Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial.

Background: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed by public sector manufacturers in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. Methods: This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy males and non-pregnant females, aged 18-59 years and negative for SARS-CoV-2 antibodies, were eligible. Participants were randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 µg, 1 µg+CpG1018 (a toll-like receptor 9 agonist), 3 µg, 3 µg+CpG1018, 10 µg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422). Findings: Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enroled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5·7% to 17·1% among vaccine groups and was 2·9% in controls; there was no vaccine-related serious adverse event. The 10 µg formulation's immunogenicity ranked best, followed by 3 µg+CpG1018, 3 µg, 1 µg+CpG1018, and 1 µg formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122·23 international units per mL (IU/mL; 1 µg, 95% confidence interval (CI) 86·40-172·91) to 474·35 IU/mL (10 µg, 95% CI 320·90-701·19), with 93·9% to 100% of vaccine groups attaining a ≥ 4-fold increase over baseline. Interpretation: NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 µg and 3 µg+CpG1018 formulations advanced to phase 2. Funding: National Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA).

Safety and Immunogenicity of an Inactivated Recombinant Newcastle Disease Virus Vaccine Expressing SARS-CoV-2 Spike: Interim Results of a Randomised, Placebo-Controlled, Phase 1/2 Trial.

BACKGROUND: Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed in Thailand, Vietnam, and Brazil; herein are initial results from Thailand. METHODS: This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy adults aged 18-59 years, non-pregnant and negative for SARS-CoV-2 antibodies were eligible. Participants were block randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 µg±CpG1018 (a toll-like receptor 9 agonist), 3 µg±CpG1018, 10 µg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov ( NCT04764422 ). FINDINGS: Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enrolled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5·7% to 17·1% among vaccine groups and was 2·9% in controls; there was no vaccine-related serious adverse event. The 10 µg formulation's immunogenicity ranked best, followed by 3 µg+CpG1018, 3 µg, 1 µg+CpG1018, and 1 µg formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122·23 IU/mL (1 µg, 95% CI 86·40-172·91) to 474·35 IU/mL (10 µg, 95% CI 320·90-701·19), with 93·9% to 100% of vaccine groups attaining a ≥4-fold increase over baseline. INTERPRETATION: NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 µg and 3 µg+CpG1018 formulations advanced to phase 2. FUNDING: National Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA).

Antibody persistence 2 and 3 years after booster vaccination of adolescents with recombinant acellular pertussis monovalent aPgen or combined TdaPgen vaccines.

BACKGROUND: Recombinant pertussis vaccines inducing long-lasting immune responses could help to control the rise in pertussis. We here report on persisting antibody responses 2 and 3 years after booster vaccination with a new generation recombinant acellular pertussis vaccine. METHODS: Participants of a phase 2/3 randomised-controlled clinical trial with a monovalent pertussis vaccine containing genetically inactivated pertussis toxin (aPgen) or its tetanus and diphtheria toxoids combination (TdaPgen), or a chemically detoxified comparator vaccine (Tdapchem), (originally conducted between July and August 2015) were invited to participate in observational studies of persisting antibody responses 2 and 3 years after vaccination. Serum IgG against pertussis toxin (PT-IgG) and filamentous hemagglutinin (FHA-IgG) were assessed by ELISA, and PT-neutralising antibodies (PT-Nab) by Chinese Hamster Ovary cell assay. FINDINGS: Waning of antibodies stabilised in aPgen and TdaPgen vaccinees 2 and 3 years after vaccination. Three years post-vaccination PT-neutralising antibodies remained 4·6-fold (95% Confidence Interval (CI) 2·6-8·1) and 3·7-fold (95% CI 2·2-6·1) higher, PT-IgG antibodies 3·0-fold (95% CI 2·2-4·1) and 2·5-fold (95% CI 1·9-3·3) higher, and FHA-IgG antibodies 1·8-fold (95% CI 1·3-2·5) and 1·6-fold (95% CI 1·2-2·1) higher than baseline in aPgen and TdaPgen recipients, respectively. In the Tdapchem group, PT-neutralising and PT-IgG and FHA-IgG antibodies were back at baseline levels 2 years post-vaccination. Three years post-vaccination seroconversion rates for PT-neutralising antibodies were 65·0% (95% CI 44·1-85·9) and 55·0% (95% CI 33·2-76·8) in aPgen and TdaPgen recipients, respectively. INTERPRETATION: Considering the persistence of elevated antibody responses 3 years post-booster vaccination, genetically detoxified monovalent aPgen and TdaPgen vaccines can be expected to induce longer-lasting protection than chemically inactivated Tdap vaccines. FUNDING: BioNet-Asia.

Antibody persistence after vaccination of adolescents with monovalent and combined acellular pertussis vaccines containing genetically inactivated pertussis toxin: a phase 2/3 randomised, controlled, non-inferiority trial.

BACKGROUND: The immunogenicity of acellular pertussis vaccines and persistence of immunity after vaccination might be improved by using genetically inactivated pertussis toxin (PTgen) instead of chemically inactivated pertussis toxin (PTchem) because of the preservation of conformational epitopes. We assessed the safety and immunogenicity of two vaccines containing PTgen 1 year after vaccination. METHODS: We did a phase 2/3 non-inferiority, randomised, controlled trial involving 450 adolescents (age 12-17 years) enrolled between July 6, 2015, and Aug 20, 2015. Participants were randomised 1:1:1 to receive one dose of vaccine containing PTgen and filamentous haemagglutinin (FHA) either in a monovalent formulation (aP[PTgen/FHA]) or in a combined formulation with tetanus and reduced-dose diphtheria toxoids (TdaP[PTgen/FHA]) or to receive a commercial vaccine containing reduced-dose PTchem (Tdap) as a comparator. We report a secondary trial outcome, namely antibody persistence 1 year after vaccination, assessed per protocol in 150 randomly preselected participants (50 per group). Seroconversion was defined as antibody titres at least four times greater than at baseline. Safety was assessed in all trial participants. This study is registered in the Thai Clinical Trial Registry, number TCTR20150703002. FINDINGS: Between June 5, 2016, and Aug 9, 2016, 442 (98%) of 450 enrolled participants attended a 1-year follow-up visit. After 1 year, persistent seroconversion for pertussis toxin neutralising antibodies was seen in 38 (76%, 95% CI 64-88) participants in the aP(PTgen/FHA) group and 41 (81%, 70-92) in the TdaP(PTgen/FHA) group, but in only four (8%, 1-16) in the Tdap comparator group. Seroconversion rates for IgG antibodies against pertussis toxin and FHA were also greater in the aP(PTgen/FHA) group (82%, 95% CI 71-93 and 64%, 51-77, respectively) and TdaP(PTgen/FHA) group (75%, 63-87 and 56%, 42-70, respectively) than in the Tdap group (4%, 0-9, p<0·0001, and 28%, 16-41, p=0·0007, respectively). 13 serious adverse events were reported in 12 participants and all were judged to be unrelated to the study vaccines. Five pregnancies were reported during follow-up, none of which had any maternal or neonatal complications. INTERPRETATION: A monovalent and a combined recombinant acellular pertussis vaccine containing PTgen induced antibody responses that were greater and sustained for longer than those achieved with the Tdap comparator vaccine. New recombinant pertussis vaccines containing PTgen might offer new opportunities to limit pertussis resurgence and can be widely used, including in pregnant women. FUNDING: BioNet-Asia.

A genetically inactivated two-component acellular pertussis vaccine, alone or combined with tetanus and reduced-dose diphtheria vaccines, in adolescents: a phase 2/3, randomised controlled non-inferiority trial.

BACKGROUND: Increasing evidence shows that protection induced by acellular pertussis vaccines is short-lived, requiring repeated booster vaccination to control pertussis disease. We aimed to assess the safety and immunogenicity of a recombinant acellular pertussis vaccine containing genetically inactivated pertussis toxin and filamentous haemagglutinin, as either a monovalent vaccine (aP[PTgen/FHA]) or in combination with tetanus and reduced-dose diphtheria vaccines (TdaP[PTgen/FHA]), versus a licensed tetanus and reduced-dose diphtheria and acellular pertussis combination vaccine (Tdap). METHODS: We did this phase 2/3, randomised controlled non-inferiority trial at two sites in Bangkok, Thailand. Healthy adolescents (aged 12-17 years) were randomly assigned (1:1:1), via a computer-generated randomisation list with block sizes of three, to receive one dose (0·5 mL) of aP(PTgen/FHA), TdaP(PTgen/FHA), or Tdap (comparator). Clinical research staff responsible for participant randomisation, vaccine preparation and administration, and accountability were aware of group allocation. However, allocation was concealed from all other site study staff, data management personnel, statisticians, laboratory staff, and study participants. The primary outcome was non-inferior immunogenicity of TdaP(PTgen/FHA) to Tdap based on seroconversion rates (a four-fold increase or more) for pertussis toxin and filamentous haemagglutinin IgG antibodies 28 days after vaccination, with a predefined 10% margin of equivalence. We did analysis by per protocol. This study is registered with the Thai Clinical Trial Registry, number TCTR20150703002. FINDINGS: Between July 6 and Aug 20, 2015, we allocated 450 participants to receive one dose of TdaP(PTgen/FHA) (n=150), aP(PTgen/FHA) (n=150), or comparator Tdap (n=150). 28 days after vaccination, seroconversion rates for anti-pertussis toxin IgG were 96·6% (95% CI 93·8-99·5; n=144) in the TdaP(PTgen/FHA) group and 55·0% (47·1-63·0; n=82) in the comparator Tdap group (difference 41·6%, 95% CI 33·1-50·1; p<0·0001). Seroconversion rates for anti-filamentous haemagglutinin were 82·6% (95% CI 76·5-88·6; n=123) in the TdaP(PTgen/FHA) group and 54·4% (46·4-62·4; n=81) in the comparator group (difference 28·2%, 95% CI 18·1-38·2 p<0·0001). 28 days after vaccination, seroconversion rates in the aP(PTgen/FHA) group were 96·0% (95% CI 92·8-99·1; n=142) for anti-pertussis toxin IgG and 93·2% (89·2-97·3; n=138) for anti-filamentous haemagglutinin IgG. These findings support the non-inferior immunogenicity of TdaP(PTgen/FHA) over comparator Tdap. Reactogenicity and incidence of adverse events were similar between groups. INTERPRETATION: The new TdaP(PTgen/FHA) vaccine is safe and induces higher pertussis responses 28 days after vaccination than does the available licensed Tdap booster vaccine. Results of our trial led to the licensure of new acellular pertussis vaccines containing genetically inactivated pertussis toxin in Thailand. The availability of recombinant monovalent pertussis vaccines that induce high antibody responses provides the medical community and consumers with the opportunity to vaccinate against pertussis when immunisation against diphtheria and tetanus is not required or not desired. Studies are underway to pave the way for licensure studies of this acellular pertussis vaccine in other countries. FUNDING: BioNet-Asia.

Expectation of volunteers towards the vaccine efficacy of the prime-boost HIV vaccine phase III trial during unblinding.

A Phase III community-based HIV vaccine trial using the ALVAC-HIV and AIDSVAX B/E prime-boost regimen (RV144) showed a modest vaccine efficacy of 31.2% against HIV acquisition. Participant's understanding of the trial is a key element of its success. This study aimed to understand participant's expectation and response to the overall results of the trial as well after unblinding. Using an open-ended questionnaire, data were collected from 400 participants who came for the unblinding visit. Fifty-three percent received the vaccine and 47% were placebo recipients. The median age was 30 years (range: 22-37). The observed vaccine efficacy of 31.2% was lower than expected by 67.75% of participants compared to higher than expected (by 6%), as expected (by 11.25%), and those with no expectation (15%). A majority of participants (71.5%) were happy and proud, and indicated that it was a good result. The rest were sad or disappointed (22.75%) or acquiescent (5.75%). After unblinding, 67.92% of the vaccine recipients had a positive response and 32.08% were acquiescent. Among placebo recipients, 85.11% were acquiescent and 10.11% indicated that being assigned to the vaccine group would have been better even though vaccine efficacy was only 31.2%. Despite the modest vaccine efficacy, a majority of study participants acknowledged the value of the trial and hoped that information from RV144 could be used for future vaccine development.

Issues in women's participation in a phase III community HIV vaccine trial in Thailand.

To assess qualities and outcomes of women participating in a large, community-based HIV vaccine trial, the present study was conducted among female participants of the RV 144 prime-boost trial in Thailand from 2003 to 2009. Qualities of participation refer to complete vaccination, retention, and status change. Outcomes of participation refer to incident rate, adverse event, and participation impact event. A total of 6,334 (38.6%) women participated in the trial, of whom about 50% were classified as low risk and 11% as high risk. About 85% of participants completed four vaccinations and 76% were included in the per-protocol analysis of the on-time vaccination schedule. More women (88%) completed 42 months follow-up compared with men (85%). Women aged 21 and above had more adverse events compared to younger age groups. More women (5%) compared with men (3%) reported participation impact events (PIEs). High-risk women had more PIEs and a higher infection rate compared to the low-risk group. Complete vaccination and retention on last follow-up were more common in married women aged above 21, and being a housewife. Female volunteers showed the same qualities and outcomes of participation as males in the HIV vaccine trial. There was no statistically significant difference in vaccine efficacy between men and women, especially among the high-risk and married women. The study highlighted the important behavioral, social, and cultural issues that could be considered for future HIV vaccine trial designs.