Beneficial non-specific effects of live vaccines against COVID-19 and other unrelated infections

Aaby, Péter; Netea, Mihai G.; Benn, Christine Stabell

doi:10.1016/s1473-3099(22)00498-4

Cited by 50 publications

(26 citation statements)

References 81 publications

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“…A recent experimental study demonstrating strong protection induced by BCG against influenza, but not COVID-19, suggested that important immunological and pathophysiological differences between the two infections may explain this observation (Kaufmann, et al, 2022). Noteworthy, a recent meta-analysis of all the published BCG-COVID-19 trials that reported deaths within the trials showed that BCG was associated with 39% (1-62%) reduction in all-cause mortality (Aaby, Netea, & Benn, 2022).…”

Section: Discussionmentioning

confidence: 99%

Bacillus Calmette-Guérin vaccine to reduce COVID-19 infections and hospitalisations in healthcare workers – a living systematic review and prospective ALL-IN meta-analysis of individual participant data from randomised controlled trials

Schure

Belin

et al. 2022

Preprint

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BACKGROUND: The objective is to determine the impact of the Bacillus Calmette-Guerin (BCG) vaccine compared to placebo or no vaccine on COVID-19 infections and hospitalisations in healthcare workers. We are using a living and prospective approach to Individual-Participant-Data (IPD) meta-analysis of ongoing studies based on the Anytime Live and Leading Interim (ALL-IN) meta-analysis statistical methodology. METHODS: Planned and ongoing randomised controlled trials were identified from trial registries and by snowballing (final elicitation: Oct 3 2022). The methodology was specified prospectively -- with no trial results available -- for trial inclusion as well as statistical analysis. Inclusion decisions were made collaboratively based on a risk-of-bias assessment by an external protocol review committee (Cochrane risk-of-bias tool adjusted for use on protocols), expected homogeneity in treatment effect, and agreement with the predetermined event definitions. The co-primary endpoints were incidence of COVID-19 infection and COVID-19-related hospital admission. Accumulating IPD from included trials was analysed sequentially using the exact e-value logrank test (at level alpha = 0.5% for infections and level alpha = 4.5% for hospitalisations) and anytime-valid 95%-confidence intervals (CIs) for the hazard ratio (HR) for a predetermined fixed-effects approach to meta-analysis (no measures of statistical heterogeneity). Infections were included if demonstrated by PCR tests, antigen tests or suggestive lung CTs. Participants were censored at date of first COVID-19-specific vaccination and two-stage analyses were performed in calendar time, with a stratification factor per trial. RESULTS: Six trials were included in the primary analysis with 4 433 participants in total. The e-values showed no evidence of a favourable effect of minimal clinically relevance (HR < 0.8) in comparison to the null (HR = 1) for COVID-19 infections, nor for COVID-19 hospitalisations (HR < 0.7 vs HR = 1). COVID-19 infection was observed in 251 participants receiving BCG and 244 participants not receiving BCG, HR 1.02 (anytime-valid 95%-CI 0.78-1.35). COVID-19 hospitalisations were observed in 13 participants receiving BCG and 7 not receiving BCG, resulting in an uninformative estimate (HR 1.88; anytime-valid 95%-CI 0.26-13.40). DISCUSSION: It is highly unlikely that BCG has a clinically relevant effect on COVID-19 infections in healthcare workers. With only limited observations, no conclusion could be drawn for COVID-19 related hospitalisation. Due to the nature of ALL-IN meta-analysis, emerging data from new trials can be included without violating type-I error rates or interval coverage. We intend to keep this meta-analysis alive and up-to-date, as more trials report. For COVID-19 related hospitalisations, we do not expect enough future observations for a meaningful analysis. For BCG-mediated protection against COVID-19 infections, on the other hand, more observations could lead to a more precise estimate that concludes the meta-analysis for futility, meaning that the current interval excludes the HR of 0.8 predetermined as effect size of minimal clinical relevance. OTHER: No external funding. Preregistered at PROSPERO: CRD42021213069.

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Section: Discussionmentioning

confidence: 99%

Bacillus Calmette-Guérin vaccine to reduce COVID-19 infections and hospitalisations in healthcare workers – a living systematic review and prospective ALL-IN meta-analysis of individual participant data from randomised controlled trials

Schure

Belin

et al. 2022

Preprint

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“…The authors showed increased frequency of monocytes in peripheral blood for up to 3 months after vaccination. Moreover, monocyte membrane expression of activation markers and costimulatory molecules, such as HLA-DR, CD40, and CD80, was also enhanced for infections, but beneficial effects on disease severity, has been reported for other trained immunity-inducing vaccines, such as BCG (11) and MMR (12). Future studies should assess the intriguing possibility that induction of trained immunity may contribute to the beneficial effects of the ChAdOx1 nCoV-19 vaccine and, thus, induce cross-protection against emerging variants.…”

Section: Inducing Trained Immunitymentioning

confidence: 99%

Beyond adaptive immunity: induction of trained immunity by COVID-19 adenoviral vaccines

Netea

Joosten

2023

Journal of Clinical Investigation

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“…While data have not shown this to occur with COVID-19 vaccine, it cannot yet be ruled out as an important side effect of repeat vaccination, including with the new bivalent booster. Non-specific effects of vaccination refer to the effects of a vaccine on overall health and all-cause mortality, which have been shown to differ based on the type of vaccine (eg, live vs non-live) and age/sex 94 95. Both of these theoretical issues are at the frontiers of our current knowledge of vaccinology and are rarely considered in the media and by the lay public.…”

Section: Five Ethical Arguments Against University Booster Mandatesmentioning

confidence: 99%

COVID-19 vaccine boosters for young adults: a risk benefit assessment and ethical analysis of mandate policies at universities

et al. 2022

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In 2022, students at North American universities with third-dose COVID-19 vaccine mandates risk disenrolment if unvaccinated. To assess the appropriateness of booster mandates in this age group, we combine empirical risk-benefit assessment and ethical analysis. To prevent one COVID-19 hospitalisation over a 6-month period, we estimate that 31 207–42 836 young adults aged 18–29 years must receive a third mRNA vaccine. Booster mandates in young adults are expected to cause a net harm: per COVID-19 hospitalisation prevented, we anticipate at least 18.5 serious adverse events from mRNA vaccines, including 1.5–4.6 booster-associated myopericarditis cases in males (typically requiring hospitalisation). We also anticipate 1430–4626 cases of grade ≥3 reactogenicity interfering with daily activities (although typically not requiring hospitalisation). University booster mandates are unethical because they: (1) are not based on an updated (Omicron era) stratified risk-benefit assessment for this age group; (2) may result in a net harm to healthy young adults; (3) are not proportionate: expected harms are not outweighed by public health benefits given modest and transient effectiveness of vaccines against transmission; (4) violate the reciprocity principle because serious vaccine-related harms are not reliably compensated due to gaps in vaccine injury schemes; and (5) may result in wider social harms. We consider counterarguments including efforts to increase safety on campus but find these are fraught with limitations and little scientific support. Finally, we discuss the policy relevance of our analysis for primary series COVID-19 vaccine mandates.

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Beneficial non-specific effects of live vaccines against COVID-19 and other unrelated infections

Cited by 50 publications

References 81 publications

Bacillus Calmette-Guérin vaccine to reduce COVID-19 infections and hospitalisations in healthcare workers – a living systematic review and prospective ALL-IN meta-analysis of individual participant data from randomised controlled trials

Bacillus Calmette-Guérin vaccine to reduce COVID-19 infections and hospitalisations in healthcare workers – a living systematic review and prospective ALL-IN meta-analysis of individual participant data from randomised controlled trials

Beyond adaptive immunity: induction of trained immunity by COVID-19 adenoviral vaccines

COVID-19 vaccine boosters for young adults: a risk benefit assessment and ethical analysis of mandate policies at universities

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