FIGURE LEGENDS
Figure 1. Pathobiology of COVID-19 . SARS-CoV-2 infects cells in the lung and the gut via the angiotensin converting enzyme two (ACE2). This blocks ACE2-induced formation of anti-oxidant angiotensin, facilitating oxygen free-radical formation and vascular damage. The innate immune response provides the initial line of defence against the virus, while a CD8 anti-viral T-cell response and neutralizing and complement-fixing antibody response serve to remove the virus in the majority of people. However, the virus triggers suppression of interferon responses and other viral escape mechanisms that in a minority of people stimulate the innate immune response leading to lymphocyte apoptosis that blocks their regulatory signals and in some cases releases a cytokine storm that drives hyper-innate-inflammation. This in part causes acute respiratory distress. Importantly, this augments vascular damage that accentuates the respiratory distress and leads to von Willebrand factor release into the blood. This contributes to the formation of microthrombi, contributing to respiratory distress and vascular embolism that may be fatal. Adapted from Henry et al. 2020 [22].
Figure 2 . Ocrelizumab inhibits vaccination responses.People with multiple sclerosis did not received ocrelizumab (control) or were infused with 300mg ocrelizumab on day 0 and 15 and were vaccinated from week 12-24 after ocrelizumab. The experimental details and results were from www.clinicaltrials.gov NCT02545868 [87]. The results show: (A) The frequency of seroconversion in people treated with ocrelizumab following injection pneumococcal 23-PPV vaccine, 4 weeks after vaccination (n=66-68). A 23-PPV vaccine response against a serotype was defined by a 2-fold increase in anti-pneumococcal antibody or >1µg/ml compared with pre-vaccination levels, following Food and Drug Administration guidance. (B) The titre of response to the initial challenge with 23-PPV 4 weeks after vaccination. (C) The frequency of seroconversion in people treated with ocrelizumab following injection of a booster pneumococcal 13-PPV vaccine 4 weeks after 23-PPV. (n=33-34). The frequency of responders is shown 8 weeks after 23-PPV vaccination. (D) The geometric mean and 95% confidence interval (CI) anti-tetanus toxoid antibody levels measured by ELISA before and following vaccination (n=34-68). (E,F) The geometric mean and 95% CI titre of (E) IgM or (F) IgG KLH specific antibody after vaccination with keyhole limpet haemocyanin at baseline, week 4 and week 8 started 12 weeks after ocrelizumab infusion (n=34-68). (G-I). The response to: A/California/7/2009 (H1N1. n=33-35); B/Phuket/3073/2013 (BPH. n=31-33), A/Switzerland/ 9715293/2013 (H3N2. n=27-30), B/Brisbane/60/2008 (BBR. n=16-18), A/Hong Kong/4801/2014 (AHK. n=5-6) influenza strain vaccination 12 weeks after ocrelizumab infusion was assessed. The results represent (G) the percentage of people with seroconversion, defined either a pre-vaccination haemagglutination inhibition (HI) titre <10 and ≥40 at 4 weeks or a pre-vaccination ≥10 and at least a 4 fold increase in HI titre, and seroprotection defined by titres >40 at 4 weeks after vaccination. (H) The change in the geometric mean HI titres before and after vaccination (I) The percentage of people with a 4-fold increase in strain-specific >40) at 4 weeks after vaccination.
Figure 3. Long-term depletion of memory B-cells induced by ocrelizumab. These data were extracted from the ocrelizumab phase II clinical study report [101], supplied by the trial sponsor via the www.clinicaltrialdatarequest.com portal. (A) The data represents the mean percentage change from baseline, defined as the last observation up to first day of ocrelizumab treatment. The subjects received placebo and three cycles of 600mg ocrelizumab every 24 weeks. This was followed by a treatment-free period to monitor B-cell repletion in the phase II extension study. The time represents the period from the last ocrelizumab infusion (n=22-43). Naive (CD19+, CD21+, IgD+, IgM+) and memory B-cell (CD19+, CD27+, CD38low) and other immune subsets were assessed (n=22-43/group). However the numbers at week 36 for B-cell subsets were based on only n=2, with all other groups n=43-44, and therefore caution for interpretation is required. At 120 weeks post-infusion memory B cell levels were 13.59% (n=7 placebo and 3 ocrelizumab cycles) and 17.73% (n=12 4 ocrelizumab cycles) of baseline levels. (B) Depletion of memory B-cells was maintained during treatment. These data were obtained from people (n=88) entering the open label extension (OLE) study after the treatment free period that had received three or four 6 monthly cycles of at least 600mg ocrelizumab to week 72 followed by a treatment-free period to week 144, before entering the OLE phase were 600mg cycles of ocrelizumab was maintained at 24 week intervals. The results represent the mean ± standard deviation of cells/μL (n=22-69/group week 22-72). Although CD19 B-cells numbers were consistent with the original levels, the baseline memory B-cell levels failed to return to original levels at the start of the OLE. PMN = polymorphonuclear neutrophil.