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BackgroundMore understanding of antibody responses in the SARS-CoV-2 infected population is useful for vaccine development. AimTo investigate SARS-CoV-2 IgA and IgG among COVID-19 Thai patients with different severity. MethodsWe 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. ResultsFrom 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). ConclusionThe 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.
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BackgroundImmunogenicity 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. ObjectiveTo evaluate immunogenicity and reactogenicity of standard- versus low-dose ChAdOx1 nCoV-19 vaccine booster after CoronaVac in healthy adults. MethodsA 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. ResultsFrom 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. ConclusionHalf-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. Highlights- Low dose AZD1222 could boost comparable immunity to standard dose in healthy adult who completed 2 doses of inactivated SARS-CoV-2 vaccines. - Less reactogenicity occurred in low-dose AZD1222 booster than standard-dose recipients. Thai Clinical Trials Registry (thaiclinicaltrials.org): TCTR20210722003
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BackgroundCurrently, 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. ObjectiveTo 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. MethodsThis 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. ResultsFrom 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. ConclusionLow-dose ID AZD1222 booster enhanced lower neutralizing antibodies at 3 months compared with IM route. Less systemic reactogenicity occurred, but higher local reactogenicity. HighlightsO_LIIntradermal AZD1222 booster vaccine gave comparable short-term immunogenicity but lower 90-day immunogenicity with conventional intramuscular vaccine. C_LIO_LILower systemic but higher local reactogenicity was found in intradermal AZD1222 booster vaccine. C_LIO_LIBlister and pruritus could be seen after intradermal AZD1222 booster vaccine. C_LI
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BackgroundInactivated SARS-CoV-2 (CoronaVac(R),Sinovac, or SV) and ChAdOx1 nCoV-19 (Vaxzevria(R),Oxford-Astra Zeneca, or AZ) vaccines have been administered to the health care workers (HCWs) in Thailand. ObjectiveTo determine the short-term immune response after the SV and AZ vaccinations in HCWs. MethodsIn 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. ResultsOverall, 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. ConclusionA 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.
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SummaryHalf-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. MethodsAt 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. FindingsNo 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. InterpretationCombining heterologous schedules, fractional dosing, and extended post-second dose intervals, broadens population-level protection and prevents disruptions, especially in resource-limited settings. FundingFunding 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. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSO_LIAlthough nAb titers from CoronaVac primary series waned after 3-4 months, nAb were more increased when boosted at 8 months than at 2 months post-primary series. C_LIO_LISix months post-vaccination with a one-fourth dose of primary mRNA-1273, nAb responses were half as robust as full doses, but VE was over 80% of that of full-dose vaccinations. C_LIO_LIThai adults boosted with 30g-BNT162b2 and 15g-BNT162b2 at 8-12 weeks after two-dose CoronaVac or AZD1222 had high antibodies to the virus receptor-binding domain, nAb titers against all variants, and T-cell responses. C_LIO_LIThird-dose boosting at a 44-45-week interval significantly increased antibody levels compared to boosting at 15-25-week or 8-12-week intervals. C_LIO_LIA third dose of CoronaVac administered eight months after the second dose increased antibody levels more than when administered at two months, while antibody responses were two-fold higher with a booster dose of AZD1222 administered at a 12-weeks or longer interval than a 6-weeks or shorter interval.Error! Bookmark not defined. C_LIO_LIIn the UK, third doses of AZD1222 led to higher antibody levels that correlated with high efficacy and T-cell responses, after a prolonged, dose-stretched interval between vaccine doses, than shorter intervals. C_LIO_LIOmicron-neutralizing antibodies were detected in only 56% of short-interval vaccine recipients versus all (100%) prolonged-interval vaccine recipients, 69% of whom also demonstrated Omicron-neutralizing antibodies at 4-6 months post-booster. C_LIO_LIIsraeli studies noted a restoration of antibody levels and enhanced immunogenic protection against severe disease when a second booster (fourth dose) was given 4 months or longer after a first booster, with no new safety concerns. C_LI Added value of this studyThere were no studies designed specifically aimed to analyzed non inferiority between the full dose and half dose of AZD1222 or BNT162b2 boosters after CoronaVac two doses which is important research question when we started the study and the situation of limited vaccine supply, global inequity and high disease burden in the Lower middle-income countries Data on the optimal prime-boost interval is limited, especially data that combines lower (fractional) dosing from resource-limited countries, which is provided by our study. Implications of all the available evidenceWe confirm the feasibility of a booster strategy that accounts for the needs of resource-limitations, through the use of fractional dosing, dose-stretching and heterologous schedules, which can broaden population-level protection and prevent vaccination disruptions.
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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 5,085 severe disease cases and 571,737 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). This association was consistent across sexes. 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. Author SummaryCOVID-19 clinical outcomes vary immensely, but a patients genetic make-up is an important determinant of how they will fare against the virus. While many genetic variants commonly found in the populations were previously found to be contributing to more severe disease by the COVID-19 Host Genetics Initiative, it isnt clear if more rare variants found in less individuals could also play a role. This is important because genetic variants with the largest impact on COVID-19 severity are expected to be rarely found in the population, and these rare variants require different technologies to be studies (usually whole-exome or whole-genome sequencing). Here, we combined sequencing results from 21 cohorts across 12 countries to perform a rare variant association study. In an analysis comprising 5,085 participants with severe COVID-19 and 571,737 controls, we found that the gene for toll-like receptor 7 (TLR7) on chromosome X was an important determinant of severe COVID-19. Importantly, despite being found on a sex chromosome, this observation was consistent across both sexes.