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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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BackgroundEffective COVID-19 mRNA vaccines are mainly available in high-income countries. ChulaCov19, a prefusion non-stabilized Spike protein-encoding, nucleoside-modified mRNA, lipid nanoparticle encapsulated vaccine development, aims to enhance accessibility of mRNA vaccine and future pandemic preparedness for low- to middle-income countries. MethodsSeventy-two eligible volunteers, 36 aged 18-55 (adults) followed by 36 aged 56-75 (elderly) enrolled in a dose escalation study of ChulaCov19 mRNA vaccine. Two doses of vaccine were given 21 days apart at 10, 25, or 50 {micro}g/dose (12/group). Safety was the primary and immunogenicity the secondary outcome. Human convalescents (HCS) and Pfizer/BioNTech vaccinees sera provided comparison panels. ResultsAll three doses of ChulaCov19 were well tolerated and elicited robust dose-dependent and age- dependent B- and T-cell responses. Transient mild/moderate injection site pain, fever, chills, fatigue, and headache were more common after the second dose. Four weeks after the second ChulaCov19: dose at 10, 25, and 50 {micro}g dose, MicroVNT-50 Geometric mean titer (GMT) against wild-type was 848, 736 and 1,140 IU/mL, respectively, versus 267 IU/mL for HCS. All dose levels elicited 100% seroconversion, with GMT ratio 4-8-fold higher than for HCS (p<0.01), and high IFN{gamma} spot-forming cells/million peripheral blood mononuclear cells. The 50 {micro}g dose induced better cross-neutralization against Alpha, Beta, Gamma, and Delta variants than lower doses. ConclusionsChulaCov19 at 50 {micro}g/dose is well tolerated and elicited higher neutralizing antibodies than HCS with strong T-cell responses. These antibodies cross neutralized four variants of concern and ChulaCov19 has therefore proceeded to phase 2 and 3 clinical trials. Trial registration numberClinicalTrials.gov Identifier NCT04566276 Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/22274989v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@3f6e6corg.highwire.dtl.DTLVardef@6aa1b7org.highwire.dtl.DTLVardef@9f0c29org.highwire.dtl.DTLVardef@1d75e38_HPS_FORMAT_FIGEXP M_FIG C_FIG
