The following critical but unresolved questions are an attempt to outline an urgent open scientific debate with expert scientists in virology, vaccinology and immunology, preferably in a joined constructive effort to find a way out of the ongoing world crisis.
More infectious variants
- How to explain the sudden emergence of several, more infectious variants (e.g., UK, South-African, Brazilian variants) in QIV 2020 (i.e., prior to the roll-out of mass vaccination campaigns and despite relatively low infection rates)?
- Will highly infectious variants persist in the human population? (How) can these variants be controlled?
- What is the likelihood for mutations rendering these variants less infectious and/or less virulent (cfr. ‘common cold’) to be selected? What would be the likelihood for such less infectious variants to adapt to the human population?
Innate immunity
- What is the contribution of variant-nonspecific innate immunity to anti-Covid-19 immune defense?
- Can spike(S)-specific antibodies (Abs) outcompete multimeric, variant-nonspecific sIgMs for binding to S protein? If so, can S-specific Abs interfere with natural Abs even if the former are unable to neutralize the virus?
Asymptomatic infection
- How to explain the increase in cases of severe Covid-19 disease in younger (< 60 years), previously protected, age groups as currently observed in several countries?
- What is the role of short-lived anti-S Ab titers in a subset of asymptomatically infected subjects? Are those protective or do they interfere with the host’s innate immunity?
- Which immune mechanisms prevent Sars-CoV-2 infections from causing (severe) symptoms in the vast majority of the population?
- Which mechanisms are responsible for rapid viral clearance in asymptomatically infected subjects?
- To what extent do young healthy people contribute to the emergence of new variants?
Ongoing mass vaccination campaigns
- What is the likelihood that ongoing mass vaccination campaigns will provide herd immunity?
- Which objective criteria could be considered reliable indicators of potential selective immune escape of Sars-CoV-2? How to investigate whether or not a correlation exists between these criteria and external influences such as those brought about by pharmaceutical or nonpharmaceutical interventions?
- How would the expected impact of mass vaccination with a live attenuated Coronavirus compare to that of the ongoing mass vaccination campaigns?
Miscellaneous
- What is our current understanding of the mechanism causing ‘common cold’ coronaviruses to provide short-lived protection against Covid-19 disease?
- How can we explain re-infection with Sars-CoV-2 to occur in the presence of neutralizing Abs?
- What is the role of CD8+ T cells in immune protection against Covid-19?
- What is currently known about the evolution of Ab titers and protection against more infectious viral variants in subjects who were enrolled in pivotal vaccine trials?
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