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?
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?
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?
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?