likewise exaggerate the perceived safety of COVID-19 vaccines in observational studies. 2 Doshi and Fung then added further to the discussion by finding issues with case counting windows in COVID-19 vaccine clinical trials, relating to vaccine effectiveness. 3 In this final article, I shall provide an example justifying my prior concern about counting windows in observational studies concerning safety, and further explain that there are also concerns around adverse effect counting windows in COVID-19 vaccine clinical trials, which may have exaggerated claims about vaccine safety.

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Section: Potentially Overstating Safety In Vaccine Clinical Trialsmentioning

confidence: 99%

How the adverse effect counting window affected vaccine safety calculations in randomised trials of COVID‐19 vaccines

Lataster

2024

Evaluation Clinical Practice

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“…From the RCTs in children aged 6 months to 15 (17) years, neither of the mRNA vaccines had a beneficial effect on overall health, assessed as the incidence of SAEs, Severe AEs, RTIs, and other organ-specific diseases. mRNA vaccines were not associated with an increased risk of SAEs, but the risk of Severe AEs was more than 3.5-fold higher in the older children.…”

Section: Discussionmentioning

confidence: 99%

“…In this review, as previously performed for the adults’ phase 2-3-trials, 17 the available phase 3 trial reports were used to examine the overall health effect of COVID-19 mRNA vaccines in children, with a particular focus on non-COVID-19 infectious disease outcomes.…”

Section: Introductionmentioning

confidence: 99%

Overall Health Effects of mRNA COVID-19 Vaccines in Children and Adolescents A Systematic Review and Meta-Analysis

Hoffmann,

Nielsen,

Thysen

et al. 2023

Preprint

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ImportancePhase 3 randomized controlled trials (RCTs) of mRNA COVID-19 vaccines in children and adolescents showed efficacy in preventing COVID-19 infections. Vaccines may have non-specific effects which are not assessed within the current regulatory framework.ObjectiveConduct a systematic review and meta-analysis of the phase 3 trials to assess overall and non-specific health effects of the mRNA COVID-19 vaccines in children.Data SourcesPubMed, Embase, Clinical Trials, Web of Science, and regulatory websites were searched for RCTs of mRNA vaccines. The latest trial data was included.Study SelectionAll RCTs conducted with mRNA vaccines BNT162b2 and mRNA-1237 in children and adolescents below 18 years of age, with placebo, adjuvant, or other vaccines as controls. Two authors independently screened 1199 studies, six were included in the analysis.Data Extraction and SynthesisData on serious adverse events (SAEs) and severe adverse events (AEs) as well as organ-specific diseases was extracted following the PRISMA reporting guideline, with a focus on non-specific infectious events. Risk Ratios (RRs) comparing vaccine and placebo cohorts were calculated separately for each vaccine and combined in Mantel-Haenszel estimates.Main Outcomes and MeasuresThe primary outcome was SAEs -- overall and infectious. Secondary outcomes were severe AEs and lower respiratory tract infection (LRTI) including RSV.ResultsThe analyses included 25,549 individuals (17,538 mRNA vaccine recipients and 8,011 placebo recipients). The risk of SAEs were similar for vaccine and placebo recipients. Both mRNA vaccines were associated with increased risk of severe AEs in older children. In a combined analysis, the RR was 3.77 (1.56-9.13[0.4% vs 0.1% in vaccine vs placebo recipients]) in above 5 year-olds, and 0.82 (0.53-1.29)[0.8% vs 0.9%])in younger children (p=0.003 for same effect in older and younger children). In the younger children, mRNA vaccines were associated with higher risk of LRTI (3.03 (1.29-7.09) [0.6% vs 0.2%]).Conclusions and RelevancemRNA vaccines did not increase the risk of SAEs but were associated with an increased risk of severe AEs in older children, and an increased risk of LRTI in the young. Further research into the overall and non-specific health effects of mRNA vaccines is warranted.Question, Findings, and MeaningQuestionWhat is the overall health effect of mRNA COVID-19 vaccines in children?FindingsIn this systematic review and meta-analysis of phase 3 trials, mRNA vaccine vs. placebo was not associated with increased risk of serious adverse events. The mRNA vaccines were associated with higher risk of severe adverse events in children aged 5 years and older. In children younger than 5 years, mRNA vaccines were associated with a 3-fold higher risk of lower respiratory tract infections.MeaningDespite the low risk of adverse events, the results suggest that mRNA vaccines increase the risk of severe adverse events. However, given the low risk of COVID-19 infection in children, this is relevant to consider. The results suggest that mRNA vaccines are associated with increased risk of severe adverse events and increased risk of LRTI. Given the low risk of severe COVID-19 infection in children, it is not clear that the benefit of COVID-19 vaccines in children outweigh the harms.

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“…There is not enough information regarding the NSEs of COVID-19 mRNA vaccines. By analyzing the randomized control trials (RCTs) of mRNA and adenovirus-vector COVID-19 vaccines, a recent investigation evaluated the potential non-specific outcomes of these vaccines [152]. Researchers estimated mortality risk ratios (RRs) for COVID-19 vaccines in participants receiving mRNA vaccines in comparison to placebo receivers and contrasted them to RRs for COVID-19 vaccine recipients receiving adenovirus-vector vaccines compared to controls.…”

Section: The Negative Nses Induced By Covid-19-mrna Vaccines Could Be...mentioning

confidence: 99%

“…The mortality risk ratio was 3 times higher for the mRNA vaccines than that of the adenovirus-vector vaccine. Unfortunately, the COVID-19 RCTs were quickly unblinded, and controls received vaccinations; as a result, the chance to conduct extensive RCTs vaccine-vs.-placebo trials that would have offered significant data was eliminated [152].…”

Section: The Negative Nses Induced By Covid-19-mrna Vaccines Could Be...mentioning

confidence: 99%

Do Vaccines Increase or Decrease Susceptibility to Diseases Other Than Those They Protect Against?

Rubio‐Casillas¹,

Redwan²,

Uversky³

et al. 2023

Preprint

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Contrary to the long-held belief that the effects of vaccines are specific for the disease they were created; compelling evidence has demonstrated that vaccines can exert positive or deleterious non-specific effects (NSEs). In this review, we compiled research reports from the last 40 years, showing that live vaccines induce positive NSEs, whereas non-live vaccines induce several negative NSEs, including increased female mortality associated with enhanced susceptibility to other infectious diseases, especially in developing countries. These negative NSEs are determined by the vaccination sequence, the antigen concentration in vaccines, the type of vaccine used (live vs. non-live), and also by repeated vaccination. We do not recommend stopping using non-live vaccines, as they have demonstrated to protect against their target disease, so the suggestion is that their detrimental NSEs can be minimized simply by changing the current vaccination sequence. High IgG4 antibody levels generated in response to repeated inoculation with mRNA COVID-19 vaccines could be associated with a higher mortality rate from unrelated diseases and infections by suppressing the immune system. Since most COVID-19 vaccinated countries are reporting high percentages of excess mortality not directly attributable to deaths from such disease, the NSEs of mRNA vaccines on overall mortality should be studied in depth.

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

Cited by 16 publications

References 37 publications

How the adverse effect counting window affected vaccine safety calculations in randomised trials of COVID‐19 vaccines

How the adverse effect counting window affected vaccine safety calculations in randomised trials of COVID‐19 vaccines

Overall Health Effects of mRNA COVID-19 Vaccines in Children and Adolescents A Systematic Review and Meta-Analysis

Do Vaccines Increase or Decrease Susceptibility to Diseases Other Than Those They Protect Against?

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