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The COVID-19 vaccine R&D landscape has developed at unprecedented scale and speed since our initial analysis in April identified 115 candidates in the pipeline (Nat. Rev. Drug Discov. 19, 305-306; 2020). In this updated overview, we focus on candidates in clinical trials and provide some initial perspectives on their clinical development.

Purpose:To estimate the importance of respiratory and cardiac effects on signal variability found in functional magnetic resonance imaging data recorded from the brainstem. Materials and Methods:A modified version of the retrospective image correction (RETROICOR) method (Glover et al, [2000] Magn Reson Med 44:162-167) was implemented on resting brainstem echo-planar imaging (EPI) data in 12 subjects. Fourier series were fitted to image data based on cardiac and respiratory recordings (pulseoximetry and respiratory turbine), including multiplicative terms that accounted for interactions between cardiac and respiratory signals. F-tests were performed on residuals produced by regression analysis. Additionally, we evaluated whether modified RETROICOR improved detection of brainstem activation (in 11 subjects) during a finger opposition task. Results:The optimal model, containing three cardiac (C) and four respiratory (R) harmonics, and one multiplicative (X) term, "3C4R1X," significantly reduced signal variability without overfitting to noise. The application of modified RETROICOR to activation data increased group Z-statistics and reduced putative false-positive activation. Conclusion:In addition to cardiac and respiratory effects, their interaction was also a significant source of physiological noise. The modified RETROICOR model improved detection of brainstem activation and would be usefully applied to any study examining this brain region.

Unambiguous interpretation of changes in the BOLD signal is challenging because of the complex neurovascular coupling that translates changes in neuronal activity into the subsequent haemodynamic response. In particular, the neurophysiological origin of the negative BOLD response (NBR) remains incompletely understood. Here, we simultaneously recorded BOLD, EEG and cerebral blood flow (CBF) responses to 10 s blocks of unilateral median nerve stimulation (MNS) in order to interrogate the NBR. Both negative BOLD and negative CBF responses to MNS were observed in the same region of the ipsilateral primary sensorimotor cortex (S1/M1) and calculations showed that MNS induced a decrease in the cerebral metabolic rate of oxygen consumption (CMRO2) in this NBR region. The ∆CMRO2/∆CBF coupling ratio (n) was found to be significantly larger in this ipsilateral S1/M1 region (n=0.91±0.04, M=10.45%) than in the contralateral S1/M1 (n=0.65±0.03, M=10.45%) region that exhibited a positive BOLD response (PBR) and positive CBF response, and a consequent increase in CMRO2 during MNS. The fMRI response amplitude in ipsilateral S1/M1 was negatively correlated with both the power of the 8-13 Hz EEG mu oscillation and somatosensory evoked potential amplitude. Blocks in which the largest magnitude of negative BOLD and CBF responses occurred therefore showed greatest mu power, an electrophysiological index of cortical inhibition, and largest somatosensory evoked potentials. Taken together, our results suggest that a neuronal mechanism underlies the NBR, but that the NBR may originate from a different neurovascular coupling mechanism to the PBR, suggesting that caution should be taken in assuming the NBR simply represents the neurophysiological inverse of the PBR.