Comparative antibody and cell-mediated immune responses, reactogenicity, and efficacy of homologous and heterologous boosting with CoronaVac and BNT162b2 (Cobovax): an open-label, randomised trial.

Leung NHL ，Cheng SMS ，Cohen CA ，Martín-Sánchez M ，Au NYM ，Luk LLH ，Tsang LCH ，Kwan KKH ，Chaothai S ，Fung LWC ，Cheung AWL ，Chan KCK ，Li JKC ，Ng YY ，Kaewpreedee P ，Jia JZ ，Ip DKM ，Poon LLM ，Leung GM ，Peiris JSM ，Valkenburg SA ，Cowling BJ ... -  《Lancet Microbe》

Heterologous versus homologous COVID-19 booster vaccination in previous recipients of two doses of CoronaVac COVID-19 vaccine in Brazil (RHH-001): a phase 4, non-inferiority, single blind, randomised study.

The inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac, Sinovac) has been widely used in a two-dose schedule. We assessed whether a third dose of the homologous or a different vaccine could boost immune responses. RHH-001 is a phase 4, participant masked, two centre, safety and immunogenicity study of Brazilian adults (18 years and older) in São Paulo or Salvador who had received two doses of CoronaVac 6 months previously. The third heterologous dose was of either a recombinant adenoviral vectored vaccine (Ad26.COV2-S, Janssen), an mRNA vaccine (BNT162b2, Pfizer-BioNTech), or a recombinant adenoviral-vectored ChAdOx1 nCoV-19 vaccine (AZD1222, AstraZeneca), compared with a third homologous dose of CoronaVac. Participants were randomly assigned (5:6:5:5) by a RedCAP computer randomisation system stratified by site, age group (18-60 years or 61 years and over), and day of randomisation, with a block size of 42. The primary outcome was non-inferiority of anti-spike IgG antibodies 28 days after the booster dose in the heterologous boost groups compared with homologous regimen, using a non-inferiority margin for the geometric mean ratio (heterologous vs homologous) of 0·67. Secondary outcomes included neutralising antibody titres at day 28, local and systemic reactogenicity profiles, adverse events, and serious adverse events. This study was registered with Registro Brasileiro de Ensaios Clínicos, number RBR-9nn3scw. Between Aug 16, and Sept 1, 2021, 1240 participants were randomly assigned to one of the four groups, of whom 1239 were vaccinated and 1205 were eligible for inclusion in the primary analysis. Antibody concentrations were low before administration of a booster dose with detectable neutralising antibodies of 20·4% (95% CI 12·8-30·1) in adults aged 18-60 years and 8·9% (4·2-16·2) in adults 61 years or older. From baseline to day 28 after the booster vaccine, all groups had a substantial rise in IgG antibody concentrations: the geometric fold-rise was 77 (95% CI 67-88) for Ad26.COV2-S, 152 (134-173) for BNT162b2, 90 (77-104) for ChAdOx1 nCoV-19, and 12 (11-14) for CoronaVac. All heterologous regimens had anti-spike IgG responses at day 28 that were superior to homologous booster responses: geometric mean ratios (heterologous vs homologous) were 6·7 (95% CI 5·8-7·7) for Ad26.COV2-S, 13·4 (11·6-15·3) for BNT162b2, and 7·0 (6·1-8·1) for ChAdOx1 nCoV-19. All heterologous boost regimens induced high concentrations of pseudovirus neutralising antibodies. At day 28, all groups except for the homologous boost in the older adults reached 100% seropositivity: geometric mean ratios (heterologous vs homologous) were 8·7 (95% CI 5·9-12·9) for Ad26.COV2-S vaccine, 21·5 (14·5-31·9) for BNT162b2, and 10·6 (7·2-15·6) for ChAdOx1 nCoV-19. Live virus neutralising antibodies were also boosted against delta (B.1.617.2) and omicron variants (B.1.1.529). There were five serious adverse events. Three of which were considered possibly related to the vaccine received: one in the BNT162b2 group and two in the Ad26.COV2-S group. All participants recovered and were discharged home. Antibody concentrations were low at 6 months after previous immunisation with two doses of CoronaVac. However, all four vaccines administered as a third dose induced a significant increase in binding and neutralising antibodies, which could improve protection against infection. Heterologous boosting resulted in more robust immune responses than homologous boosting and might enhance protection. Ministry of Health, Brazil.

Costa Clemens SA ，Weckx L ，Clemens R ，Almeida Mendes AV ，Ramos Souza A ，Silveira MBV ，da Guarda SNF ，de Nobrega MM ，de Moraes Pinto MI ，Gonzalez IGS ，Salvador N ，Franco MM ，de Avila Mendonça RN ，Queiroz Oliveira IS ，de Freitas Souza BS ，Fraga M ，Aley P ，Bibi S ，Cantrell L ，Dejnirattisai W ，Liu X ，Mongkolsapaya J ，Supasa P ，Screaton GR ，Lambe T ，Voysey M ，Pollard AJ ，RHH-001 study team ... -  《-》

Omicron BA.1-specific T-cell responses in adults vaccinated with CoronaVac or BNT162b2 in Hong Kong: an observational cohort study.

The primary aim of using vaccines in public health responses to SARS-CoV-2 variants of concern is to reduce incidence of severe disease, for which T-cell responses are essential. There is a paucity of data on vaccine-induced T-cell immunity to omicron (B.1.1.529). We aimed to compare SARS-CoV-2 omicron BA.1-specific T-cell responses in adults vaccinated with CoronaVac or BNT162b2. For this observational cohort, we recruited adults (aged ≥18 years) from three vaccination centres in Hong Kong. We included participants from four cohorts (cohort 1: participants who received two doses of either BNT162b2 or CoronaVac, cohort 2: participants who received two doses and a booster, cohort 3: participants who received two doses and a booster and had a breakthrough omicron infection, and cohort 4: participants who had a previous non-omicron infection and subsequently received one dose of vaccine). People with confirmed history of COVID-19 at recruitment were excluded from cohort 1 and cohort 2. We collected blood samples before vaccination (for cohort 1 and 2), 1-month following vaccination (for all cohorts), and during convalescence for cohort 3 and 4) and determined the proportion of IFNγ+CD4+ and IFNγ+CD8+ T cells in peripheral blood against SARS-CoV-2 using flow cytometry with peptide pools of SARS-CoV-2 wild type or omicron BA.1. The primary outcome was proportion of CD4+ and CD8+ T cells against SARS-CoV-2 1 month after exposure (ie, vaccination or breakthrough infection). Overall, between May 21, 2020, and Aug 31, 2021, we recruited 659 participants (231 [35%] men and 428 [65%] women). Of these participants, 428 were included in cohort 1 (214 [50%] received BNT162b2 and 214 [50%] received CoronaVac); 127 in cohort 2 (48 [38%] received all BNT162b2, 40 [31%] received all CoronaVac, and 39 [31%] received two CoronaVac and a booster with BNT162b2); 58 in cohort 3, and 46 in cohort 4 (16 [35%] received CoronaVac and 30 [65%] received BNT162b2). Vaccine-induced T-cell responses to the wild-type and omicron BA.1 variants were generally similar in adults receiving two doses of either CoronaVac (CD4+ cells p=0·33; CD8+ cells p=0·70) or BNT162b2 (CD4+ cells p=0·28; CD8+ cells p=1·0). Using a peptide pool of all structural proteins for stimulation, BNT162b2 induced a higher median frequency of omicron-specific CD4+ T cells in adults younger than 60 years (CD4+ cells 0·012% vs 0·010%, p=0·031; CD8+ cells 0·003% vs 0·000%, p=0·055) and omicron-specific CD8+ T cells in people aged 60 years or older (CD4+ cells 0·015% vs 0·006%, p=0·0070; CD8+ cells 0·007% vs 0·000%, p=0·035). A booster dose of either BNT162b2 or CoronaVac after two doses of CoronaVac boosted waning T-cell responses, but T-cell responses did not exceed those at 1 month after the second dose (CoronaVac CD4+ p=0·41, CD8+ p=0·79; BNT162b2 CD4+ p=0·70 CD8+ p=0·80). The evidence that mRNA and inactivated vaccines based on the ancestral SARS-CoV-2 virus elicited T-cell responses to SARS-CoV-2 omicron variants might explain the high observed vaccine effectiveness against severe COVID-19 shown by both types of vaccine, despite great differences in neutralising antibody responses. The use of either vaccine can be considered if the primary aim is to reduce severity and death caused by the new omicron subvariants; however, BNT162b2 is preferable for adults older than 60 years. The Health and Medical Research Fund Commissioned Research on the Novel Coronavirus Disease and S H Ho Foundation.

Mok CKP ，Chen C ，Zhao S ，Sun Y ，Yiu K ，Chan TO ，Lai HL ，Lai KC ，Lau KM ，Ling KC ，Chan KKP ，Ng SS ，Ko FW ，Peiris M ，Hui DS ... -  《Lancet Microbe》

Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial.

Oda Y ，Kumagai Y ，Kanai M ，Iwama Y ，Okura I ，Minamida T ，Yagi Y ，Kurosawa T ，Greener B ，Zhang Y ，Walson JL ... -  《-》

Immunogenicity and safety in healthy adults of full dose versus half doses of COVID-19 vaccine (ChAdOx1-S or BNT162b2) or full-dose CoronaVac administered as a booster dose after priming with CoronaVac: a randomised, observer-masked, controlled trial in I

Inactivated COVID-19 vaccines effectively prevent death, but their effectiveness for preventing infection or severe illness is known to decrease within 3-6 months following the second priming dose. Here we aimed to evaluate the immunogenicity and safety of three potential booster vaccines administered as a full-dose homologous booster or full-dose or half-dose heterologous boosters among individuals primed with CoronaVac. We did an observer and participant masked, randomised controlled trial study of healthy Indonesian adults from five recruitment sites in Bandung and Jakarta, Indonesia, aged 18 years and older who had previously received two doses of CoronaVac within 3 to less than 6 months or 6 to 9 months before the booster dose. Participants were randomly assigned (1:1:1:1:1) by means of stratified randomisation with random block size to a homologous booster with full-dose CoronaVac or heterologous boosters with ChAdOx1-S or BNT162b2 in full dose or half dose. The primary outcome was to evaluate the seropositive, seroconversion rate, and the geometric mean titres of IgG anti-spike-receptor binding domain and neutralising antibodies, 28 days after booster dose vaccination in the per-protocol population. Safety was assessed as a secondary outcome in all vaccinated booster participants by the incidence rate and intensity of adverse events within 24 h, 7 days, and 28 days after the booster dose. This study is registered with ina-registry.org, INA-GO0HLGB, and is complete. Between Nov 26 and Dec 16, 2021, 1015 people were screened, and 960 healthy adults were enrolled; 190-193 were included in each group. 28 days after receiving the booster, combining the 3 to less than 6 months and 6 to 9 months groups, the proportions of seroconversion rates in each vaccine group were ChAdOx1-S 75 (82%) of 92 to 87 (88%) of 99 for full dose and half dose, BNT162b2 92 (92%) of 100 to 90 (98%) of 92 for full dose and half dose, and CoronaVac in 38 (41%) of 92 to 65 (66%) of 98. All booster groups achieved 100% seropositivity 28 days after the booster dose. Participants in the 6 to 9 months priming group achieved higher titres compared with participants in the 3 to less than 6 months priming group. The geometric mean titres in participants in the 6 to 9 months priming group in each vaccine group were ChAdOx1-S 11258·69 (9562·43-13 255·85) and 7853·04 (6698·92-9206·00) for full dose and half dose, BNT162b2 19999·84 (17 720·58-22 572·25) and 17 017·62 (14 694·40-19 708·16) for full dose and half dose and CoronaVac 1440·55 (1172·81-1769·42) achieved higher titres compared with participants in the 3 to less than 6 months priming group which in each vaccine group were ChAdOx1-S 7730·39 (6401·87-9334·60) and 6684·34 (5678·94-7867·73) for full dose and half dose, BNT162b2 16594·08 (13 993·08-19 678·55) and 12 121·67 (9925·21-14 804·19) for full dose and half dose, and CoronaVac 1210·23 (976·49-1499·92). The median percentage inhibition for the surrogate virus neutralisation test against the delta B.1.617.2 and wild-type (WT) variant before the booster and 28 days after the booster dose was very high in all groups (p<0·001), all with greater than 90% inhibition against both delta and WT strains. No serious adverse events were associated with the vaccines. Within the heterologous booster groups, the adverse event rates in the half-dose groups were lower compared with the full-dose groups. Geometric mean titre values between participants in the 6 to 9 months priming group and the 3 to less than 6 months priming group before the booster dose and between half-dose and full-dose groups 28 days before the booster were not significantly different for half-dose ChAdOx1-S, full-dose BNT162b2, and CoronaVac and were significantly different for full-dose ChAdOx1-S and half-dose BNT162b2. Among individuals primed with CoronaVac, boosting with BNT162b2 (full dose or half dose) or ChAdOx1-S (full dose or half dose) produces substantially better immune responses than in those boosted with CoronaVac. Full-dose and half-dose boosting with either BNT162b2 or ChAdOx1-S produced similar responses. Heterologous booster with half-dose might be considered in adults primed with two doses of CoronaVac vaccine. Ministry of Health, Indonesia. For the Indonesian translation of the abstract see Supplementary Materials section.

Fadlyana E ，Setiabudi D ，Kartasasmita CB ，Putri ND ，Rezeki Hadinegoro S ，Mulholland K ，BCOV21 study group ... -  《-》