ABSTRACT
Summary. Half-dose AZD1222 or BNT162b2 boosters maintained immunogenicity and safety, and were non-inferior to full doses. All doses elicited high immunogenicity and best with extended post-CoronaVac primary-series intervals (120-180 days) and high-transmissibility Omicron. Methods. At 60-to-<90, 90-to-<120, or 120-to-180 days (intervals) post-CoronaVac primary-series, participants were randomized to full-dose or half-dose AZD1222 or BNT162b2, and followed up at day-28, -60 and -90. Vaccination-induced immunogenicity to Ancestral, Delta and Omicron BA.1 strains were evaluated by assessing anti-spike (anti-S), anti-nucleocapsid antibodies, pseudovirus neutralization (PVNT), micro-neutralization titers, and T-cells assays. Descriptive statistics and non-inferiority cut-offs were reported as geometric mean concentration (GMC) or titer (GMT) and GMC/GMT ratios comparing baseline to day-28 and day-90 seroresponses, and different intervals post-CoronaVac primary-series. Omicron immunogenicity was only evaluated in full-dose recipients. Findings. No serious or severe vaccine-related safety events occurred. All assays and intervals showed non-inferior immunogenicity between full-doses and half-doses. However, full-dose vaccines and/or longer, 120-to-180-day intervals substantially improved immunogenicity (in GMC measured by anti-S assays or GMT measured by PVNT50; p <0.001). Within platforms and regardless of dose or platform, seroconversions were over 97%, and over 90% for pseudovirus neutralizing antibodies, but similar against the SARS-CoV-2 strains. Immunogenicity waned more quickly with half-doses than full-doses between day 60-to-90 follow-ups, but remained high against Ancestral or Delta strains. Against Omicron, the day-28 immunogenicity increased with longer intervals than shorter intervals for full-dose vaccines. Interpretation. Combining heterologous schedules, fractional dosing, and extended post-second dose intervals, broadens population-level protection and prevents disruptions, especially in resource-limited settings. Funding. Funding was provided by the Program Management Unit for Competitiveness Enhancement (PMU-C) National research, National Higher Education, Science, Research and Innovation Policy Council, Thailand through Clinixir Ltd.
ABSTRACT
Inactivated SARS-CoV-2 vaccine (CoronaVac) is commonly used in national immunization programs. However, the immune response significantly declined within a few months. Our study assessed the immune response against SARS-CoV-2 after receiving booster shots of BNT162b2 or ChAdOx1 among health care workers who previously received CoronaVac as their primary immunization. Fifty-six participants received ChAdOx1 and forty-two participants received BNT162b2 were enrolled into this study which evaluated the immune responses including anti-SARS-CoV-2 spike total antibodies (Elecsys®), surrogated viral neutralization test (sVNT) to ancestral strain (cPass™; GenScript) and five variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) (Luminex; multiplex sVNT) and the ELISpot with spike (S1 and S2) peptide pool against the ancestral SARS-CoV-2 strain. The samples were analyzed at baseline, 4, and 12 weeks after primary immunization as well as 4 and 12 weeks after receiving the booster. This study showed a significantly higher B-cell response among the BNT162b2 than the ChAdOx1 booster group, particularly against the Omicron variant, as well as a trend of good T-cell immune response in the BNT162b2 group. Moreover, the immune response rapidly declined at 12 weeks after the booster. A fourth dose or a second booster should be recommended, especially for reducing Omicron severity.
ABSTRACT
Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,048 severe disease cases and 571,009 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p=5.41x10-7). These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.
Subject(s)
COVID-19ABSTRACT
Background: Immunogenicity of inactivated SARS-CoV-2 vaccine has waning antibody over time. With the emergence of the SARS-CoV-2 delta variant, which requires higher neutralizing antibody to prevent infection, a booster dose is needed. Objective: To evaluate immunogenicity and reactogenicity of standard- versus low-dose ChAdOx1 nCoV-19 vaccine booster after CoronaVac in healthy adults. Methods: A double-blinded, randomized, controlled trial of adult, aged 18-59 years, with completion of 2-dose CoronaVac at 21-28 days apart for more than 2 months was conducted. Participants were randomized to receive AZD1222 (Oxford/AstraZeneca) intramuscularly; standard dose (SD, 5x1010 viral particles) or low dose (LD, 2.5x1010 viral particles). Surrogate virus neutralization test (sVNT) against wild type and delta variant, and anti-spike-receptor-binding-domain IgG (anti-S-RBD IgG) were compared as geometric mean ratio (GMR) at day 14 and 90 between LD and SD arms. Results: From July-August 2021, 422 adults with median age of 44 (IQR 36-51) years were enrolled. The median interval from CoronaVac to AZD1222 booster was 77 (IQR 64-95) days. At baseline, geometric means (GMs) of sVNT against delta variant and anti-S-RBD IgG were 18.1%inhibition (95%CI 16.4-20.0) and 111.5 (105.1-118.3) BAU/ml. GMs of sVNT against delta variant and anti-S-RBD IgG in SD were 95.6%inhibition (95%CI 94.3-97.0) and 1975.1 (1841.7-2118.2) BAU/ml at day 14, and 89.4%inhibition (86.4-92.4) and 938.6 (859.9-1024.4) BAU/ml at day 90, respectively. GMRs of sVNT against delta variant and anti-S-RBD IgG in LD compared to SD were 1.00 (95%CI 0.98-1.02) and 0.84 (0.76-0.93) at day 14, and 0.98 (0.94-1.03) and 0.89 (0.79-1.00) at day 90, respectively. LD recipients had significantly lower rate of fever (6.8%vs25.0%) and myalgia (51.9%vs70.7%) compared to SD. Conclusion: Half-dose AZD1222 booster after 2-dose inactivated SARS-CoV-2 vaccination had non-inferior immunogenicity, yet lower systemic reactogenicity. Fractional low-dose AZD1222 booster should be considered especially in resource-constrained settings.
Subject(s)
MyalgiaABSTRACT
Background Currently, booster dose is needed after 2 doses of inactivated COVID-19 vaccine. With limited resource and shortage of COVID-19 vaccine, intradermal(ID) administration might be a potential dose-sparing strategy. Objective To determine antibody response and reactogenicity of ID ChAdOx1 nCoV-19 vaccine(AZD1222,Oxford/AstraZeneca) as a booster dose after completion of 2-dose CoronaVac(SV) in healthy adult. Methods This is a prospective cohort study of adult aged 18-59 years who received 2-dose SV at 14-35 days apart for more than 2 months. Participants received ID AZD1222 at fractional low dose(1x1010 viral particles,0.1ml). Antibody responses were evaluated by surrogate virus neutralization test(sVNT) against wild type and delta variant and anti-spike-receptor-binding-domain immunoglobulin G(anti-S-RBD IgG) at prior, day14 or 28, and day90 post booster. Solicited reactogenicity was collected during 7 days post-booster. Primary endpoint was the differences of sVNT against delta strain [≥]80%inhibition at day14 and 90 compared with the parallel cohort study of 0.5-ml intramuscular(IM) route. Results From August2021, 100 adults with median(IQR) age of 46(41-52) years participated. At baseline, geometric means(GMs) of sVNT against delta strain prior to booster were 22.4%inhibition(95%CI 18.7-26.9) and of anti-S-RBD IgG were 109.3(95.4-125.1)BAU/ml. GMs of sVNT against delta strain were 92.9%inhibition(95%CI 87.7-98.3) at day14 and 73.1%inhibition(66.7-80.2) at day90 post ID booster. The differences of proportion of participants with sVNT to delta strain[≥]80%inhibition in ID recipients versus IM were +4.2%(95%CI-2.0to10.5) at day14, and -37.3%(-54.2to-20.3) at day90. Anti-S-RBD IgG GMs were 2037.1(95%CI1770.9-2343.2) at day14 and 744.6(650.1-852.9) BAU/ml at day90, respectively. Geometric mean ratios(GMRs) of anti-S-RBD IgG were 0.99(0.83-1.20) at day14, and 0.82(0.66-1.02) at day90. Only 18% reported feverish, compared with 37% of IM(p=0.003). Only 18% reported feverish, compared with 37% of IM(p=0.003). Common reactogenicity was erythema(55%) at injection site while 7% reported blister. Conclusion Low-dose ID AZD1222 booster enhanced lower neutralizing antibodies at 3 months compared with IM route. Less systemic reactogenicity occurred, but higher local reactogenicity.
Subject(s)
COVID-19 , ErythemaABSTRACT
Background Inactivated SARS-CoV-2 (CoronaVac®,Sinovac, or SV) and ChAdOx1 nCoV-19 (Vaxzevria®,Oxford-Astra Zeneca, or AZ) vaccines have been administered to the health care workers (HCWs) in Thailand. Objective To determine the short-term immune response after the SV and AZ vaccinations in HCWs. Methods In this prospective cohort study, HCWs who completed a 2-dose regimen of the SV or AZ were included. Immune response was evaluated by surrogate viral neutralization test (sVNT) and anti-SARS-CoV-2 total antibody. Blood samples were analyzed at 4 and 12 weeks after the complete SV vaccination and at 4 weeks after each dose of the AZ vaccination. The primary outcome was the seroconversion rate at 4-weeks after complete immunization. Results Overall, 185 HCWs with a median (IQR) age of 40.5(30.3-55.8) years (94 HCWs in the SV group and 91 in the AZ group) were included. At 4 weeks after completing the SV vaccination, 60.6% (95%CI:50.0-70.6%) had seroconversion evaluated by sVNT(≥68%inhibition), comparable to the patients recovered from mild COVID-19 infection(69.0%), with a rapid reduction to 12.2%(95%CI:6.3-20.8) at 12 weeks. In contrast, 85.7%(95%CI:76.8-92.2%) HCWs who completed the second dose of the AZ for 4 weeks had seroconversion, comparable to the COVID-19 pneumonia patients(92.5%). When using the anti-SAR-CoV-2 total antibody level(≥132 U/ml) criteria, only 71.3% HCWs in the SV group had seroconversion, compared to 100% in the AZ group. Conclusion A rapid decline of short-term immune response in the HCWs after the SV vaccination indicates the need for a vaccine booster, particularly during the ongoing spreading of the SAR-CoV-2 variants of concern.
Subject(s)
COVID-19ABSTRACT
Background: More understanding of antibody responses in the SARS-CoV-2 infected population is useful for vaccine development. Aim: To investigate SARS-CoV-2 IgA and IgG among COVID-19 Thai patients with different severity. Methods: We used plasma from 118 adult patients who have confirmed SARS-CoV-2 infection and 49 patients under investigation without infection, 20 patients with other respiratory infections, and 102 healthy controls. Anti-SARS-CoV-2 IgA and IgG were performed by enzyme-linked immunosorbent assay from Euroimmun. The optical density ratio cut off for positive test was 1.1 for IgA and 0.8 for IgG. The association of antibody response with the severity of diseases and the day of symptoms was performed. Results: From Mar 10 to May 31, 2020, 289 participants were enrolled, and 384 samples were analyzed. Patients were categorized by clinical manifestations to mild (n=59), moderate (n=27) and severe (n=32). The overall sensitivity of IgA and IgG from samples collected after day 7 is 87.9% (95% CI 79.8-93.6) and 84.8% (95% CI 76.2-91.3), respectively. The severe group had a significantly higher level of specific IgA and IgG to S1 antigen compared to the mild group. All moderate to severe patients have specific IgG while 20% of the mild group did not have any IgG detected after two weeks. Interestingly, SARS-CoV-2 IgG level was significantly higher in males compared to females among the severe group (p=0.003). Conclusion: The serologic test for SARS-CoV-2 has high sensitivity after the second week after onset of illness. Serological response differs among patients with different severity and different sex.