The Lancet Infectious Diseases

1BackgroundAdults [≥]65 years of age are at increased risk for atypical presentations of chikungunya disease as well as severe outcomes including death. MethodsA phase 3, randomized, double-blind, placebo-controlled, parallel-group trial was conducted in adults [≥]65 years of age where participants received a single intramuscular dose of chikungunya virus (CHIKV) virus-like particle (VLP) vaccine or placebo on Day 1. Baseline and postvaccination CHIKV serum neutralizing antibody (SNA) titers (NT80) were assessed at selected timepoints. Safety was assessed through Day 183. ResultsA total of 413 participants (206 vaccine, 207 placebo) were randomized. Coprimary endpoints were met including 1) immunologic superiority of CHIKV SNA titers compared to placebo and 2) by geometric mean titer at Day 22. CHIKV VLP vaccine induced a protective seroresponse (SNA NT80 [≥]100; considered the presumptive seroprotective antibody response), in 82% of individuals at Day 15, in 87% of individuals at Day 22, and in 76% of individuals at Day 183. There were no notable differences in AE rates between groups and most AEs were grade 1 or 2 in severity. No vaccine-related serious adverse events or deaths occurred. ConclusionsWe provide robust data from adults [≥]65 years of age demonstrating that CHIKV VLP vaccine has a favorable safety profile and can provide a high rate of protection within 2 weeks postvaccination and through 6 months of follow-up. (Funded by Emergent BioSolutions Inc. and Bavarian Nordic A/S [as successor in interest to Emergent BioSolutions Inc.]; ClinicalTrials.gov number, NCT05349617).

In early May 2022 a global outbreak of monkeypox (MPX) started among persons without a travel history to regions known to be enzootic for monkeypox-virus. On August 8 2022, the Netherlands reported its 1000th monkeypox case representing a cumulative incidence of 55 per million population, one of the highest cumulative incidences worldwide. Here we describe the epidemiological characteristics and clinical presentation of the first 1000 monkeypox cases in the Netherlands, within the context of the public health response. Additionally, we explored risk factors for and estimated the protective effect of first-generation smallpox vaccine against more severe MPX. The first 1000 MPX cases, reported between May 20 and August 8 2022, were predominantly MSM aged 31-45 years. The vast majority of infections were acquired through sexual contact with casual partners in private or recreational settings including LGBTQIA+ venues in the Netherlands. This indicates that, although some larger upsurges occurred from point-source and/or travel related events, the outbreak is mainly characterised by sustained transmission within the Netherlands. More severe MPX was associated with having one or more comorbidities as well as having participated in more (3+) different sexual activities 21 days before symptom onset. We found a vaccine effectiveness of the prior first-generation smallpox vaccine against more severe MPX of 58% (95% CI 17-78%), suggesting moderate protection against more severe MPX symptoms on top of any possible protection by this vaccine against MPXV infection and disease.

1BackgroundChikungunya disease is a growing global public health concern. Chikungunya virus (CHIKV) virus-like particle (VLP) vaccine is a single dose, pre-filled syringe for intramuscular injection. MethodsA pivotal phase 3 randomized, double-blind, placebo-controlled trial was conducted in healthy adolescents and adults 12-64 years of age. Participants received either CHIKV VLP vaccine or placebo on Day 1. Immunogenicity objectives assessed CHIKV serum neutralizing antibody (SNA) titers (NT80) at selected timepoints. Safety was assessed through Day 183 postvaccination. ResultsA total of 2790 participants received CHIKV VLP vaccine and 464 received placebo (n=3454). Coprimary endpoints were met including 1) immunologic superiority to placebo and 2) geometric mean titer at Day 22. Results demonstrated that CHIKV VLP vaccine induced a protective seroresponse (SNA NT80 [≥]100; considered the presumptive seroprotective antibody response), in 97% of individuals at Day 15 (2 weeks), in 98% of individuals at Day 22, and in 86% of individuals at Day 183 (6 months). CHIKV VLP vaccine demonstrated a favorable safety profile. The majority of adverse events were self-limited and grade 1 or 2 in severity. The most common adverse events were injection site pain, fatigue, headache, and myalgia. ConclusionsCHIKV VLP vaccine induces a rapid and robust immune response by Day 15 that lasts through Day 183 postvaccination. These findings support the potential for this vaccine to protect individuals 12-64 years of age from disease caused by CHIKV. (Funded by Emergent BioSolutions Inc. and Bavarian Nordic A/S [as successor in interest to Emergent BioSolutions Inc.]; ClinicalTrials.gov number, NCT05072080).

BackgroundNanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. In a Phase 1 and 2 studies, (NCT04683484) the vaccine was found to be safe and induce a robust immune response in healthy adult participants. MethodsWe conducted a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, immunogenicity, and protective efficacy of the Nanocovax vaccine against Covid-19 in approximately 13,007 volunteers aged 18 years and over. The immunogenicity was assessed based on Anti-S IgG antibody response, surrogate virus neutralization, wild-type SARS-CoV-2 neutralization and the types of helper T-cell response by intracellular staining (ICS) for interferon gamma (IFNg) and interleukin-4 (IL-4). The vaccine efficacy (VE) was calculated basing on serologically confirmed cases of Covid-19. FindingsUp to day 180, incidences of solicited and unsolicited adverse events (AE) were similar between vaccine and placebo groups. 100 serious adverse events (SAE) were observed in both vaccine and placebo groups (out of total 13007 participants). 96 out of these 100 SAEs were determined to be unrelated to the investigational products. 4 SAEs were possibly related, as determined by the Data and Safety Monitoring Board (DSMB) and investigators. Reactogenicity was absent or mild in the majority of participants and of short duration. These findings highlight the excellent safety profile of Nanocovax. Regarding immunogenicity, Nanocovax induced robust IgG and neutralizing antibody responses. Importantly, Anti S-IgG levels and neutralizing antibody titers on day 42 were higher than those of natural infected cases. Nanocovax was found to induce Th2 polarization rather than Th1. Post-hoc analysis showed that the VE against symptomatic disease was 51.5% (95% confidence interval [CI] was [34.4%-64.1%]. VE against severe illness and death were 93.3% [62.2-98.1]. Notably, the dominant strain during the period of this study was Delta variant. InterpretationNanocovax 25 microgram (mcg) was found to be safe with the efficacy against symptomatic infection of Delta variant of 51.5%. FundingResearch was funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04922788.

BackgroundCold chain requirements limit vaccine accessibility and deployment. SPVX02 (Stablepharma Ltd), is a lyophilised, fridge-free version of Tetadif (BB-NCIPD EAD) tetanus-diphtheria vaccine, stable for at least 18 months at temperatures up to 30{degrees}C. MethodsA multicentre, first-in-human phase 1, blinded, randomised clinical trial to evaluate the safety and tolerability of SPVX02 compared to existing approved tetanus-diphtheria (Td) vaccines was conducted. Healthy adults aged 18-55 (BMI <=32 kg/m2) who had received Td vaccination >=10 years previously were randomly assigned (1:1:1) to receive SPVX02, Tetadif, or diTeBooster (AJ Vaccines A/S). Participants and all investigatory staff were blinded to treatment allocation. Primary outcomes were incidence of adverse events during the trial period including incidence of adverse events reported in participant diaries for 7 days post-dose. Secondary outcomes were day 28 seroprotection rates. Analyses were descriptive. The trial is registered with ISRCTN (98920861). FindingsBetween April 1st and September 22nd, 2025, 120 healthy volunteers were screened and sixty participants enrolled at two of three sites. The demographic characteristics of participants were equivalent between groups. No serious adverse reactions, suspected unexpected adverse reactions, or serious adverse events occurred. Fifty-four participants experienced mild or moderate adverse events (AEs); none were severe (grade 3 or higher) AEs. Reactogenicity and tolerability profiles were similar across all groups. All participants had anti-tetanus toxoid (TT) levels >=1{middle dot}0 IU/ml at Day 28. All participants in both the SPVX02 and Tetadif groups and 19 (95%) in the diTeBooster group had anti-diphtheria (DT) toxoid levels >=0{middle dot}1 IU/ml at Day 28. InterpretationSPVX02 is safe, well tolerated, with TT and DT immunogenicity similar to approved Td vaccines. This trial provides first-in-human evidence that StablevaX (Stablepharma, UK) technology can safely reformulate an aluminium-adjuvanted vaccine stable up to 30{degrees}C for 18 months. FundingFunded by Innovate UK Smart Grant project #10083165 and Stablepharma Ltd. Research In ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for randomised controlled trials with thermostable vaccines between database inception and June 2024 using the terms ("temperature stable") OR ("thermostable") AND ("vaccin*") OR ("thermostable vaccine") with no language restrictions. We identified 33 publications which described various in vitro and in vivo studies that have been performed by researchers as part of their efforts to develop thermostable vaccines. We also identified 2 publications which described randomised, controlled clinical trials that were conducted with thermostable vaccines; (1) a phase 2 clinical trial with ROTASIL, an oral rotavirus vaccine (Isanaka et al, NEJM, 2017) which is now licenced and distributed as a refrigerated product that must be stored but must be stored at 2-8{degrees}C; and (2) a phase 1 clinical trial with a current unapproved TB vaccine candidate, ID93+GLE-SE (Sagawa et al, Nature Comms, 2023) where there is no current public information regarding vaccine tolerance to freezing. Added value of this studyThis first in human study demonstrates that the reformulated thermostable aluminium hydroxide adjuvanted tetanus-diphtheria vaccine, SPVX02, is safe, well tolerated, and can boost immune responses to tetanus and diphtheria to similar levels as approved comparator vaccines. This vaccine can be stored and distributed at room temperature and is not affected by freezing. A larger Phase 2/3 trial is now planned to confirm these findings prior to consideration for market authorisation. Implications of all the available evidenceThe evidence presented here demonstrates that StablevaX technology can be successfully utilised to reformulate a vaccine to be thermostable at room temperature for an extended period of time, without compromising reactogenicity or immunogenicity. While we present data pertaining to a single vaccine, the reformulation and lyophilisation technology underpinning SPVX02 can be applied to many liquid vaccines and biological products. The WHO Immunization Agenda 2030 sets out the global strategy to improve vaccine access in resource-limited settings, prevent vaccine wastage and to reduce the logistical, financial and environmental impact of cold chain requirements. If proven successful across a broader range of vaccine products this technology has potential to significantly benefit global health.

ObjectivesThe novel coronavirus (2019-nCoV) originating from Wuhan has rapidly spread throughout China. While the origin of the outbreak remains uncertain, accumulating evidence links a wet market in Wuhan for the early spread of 2019-nCoV. Similarly, the influence of the marketplace on the early transmission dynamics is yet to be investigated. MethodsUsing the daily series of 2019-nCov incidenceincluding contact history with the market, we have conducted quantitative modeling analyses to estimate the reproduction numbers (R) for the market-to-human and human-to-human transmission together with the reporting probability and the early effects of public health interventions. ResultsOur mean R estimates for China in 2019-2020 are estimated at 0.37 (95%CrI: 0.02-1.78) for market-to-human transmission, and 3.87 (95%CrI: 3.18-4.78) for human-to-human transmission, respectively. Moreover we estimated that the reporting rate cases stemming from market-to-human transmission was 3-31 fold higher than that for cases stemming from human-to-human transmission, suggesting that contact history with the wet market played a key role in identifying 2019-nCov cases. ConclusionsOur findings suggest that the proportions of asymptomatic and subclinical patients constitute a substantial component of the epidemics magnitude. Findings suggest that the development of rapid diagnostic tests could help bring the epidemic more rapidly under control.

In September 2023, the SARS-CoV-2 XBB descendants, such as XBB.1.5 and EG.5.1 (originally XBB.1.9.2.5.1), are predominantly circulating worldwide. Unexpectedly, however, a lineage distinct from XBB was identified and named BA.2.86 on August 14, 2023. Notably, BA.2.86 bears more than 30 mutations in the spike (S) protein when compared to XBB and the parental BA.2, and many of them are assumed to be associated with immune evasion. Although the number of reported cases is low (68 sequences have been reported as of 7 September 2023), BA.2.86 has been detected in several continents (Europe, North America and Africa), suggesting that this variant may be spreading silently worldwide. On 17 August 2023, the WHO designated BA.2.86 as a variant under monitoring. Here we show evidence suggesting that BA.2.86 potentially has greater fitness than current circulating XBB variants including EG.5.1. The pseudovirus assay showed that the infectivity of BA.2.86 was significantly lower than that of B.1.1 and EG.5.1, suggesting that the increased fitness of BA.2.86 is not due to the increased infectivity. We then performed a neutralization assay using XBB breakthrough infection sera to address whether BA.2.86 evades the antiviral effect of the humoral immunity induced by XBB subvariants. The 50% neutralization titer of XBB BTI sera against BA.2.86 was significantly (1.6-fold) lower than those against EG.5.1. The sera obtained from individuals vaccinated with 3rd-dose monovalent, 4th-dose monovalent, BA.1 bivalent, and BA.5 bivalent mRNA vaccines exhibited very little or no antiviral effects against BA.2.86. Moreover, the three monoclonal antibodies (Bebtelovimab, Sotrovimab and Cilgavimab), which worked against the parental BA.2, did not exhibit antiviral effects against BA.2.86. These results suggest that BA.2.86 is one of the most highly immune evasive variants ever.

BackgroundGBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) up to 2 weeks after the second dose, and safety data up to a median of 2.5 months follow-up. MethodsRandomised, active-controlled, observer-blinded, multinational study: Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination, n=1956) randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety); Cohort 2 (regardless of baseline serostatus; n=2080) randomised 5:1 (safety). Primary objectives: demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; [&ge;]4-fold rise from baseline) of GBP510/AS03 versus ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity. FindingsAt 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03 / ChAdOx1-S) was 2.93 (95% CI 2.63-3.27), demonstrating superiority (95% CI lower limit >1). The between-group SCR difference of 10.76% (95% CI 7.68-14.32) satisfied the non-inferiority criterion (95% CI lower limit > -5%).The proportion of subjects with adverse events (AEs) after any vaccination was higher with GBP510/AS03 versus ChAdOx1-S for solicited local AEs (56.69% vs 49.20%), but was similar for solicited systemic AEs (51.21% vs 53.51%) and unsolicited AEs (13.27% vs 14.56%). No safety concerns were identified during follow-up for a median 2.5-months after the second vaccination. InterpretationGBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. FundingThis work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSImmunobridging has been proposed as an approach for assessing new COVID-19 vaccines by comparing the immunogenicity of candidate vaccines with an active comparator with demonstrated clinical efficacy. We searched PubMed up to 26 October 2022 for immunobridging clinical trials comparing a candidate vaccine with an approved vaccine, using the terms "immunobridging", "SARS-CoV-2", "COVID-19", and "vaccine". A phase 2/3 study showed that the ChAdOx1 vaccine, manufactured by the Serum Institute of India after technology transfer from Oxford University/AstraZeneca, had a non-inferior immune response compared to the original ChAdOx1 (AZD1222) vaccine. A post hoc analysis of phase 2 data found that MVC-COV1901 vaccine (a protein subunit vaccine developed by Medigen Vaccine Biologics Corporation, Taiwan) was non-inferior to ChAdOx1 (AZD1222) with respect to neutralising antibody titres. A phase 3 study found that VLA2001 (an adjuvanted, inactivated whole-virus vaccine developed by Valneva, Austria) was superior to ChAdOx1 with respect to neutralising antibody titres and non-inferior with respect to seroconversion rates. Added value of this studyThis is the first study comparing the immunogenicity of recombinant SARS-CoV-2 protein nanoparticle vaccine GBP510 adjuvanted with AS03 versus ChAdOx1-S. Interim analysis found that two-dose vaccination with GBP510/AS03 induced stronger neutralising antibody immune responses compared with ChAdOx1-S against the ancestral D614G strain at 2 weeks after the second dose. GBP510/AS03 had an acceptable safety profile during a median 2.5 months of follow-up. Implications of the available evidenceThis interim analysis suggests that GBP510/AS03 induces strong neutralising antibody responses against SARS-CoV-2 ancestral strain and has an acceptable safety profile.

BackgroundWe assessed the safety, tolerability and immunogenicity of VLA2001 is a whole-virion inactivated SARS-CoV-2 vaccine adsorbed to alum with a toll-like receptor 9 agonist adjuvant in healthy volunteers aged 18-55. MethodsThe first 15 participants were enrolled, in groups of 5, to receive two doses, separated by 21 days, of one of three dose concentrations, administered intramuscularly. 138 further participants were randomised 1:1:1 to receive the same 3 dose concentrations, in a double blinded manner. Primary outcomes were solicited adverse reactions 7 days after each vaccination and neutralising antibody geometric mean titres (GMT) against SARS-CoV-2, 2 weeks after the second vaccination (day 36), measured by live microneutralisation assay against wild-type virus (MNA50). Secondary outcomes included unsolicited adverse events, and humoral and cellular responses at day 36, measured by IgG ELISA against Spike protein and interferon-{gamma} secreting T-cells by ELISpot stimulated with multiple SARS-CoV-2 antigens. (ClinicalTrials.gov NCT04671017, ISRCTN 82411169) FindingsBetween December 16, 2020 and January 21, 2021, 153 participants were enrolled and randomised evenly between the dose groups. The rates of solicited reactions were similar after the first and second doses and between the three dose groups. The most frequent local reactions were tenderness (58{middle dot}2%) and pain (41{middle dot}8%) and systemic reactions were headache (46%) and fatigue (39{middle dot}2%). In the high dose group, two weeks following the second dose, the geometric mean titres were 530.4 (95% CI: 421{middle dot}49, 667{middle dot}52) for neutralizing antibodies and 2147{middle dot}9 (95% CI: 1705{middle dot}98, 2704{middle dot}22) for S-binding antibodies. There was a dose dependent response with 90{middle dot}0% (95% CI:78{middle dot}0%.,97{middle dot}0%) seroconversion (4-fold rise) at day 36 in the high dose group, which was significantly higher than rates in both the medium (73.5%; 95% CI: 59%,85%), CIs) and low dose (51%; 95%CI: 37%,65%) rate, CIs) groups (both p < 0.001). Antigen-specific interferon-{gamma} T-cells reactive against the S, M and N proteins were observed in 76, 36 and 49% of high dose recipients, respectively. InterpretationVLA2001-201 was well tolerated and produced both humoral and cellular immune responses, with a clear dose-response effect. FundingThis study was funded by the Department of Health and Social Care, UK The funder had no role in the study design, implementation or analysis.

BackgroundModified vaccinia Ankara-Bavarian Nordic (MVA-BN) is a third generation, replication- deficient, smallpox and mpox vaccine prepared in liquid and lyophilized formulations. The Democratic Republic of the Congo reports the highest number of cases of clade I mpox annually. MethodsDuring the summer of 2017 and 2019, 1,600 healthcare personnel were enrolled in an investigational prospective cohort study to evaluate safety of the 2-dose MVA-BN vaccine series; 1000 were administered liquid and 600 were administered reconstituted lyophilized MVA-BN. Vaccine doses were given on study days 0 and 28 and presence or absence of adverse events were evaluated at routine follow-up appointments for up to two years. ResultsThere were 49% of liquid and 54% of lyophilized formulation participants who experienced at least one adverse event within 7 days. Eighteen serious adverse events, including seventeen deaths and one stillbirth, occurred within the 2-year study period; safety monitors deemed none were causally associated with vaccine administration. Fourteen pregnancies occurred within one month of vaccination, 13 gave birth to healthy infants. ConclusionsThis study adds to the growing body of literature on the safety of MVA-BN in different populations. The data from this Congolese cohort demonstrate good safety outcomes for up to two years with both liquid and lyophilized vaccine formulations. As MVA-BN vaccination campaigns are launched in endemic and surrounding countries in late 2024 as part of clade I mpox outbreak response efforts, the data from this study supporting safety of MVA-BN in an African population are crucial to build vaccine confidence. Trial registry number: NCT02977715

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

BackgroundThis study (ARVAC-F2-3-002) assessed the immunogenicity, safety, and tolerability of a recombinant booster vaccine (ARVAC) containing the receptor binding domain of the SARS-CoV-2 Spike protein in three different versions: Gamma (ARVACGamma), Omicron BA.4/5 (ARVACOmicron), and Gamma/Omicron Bivalent (ARVACBivalent). MethodsRandomized, double-blind, crossover, placebo-controlled, multicenter (11 centers in Argentina) Phase II/III trial including adult volunteers previously vaccinated against SARS-CoV-2 with [&le;]3 booster doses. Participants were randomized to receive ARVACGamma (50 {micro}g)+placebo and vice-versa (1:1 ratio) (Phase II), and ARVACGamma (50 {micro}g)+placebo, ARVACOmicron (50 {micro}g)+placebo, and ARVACBivalent (Gamma/Omicron 25 {micro}g/25 {micro}g)+placebo and vice-versa (Phase III) (1:1:1:1:1:1 ratio) 28 days apart. The primary endpoint was the seroconversion rate of neutralizing antibodies compared to placebo. The vaccine immunogenicity was considered acceptable at >75% seroconversion rate to variants homologous to the antigen contained in the vaccine (prespecified primary endpoint). ResultsParticipants (n=2012) (mean 48.2 years, SD 16.7; 48.1% women) were randomized and allocated to ARVACGamma (n=232 in Phase II and n=592 in Phase III), ARVACOmicron (n=594), and ARVACBivalent (n=594); 232 in Phase II and 370 in each Phase III group were included in the immunogenicity subset. Seroconversion rates to all SARS-CoV-2 variants were significantly higher after receiving any vaccine than placebo. All vaccine versions met the prespecified primary endpoint in all participants and in those 18-60 years old. In participants >60 years, the ARVACOmicron and the ARVACBivalent met the prespecified primary endpoint, whereas the ARVACGamma did not. The ARVACBivalent induced seroconversion rates were significantly higher than 75% across all tested SARS- CoV-2 variants (homologous and heterologous) and age groups. No vaccine-related serious adverse events were recorded; most local and systemic adverse events were grade 1-2. ConclusionBooster vaccination with Gamma, Omicron BA.4/5, and Bivalent protein subunit recombinant ARVAC vaccine versions elicited protective neutralizing antibody responses to several SARS-CoV-2 variants, with very low reactogenicity and a favorable safety profile. Trial registration: NCT05752201

BACKGROUND Current polio vaccines face challenges including vaccine-derived poliovirus and high-containment manufacturing. We evaluated a recombinant trivalent virus-like particle (VLP)-based poliovirus vaccine (VPV) for safety and immunogenicity in a first-in-human phase 1 trial. METHODS In this randomized, observer-blind, active-controlled trial, 72 healthy adults (18 to 54 years) were assigned (1:1:1:1) to receive a single dose of VPV at low (45:8:25 D-antigen units [DU] + 0.1 mg aluminum phosphate [AP]), medium (45:8:25 DU + 0.3 mg AP), or high (90:12:45 DU + 0.3 mg AP) doses, or conventional inactivated poliovirus vaccine (cIPV). Primary outcomes were safety and tolerability. Secondary outcomes included neutralizing antibody titers through day 180. RESULTS No serious adverse events or Grade 3 reactions were reported. Solicited adverse events were reported in 77.8%, 55.6%, and 72.2% of the low-, medium-, and high-dose VPV groups, respectively, and 66.7% in the cIPV group. By day 29, VPV induced dose-dependent neutralizing antibody responses. For serotypes 1 and 2, the high-dose VPV group achieved geometric mean titers (GMTs) of 73,582 (95% CI, 31,198-173,545) and 110,623 (95% CI, 59,276-206,451), respectively, comparable to cIPV at 45,161 (95% CI, 20,973-97,244) and 112,361 (95% CI, 58,280-216,625). Although serotype 3 GMTs were lower for the high-dose VPV at 18,905 (95% CI, 8737-40,906) than for cIPV at 61,431 (95% CI, 31,123-121,251), 100% of high-dose VPV recipients achieved neutralizing titers [&ge;]1:1024. CONCLUSIONS A single dose of VPV was safe and highly immunogenic, supporting its potential as a next-generation vaccine to advance global polio eradication. (Funded by the Gates Foundation and Tianjin Leading Enterprises Innovative project 23YDLQSY00100; ClinicalTrials.gov number, NCT06101173).

As a novel coronavirus (COVID-19) continues to spread widely and claim lives worldwide, its transmission characteristics remain uncertain. Here, we present and analyze the serial intervals-the time period between the onset of symptoms in an index (infector) case and the onset of symptoms in a secondary (infectee) case-of 339 confirmed cases of COVID-19 identified from 264 cities in mainland China prior to February 19, 2020. Here, we provide the complete dataset in both English and Chinese to support further COVID-19 research and modeling efforts.

BackgroundWe report the clinical efficacy against COVID-19 infection of BBV152, a whole-virion inactivated SARS-CoV-2 vaccine formulated with a Toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG). MethodsWe did a double-blind, randomised, multicentre, phase 3 clinical trial in 25 Indian hospitals to evaluate the efficacy, safety, and immunological lot consistency of BBV152. Healthy adults (age 18-98 years) randomised 1:1 using a computer-generated randomisation scheme received two intramuscular doses of vaccine or placebo administered four weeks apart. The primary outcome was laboratory-confirmed symptomatic COVID-19, occurring at least 14 days after the second dose. Secondary outcomes were efficacy in sub-groups for age (18-< 60 years and [&ge;] 60 years) and in participants with pre-existing stable medical conditions. We also evaluated safety, reactogenicity, and consistency of immune responses for three consecutive manufacturing lots. FindingsBetween November 16, 2020 and January 7, 2021 we recruited 25,798 participants who were randomised to BBV152 or placebo groups; 24,419 received two doses of BBV152 (n = 12,221) or placebo (n = 12,198). In a case-driven analysis, 130 cases of symptomatic COVID-19 were reported in 16,973 (0{middle dot}77%) participants with follow-up at least two weeks after the second vaccination; 24 occurred in the vaccine group and 106 in placebo recipients giving an overall vaccine efficacy of 77{middle dot}8% (95% CI: 65{middle dot}2-86{middle dot}4). Sixteen cases, one vaccinee and 15 placebo recipients, met the severe symptomatic COVID-19 case definition giving a vaccine efficacy of 93{middle dot}4% (57{middle dot}1-99{middle dot}8). Efficacy against asymptomatic COVID-19 was 63{middle dot}6% (29{middle dot}0-82{middle dot}4). BBV152 conferred 65{middle dot}2% (95% CI: 33{middle dot}1-83{middle dot}0) protection against the SARS-CoV-2 Variant of Concern, B.1.617.2 (Delta). BBV152 was well tolerated with no clinically or statistically significant differences in the distributions of solicited, unsolicited, or serious adverse events between vaccine and placebo groups. No cases of anaphylaxis or vaccine-related deaths were reported. InterpretationBBV152 was immunogenic and highly efficacious against symptomatic and asymptomatic COVID-19 variant associated disease, particularly against severe disease in adults. Vaccination was well tolerated with an overall incidence of adverse events observed over a median of 146 days that was lower than that observed with other COVID-19 vaccines. FundingThis work was supported and funded by Bharat Biotech International Limited and partly co-funded by the Indian Council of Medical Research. Clinicaltrials.gov: NCT04641481

BackgroundThere is an urgent need for fair and equitable access to safe and effective vaccines to end the COVID-19 pandemic. Shortages in reagents and vaccines are a major challenge, as well as limited knowledge on dose response relationship with mRNA COVID-19 vaccines. We explored intradermal fractional dose administration of a mRNA SARS-CoV-2/COVID-19 vaccine as a potential dose-sparing strategy. MethodsWe conducted a proof-of-concept, dose-escalation, open-label, randomised-controlled vaccine trial (IDSCOVA) in healthy adults aged 18-30 years. To test initial safety, ten participants received 10 {micro}g mRNA-1273 vaccine through intradermal injection at day 1 and 29. Following a favourable safety review, thirty participants were 1:1 randomised to receive 20 {micro}g mRNA-1273 either intradermally or intramuscularly. The primary endpoint was tolerability and safety. The secondary endpoint was seroconversion and specific IgG concentration against SARS-CoV-2 spike S1 and Receptor Binding Domain (RBD) after the second dose at day 43. We compared results to two historical cohorts of non-hospitalised COVID-19 patients and vaccinated individuals. FindingsThirty-eight of forty included participants (median age 25 years) completed the study. There were no serious adverse events. Self-reported local adverse reactions after intradermal delivery were mild, both in the 10 {micro}g and the 20 {micro}g group. In the higher dose group, systemic adverse reactions were more common, but still well tolerated. All 38 participants mounted substantially higher IgG-anti-S1 and IgG-anti-RBD concentrations at day 43 than COVID-19 controls. At day 43, anti-S1 (95% CI) was 1,696 (1,309-2,198) BAU/mL for the 10 {micro}g intradermal group, 1,406 (953{middle dot}5-2,074) BAU/mL for the 20 {micro}g intramuscular group and 2,057 (1,421-2,975) BAU/mL for the 20 {micro}g intradermal group. Anti-S1 was 107{middle dot}2 (63-182{middle dot}2) BAU/mL for the convalescent plasma control group and 1,558 (547{middle dot}8-4,433) BAU/mL for the individuals vaccinated with 100 {micro}g mRNA-1273. InterpretationIntradermal administration of 10 {micro}g and 20 {micro}g mRNA-1273 vaccine was well tolerated and safe, and resulted in a robust antibody response. Intradermal vaccination has the potential to be deployed for vaccine dose-sparing. FundingThe trial was supported by crowdfunding (Wake Up to Corona).

Background: The World Health Organization has expanded its recommendations for prophylactic Ebola vaccination for at-risk populations. Durable vaccine-induced immunity is important for sustaining outbreak preparedness in regions with recurrent Ebola virus disease (EVD). We assessed five-year persistence of vaccine-induced immune responses in adults and children from the PREVAC trial. Methods: Two large randomised phase 2 trials (NCT02876328), in adults and children aged [&ge;]1 year, were conducted in four west African countries. Participants were randomly assigned to placebo or to one of three Ebola vaccine strategies: Ad26.ZEBOV followed by MVA-BN-Filo at 56 days; rVSV{Delta}G-ZEBOV-GP followed by placebo; or rVSV{Delta}G-ZEBOV-GP followed by a homologous booster dose at 56 days. After 12 months of follow-up, the primary results were published, participants unblinded to their vaccine assignment, and follow-up continued for 60 months. After Month 24, placebo group recipients were offered active vaccination. Anti Ebola virus glycoprotein Immunoglobulin G (IgG) concentrations were measured for 5 years. Findings: 1401 adults and 1401 children were initially randomized, and 1315 (93.9%) adults and 1322 (94.4%) children attended at least one long-term visit. Retention was high, with 95% followed beyond 1 year and 83% completion at 5-year follow-up. For the three vaccine strategies, antibody geometric mean concentrations (GMC) declined modestly between Months 12 and 24, followed by a stable plateau from Months 24 to 60. At Month 60, antibody GMC were higher in the rVSV-based groups (1099 and 1216 EU/ml for adults; 1982 and 2347 EU/ml for children) than in the Ad26.ZEBOV, MVA-BN-Filo group (252 adults and 645 EU/ml children). Antibody persistence at Month 60 was heterogeneous, varying by age, sex, country, and baseline IgG concentration. Interpretation: Licensed Ebola vaccines induced sustained antibody responses in adults and children for up to 5 years. While the protective antibody level is unknown, these data demonstrate long-lasting immune responses from currently employed vaccine strategies.

BackgroundCoronaVac, an inactivated COVID-19 vaccine, underwent evaluation for its efficacy and safety during the PROFISCOV study conducted in Brazil. MethodsBetween July 21, 2020, and July 29, 2021, 13,166 participants provided informed consent, with 12,688 randomized for the trial. Participants were allocated between vaccine and placebo arms (1:1) and monitored for symptomatic COVID-19 cases, severity of disease, and adverse reactions after two doses given 14 days apart. FindingsThe primary efficacy analysis revealed a vaccine efficacy of 50{square}39% (95% confidence interval [CI], 35{middle dot}26% to 61{middle dot}98%; p=0{middle dot}0049) in preventing symptomatic COVID-19, leading to the issuance of Emergency Use Authorization for CoronaVac in January 2021. Upon completion of follow-up, vaccine efficacy was 44{square}58% [95% CI, 34{middle dot}89% to 52{middle dot}83%; p= 0{middle dot}0023] in preventing COVID-19 and 82{square}14% (95% CI, 64{middle dot}93% to 90{middle dot}90%; p<0{middle dot}0001) in preventing severe COVID-19. Safety data indicated that adverse reactions were more frequent in the vaccine arm, primarily mild to moderate, with pain at the injection site and headache being the most common. InterpretationCoronaVac demonstrated moderate efficacy in preventing symptomatic COVID-19 and high efficacy against severe disease. While reactions were slightly more common in the vaccine group, they were generally mild and manageable. FundingFundacao Butantan, Instituto Butantan, and Sao Paulo Research Foundation (FAPESP; Grants 2020/10127-1 and 2020/06409-1). Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSAt the time of the studys design in 2020, the world was grappling with the COVID- 19 pandemic, with no licensed vaccine available. A global race to develop a safe and effective vaccine was underway, leading to the exploration of several vaccine candidates based on various technologies and mechanisms of action. Among these candidates was CoronaVac, an inactivated vaccine developed by Sinovac Life Sciences. PubMed was searched for pre-clinical and clinical trials using terms "COVID-19", "SARS-CoV-2", "Vaccine", "Vaccine Efficacy", without language or data restrictions. Additionally, information on clinical trials was sought from the ClinicialTrials.gov database and regulatory agencies. The focus was on late-stage clinical trials evaluating the safety, immunogenicity, and efficacy of CoronaVac. Positive safety and immunogenicity results from phase I/II clinical trials in younger and older adults, coupled with expanding pandemic, motivated the design and implementation of this phase III trial in healthcare professionals directly caring for or likely to be in close contact with COVID-19 patients in Brazil. No previous phase III study focusing on the efficacy and safety of CoronaVac in this high-risk population was identified. Added value of this studyBetween July 21, 2020, and July 29, 2021, 12,688 participants were randomized to receive either CoronaVac or placebo. We evaluated symptomatic COVID-19 cases, disease severity, and adverse reactions after two doses given 14 days apart. We found that CoronaVac met the predefined efficacy criteria, providing a moderate efficacy against symptomatic COVID-19 of 50{square}39% (95% CI: 35{middle dot}26-61{middle dot}98) in the primary analysis. Notably, CoronaVac demonstrated high effective against severe disease, with a vaccine efficacy of 82{square}14% (64{middle dot}93-90{middle dot}90) in the final analysis. Regarding safety, CoronaVac was shown to be safe, with most reactions being mild and manageable, albeit more commonly reported in the CoronaVac group. The inclusion of a high-risk study population comprising healthcare workers directly involved in the care of COVID-19 patients in Brazil is a key differentiator of our trial, as other studies of CoronaVac in China, Indonesia, Chile and Turkey at that time were not restricted to healthcare workers. Implications of all the available evidence.The primary efficacy analysis data from this study supported the Emergency Use Authorization issued for CoronaVac in Brazil in January 2021. Subsequently, a national vaccination campaign was initiated, with CoronaVac being the first vaccine to be incorporated in the COVID-19 vaccination program in Brazil. Since then, more than 100 million doses of CoronaVac have been administered in Brazil through the National Health System. The efficacy and safety of two doses of CoronaVac were demonstrated in the final analysis of the study. CoronaVacs ability to prevent severe disease is a crucial attribute that has had a positive impact on pandemic control and public health. It represents a promising option for COVID-19 vaccination, especially in low- or middle-income countries, given its moderate efficacy against symptomatic disease and favorable safety profile, in addition to its lower cost and ease of manufacturing compared to other vaccines available early in the pandemic. The impact on the immunogenicity and safety profile of XBB-updated versions of the vaccine used as a booster vaccination needs to be investigated in future studies.

ImportanceWhether herd immunity through mass vaccination is sufficient to curb SARS-CoV-2 transmission requires an understanding of the duration of vaccine-induced immunity, and the necessity and timing of booster doses. Objective: To evaluate immune persistence of two priming doses of CoronaVac, and immunogenicity and safety of a third dose in healthy adults [&ge;]60 years. Design, setting, and participants: We conducted a vaccine booster study built on a single-center, randomized, double-blind phase 1/2 trial of the two-dose schedule of CoronaVac among healthy adults[&ge;]60 years in Hebei, China. We examined neutralizing antibody titres six months or more after the second dose in all participants. We provided a third dose to 303 participants recruited in phase 2 trial to assess their immune responses. InterventionsTwo formulations (3 g, and 6 g) were used in phase 1 trial, and an additional formulation of 1.5 g was used in phase 2 trial. All participants were given two doses 28 days apart and followed up 6 months after the second dose. Participants in phase 2 received a third dose 8 months after the second dose. Main outcomes and measuresGeometric mean titres (GMT) of neutralizing antibodies to live SARS-CoV-2 and adverse events were assessed at multiple time points following vaccination. ResultsNeutralizing antibody titres dropped below the seropositive cutoff of 8 at 6 months after the primary vaccination in all vaccine groups in the phase 1/2 trial. A third dose given 8 months or more after the second dose significantly increased neutralizing antibody levels. In the 3 g group (the licensed formulation), GMT increased to 305 [95%CI 215.3-432.0] on day 7 following the third dose, an approximately 7-fold increase compared with the GMT 28 days after the second dose. All solicited adverse reactions reported within 28 days after a booster dose were of grade 1 or 2 severity. Conclusion and relevanceNeutralizing antibody titres declined substantially six months after two doses of CoronaVac among older adults. A booster dose rapidly induces robust immune responses. This evidence could help policymakers determine the necessity and the timing of a booster dose for older adults. Trial registrationClinicalTrials.gov (NCT04383574).

BackgroundMany people worldwide have now acquired immune responses against the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) following previous vaccination and/or infection. As a result, national vaccination programs are now implementing a simplified schedule of single-dose administration and seasonal boosters. In this phase 3 non-inferiority study, we assessed the immunogenicity and safety of a single dose of the lipid nanoparticle-messenger ribonucleic acid vaccine DS-5670d, a monovalent composition for the 2023/24 season, containing an omicron XBB.1.5-derived antigen. Methods and FindingsAdults and children aged [&ge;]12 years were stratified according to their history of both prior SARS-CoV-2 infection plus prior coronavirus disease 2019 (COVID-19) vaccination (subpopulation A), prior infection only (subpopulation B), prior vaccination only (subpopulation C), or no history of either infection or vaccination (subpopulation D), and randomly assigned (1:1) to receive DS-5670d or monovalent BNT162b2 omicron XBB.1.5. In the combined ABC subpopulations (DS-5670d, n = 362 vs BNT162b2, n = 363), the adjusted geometric mean titer ratio of blood neutralizing activity against SARS-CoV-2 (omicron XBB.1.5) was 1.218 (95% confidence interval [CI], 1.059, 1.401) and the seroresponse rates were 87.3% (DS-5670d) and 82.9% (BNT162b2) with an adjusted difference of 4.5% (95% CI, -0.70, 9.71). Both results exceeded prespecified non-inferiority margins and the study met the primary endpoint. Immunogenicity data in the overall ABCD population also met non-inferiority criteria. There were no apparent differences in immunogenicity according to age or sex, and analyses suggested that even unvaccinated persons achieved an adequate immune response following a single dose of DS-5670d. There were no major differences in the incidence or severity of adverse events between the study vaccination groups. ConclusionsA single dose of DS-5670d was immunogenically non-inferior to BNT162b2 and acceptably safe in persons with or without a history of prior infection and/or vaccination. Trial RegistrationJapan Registry of Clinical Trials (jRCT2031230424) Author summaryWhy was this study done? O_LIThe global emergency response against the coronavirus disease 2019 (COVID-19) pandemic is now being superseded by annual immunization using an updated vaccine composition to reduce the disease burden associated with newly emerging variants. C_LIO_LIWe conducted a comparative study of two newly authorized updated vaccine compositions containing the antigen derived from omicron XBB.1.5, which was recommended for the 2023/24 season. C_LIO_LIWe intended to assess the immunogenicity and safety of a single dose of DS-5670d compared with BNT162b2 in Japanese adults and children aged [&ge;]12 years. C_LI What did the researchers do and find? O_LIIn persons who had received prior vaccination, or who had previously had COVID-19, or both, DS-5670d was non-inferior to BNT162b2 in terms of blood neutralizing activity and seroresponse rates, and immune responses were not influenced by age or sex. C_LIO_LIAmong unvaccinated persons, those who had been exposed to SARS-CoV-2 by prior infection achieved an adequate immune response following a single dose of DS-5670d; however, the group who had had no previous exposure at all was too small to properly evaluate. C_LIO_LIThere were no major differences in the frequency or severity of adverse events between the study vaccination groups, and there were no DS-5670d-related serious adverse events. C_LI What do these findings mean? O_LIDS-5670d was immunogenically non-inferior to BNT162b2, which has already been widely administered in Japan. C_LIO_LIThere were no new critical safety concerns associated with DS-5670d, suggesting that it could be a useful SARS-CoV-2 vaccine option. C_LIO_LITaken together, the results from this study of DS-5670d and those from previous studies evaluating other compositions of DS-5670, i.e., those containing antigens from different strains of SARS-CoV-2, provide corroborating evidence that the DS-5670 vaccine platform can be applied to produce effective and safe seasonal vaccines against future emerging strains. C_LI