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Influenza is associated with significant morbidity and mortality worldwide. Whilst vaccination is key for the prevention of influenza infection, there are many factors which may contribute to reduced vaccine effectiveness, including antigenic evolution via both antigenic drift and egg-adaptations. Due to the currently dissociated and indirect evidence supporting both the occurrence of these two phenomena in the egg-based manufacturing process and their effects on vaccine effectiveness, this topic remains a subject of debate. To review the evidence and level of agreement in expert opinion supporting a mechanistic basis for reduced vaccine effectiveness due to egg-based manufacturing, using an expert consensus-based methodology and literature reviews. Ten European influenza specialists were recruited to the expert panel. The overall research question was deconstructed into four component principles, which were examined in series using a novel, online, two-stage assessment of proportional group awareness and consensus. The first stage independently generated a list of supporting references for each component principle via literature searches and expert assessments. In the second stage, a summary of each reference was circulated amongst the experts, who rated their agreement that each reference supported the component principle on a 5-point Likert scale. Finally, the panel were asked if they agreed that, as a whole, the evidence supported a mechanistic basis for reduced vaccine effectiveness due to egg-based manufacturing. All component principles were reported to have a majority of strong or very strong supporting evidence (70–90%). On reviewing the evidence for all component principles, experts unanimously agreed that there is a mechanistic basis for reduced vaccine effectiveness resulting from candidate influenza virus variation due to egg-based manufacturing, particularly in the influenza A/H3N2 strain. Experts pointed to surveillance, candidate vaccine virus selection and manufacturing stages involving eggs as the most likely to impact vaccine effectiveness. [ABSTRACT FROM AUTHOR]