COVID-19 vaccine-induced neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 are diminished in patients with inflammatory bowel disease on anti-TNF or JAK-inhibitor therapy

Background: Patients with Inflammatory bowel disease (IBD) receiving anti-TNF or JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the currently dominant Omicron BA.4/5 variants. Method(s): We prospectively recruited 329 adults (68 healthy controls (HC) and 261 IBD) who had received three doses of COVID-19 vaccine at nine UK centres. The IBD population was established (>12 weeks therapy) on either thiopurine (n=60), infliximab (IFX) (n=43), thiopurine and IFX combination (n=46), ustekinumab (n=43), vedolizumab (n=46) or tofacitinib (n=23). Pseudoneutralisation assays were performed and the half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARSCoV-2 neutralising response against wild-type (WT) virus and the BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, ethnicity, vaccine type and age. Result(s): Heterologous (two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both WT SARS-CoV-2 virus and the BA.4/5 variants in HCs and IBD (fig 1). Antibody titres against BA.4/5 were significantly lower than antibodies against WT virus in both groups (Geometric Mean Ratio (GMR) [95% CI], 0.11 [0.09, 0.15], P<0.0001 in healthy participants;GMR 0.07 [0.06, 0.08], P<0.0001 in IBD patients). Multivariable models showed that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in IBD patients on IFX (GMR 0.44 [0.20, 0.97], P=0.042), IFX and thiopurine combination (GMR 0.34 [0.15, 0.77], P=0.0098) or tofacitinib (GMR 0.37 [0.15, 0.92], P=0.032), but not in patients on thiopurine monotherapy, ustekinumab or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against WT and BA.4/5 (P<0.05). Conclusion(s): A third dose of COVID-19 vaccine based on the WT spike glycoprotein boosts neutralising antibody titres in patients with IBD. However, responses are lower against the currently dominant variant BA.4/5, particularly in patients taking anti-TNF or JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed IBD patients may receive additional benefit from bivalent vaccine boosters which target Omicron variants. .

COVID-19 VACCINATION RESPONSE IN IMMUNOSUPPRESSED PATIENTS WITH IBD IS ASSOCIATED WITH ALTERED GUT MICROBIOTA FUNCTION

Introduction Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients. Methods Faecal and serum samples were prospectively collected from patients with IBD established on infliximab therapy (for >12 weeks) who were undergoing vaccination against SARS-CoV-2. The Roche Elecsys Anti-SARS-CoV-2 spike (S) and nucleocapsid (N) immunoassays were used to measure antibody responses following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Seroconversion was defined by a cut-off anti-S concentration of 15 U/ml, which correlated with 20% viral neutralization;anti-S antibody concentration of < 380 U/ml was indicative of poor response to vaccination. Patients with serological evidence of prior SARS-CoV-2 infection were excluded from the analysis. Faecal calprotectin measurement, 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-performance liquid chromatography mass spectrometry (UPLC-MS) were performed on faecal samples. Results Forty-five infliximab-treated patients were recruited (median age 40 [range 19-67];32 Crohn's disease, 13 ulcerative colitis;28 with concomitant immunomodulator therapy;six with prior infection). 14 patients (35%) had seroconverted after one dose of vaccine and 37 (95%) seroconverted after two doses. 18 patients (46%) had a poor response after two doses of vaccine. There was no association between faecal calprotectin and vaccine response (p=0.41). No differences between satisfactory and poor vaccine responders were noted in alpha or beta diversity of the gut microbiota. The faecal metabolome of satisfactory responders was enriched in the microbial metabolite trimethylamine (q=0.03). Trends were noted linking the short chain fatty acid butyrate with satisfactory response (P=0.01) and succinate with poor response (P=0.06). No significant differences in primary or secondary bile acids were found to associate with vaccine response. The butyrate-producing genus Roseburia was positively correlated with faecal butyrate abundance (q=0.03). Conclusions Our data suggest an association between gut microbiota function and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine and butyrate may be important in mitigating anti-TNF-induced attenuation of the immune response.

POOR RESPONSE TO ANTI-SARS-COV-2 VACCINATION IN IMMUNOSUPPRESSED INFLAMMATORY BOWEL DISEASE PATIENTS IS ASSOCIATED WITH ALTERED GUT MICROBIOTA FUNCTION

Introduction: Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients. Methods: Faecal and serum samples were prospectively collected from patients with IBD established on infliximab therapy (for >12 weeks) who were undergoing vaccination against SARS-CoV-2. The Roche Elecsys Anti-SARS-CoV-2 spike (S) and nucleocapsid (N) immunoassays were used to measure antibody responses following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Seroconversion was defined by a cut-off anti-S concentration of 15 U/ml, which correlated with 20% viral neutralization;anti-S antibody concentration of < 380 U/ml was indicative of poor response to vaccination. Patients with serological evidence of prior SARS-CoV-2 infection were excluded from the analysis. Faecal calprotectin measurement, 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-performance liquid chromatography mass spectrometry (UPLC-MS) were performed on faecal samples. Results: Forty-five infliximab-treated patients were recruited (median age 40 [range 19-67];32 Crohn's disease, 13 ulcerative colitis;28 with concomitant immunomodulator therapy;six with prior infection). 14 patients (35%) had seroconverted after one dose of vaccine and 37 (95%) seroconverted after two doses. 18 patients (46%) had a poor response after two doses of vaccine. There was no association between faecal calprotectin and vaccine response (p=0.41). No differences between satisfactory and poor vaccine responders were noted in alpha or beta diversity of the gut microbiota. The faecal metabolome of satisfactory responders was enriched in the microbial metabolite trimethylamine (q=0.03). Trends were noted linking the short chain fatty acid butyrate with satisfactory response (P=0.01) and succinate with poor response (P=0.06). No significant differences in primary or secondary bile acids were found to associate with vaccine response. The butyrate-producing genus Roseburia was positively correlated with faecal butyrate abundance (q=0.03). Conclusion: Our data suggest an association between gut microbiota function and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine and butyrate may be important in mitigating anti-TNF-induced attenuation of the immune response.

COVID-19 VACCINE-INDUCED ANTIBODY RESPONSES ARE IMPAIRED IN IBD PATIENTS TREATED WITH INFLIXIMAB, USTEKINUMAB OR TOFACITINIB, BUT NOT THIOPURINES OR VEDOLIZUMAB

Background : Robust COVID-19 vaccine-induced antibody (Ab) responses are important for protective anti-viral immunity. Data are urgently needed to determine whether vaccineinduced immunity is impacted by commonly used immunosuppressive drug regimens in IBD. Methods: We prospectively recruited 447 adults (90 healthy controls and 357 IBD) at nine UK centres. The IBD study population was established (>12 weeks therapy) on either thiopurine monotherapy (n=78), infliximab (IFX) monotherapy (n=61), thiopurine & IFX combination therapy (n=70), ustekinumab (uste) monotherapy (n=56), vedolizumab (vedo) monotherapy (n=62) or tofacitinib (tofa) monotherapy (n=30). Participants had two doses of either ChAdOx1 nCoV-19, BNT162b2 or mRNA1273 vaccines. The primary outcome was anti-SARS-CoV-2 spike (S1 RBD) Ab concentrations, measured using the Elecsys anti- SARS-CoV-2 spike (S) Ab assay, 53-92 days after second vaccine dose, in participants without prior infection, adjusted by age & vaccine type. Secondary outcomes included proportions failing to generate protective Ab responses (defined cut-off anti-S concentration 15 U/ml, which correlated with 20% viral neutralization). Results: Geometric mean S Ab concentrations (figure 1) were lower in patients treated with IFX (153U/ml;p<0.0001), IFX and thiopurine combination (109U/mL;p<0.0001), tofa (430U/ml;p<0.0001) and uste (561U/ml;p=0.013) compared to controls (1596U/ml). No differences in S Ab concentrations were found between controls and thiopurine monotherapy-treated patients (1020U/ml;p=0.62), nor between controls and vedo-treated patients (944U/ml;p=0.69). In multivariable modelling (figure 2), lower S Ab concentrations were independently associated with IFX (FC 0.10 [95% CI 0.07-0.14], p<0.0001), tofa (0.36 [95% CI 0.19-0.69], p=0.002) and uste (0.56 [95% CI 0.31-1.00], p=0.049), but not with thiopurine (0.77 [95% CI 0.54-1.11], p=0.17) or vedo (1.01 [95% CI 0.61-1.68], p=0.96). mRNA vaccines (3.67 [95% CI 2.72-4.96], p<0.0001) and older age (0.82 [95% CI 0.73-0.91], p=0.0003) were independently associated with higher & lower S Ab concentrations respectively. Protective Ab responses were generated by all thiopurine monotherapy, vedo, tofa and healthy control participants, but not by 11% of patients on IFX monotherapy, 13% on thiopurine & IFX combination therapy and 4% on uste. Conclusions : COVID-19 vaccine-induced Ab responses are significantly reduced in patients treated with IFX, or tofa, and to a lesser extent with uste. No significant reduction was seen in vedo or thiopurine monotherapy-treated patients. Our data suggest that 3rd primary or booster vaccine doses for IBD patients might be tailored to an individual's immunosuppressive treatment. (Figure Presented) (Figure Presented)

Assessing urban heat island in Jakarta, Indonesia during the pandemic of Covid-19

Jakarta, the capital city of Indonesia, is the most populated area in Indonesia, with a population of 10.56 million people or around 3.91% of the total Indonesian population. Jakarta has also become an important city in Indonesia as around 80% of Indonesian economic activity is located in this area. No doubt, the urban activity caused the air pollution to infuriate its microclimate, including the urban heat island phenomena. During the Covid-19 pandemic, Indonesia applied the partial lockdown for several areas to decrease virus transmission. Most of the transportation and commercial areas were closed, and most people worked from home. This significant shifting will affect the temperature and urban heat island conditions. Thus, the main objective of this research was to analyse the urban heat island during the early stage of the pandemic in Jakarta. We used Landsat 8 imagery to extract the land surface temperature (LST) and generated the urban heat island (UHI). The correlation was used to determine the relationship between the distribution of covid-19 cases with the UHI distribution. From the four different recording times (May, July, September, and December 2020) of Landsat 8 imagery, the highest UHI, 7.76°C was found in December 2020 (the late first year of the pandemic). The lowest UHI, 4.91°C was found in May 2020 (The early stage of the first year). Furthermore, the UHI hot spot moved from almost evenly in East Jakarta in May 2020, a tiny spot in East Jakarta in July and September 2020, and evenly distributed in Southeast Jakarta in December 2020. In addition, we found that the increase of covid-19 cases had a positive correlation with the UHI in Jakarta, which means the areas with the high UHI value have high new covid-19 cases. These results showed that the area with high activities is very prone to covid-19 transmission.

PREPARE-IBD: Physician responses to disease flares and patient adaptation in relation to events in inflammatory bowel disease during the COVID-19 pandemic: A multicentre cohort analysis

Background: The COVID-19 pandemic continues to pose complex problems across Europe and the world, with rising numbers of infections and the ongoing need for drastic public health interventions. This is difficult for patients with immune-mediated disorders like Inflammatory Bowel Disease (IBD), where immunosuppressive medications may affect susceptibility to serious infection. It was particularly challenging for physicians and patients during the first wave of the pandemic, when it was unclear whether anti-inflammatory flare treatment should be adapted to reduce infection risk, whilst trying to ensure symptomatic control and avoid admission to overwhelmed hospitals. Despite the development of various IBD / COVID-19 databases, the treatment adaptations and outcomes of patients experiencing IBD flares during the COVID-19 pandemic remain undefined. We aimed to compare IBD management and outcomes between pandemic and prepandemic cohorts. Methods: An observational cohort study was performed, comprising patients who contacted IBD teams for a symptom flare between March - June, 2020 in, 60 National Health Service trusts in the United Kingdom. Data were compared to a pre-pandemic cohort after propensity- matching for age and disease severity. Statistical analyses were performed using R (version, 4.1.0, Vienna, Austria). Results: In total, 3728 patients in the pandemic (n=1864) and pre-pandemic (n=1864) cohorts were included. The principal findings were reduced systemic corticosteroid prescription during the pandemic in both Crohn's disease (prednisolone: pandemic, 199/752, 26.5% vs, 263/708, 37.1%;p<0.001) and ulcerative colitis (UC) (prednisolone: pandemic, 372/1112, 33.5% vs, 470/1156, 40.7%, p<0.001), with increases in poorly bioavailable oral corticosteroids in Crohn's (pandemic, 117/752, 15.6% vs, 48/708, 6.8%;p<0.001) and UC (pandemic, 131/1112, 11.8% vs, 60/1156, 5.2%;p<0.001). Ustekinumab (Crohn's and UC) and vedolizumab (UC) treatment also significantly increased during the pandemic. Three-month steroid-free remission was similar in both Crohn's (pandemic, 175/616, 28.4% vs, 195/608, 32.1%;p=0.17) and UC (pandemic, 312/858, 36.4% vs, 404/1006, 40.2%;p=0.095). The, 65 patients experiencing a flare and COVID-19 were more likely to have moderate-to-severely active disease at three months compared to those with a flare alone. Conclusion: Despite several treatment adaptations during the pandemic, steroid-free outcomes were comparable to pre-pandemic levels, though patients with a flare and COVID-19 experienced worse outcomes. These findings have implications for IBD management during future waves or pandemics.

Antibody decay, T cell immunity and breakthrough infections following SARS-CoV-2 vaccination in infliximab- and vedolizumab-treated patients

Background: Antibody responses following SARS-CoV-2 infection or a single-dose of SARS-CoV-2 vaccine are impaired in patients with inflammatory bowel disease treated with anti-TNF compared to those treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody. Here we sought to determine if patients treated with infliximab have attenuated serological and T cell responses and an increased risk of breakthrough COVID-19 infection following primary SARS-CoV-2 vaccination. Methods: Anti-spike (S) receptor binding domain (RBD) antibody concentration in 2306 infliximab-treated patients were compared to a cohort of 1045 vedolizumab-treated patients. Our primary outcome was anti-S RBD antibodies 2 to 10 weeks after a second dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines. Secondary outcomes were anti-spike T cell responses, durability of vaccine responses and risk of breakthrough infections following two doses of vaccine. Results: Anti-S RBD antibody concentrations were lower in patients treated with infliximab than in those treated with vedolizumab, following a second dose of BNT162b2 (567.3 U/mL [6.1] vs 4601.1 U/ mL [5.3], p <0.0001) and ChAdOx1 nCoV-19 (183.9 U/mL [5.0] vs 789.4 U/mL [3.5], p <0.0001) vaccines (Fig. 1). Vaccination with the BNT162b2 vaccine compared to the ChAdOx1 nCoV-19 was independently associated with a 3.7-fold [95% CI 3.30 - 4.13] higher anti-S RBD antibody concentration (p < 0.0001) (Fig. 2). There were no significant differences in the magnitude of anti-spike T cell responses observed in infliximab- compared with vedolizumabtreated patients after one or two doses of either vaccine. Antibody half-life was shorter in infliximab- than vedolizumabtreated patients following two-doses of BNT162b2 (4.0 weeks [95% CI 3.8 - 4.1] vs 7.2 weeks [95% CI 6.8 - 7.6]) and ChAdOx1 nCoV- 19 (5.3 weeks [95% CI 5.1 - 5.5] vs 9.3 weeks [95% CI 8.5 - 10.2], p value < 0.0001). Breakthrough SARS-CoV-2 infections were more frequent (5.8% (202/3467) vs 3.9% (66/1691), p = 0.0032) and the time to breakthrough shorter in patients treated with infliximab than vedolizumab (p = 0.0023) (Fig. 3). Higher anti-S RBD antibody concentrations following a second dose of SARS-CoV-2 vaccine protected against breakthrough SARS-CoV-2 infection: overall, for every 10-fold rise in anti-S RBD antibody level we observed a 0.8-fold reduction in odds of breakthrough infection ([95% CI 0.70 - 0.99], p = 0.035). Conclusion: Infliximab was associated with attenuated, less durable vaccine induced anti-S RBD antibody responses and a 50% increase in breakthrough SARS-CoV-2 infection. Further follow-up is required to assess whether third primary doses can mitigate the effects of infliximab on anti-S RBD antibody responses.

COVID-19 vaccine-induced antibody responses are impaired in Inflammatory Bowel Disease patients treated with infliximab, ustekinumab or tofacitinib, but not thiopurines or vedolizumab

Background: Robust COVID-19 vaccine-induced antibody (Ab) responses are important for protective anti-viral immunity. Data are urgently needed to determine whether vaccine-induced immunity is impacted by commonly used immunosuppressive drug regimens in IBD. Methods: We prospectively recruited 447 adults (90 healthy controls and 357 IBD) at nine UK centres. The IBD study population was established (>12 weeks therapy) on either thiopurine monotherapy (n=78), infliximab (IFX) monotherapy (n=61), thiopurine & IFX combination therapy (n=70), ustekinumab (uste) monotherapy (n=56), vedolizumab (vedo) monotherapy (n=62) or tofacitinib (tofa) monotherapy (n=30). Participants had two doses of either ChAdOx1 nCoV-19, BNT162b2 or mRNA1273 vaccines. The primary outcome was anti-SARS-CoV-2 spike (S1 RBD) Ab concentrations, measured using the Elecsys anti- SARS-CoV-2 spike (S) Ab assay, 53-92 days after second vaccine dose, in participants without prior infection, adjusted by age & vaccine type. Secondary outcomes included proportions failing to generate protective Ab responses (defined cut-off anti-S concentration 15 U/mL, which correlated with 20% viral neutralization). Results: Geometric mean S Ab concentrations (figure 1) were lower in patients treated with IFX (153U/mL;p<0.0001), IFX and thiopurine combination (109U/mL;p<0.0001), tofa (430U/mL;p<0.0001) and uste (561U/mL;p=0.013) compared to controls (1596U/ml). No differences in S Ab concentrations were found between controls and thiopurine monotherapy- treated patients (1020U/mL;p=0.62), nor between controls and vedo-treated patients (944 U/mL;p=0.69). In multivariable modelling (figure 2), lower S Ab concentrations were independently associated with IFX (FC 0.10 [95% CI 0.07-0.14], p<0.0001), tofa (0.36 [95% CI 0.19-0.69], p=0.002) and uste (0.56 [95% CI 0.31-1.00], p=0.049), but not with thiopurine (0.77 [95% CI 0.54-1.11], p=0.17) or vedo (1.01 [95% CI 0.61-1.68], p=0.96). mRNA vaccines (3.67 [95% CI 2.72- 4.96], p<0.0001) and older age (0.82 [95% CI 0.73-0.91], p=0.0003) were independently associated with higher & lower S Ab concentrations respectively. Protective Ab responses were generated by all thiopurine monotherapy, vedo, tofa and healthy control participants, but not by 11% of patients on IFX monotherapy, 13% on thiopurine & IFX combination therapy and 4% on uste. Conclusion: COVID-19 vaccine-induced Ab responses are significantly reduced in patients treated with IFX, or tofa, and to a lesser extent with uste. No significant reduction was seen in vedo or thiopurine monotherapy-treated patients. Our data suggest that 3rd primary or booster vaccine doses for IBD patients might be tailored to an individual's immunosuppressive treatment.

COVID Arm After Moderna Booster in Healthcare Worker: A Case Report

SARS CoV-2 virus has infected more than 200 million people worldwide and more than 4.4 million in Indonesia. The vaccination program has become one of the solutions launched by many countries globally, including Indonesia, to reduce the transmission rate of COVID-19. Various vaccination platforms are produced, such as inactivated, viral vector, mRNA, and protein subunit. The vaccination booster program with mRNA platform (Moderna) was launched by the Indonesian government to give better protection for health care workers, particularly from delta variant. In this case report, we discuss one of the typical side effects of Moderna vaccine, which is referred to as the COVID arm.