A Phase 1, Randomized, Double-Blinded, Placebo-Controlled and Dose-Escalation Study to Evaluate the Safety and Immunogenicity of the Intranasal DelNS1-nCoV-RBD LAIV for COVID-19 in Healthy Adults.

An intranasal COVID-19 vaccine, DelNS1-based RBD vaccines composed of H1N1 subtype (DelNS1-nCoV-RBD LAIV) was developed to evaluate the safety and immunogenicity in healthy adults. We conducted a phase 1 randomized, double-blinded, placebo-controlled study on healthy participants, age 18-55 and COVID-19 vaccines naïve, between March and September 2021. Participants were enrolled and randomly assigned (2:2:1) into the low and high dose DelNS1-nCoV-RBD LAIV manufactured in chicken embryonated eggs or placebo groups. The low and high-dose vaccine were composed of 1 × 107 EID50/ dose and 1 × 107.7 EID50/ dose in 0.2 mL respectively. The placebo vaccine was composed of inert excipients/dose in 0.2 mL. Recruited participants were administered the vaccine intranasally on day 0 and day 28. The primary end-point was the safety of the vaccine. The secondary endpoints included cellular, humoral, and mucosal immune responses post-vaccination at pre-specified time-points. The cellular response was measured by the T-cell ELISpot assay. The humoral response was measured by the serum anti-RBD IgG and live-virus neutralizing antibody against SARS-CoV-2. The saliva total Ig antibody responses in mucosal secretion against SARS-CoV-2 RBD was also assessed. Twenty-nine healthy Chinese participants were vaccinated (low-dose: 11; high-dose: 12 and placebo: 6). The median age was 26 years. Twenty participants (69%) were male. No participant was discontinued due to an adverse event or COVID-19 infection during the clinical trial. There was no significant difference in the incidence of adverse events (p = 0.620). For the T-cell response elicited after full vaccination, the positive PBMC in the high-dose group increased to 12.5 SFU/106 PMBC (day 42) from 0 (baseline), while it increased to 5 SFU/106 PBMC (day 42) from 2.5 SFU/106 PBMC (baseline) in the placebo group. The high-dose group showed a slightly higher level of mucosal Ig than the control group after receiving two doses of the vaccine (day 31, 0.24 vs. 0.21, p = 0.046; day 56 0.31 vs. 0.15, p = 0.45). There was no difference in the T-cell and saliva Ig response between the low-dose and placebo groups. The serum anti-RBD IgG and live virus neutralizing antibody against SARS-CoV-2 were undetectable in all samples. The high-dose intranasal DelNS1-nCoV-RBD LAIV is safe with moderate mucosal immunogenicity. A phase-2 booster trial with a two-dose regimen of the high-dose intranasal DelNS1-nCoV-RBD LAIV is warranted.

TLR7 agonist RO7020531 versus placebo in healthy volunteers and patients with chronic hepatitis B virus infection: a randomised, observer-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Toll-like receptor 7 (TLR7) agonists augment immune activity and have potential for the treatment of chronic hepatitis B virus (HBV) infection. We aimed to assess the safety and tolerability of RO7020531 (also called RG7854), a prodrug of the TLR7 agonist RO7011785, in healthy volunteers and patients with chronic HBV infection. METHODS: This randomised, observer-blind, placebo-controlled, phase 1 study was done in two parts. Part 1 was done at one site in New Zealand and part 2 was done at 12 sites in Bulgaria, Hong Kong, Italy, New Zealand, the Netherlands, Taiwan, Thailand, and the UK. In part 1, healthy volunteers were randomly assigned (4:1) within one of eight dose cohorts (3 mg, 10 mg, 20 mg, 40 mg, 60 mg, 100 mg, 140 mg, or 170 mg) to receive a single RO7020531 dose or placebo or randomly assigned (4:1) within one of three dose cohorts (100 mg, 140 mg, or 170 mg) to receive either RO7020531 or placebo every other day for 13 days. In part 2, nucleoside or nucleotide analogue-suppressed patients with chronic HBV infection were randomly assigned (4:1) within cohorts 1-3 (150 mg, 150 mg, or 170 mg) to receive either RO7020531 or placebo and treatment-naive patients with chronic HBV infection were randomly assigned (3:1) in cohort 4 to receive either 150 mg of RO7020531 or placebo. Patients were treated every other day for 6 weeks. Study medication was administered orally to participants after they had fasted. Study participants and investigational staff were masked to treatment allocation. The primary outcome was the safety and tolerability of RO7020531, as measured by the incidence and severity of adverse events and the incidence of laboratory, vital sign, and electrocardiogram abnormalities, and was analysed in all participants who received at least one dose of the study medication. This trial is registered with ClinicalTrials.gov, NCT02956850, and the study is complete. FINDINGS: Between Dec 12, 2016, and March 21, 2021, 340 healthy volunteers were screened in part 1, of whom 80 were randomly assigned in the single ascending dose study (eight assigned RO7020531 in each cohort and 16 assigned placebo) and 30 were randomly assigned in the multiple ascending dose study (eight assigned RO7020531 in each cohort and six assigned placebo), and 110 patients were screened in part 2, of whom 30 were randomly assigned in cohorts 1-3 (16 assigned RO7020531 150 mg, eight assigned RO7020531 170 mg, and six assigned placebo) and 20 were randomly assigned in cohort 4 (15 assigned RO7020531 and five assigned placebo). All randomly assigned participants received at least one dose of a study drug and were included in the safety analysis. All tested doses of RO7020531 were safe and had acceptable tolerability in healthy volunteers and patients. The most frequent treatment-related adverse events among the total study population were headache (15 [9%] of 160 participants), influenza-like illness (seven [4%] of 160 participants), and pyrexia (ten [6%] of 160 participants). Most adverse events were mild and transient. There were no severe or serious adverse events in healthy volunteers. In the patient cohorts, there was one severe adverse event (influenza-like illness with 170 mg of RO7020531) and one serious adverse event (moderate influenza-like illness with a 3-day hospitalisation in a treatment-naive patient receiving RO7020531). There were no treatment-related deaths. INTERPRETATION: Due to acceptable safety and tolerability, RO7020531 should continue to be developed for the treatment of patients with chronic HBV infection. FUNDING: F Hoffmann-La Roche.

Effect of Moderate to Severe Hepatic Steatosis on Vaccine Immunogenicity against Wild-Type and Mutant Virus and COVID-19 Infection among BNT162b2 Recipients.

BACKGROUND: We aimed to investigate the effect of non-alcoholic fatty liver disease (NAFLD) on BNT162b2 immunogenicity against wild-type SARS-CoV-2 and variants and infection outcome, as data are lacking. METHODS: Recipients of two doses of BNT162b2 were prospectively recruited. Outcomes of interest were seroconversion of neutralizing antibody by live virus microneutralization (vMN) to SARS-CoV-2 strains (wild-type, delta and omicron variants) at day 21, 56 and 180 after first dose. Exposure of interest was moderate-to-severe NAFLD (controlled attenuation parameter ≥ 268 dB/M on transient elastography). We calculated adjusted odds ratio (aOR) of infection with NAFLD by adjusting for age, sex, overweight/obesity, diabetes and antibiotic use. RESULTS: Of 259 BNT162b2 recipients (90 (34.7%) male; median age: 50.8 years (IQR: 43.6-57.8)), 68 (26.3%) had NAFLD. For wild type, there was no difference in seroconversion rate between NAFLD and control groups at day 21 (72.1% vs. 77.0%; p = 0.42), day 56 (100% vs. 100%) and day 180 (100% and 97.2%; p = 0.22), respectively. For the delta variant, there was no difference also at day 21 (25.0% vs. 29.5%; p = 0.70), day 56 (100% vs. 98.4%; p = 0.57) and day 180 (89.5% vs. 93.3%; p = 0.58), respectively. For the omicron variant, none achieved seroconversion at day 21 and 180. At day 56, there was no difference in seroconversion rate (15.0% vs. 18.0%; p = 0.76). NAFLD was not an independent risk factor of infection (aOR: 1.50; 95% CI: 0.68-3.24). CONCLUSIONS: NAFLD patients receiving two doses of BNT162b2 had good immunogenicity to wild-type SARS-CoV-2 and the delta variant but not the omicron variant, and they were not at higher risk of infection compared with controls.

COVID-19 vaccine immunogenicity among chronic liver disease patients and liver transplant recipients: A meta-analysis.

BACKGROUND/AIMS: Data of coronavirus disease 2019 (COVID-19) vaccine immunogenicity among chronic liver disease (CLD) and liver transplant (LT) patients are conflicting. We performed meta-analysis to examine vaccine immunogenicity regarding etiology, cirrhosis status, vaccine platform and type of antibody. METHODS: We collected data via three databases from inception to February 16, 2022, and reported pooled seroconversion rate, T cell response and safety data after two vaccine doses. RESULTS: Twenty-eight (CLD only: 5; LT only: 18; both: 2; LT with third dose: 3) observational studies of 3,945 patients were included. For CLD patients, seroconversion rate ranged between 84% (95% confidence interval [CI], 76-90%) and 91% (95% CI, 83-95%), based predominantly on neutralizing antibody and anti-spike antibody, respectively. Seroconversion rate was 81% (95% CI, 76-86%) in chronic hepatitis B, 96% (95% CI, 93-97%) in non-alcoholic fatty liver disease, 85% (95% CI, 75-91%) in cirrhosis and 85% (95% CI, 78-90%) in non-cirrhosis, 86% (95% CI, 78-92%) for inactivated vaccine and 89% (95% CI, 71-96%) for mRNA vaccine. The pooled seroconversion rate of anti-spike antibody was 66% (95% CI, 55-75%) after two doses of mRNA vaccines and 88% (95% CI, 58-98%) after third dose among LT recipients. T cell response rate was 65% (95% CI, 30-89%). Prevalence of adverse events was 27% (95% CI, 18-38%) and 63% (95% CI, 39-82%) among CLD and LT groups, respectively. CONCLUSION: CLD patients had good humoral response to COVID-19 vaccine, while LT recipients had lower response.

Risk of acute liver injury following the mRNA (BNT162b2) and inactivated (CoronaVac) COVID-19 vaccines.

BACKGROUND & AIMS: Case reports of severe acute liver injury (ALI) following COVID-19 vaccination have recently been published. We evaluated the risks of ALI following COVID-19 vaccination (BNT162b2 or CoronaVac). METHODS: We conducted a modified self-controlled case series analysis using the vaccination records in Hong Kong with data linkage to electronic medical records from a territory-wide healthcare database. Incidence rate ratios (IRRs) for ALI outcome in the 56-day period following first and second doses of COVID-19 vaccines in comparison to the non-exposure period were estimated and compared to the ALI risk in patients with SARS-CoV-2 infection. RESULTS: Among 2,343,288 COVID-19 vaccine recipients who were at risk, 4,677 patients developed ALI for the first time between 23rd February 2021 to 30th September 2021. The number of ALI cases within 56 days after the first and second dose of vaccination were 307 and 521 (335 and 334 per 100,000 person-years) for BNT162b2, and 304 and 474 (358 and 403 per 100,000 person-years) for CoronaVac, respectively, compared to 32,997 ALI cases per 100,000 person-years among patients within 56 days of SARS-CoV-2 infection. Compared to the non-exposure period, no increased risk was observed in the 56-day risk period for first (IRR 0.800; 95% CI 0.680-0.942) and second (IRR 0.944; 95% CI 0.816-1.091) dose of BNT162b2, or first (IRR 0.689; 95% CI 0.588-0.807) and second (IRR 0.905; 95% CI 0.781-1.048) dose of CoronaVac. There were no severe or fatal cases of ALI following COVID-19 vaccination. CONCLUSION: There was no evidence of an increased risk of ALI associated with BNT162b2 or CoronaVac vaccination. Based on all current available evidence from previous studies and our study, the benefit of mass vaccination far outweighs the ALI risk from vaccination. LAY SUMMARY: There have been some recent reports that COVID-19 vaccination could be associated with acute liver injury. In our study, we found no evidence that COVID-19 vaccination increased the risk of acute liver injury, which was much more common after SARS-CoV-2 infection than after vaccination. Hence, our study provides further data indicating that the benefits of mass COVID-19 vaccination outweigh the potential risks.

Effect of moderate-to-severe hepatic steatosis on neutralising antibody response among BNT162b2 and CoronaVac recipients.

BACKGROUND/AIMS: Studies of hepatic steatosis (HS) effect on COVID-19 vaccine immunogenicity are lacking. We aimed to compare immunogenicity of BNT162b2 and CoronaVac among moderate/severe HS and control subjects. METHODS: Two hundred ninety-five subjects who received BNT162b2 or CoronaVac vaccines from five vaccination centers were categorized into moderate/severe HS (controlled attenuation parameter ≥268 dB/m on transient elastography) (n=74) or control (n=221) groups. Primary outcomes were seroconversion rates of neutralising antibody by live virus Microneutralization (vMN) assay (titer ≥10) at day21 (BNT162b2) or day28 (CoronaVac) and day56 (both). Secondary outcome was highest-tier titer response (top 25% of vMN titer; cutoff: 160 [BNT162b2] and 20 [CoronaVac]) at day 56. RESULTS: For BNT162b2 (n=228, 77.3%), there was no statistical differences in seroconversion rates (day21: 71.7% vs. 76.6%; day56: 100% vs. 100%) or vMN geometric mean titer (GMT) (day21: 13.2 vs. 13.3; day56: 91.9 vs. 101.4) among moderate/severe HS and control groups respectively. However, lower proportion of moderate/severe HS patients had highest-tier response (day56: 5.0% vs. 15.5%; P=0.037). For CoronaVac (n=67, 22.7%), there was no statistical differences in seroconversion rates (day21: 7.1% vs. 15.1%; day56: 64.3% vs. 83.0%) or vMN GMT (5.3 vs. 5.8,) at day28. However, moderate/severe HS patients had lower vMN GMT (9.1 vs. 14.8, P=0.021) at day 56 with lower proportion having highest-tier response (21.4% vs. 52.8%, P=0.036). CONCLUSION: While there was no difference in seroconversion rate between moderate/severe HS and control groups after two doses of vaccine, a lower proportion of moderate/severe HS patients achieved highest-tier response for either BNT162b2 or CoronaVac.