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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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NDV-HXP-S is a recombinant Newcastle disease virus based-vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which expresses an optimized (HexaPro) spike protein on its surface. The vaccine can be produced in embryonated chicken eggs using the same process as that employed for the production of influenza virus vaccines. Here we performed a secondary analysis of the antibody responses after vaccination with inactivated NDV-HXP-S in a Phase I clinical study in Thailand. The SARS-CoV-2 neutralizing and spike binding activity of NDV-HXP-S post-vaccination serum samples was compared to that of matched samples from mRNA BNT162b2 (Pfizer) vaccinees. Neutralizing activity of sera from NDV-HXP-S vaccinees was comparable to that of individuals vaccinated with BNT162b2. Interstingly, the spike binding activity of the NDV-HXP-S vaccinee samples was lower than that of sera obtained from individuals vaccinated with the mRNA vaccine. This let us to calculate ratios between binding and neutralizing antibody titers. Samples from NDV-HXP-S vaccinees had binding to neutralizing activity ratios similar to those of convalescent sera suggesting a very high proportion of neutralizing antibodies and low non-neutralizing antibody titers. Further analysis showed that, in contrast to mRNA vaccination, which induces strong antibody titers to the receptor binding domain (RBD), the N-terminal domain, and the S2 domain, NDV-HXP-S vaccination induces a very RBD focused response with little reactivity to S2. This explains the high proportion of neutralizing antibodies since most neutralizing epitopes are located in the RBD. In conclusion, vaccination with inactivated NDV-HXP-S induces a high proportion of neutralizing antibodies and absolute neutralizing antibody titers comparable to those after mRNA vaccination.
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BackgroundProduction of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its being developed in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. MethodsThis phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy adults aged 18-59 years, non-pregnant and negative for SARS-CoV-2 antibodies were eligible. Participants were block randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 {micro}g{+/-}CpG1018 (a toll-like receptor 9 agonist), 3 {micro}g{+/-}CpG1018, 10 {micro}g, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422). FindingsBetween March 20 and April 23, 2021, 377 individuals were screened and 210 were enrolled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5{middle dot}7% to 17{middle dot}1% among vaccine groups and was 2{middle dot}9% in controls; there was no vaccine-related serious adverse event. The 10 {micro}g formulations immunogenicity ranked best, followed by 3 {micro}g+CpG1018, 3 {micro}g, 1 {micro}g+CpG1018, and 1 {micro}g formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122{middle dot}23 IU/mL (1 {micro}g, 95% CI 86{middle dot}40-172{middle dot}91) to 474{middle dot}35 IU/mL (10 {micro}g, 95% CI 320{middle dot}90-701{middle dot}19), with 93{middle dot}9% to 100% of vaccine groups attaining a [≥]4-fold increase over baseline. InterpretationNDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 {micro}g and 3 {micro}g+CpG1018 formulations advanced to phase 2. FundingNational Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA)
