As part of the accelerated development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we report a dose-finding and adjuvant justification study of SCB-2019, a ...protein subunit vaccine candidate containing a stabilised trimeric form of the spike (S)-protein (S-Trimer) combined with two different adjuvants.
Our study is a phase 1, randomised, double-blind placebo-controlled trial at a specialised clinical trials centre in Australia. We enrolled healthy adult volunteers in two age groups: younger adults (aged 18–54 years) and older adults (aged 55–75 years). Participants were randomly allocated either vaccine or placebo using a list prepared by the study funder. Participants were to receive two doses of SCB-2019 (either 3 μg, 9 μg, or 30 μg) or a placebo (0·9% NaCl) 21 days apart. SCB-2019 either had no adjuvant (S-Trimer protein alone) or was adjuvanted with AS03 or CpG/Alum. The assigned treatment was administered in opaque syringes to maintain masking of assignments. Reactogenicity was assessed for 7 days after each vaccination. Humoral responses were measured as SCB-2019 binding IgG antibodies and ACE2-competitive blocking IgG antibodies by ELISA and as neutralising antibodies by wild-type SARS-CoV-2 microneutralisation assay. Cellular responses to pooled S-protein peptides were measured by flow-cytometric intracellular cytokine staining. This trial is registered with ClinicalTrials.gov, NCT04405908; this is an interim analysis and the study is continuing.
Between June 19 and Sept 23, 2020, 151 volunteers were enrolled; three people withdrew, two for personal reasons and one with an unrelated serious adverse event (pituitary adenoma). 148 participants had at least 4 weeks of follow-up after dose two and were included in this analysis (database lock, Oct 23, 2020). Vaccination was well tolerated, with two grade 3 solicited adverse events (pain in 9 μg AS03-adjuvanted and 9 μg CpG/Alum-adjuvanted groups). Most local adverse events were mild injection-site pain, and local events were more frequent with SCB-2019 formulations containing AS03 adjuvant (44–69%) than with those containing CpG/Alum adjuvant (6–44%) or no adjuvant (3–13%). Systemic adverse events were more frequent in younger adults (38%) than in older adults (17%) after the first dose but increased to similar levels in both age groups after the second dose (30% in older and 34% in younger adults). SCB-2019 with no adjuvant elicited minimal immune responses (three seroconversions by day 50), but SCB-2019 with fixed doses of either AS03 or CpG/Alum adjuvants induced high titres and seroconversion rates of binding and neutralising antibodies in both younger and older adults (anti-SCB-2019 IgG antibody geometric mean titres at day 36 were 1567–4452 with AS03 and 174–2440 with CpG/Alum). Titres in all AS03 dose groups and the CpG/Alum 30 μg group were higher than were those recorded in a panel of convalescent serum samples from patients with COVID-19. Both adjuvanted SCB-2019 formulations elicited T-helper-1-biased CD4+ T-cell responses.
The SCB-2019 vaccine, comprising S-Trimer protein formulated with either AS03 or CpG/Alum adjuvants, elicited robust humoral and cellular immune responses against SARS-CoV-2, with high viral neutralising activity. Both adjuvanted vaccine formulations were well tolerated and are suitable for further clinical development.
Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.
Zika virus, a flavivirus transmitted by Aedes aegypti and Aedes albopictus mosquitoes, is associated with cases of congenital malformations and neurological complications. Absence of specific ...treatment makes a prophylactic Zika virus vaccine an unmet medical need. We assessed safety and immunogenicity of three doses of a purified, inactivated, Zika virus vaccine candidate in healthy flavivirus-naive and flavivirus-primed adults.
This two-part, multicentre, observer-blind, randomised, placebo-controlled, phase 1 trial was done at seven medical clinics in the USA and two in Puerto Rico. Eligible participants were healthy adults aged 18–49 years. Participants were randomly assigned (1:1:1:1), using a sponsor-supplied randomisation scheme, to four groups to receive two intramuscular injections, 28 days apart, of saline placebo or TAK-426 containing 2 μg, 5 μg, or 10 μg antigen. Participants, investigators, and vaccine administrating personnel were masked to group assignment. Part 1 of the study assessed flavivirus-naive participants and part 2 assessed flavivirus-primed participants. The primary outcomes were safety, tolerability, and immunogenicity based on solicited local reactions and solicited systemic adverse events in the 7 days after each dose; unsolicited adverse events and serious adverse events in the 28 days after each dose; and geometric mean titres (GMTs) of neutralising anti-Zika virus antibodies at 28 days after the second dose. Safety assessments were done in all participants who received at least one dose of vaccine. Immunogenicity assessments were in the per-protocol set, comprising all participants who received at least one dose of vaccine and provided valid serology results at baseline and at least one post-vaccination timepoint, with no major protocol violations. The trial is ongoing and is registered at ClinicalTrials.gov (NCT03343626).
Between Nov 13, 2017, and Oct 24, 2018, 894 volunteers were screened and 271 enrolled (125 flavivirus-naive and 146 flavivirus-primed participants). All TAK-426 doses were well tolerated with no deaths, no vaccine-related serious adverse events, and similar rates of mainly mild to moderate adverse events. TAK-426 elicited dose-dependent increases in antibody GMTs in both flavivirus-naive and flavivirus-primed participants. 28 days after dose 2, plaque-reduction neutralisation test GMTs in flavivirus-naive participants were 1130 (95% CI 749–1703) in the 2 μg TAK-426 group, 1992 (1401–2833) in the 5 μg TAK-426 group, and 3690 (2677–5086) in the 10 μg TAK-426 group. In pairwise comparisons, responses after two vaccinations in the 10 μg group were significantly greater than in the 2 μg group (GMT ratio 3·27 95% CI 1·98–5·39, p<0·0001) and the 5 μg group (GMT ratio 1·85 1·15–2·98, p=0·012).
TAK-426 was well tolerated, with an acceptable safety profile, and was immunogenic in both flavivirus-naive and flavivirus-primed adults. Based on the safety and immunogenicity profiles of all TAK-426 doses assessed, the 10 μg TAK-426 dose was selected for further clinical development.
Takeda Vaccines and the US Biomedical Advanced Research and Development Authority.
For the Spanish translation of the abstract see Supplementary Materials section.
Abstract
A significant correlation has been shown between the binding antibody responses against original severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and vaccine ...efficacy of 4 approved coronavirus disease 2019 vaccines. We therefore assessed the immune response against original SARS-CoV-2 elicited by the adjuvanted S-Trimer vaccine, SCB-2019 + CpG/alum, in the same assay and laboratory. Responses to SCB-2019 were comparable or superior for antibody to original and Alpha variant when compared with 4 approved vaccines. The comparison accurately predicted success of the recently reported efficacy trial of SCB-2019 vaccine. Immunogenicity comparisons to original strain and variants of concern should be considered as a basis for authorization of vaccines.
The antibody-binding responses to the adjuvanted S-Trimer vaccine, SCB-2019 + CpG/alum, were compared with approved vaccines and accurately predicted success of the recently reported efficacy trial of SCB-2019 vaccine. Immunogenicity comparisons should be considered as a basis for authorization of vaccines.
Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P8 rotavirus vaccine Rotarix™ significantly reduced severe rotavirus ...gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season.
Healthy infants aged 5-10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI.
Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™ = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 1% in placebo) and G8 types (15 1% in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P8 was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P4 (20 1.4% in placebo) and P6 (13 0.9% in placebo). Vaccine efficacy against P8 was 59.1% (95% CI: 32.8%; 75.3%), P4 was 70.9% (95% CI: 37.5%; 87.0%) and P6 was 55.2% (95% CI: -6.5%; 81.3%)
Rotarix™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™.
NCT00241644.
We previously reported the efficacy of the adjuvanted-protein COVID-19 vaccine candidate S-Trimer (SCB-2019) in adults who showed no evidence of previous exposure to SARS-CoV-2. In this study, we ...aimed to investigate the extent of protection afforded by previous exposure to SARS-CoV-2 on subsequent COVID-19 infection, as well as the efficacy, safety, and reactogenicity of SCB-2019 in participants who were enrolled in the Study evaluating Protective-Efficacy and safety of Clover's Trimeric Recombinant protein-based and Adjuvanted COVID-19 vaccine (SPECTRA) trial who had already been exposed to SARS-CoV-2 before vaccination.
In a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial (SPECTRA) done at 31 sites in five countries, participants were randomly assigned 1:1 using the Cenduit Interactive Response Technology system (IQVIA, Durham, NC, USA), with a block size of six, to receive two doses of either SCB-2019 or placebo 21 days apart. The primary outcomes of the SPECTRA trial were vaccine efficacy, measured by real-time PCR (rtPCR)-confirmed COVID-19 of any severity, with onset from 14 days after the second vaccine dose, as well as the safety and solicited local and systemic adverse events in the phase 2 subset. Here, we present secondary analyses to calculate the protective efficacy due to previous exposure to SARS-CoV-2 against reinfection with COVID-19 according to severity in SPECTRA participants who had evidence of exposure to SARS-CoV-2 at baseline, including efficacy against identified viral variants, as well as efficacy of SCB-2019 vaccination in this population.
We enrolled 30 174 participants between March 24, 2021, and Aug 10, 2021. In the 14 670 participants who were randomly assigned to receive placebo, there were 418 (2·8%) confirmed cases of COVID-19; 65 (0·9%) of 7339 SARS-CoV-2-exposed participants, and 353 (4·8%) of 7331 SARS-CoV-2-naive participants (attack rates of 5·5 cases per 100 person-years for SARS-CoV-2-exposed participants and 32·4 cases per 100 person-years for SARS-CoV-2-naive participants). Protective efficacy due to previous exposure to SARS-CoV-2 was 83·2% (95% CI 78·0–87·3) against any COVID-19, 92·5% (82·9–97·3) against moderate-to-severe COVID-19, and 100% (59·3–100) against severe COVID-19; no SARS-CoV-2-exposed participants had hospitalisation associated with COVID-19. Protective efficacy against variants were 100% for alpha (B.1.1.7) and lambda (C.37) variants, 88·6% (14·9–99·7) for B.1.623, 93·6% (80·1–98·7) for gamma (P.1), and 92·4% (81·2–97·6) for mu (B.1.621) variants, and lowest against beta (B.1.351; 72·2% 33·1–89·9) and delta (B.1.617.2; 77·2% 61·3–87·2) variants. In addition, one dose of SCB-2019 had 49·9% (1·5–75·6) efficacy against any symptomatic COVID-19, and two doses had 64·2% (26·5–83·8) efficacy. SCB-2019 was well tolerated in SARS-CoV-2-exposed participants, but was associated with higher rates of injection site pain (89 33·8% of 263 participants) than placebo (16 6·7% of 239 participants). Rates of solicited systemic adverse events, severe adverse events, and serious adverse events were similar between vaccine and placebo groups, and with rates in SARS-CoV-2-naive vaccine recipients.
Previous exposure to SARS-CoV-2 decreased the risk and severity of subsequent COVID-19 infection, even against newly emerging variants. Protection is further enhanced by one or two doses of SCB-2019.
Clover Biopharmaceuticals, The Coalition for Epidemic Preparedness Innovations (CEPI).
•SCB-2019 is a protein subunit vaccine candidate against COVID-19.•SCB-2019 contains the SARS-CoV-2 spike protein adjuvanted with CpG-1018/alum.•A single dose of SCB-2019 was immunogenic in ...SARS-CoV-2-exposed individuals.•Two doses are required to induce immune response in SARS-CoV-2-naïve individuals.•SCB-2019 induced cross-reactive neutralizing antibodies to SARS-CoV-2 variants.
We evaluated immunogenicity of SCB-2019, a subunit vaccine candidate containing a pre-fusion trimeric form of the SARS-CoV-2 spike (S)-protein adjuvanted with CpG-1018/alum.
The phase 2/3, double-blind, randomized SPECTRA trial was conducted in five countries in participants aged ≥ 18 years, either SARS-CoV-2-naïve or previously exposed. Participants were randomly assigned to receive two doses of SCB-2019 or placebo administered intramuscularly 21 days apart. In the phase 2 part of the study, on days 1, 22, and 36, neutralizing antibodies were measured by pseudovirus and wild-type virus neutralization assays to SARS-CoV-2 prototype and variants, and ACE2-receptor-binding antibodies and SCB-2019–binding antibodies were measured by ELISA. Cell-mediated immunity was measured by intracellular cytokine staining via flow cytometry.
1601 individuals were enrolled between 24 March and 13 September 2021 and received at least one vaccine dose. Immunogenicity analysis was conducted in a phase 2 subset of 691 participants, including 428 SARS-CoV-2-naïve (381 vaccine and 47 placebo recipients) and 263 SARS-CoV-2-exposed (235 vaccine and 28 placebo recipients). In SARS-CoV-2-naïve participants, GMTs of neutralizing antibodies against prototype virus increased 2 weeks post-second dose (day 36) compared to baseline (224 vs 12.7 IU/mL). Seroconversion rate was 82.5 %. In SARS-CoV-2-exposed participants, one SCB-2019 dose increased GMT of neutralizing antibodies by 48.3-fold (1276.1 IU/mL on day 22) compared to baseline. Seroconversion rate was 92.4 %. Increase was marginal post-second dose. SCB-2019 also showed cross-neutralization capability against nine variants, including Omicron, in SARS-CoV-2-exposed participants at day 36. SCB-2019 stimulated Th1-biased cell-mediated immunity to the S-protein in both naïve and exposed participants. The vaccine was well tolerated, no safety concerns were raised from the study.
A single dose of SCB-2019 was immunogenic in SARS-CoV-2-exposed individuals, whereas two doses were required to induce immune response in SARS-CoV-2-naïve individuals. SCB-2019 elicited a cross-neutralizing response against emergent SARS-CoV-2 variants at antibody levels associated with clinical protection, underlining its potential as a booster.
Clinicaltrials.gov: NCT04672395; EudraCT: 2020-004272-17.
Abstract
Background
We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed ...after natural infection.
Methods
A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18–49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)–naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary vaccination with 10-μg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after natural infection.
Results
TAK-426 at 10-μg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus infection.
Conclusions
These results support the further clinical development of TAK-426 for both FV-naive and FV-primed populations.
Clinical Trials Registration
NCT03343626
TAK-426 had an acceptable safety profile in flavivirus-naive and flavivirus-primed adults, and immune responses to vaccination with TAK-426 persisted up to 2 years and were comparable in magnitude and kinetics with those elicited by natural Zika virus infection.
•A novel IPV vaccine was developed from attenuated Sabin poliovirus strains.•The vaccine was generally well tolerated in adults, toddlers and infants.•The vaccine was immunogenic as a booster in ...previously polio-vaccinated toddlers.•The vaccine was insufficiently immunogenic from 6 weeks of age in the EPI schedule.•There was evidence of interference of the immune response by maternal antibodies.
To increase the global supply of affordable IPV vaccine, preferably using Sabin viruses to comply with GAPIII requirements, Takeda has assessed three dosages of a stand-alone sIPV.
In this phase I/II study two cohorts of 40 adults and 60 toddlers, respectively, were initially assessed for safety after receiving high-dosage sIPV compared with placebo (adults) or Salk IPV (toddlers). A cohort of 240 infants was then enrolled and randomized (1:1:1:1) to receive low-, medium- or high-dosage sIPV, or a reference Salk IPV in a three-dose primary schedule at 6, 10 and 14 weeks of age. Parents completed safety diaries for 4 weeks after each dose, and immunogenicity was measured as neutralization antibody titers at baseline and four weeks after vaccination.
All vaccinations were generally well-tolerated and sIPV had a comparable safety profile to the control arm in adults or the reference Salk IPV vaccine in toddlers and infants. Infants displayed dosage-dependent immune responses to sIPV when assayed using Sabin strains, which were equivalent to the reference IPV in the high-dosage sIPV group for serotypes 1 and 2, but not for Sabin and Salk serotype 3. Seroconversion rates (SCR) of the low- and medium-dosage groups were significantly lower than the Salk IPV group for both Sabin and Salk serotypes 1 and type 2 (p < 0.05), with no significant differences for Salk or Sabin serotypes 3. Responses to sIPV, particularly to Sabin types 1 and 2, were higher in initially seronegative infants, indicating possible interference by maternally-derived antibodies.
A novel stand-alone Sabin-based IPV vaccine was well tolerated with an acceptable safety profile, but less immunogenic than reference Salk IPV at 6, 10 and 14 weeks of age for Salk serotypes 1 and 2, with apparent interference by maternal antibodies. Additional preclinical assessments will be made before any further clinical development.
•We assessed immunogenicity and safety of dTpa-IPV booster vaccine in 3–4 years olds.•The immunogenicity of dTpa-IPV (Boostrix-IPV) was non-inferior to Repevax.•Both vaccines were co-administered ...with mumps-measles-rubella vaccine.•Both vaccines had clinically acceptable safety and reactogenicity profiles.
To evaluate the immunogenicity and safety of a reduced antigen diphtheria-tetanus-acellular pertussis-inactivated poliovirus (dTap-IPVB) vaccine (Boostrix-IPV, GSK) as a pre-school booster in 3–4 year old children as compared to dTap-IPVR (Repevax, Sanofi Pasteur), when co-administered with mumps-measles-rubella vaccine (MMRV).
This phase III, open label, randomised study was conducted in the UK between April 2011 and April 2012. Children due their pre-school dTap-IPV booster vaccination were randomised 2:1 to receive one of two different dTap-IPV vaccines (dTap-IPVB or dTap-IPVR) with blood sample for immunogenicity assessment just prior and one month after vaccination. Immune responses to diphtheria, tetanus and polio antigens were compared between the study vaccines (inferential comparison). In the absence of an accepted pertussis correlate of protection, the immunogenicity of dTap-IPVB vaccine against pertussis was compared with historical pertussis efficacy data (inferential comparison). Safety and reactogenicity of both study vaccines were evaluated.
387 children were randomised and 385 vaccinated: 255 in the dTap-IPVB group and 130 in the dTap-IPVR group. Prior to vaccination, ≥76.8% of children had anti-diphtheria and ≥65.5% had anti-tetanus titres above the protection threshold; for pertussis, the pre-vaccination seropositivity rate ranged between 18.1 and 70.6%. Both vaccines were immunogenic with 99.2–100% of children achieving titres above the pre-specified seroprotection/seropositivity thresholds. One serious adverse event not considered as causally related to the study vaccination by the study investigator was reported in the dTap-IPVB group.
Non-inferiority of dTap-IPVB to dTap-IPVR was demonstrated. Both vaccines had a clinically acceptable safety and reactogenicity profile when co-administered with MMRV to children 3–4 years old.
Trial registration: NCT01245049 (ClinicalTrials.gov)
Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children.
We conducted a ...randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine--the pooled vaccine group--or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale.
A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group.
Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.)
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