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Letter to the Editor| Volume 86, ISSUE 3, P256-308, March 2023

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Recommendation for broad use of Covid-19 mRNA vaccine boosters due to waning vaccine effectiveness is taking the easy way out

  • Verena Schildgen
    Correspondence
    Corresponding author.
    Affiliations
    Dipl.-Biologe, Fachvirologe GfV, Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten/Herdecke, Institut für Pathologie, Ostmerheimer Str. 200, Köln (Cologne) D-51109, Germany
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  • Jessica Lüsebrink
    Affiliations
    Dipl.-Biologe, Fachvirologe GfV, Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten/Herdecke, Institut für Pathologie, Ostmerheimer Str. 200, Köln (Cologne) D-51109, Germany
    Search for articles by this author
  • Oliver Schildgen
    Correspondence
    Dipl.-Biologe, Fachvirologe GfV, Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten/Herdecke, Institut für Pathologie, Ostmerheimer Str. 200, Köln (Cologne) D-51109, Germany
    Affiliations
    Dipl.-Biologe, Fachvirologe GfV, Kliniken der Stadt Köln gGmbH, Klinikum der Privaten Universität Witten/Herdecke, Institut für Pathologie, Ostmerheimer Str. 200, Köln (Cologne) D-51109, Germany
    Search for articles by this author
Published:December 24, 2022DOI:https://doi.org/10.1016/j.jinf.2022.12.019
      Most recently, Hannawi and co-workers presented data on the efficiency of a bivalent recombinant SARS-CoV-2 protein based vaccine that appears to induce consistent neutralizing antibodies while showing a promising safety profile.
      • Hannawi S.
      • Saifeldin L.
      • Abuquta A.
      • Alamadi A.
      • Mahmoud S.A.
      • Li J.
      • et al.
      Safety and immunogenicity of a bivalent SARS-CoV-2 protein booster vaccine, SCTV01C in adults previously vaccinated with inactivated vaccine: a randomized, double-blind, placebo-controlled phase 1/2 clinical trial.
      The authors conclude that this vaccine type could be a new tool for vaccination against emerging variants. Taking into account these data, protein based vaccination strategies should not yet drift out of focus.
      An update of the CDC's VISION network analyses confirmed the decreasing effectiveness of Covid-19 mRNA vaccines within a few months independent of the vaccine shot number.
      • Ferdinands J.M.
      • Rao S.
      • Dixon B.E.
      • Mitchell P.K.
      • DeSilva M.B.
      • Irving S.A.
      • et al.
      Waning of vaccine effectiveness against moderate and severe covid-19 among adults in the US from the VISION network: test negative, case-control study.
      Based on their test negative case-control study Ferdinandis et al. concluded that their findings support recommendations for broad use of Covid-19 mRNA vaccine booster doses. In principle, this statement is correct but oversimplified, as various issues remain disregarded.
      During the last decades, nanotechnology attracted increasing attention including drug delivery systems based on nanoparticles. In response to the Covid-19 pandemic lipid nanoparticles (LNPs) as mRNA carrier receive particular attention as they are used for vaccination against SARS-CoV-2. Randomized trials of Comirnaty® (Pfizer-BionTech, clinical trial: NCT04368728) and Spikevax® (Moderna, clinical trial: NCT04405076) showed protection against Covid-19 of about 95% using physiological saline in the control groups. While this is a commonly applied approach, it bears the risk of a systematic bias regarding unspecific immune-effects as it has already been reported that ionizable lipids may stimulate the secretion of pro-inflammatory cytokines and reactive oxygen species.
      • Hou X.
      • Zaks T.
      • Langer R.
      • Dong Y.
      Lipid nanoparticles for mRNA delivery.
      Although the immunogenicity of these lipids has to be further determined, they may induce alterations of the innate and adaptive immune response and activation.
      • Hou X.
      • Zaks T.
      • Langer R.
      • Dong Y.
      Lipid nanoparticles for mRNA delivery.
      ,
      • Qin Z.
      • Bouteau A.
      • Herbst C.
      • Igyarto B.Z.
      Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion.
      For this reason, the usage of empty or non-sense RNA containing lipid nanoparticles would have been the proper study control for NCT04368728 and NCT04405076 to exclude undirected protection-effects only based on various LNP components. Considering that protection against serious clinical courses of COVID-19 may be just influenced to some extent by innate immunity effects triggered by unspecific components of the LNP sheath (ZITAT 3), this may explain the limited duration of mRNA vaccine effectiveness.
      Beside the issue of an undirected immune system activation bias, concerns regarding potential side effects remain. Although development of biomaterials for drug delivery improved it has recently been shown that mRNA-based Covid-19 vaccines due to their structural components still have the potential to induce antibodies against PEG (polyethylene glycol) leading to various side effects
      • Carreno J.M.
      • Singh G.
      • Tcheou J.
      • Srivastava K.
      • Gleason C.
      • Muramatsu H.
      • et al.
      mRNA-1273 but not BNT162b2 induces antibodies against polyethylene glycol (PEG) contained in mRNA-based vaccine formulations.
      ). In this context a recent re-analyses of serious adverse effects of mRNA SARS-CoV-2 vaccinations suggests that these occur more frequently than initially assumed.
      • Fraiman J.
      • Erviti J.
      • Jones M.
      • Greenland S.
      • Whelan P.
      • Kaplan R.M.
      • et al.
      Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults.
      For this reason more attention has to be paid to cases of unexpected deaths after close temporal connection to SARS-CoV-2 mRNA vaccination as shown at the University Hospital Heidelberg by the Institute of Pathology together with the DZIF (German Centre for Infection Research), which identified acute myocarditis due to vaccine-induced inflammation as the likely cause of death in patients with otherwise unobtrusive health constellation.
      • Schwab C.
      • Domke L.M.
      • Hartmann L.
      • Stenzinger A.
      • Longerich T.
      • Schirmacher P.
      Autopsy-based histopathological characterization of myocarditis after anti-SARS-CoV-2-vaccination.
      In most studies vaccine and booster effectiveness is defined by a reduction of hospital admitted Covid-19 cases. On the one hand, as this measurand is highly dependant on risk factors like age and comorbidities.
      • Bajema K.L.
      • Dahl R.M.
      • Prill M.M.
      • Meites E.
      • Rodriguez-Barradas M.C.
      • Marconi V.C.
      • et al.
      Effectiveness of COVID-19 mRNA vaccines against COVID-19-associated hospitalization - five veterans affairs medical centers, United States, February 1-August 6, 2021.
      ,
      • Ioannou G.N.
      • Bohnert A.S.B.
      • O'Hare A.M.
      • Boyko E.J.
      • Maciejewski M.L.
      • Smith V.A.
      • et al.
      Effectiveness of mRNA COVID-19 vaccine boosters against infection, hospitalization, and death: a target trial emulation in the Omicron (B.1.1.529) variant era.
      it is important to identify and define risk groups that derive a substantial health benefit from SARS-CoV-2 mRNA vaccination, On the other hand, an objective assessment of vaccine effectiveness is hardly possible due to unavailable control groups as a result of legal and moral immunization requirements.
      Taking into account that safety profiles of LNPs depend on dosage and composition and that long-term adverse effects, especially after multiple dose application, cannot be seriously predicted as information on long-term health outcome is obviously not available yet. Further investigations should re-evaluate the harm-benefit ratio before a continuous broad use of mRNA vaccines in low risk groups regarding life threatening courses is considered. However, it needs more transparency regarding the documentation of adverse side effects, also taking subjective perception into account. More detailed data on long-term immunogenic properties and intracellular signalling effects is required even on structural components of the delivery vesicles, especially because mRNA vaccines become more important due to the economic factors „time and costs“ as shown by the example of influenza.
      Big mRNA
      Players focus on flu vaccines.

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