Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: A randomised, comparator-controlled, phase 2 trial.

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed the immunogenicity of NDV-HXP-S (COVIVAC) relative to an authorized vaccine. This phase 2 stage of a randomised, observer-blind, controlled, phase 1/2 trial was conducted at three community health centers in Thai Binh Province, Vietnam. Healthy males and non-pregnant females, 18 years of age and older, were eligible. Participants were randomised by age (18-59, ≥60 years) to receive one of three treatments by intramuscular injection twice, 28 days apart: COVIVAC at 3 μg or 6 μg, or AstraZeneca COVID-19 vaccine VAXZEVRIA™. Participants and personnel assessing outcomes were masked to treatment. The vaccine dose was selected based on Phase 1 results. A 6 μg dose was chosen to explore the immunogenicity gain over the 3-μg dose. The study's aim is to evaluate the safety and immunogenicity of COVIVAC at two dose levels compared to VAXZEVRIA, the most commonly used COVID-19 vaccine in Vietnam. The main outcome was the induction of 50% neutralising antibody titers against vaccine-homologous pseudotyped virus 14 days (day 43) and 6 months (day 197) after the second vaccination by age group. The primary immunogenicity and safety analyses included all participants who received one dose of the vaccine. ClinicalTrials.govNCT05940194. During August 10-23, 2021, 737 individuals were screened, and 374 were randomised (124-125 per group); all subjects received vaccine dose one and all but three received doses two four weeks later. Subjects 18-59 years of age achieved the following geometric mean titers of PNA 14 days after vaccine dose two: 153⋅28 (95 % CI 124·2-189⋅15) for COVIVAC 3 μg, 176⋅2 (95 % CI 141⋅45-220.27) for COVIVAC 6 μg, and 99⋅92(95 % CI 80.80-123⋅56) for VAXZEVRIA. Subjects ≥60 years of age also achieved potent geometric mean titers of PNA at the same timepoint: 183⋅57 (95 % CI 133.4-252⋅61) for COVIVAC 3 μg, 257⋅87 (95 % CI 181⋅6-367⋅18) for COVIVAC 6 μg, and 79⋅49(95 % CI 55⋅68-113⋅4) for VAXZEVRIA. On day 43, the geometric mean fold rise of 50 % neutralising antibody titers for subjects age 18-59 years was 31·20 (COVIVAC 3 μg N = 82, 95 % CI 25·14-38·74), 35·80 (COVIVAC 6 μg; N = 83, 95 % CI 29·03-44·15), 18·85 (VAXZEVRIA; N = 82, 95 % CI 15·10-23·54), and for subjects age ≥ 60 years was 37·27 (COVIVAC 3 μg; N = 42, 95 % CI 27·43-50·63), 50·10 (COVIVAC 6 μg; N = 40, 95 % CI 35·46-70·76), 16·11 (VAXZEVRIA; N = 40, 95 % CI 11·73-22·13). Among subjects seronegative for anti-S IgG at baseline, the day 43 geometric mean titer ratio of neutralising antibody (COVIVC 6 μg/VAXZEVRIA) was 1·77 (95 % CI 1·30-2·40) for subjects age 18-59 years and 3·24 (95 % CI 1·98-5·32) for subjects age ≥ 60 years. On day 197, the age-specific ratios were 1·11 (95 % CI 0·51-2·43) and 2·32 (0·69-7·85). Vaccines were well tolerated; reactogenicity was predominantly mild and transient. The percentage of subjects with unsolicited adverse events (AEs) during 28 days after vaccinations was similar among treatments (COVIVAC 3 μg 29·0 %, COVIVAC 6 μg 23·2 %, VAXZEVRIA 31·2 %); no vaccine-related AE was reported. Considering that induction of neutralising antibodies against SARS-CoV-2 has been correlated with the efficacy of COVID-19 vaccines, including VAXZEVRIA, our results suggest that vaccination with COVIVAC may afford clinical benefit matching or exceeding that of the VAXZEVRIA vaccine. ClinicalTrials.govNCT05940194.

Thiem VD ，Anh DD ，Ha VH ，Van Thom N ，Thang TC ，Mateus J ，Carreño JM ，Raghunandan R ，Huong NM ，Mercer LD ，Flores J ，Escarrega EA ，Raskin A ，Thai DH ，Van Be L ，Sette A ，Innis BL ，Krammer F ，Weiskopf D ... -  《-》

Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomized, placebo-controlled, phase 1/2 trial in Vietnam.

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 (NDV) vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan-Hu-1. The spike protein was stabilized and incorporated into NDV virions by removing the polybasic furin cleavage site, introducing the transmembrane domain and cytoplasmic tail of the fusion protein of NDV, and introducing six prolines for stabilization in the prefusion state. Vaccine production and clinical development was initiated in Vietnam, Thailand, and Brazil. Here the interim results from the first stage of the randomized, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial conducted at the Hanoi Medical University (Vietnam) are presented. Healthy adults aged 18-59 years, non-pregnant, and with self-reported negative history for SARS-CoV-2 infection were eligible. Participants were randomized to receive one of five treatments by intramuscular injection twice, 28 days apart: 1 μg +/- CpG1018 (a toll-like receptor 9 agonist), 3 μg alone, 10 μg alone, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited adverse events (AEs) during 7 days and subject-reported AEs during 28 days after each vaccination. Investigators further reviewed subject-reported AEs. Secondary outcomes were immunogenicity measures (anti-spike immunoglobulin G [IgG] and pseudotyped virus neutralization). This interim analysis assessed safety 56 days after first vaccination (day 57) in treatment-exposed individuals and immunogenicity through 14 days after second vaccination (day 43) per protocol. Between March 15 and April 23, 2021, 224 individuals were screened and 120 were enrolled (25 per group for active vaccination and 20 for placebo). All subjects received two doses. The most common solicited AEs among those receiving active vaccine or placebo were all predominantly mild and included injection site pain or tenderness (<58%), fatigue or malaise (<22%), headache (<21%), and myalgia (<14%). No higher proportion of the solicited AEs were observed for any group of active vaccine. The proportion reporting vaccine-related AEs during the 28 days after either vaccination ranged from 4% to 8% among vaccine groups and was 5% in controls. No vaccine-related serious adverse event occurred. The immune response in the 10 μg formulation group was highest, followed by 1 μg + CpG1018, 3 μg, and 1 μg formulations. Fourteen days after the second vaccination, the geometric mean concentrations (GMC) of 50% neutralizing antibody against the homologous Wuhan-Hu-1 pseudovirus ranged from 56.07 IU/mL (1 μg, 95% CI 37.01, 84.94) to 246.19 IU/mL (10 μg, 95% CI 151.97, 398.82), with 84% to 96% of vaccine groups attaining a ≥ 4-fold increase over baseline. This was compared to a panel of human convalescent sera (N = 29, 72.93 95% CI 33.00-161.14). Live virus neutralization to the B.1.617.2 (Delta) variant of concern was reduced but in line with observations for vaccines currently in use. Since the adjuvant has shown modest benefit, GMC ratio of 2.56 (95% CI, 1.4-4.6) for 1 μg +/- CpG1018, a decision was made not to continue studying it with this vaccine. NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 μg dose was advanced to phase 2 along with a 6 μg dose. The 10 μg dose was not selected for evaluation in phase 2 due to potential impact on manufacturing capacity. ClinicalTrials.gov NCT04830800.

Duc Dang A ，Dinh Vu T ，Hai Vu H ，Thanh Ta V ，Thi Van Pham A ，Thi Ngoc Dang M ，Van Le B ，Huu Duong T ，Van Nguyen D ，Lawpoolsri S ，Chinwangso P ，McLellan JS ，Hsieh CL ，Garcia-Sastre A ，Palese P ，Sun W ，Martinez JL ，Gonzalez-Dominguez I ，Slamanig S ，Manuel Carreño J ，Tcheou J ，Krammer F ，Raskin A ，Minh Vu H ，Cong Tran T ，Mai Nguyen H ，Mercer LD ，Raghunandan R ，Lal M ，White JA ，Hjorth R ，Innis BL ，Scharf R ... -  《-》

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study.

We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18-59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744-2746) for the low-dose group, 2269 (1792-2873) for the medium-dose group, and 2895 (2294-3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85-135) in the low-dose group, 110 (87-140) in the medium-dose group, and 141 (111-179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836-11 815) in the low-dose group, 2338 (593-9226) in the medium-dose group, and 7069 (1361-36 725) in the high-dose group. Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Sridhar S ，Joaquin A ，Bonaparte MI ，Bueso A ，Chabanon AL ，Chen A ，Chicz RM ，Diemert D ，Essink BJ ，Fu B ，Grunenberg NA ，Janosczyk H ，Keefer MC ，Rivera M DM ，Meng Y ，Michael NL ，Munsiff SS ，Ogbuagu O ，Raabe VN ，Severance R ，Rivas E ，Romanyak N ，Rouphael NG ，Schuerman L ，Sher LD ，Walsh SR ，White J ，von Barbier D ，de Bruyn G ，Canter R ，Grillet MH ，Keshtkar-Jahromi M ，Koutsoukos M ，Lopez D ，Masotti R ，Mendoza S ，Moreau C ，Ceregido MA ，Ramirez S ，Said A ，Tavares-Da-Silva F ，Shi J ，Tong T ，Treanor J ，Diazgranados CA ，Savarino S ... -  《-》

Safety and immunogenicity of a modified mRNA-lipid nanoparticle vaccine candidate against COVID-19: Results from a phase 1, dose-escalation study.

Essink BJ ，Shapiro C ，Isidro MGD ，Bradley P ，Pragalos A ，Bloch M ，Santiaguel J ，Frias MV ，Miyakis S ，Alves de Mesquita M ，Berrè S ，Servais C ，Waugh N ，Hoffmann C ，Baba E ，Schönborn-Kellenberger O ，Wolz OO ，Koch SD ，Ganyani T ，Boutet P ，Mann P ，Mueller SO ，Ramanathan R ，Gaudinski MR ，Vanhoutte N ... -  《-》

Effect of timing of casirivimab and imdevimab administration relative to mRNA-1273 COVID-19 vaccination on vaccine-induced SARS-CoV-2 neutralising antibody responses: a prospective, open-label, phase 2, randomised controlled trial.

Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes. This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA. Participants were randomly assigned (per prespecified randomisation ratios within enrolment waves) according to a computer-generated randomisation scheme, stratified by age (<65 years and ≥65 years), to various intravenous or subcutaneous doses of casirivimab and imdevimab before, after, or at the same time as mRNA-1273 or to mRNA-1273 only. The doses of casirivimab and imdevimab were chosen to mimic various time intervals between receipt of 1200 mg of the mAb and the first dose of a primary series with mRNA-1273. The primary endpoint was vaccine-induced 50% inhibitory dilution neutralising antibody titres to SARS-CoV-2 spike protein, 56 days after the first vaccination. Secondary endpoints included vaccine-induced total antibodies to SARS-CoV-2 antigens and incidence of treatment-emergent adverse events. Exploratory endpoints included blood-derived T-cell and B-cell responses. The per-protocol set was used for the analysis of the primary endpoint and included all randomly assigned participants who received both doses of the vaccine and completed the injection or infusion of casirivimab and imdevimab per protocol, had no evidence of SARS-CoV-2 infection in the past or in the 56 days after the first dose of vaccine, and did not receive any intervention outside of the study that could alter the immune response. Safety was assessed in the safety analysis set, which included all randomly assigned participants who had received one or more doses of mRNA-1273 or any study drug, and analysed based on treatment received. The study is registered with ClinicalTrials.gov, NCT04852978, and is complete. Between April 29, 2021, and Nov 21, 2022, 807 participants were assessed for eligibility and 295 were randomly assigned. 293 participants were included in the safety analysis set and 260 were included in the per-protocol set. All vaccinated participants developed neutralising antibodies to SARS-CoV-2, with median titres above the published protective threshold (100 IU/mL) against the SARS-CoV-2 D614G variant (considered a reference strain at the time the initial COVID-19 vaccines were developed). Titres were decreased up to 4-fold (median titres 280-450 IU/mL for casirivimab and imdevimab vs 1160 IU/mL for vaccine only on day 56) when casirivimab and imdevimab was given 85 days or less before vaccination (150-1200 mg intravenously) or co-administered subcutaneously (600 mg or 1200 mg) with vaccination. Minimal reduction in neutralisation titres was observed in the 48 mg and 12 mg intravenous groups, corresponding to receipt of casirivimab and imdevimab 113 days and 169 days, respectively, before vaccination, and when administering the vaccine 6 days before the mAb. Across all groups, mAbs had a minimal effect on vaccine-induced total antibodies and T-cell responses to the spike protein. Casirivimab and imdevimab plus mRNA-1273 was generally well tolerated; a slight increase in treatment-emergent adverse events was observed in the casirivimab and imdevimab plus vaccine groups versus the vaccine-only group. Casirivimab and imdevimab administration before or at the time of COVID-19 vaccination reduced the elicitation of SARS-CoV-2 neutralising antibodies, but minimal effect was observed when vaccination occurred before mAb administration. Although the clinical significance of this decrease in neutralisation is unclear, this evidence suggests that further investigation of potential interactions could be warranted before concurrent clinical use of mAbs and vaccines targeting the same viral proteins as their main modes of action for the prevention or treatment of infectious diseases. Regeneron Pharmaceuticals and F Hoffmann-La Roche.

Isa F ，Gonzalez Ortiz AM ，Meyer J ，Hamilton JD ，Olenchock BA ，Brackin T ，Ganguly S ，Forleo-Neto E ，Faria L ，Heirman I ，Marovich M ，Hutter J ，Polakowski L ，Irvin SC ，Thakur M ，Hooper AT ，Baum A ，Petro CD ，Fakih FA ，McElrath MJ ，De Rosa SC ，Cohen KW ，Williams LD ，Hellman CA ，Odeh AJ ，Patel AH ，Tomaras GD ，Geba GP ，Kyratsous CA ，Musser B ，Yancopoulos GD ，Herman GA ，Trial Working Group ... -  《-》