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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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Recent surges in SARS-CoV-2 variants of concern (VOCs) call for the need to evaluate levels of vaccine-and infection-induced SARS-CoV-2 neutralizing antibodies (NAbs). CoronaVac (Sinovac Biotech, Beijing, China) is currently being used for mass vaccination in Thailand as well as other low-income countries. Three VOCs currently circulating within Thailand include the B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) strains. We assessed NAb potency against the prototypic strain containing the original spike sequence (WT) compared to that against the 3 VOCs using sera derived from a cohort of healthcare workers who received a full 2-dose regimen of CoronaVac. Sera from two other cohorts consisting of COVID-19 patients who had been hospitalized in 2020 and 2021 were evaluated for comparison. We found that, despite equally robust production of S1-RBD-binding IgG and 100% seropositivity, sera from both CoronaVac vaccinees and naturally infected individuals had significantly reduced neutralizing capacity against all 3 VOCs compared to WT. Strikingly, NAb titers against Alpha and Beta were comparable, but Delta appears to be significantly more refractory to NAbs in all groups. Our results may help inform on CoronaVac NAb-inducing capacity, which is a proxy for vaccine efficacy, in the context of the WT strain and 3 VOCs. Our results also have critical implications for public health decision-makers who may need to maintain efficient mitigation strategies amid a potentially high risk for infection with VOCs even in those who have been previously infected.
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Updated and revised versions of COVID-19 vaccines are vital due to genetic variations of the SARS-CoV-2 spike antigen. Furthermore, vaccines that are safe, cost-effective, and logistically friendly are critically needed for global equity, especially for middle to low income countries. Recombinant protein-based subunit vaccines against SARS-CoV-2 have been reported with the use of the receptor binding domain (RBD) and the prefusion spike trimers (S-2P). Recently, a new version of prefusion spike trimers, so called "HexaPro", has been shown for its physical property to possess two RBD in the "up" conformation, as opposed to just one exposed RBD found in S-2P. Importantly, this HexaPro spike antigen is more stable than S-2P, raising its feasibility for global logistics and supply chain. Here, we report that the spike protein HexaPro offers a promising candidate for SARS-CoV-2 vaccine. Mice immunized by the recombinant HexaPro adjuvanted with aluminium hydroxide using a prime-boost regimen produced high-titer neutralizing antibodies for up to 56 days after initial immunization against live SARS-CoV-2 infection. In addition, the level of neutralization activity is comparable to that of convalescence sera. Our results indicate that the HexaPro subunit vaccine confers neutralization activity in sera collected from mice receiving the prime-boost regimen.
