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

This phase 1, open-label, dose-escalation, multi-center study (NCT05477186) assessed the safety and immunogenicity of a booster dose of an mRNA COVID-19 vaccine (CV0501) encoding the SARS-CoV-2 Omicron BA.1 spike protein. Participants aged ≥ 18 years previously vaccinated with ≥ 2 doses of an mRNA COVID-19 vaccine received CV0501 doses ranging from 12 to 200 µg. After assessment of safety and immunogenicity of the 12 µg dose in 30 adults, 30 adults ≤ 64 years were randomized to receive either a 3 or 6 µg dose. Solicited adverse events (AEs) were collected for 7 days, unsolicited AEs for 28 days, and serious AEs (SAEs), medically attended AEs (MAAEs), and AEs of special interest (AESIs) until day (D) 181 post-vaccination. Serum neutralizing titers specific to SARS-CoV-2 BA.1, wild-type, Delta, and additional Omicron subvariants were assessed at D1, D15, D29, D91, and D181. Of 180 vaccinated participants (mean age: 49.3 years; 57.8% women), 70.6% had prior SARS-CoV-2 infection. Most solicited local (98.1%) and systemic (96.7%) AEs were of mild-to-moderate severity; the most common were injection site pain (57.5%; 33.3-73.3% across groups) and myalgia (36.9%; 13.3-56.7%). Unsolicited AEs were reported by 14.4% (6.7-26.7%) of participants (mild-to-moderate severity in 88.5% of the participants). Three participants (1.7%) reported SAEs, 16.7% (6.7-30.0%) reported MAAEs, and 8.3% (0.0-13.3%) reported AESIs (15 COVID-19 cases), none related to vaccination. Geometric means of serum neutralizing titers increased from baseline to D15 and D29 (dose-dependent), and then decreased over time. The safety and immunogenicity results supported advancement to a phase 2 trial.

What is the context? Since 2019, more than 776 million people have been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, and more than 7 million people have died due to COVID-19.The virus changes over time and new variants may evade the protection provided by vaccines that are effective against previous variants.Therefore, it is necessary to develop vaccines that can be quickly updated to better protect against COVID-19 caused by new SARS-CoV-2 variants.We developed an mRNA vaccine, CV0501, that encodes a key protein on the surface of the SARS-CoV-2 Omicron BA.1 variant to instruct the immune system for future protection against COVID-19. The mRNA is encased in lipid nanoparticles that can increase the immune response to the vaccine.What is new? We administered different dose levels (that is, different amounts of mRNA) of CV0501 to adults who had previously been vaccinated at least twice with a different COVID-19 vaccine.We found that even at increased dose levels, CV0501 caused mostly mild side effects that resolved within a few days. Serious adverse events or events that required medical attention were not related to the vaccine.We also found that CV0501 generated immune responses not only against the Omicron BA.1 subvariant (vaccine antigen) but also against the original SARS-CoV-2 variant, the Delta variant, and other Omicron subvariants, at all dose levels tested.What is the impact? Our findings indicate that the CV0501 vaccine was well tolerated and induced immune responses against vaccine target variant as well as other SARS-CoV-2 variants.Other vaccines against COVID-19 based on the mRNA technology used for CV0501 will be further evaluated.

Safety and Immunogenicity of Cell-Based Quadrivalent Influenza Vaccine: A Randomized Trial.

OBJECTIVE: Young children are at increased risk for influenza-related complications. Safety and immunogenicity of a cell-based quadrivalent inactivated influenza vaccine (QIVc) was compared with a US-licensed vaccine (QIV) in children aged 6 through 47 months. METHODS: A phase 3, randomized, observer-blind, comparator-controlled, multicenter study was conducted during Northern Hemisphere 2019-2020 influenza season. Children were randomized 2:1 to QIVc or QIV and received 1 or 2 doses of the vaccine, depending upon influenza vaccination history. Safety was assessed for 180 days after last vaccination and sera were collected before and 28 days after last vaccination to measure antibody titers in hemagglutination inhibition and microneutralization assays. Noninferiority criteria were met if the upper bounds of the 2-sided 95% confidence interval (CI) for the geometric mean titer ratio (QIV:QIVc) did not exceed 1.5 and for seroconversion rate difference (QIV-QIVc) did not exceed 10% for the 4 virus strains. RESULTS: Immunogenicity was evaluated in 1092 QIVc and 575 QIV subjects. Success criteria were met for all vaccine strains. Geometric mean titer ratios (upper bound 95% CI) were A/H1N1, 0.73 (0.84); A/H3N2, 1.04 (1.16); B/Yamagata, 0.73 (0.81); and B/Victoria, 0.88 (0.97). Seroconversion differences (upper bound 95% CI) were -11.46% (-6.42), 3.13% (7.81), -14.87% (-9.98), and -5.96% (-1.44) for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria, respectively. Rates of adverse events were similar between the 2 groups with no serious adverse events related to vaccination. CONCLUSIONS: QIVc was well-tolerated and immune responses were similar to a US-licensed QIV in children 6 through 47 months of age.

Safety and Immunogenicity of an mRNA-Based Human Metapneumovirus and Parainfluenza Virus Type 3 Combined Vaccine in Healthy Adults.

Background: Human metapneumovirus (hMPV) and parainfluenza virus type 3 (PIV3) cause respiratory tract illness in children and the elderly. No licensed vaccines are available. Methods: In this phase 1, randomized, dose-ranging, first-in-human study, the safety, reactogenicity, and humoral immunogenicity of an investigational mRNA-based hMPV and PIV3 combination vaccine, mRNA-1653, were evaluated in healthy adults aged 18-49 years. Sentinel participants (n = 20) received 2 doses of mRNA-1653 (25, 75, 150, or 300 µg) in the dose escalation phase, and participants (n = 104) received 2 doses of mRNA-1653 (75, 150, or 300 µg) or placebo in the dose selection phase; injections were 28 days apart. Results: The most common solicited reactogenicity events were injection site pain, headache, fatigue, and myalgia, the majority of which were grade 1 or 2. A single mRNA-1653 dose increased neutralization titers against hMPV and PIV3 1 month after vaccination compared with baseline. No notable increases in neutralizing antibody titers were observed with escalating dose levels after mRNA-1653, although no statistical inferences were made; a second mRNA-1653 dose had little observable impact on antibody titers. Neutralizing titers through 1 year remained above baseline for hMPV and returned to baseline for PIV3. Conclusions: mRNA-1653 was well tolerated, with an acceptable safety profile and increased hMPV and PIV3 neutralization titers in healthy adults.

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Safety and Immunogenicity of a Respiratory Syncytial Virus Prefusion F Vaccine When Coadministered With a Tetanus, Diphtheria, and Acellular Pertussis Vaccine.

BACKGROUND: Prevention of respiratory syncytial virus (RSV) disease in infants is an unmet vaccine need, and maternal immunization is a potential strategy to address this need. This study evaluated concomitant administration of RSV stabilized prefusion F subunit vaccine (RSVpreF) and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed (Tdap) in healthy, nonpregnant women 18‒49 years of age. METHODS: In this phase 2b, multicenter, placebo-controlled, observer-blind, noninferiority study, participants were randomized to receive RSVpreF in a range of doses and formulations with Tdap or alone, or Tdap alone. Safety and immunogenicity were assessed. RESULTS: Local reactions and systemic events were generally similar across vaccine groups. Noninferiority of anti-RSV-A and anti-RSV-B immune responses induced by RSVpreF with Tdap was demonstrated compared to RSVpreF alone. Noninferiority of anti-diphtheria toxoid and anti-tetanus toxoid immune responses after administration of RSVpreF with Tdap was demonstrated compared to Tdap alone; noninferiority was not met for anti-pertussis component responses. CONCLUSIONS: RSVpreF was safe and well tolerated when administered with Tdap or alone in nonpregnant women 18‒49 years of age. Immune responses induced by Tdap administered with RSVpreF were noninferior for the tetanus and diphtheria components of Tdap, but not for pertussis. CLINICAL TRIALS REGISTRATION: NCT04071158.

Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1-2, dose-ranging study.

BACKGROUND: CoV2 preS dTM is a stabilised pre-fusion spike protein vaccine produced in a baculovirus expression system being developed against SARS-CoV-2. We present interim safety and immunogenicity results of the first-in-human study of the CoV2 preS dTM vaccine with two different adjuvant formulations. METHODS: This phase 1-2, randomised, double-blind study is being done in healthy, SARS-CoV-2-seronegative adults in ten clinical research centres in the USA. Participants were stratified by age (18-49 years and ≥50 years) and randomly assigned using an interactive response technology system with block randomisation (blocks of varying size) to receive one dose (on day 1) or two doses (on days 1 and 22) of placebo or candidate vaccine, containing low-dose (effective dose 1·3 µg) or high-dose (2·6 µg) antigen with adjuvant AF03 (Sanofi Pasteur) or AS03 (GlaxoSmithKline) or unadjuvanted high-dose antigen (18-49 years only). Primary endpoints were safety, assessed up to day 43, and immunogenicity, measured as SARS-C0V-2 neutralising antibodies (geometric mean titres), assessed on days 1, 22, and 36 serum samples. Safety was assessed according to treatment received in the safety analysis set, which included all randomly assigned participants who received at least one dose. Neutralising antibody titres were assessed in the per-protocol analysis set for immunogenicity, which included participants who received at least one dose, met all inclusion and exclusion criteria, had no protocol deviation, had negative results in the neutralisation test at baseline, and had at least one valid post-dose serology sample. This planned interim analysis reports data up to 43 days after the first vaccination; participants in the trial will be followed up for 12 months after the last study injection. This trial is registered with ClinicalTrials.gov, NCT04537208, and is ongoing. FINDINGS: Between Sept 3 and Sept 29, 2020, 441 individuals (299 aged 18-49 years and 142 aged ≥50 years) were randomly assigned to one of the 11 treatment groups. The interim safety analyses included 439 (>99%) of 441 randomly assigned participants (299 aged 18-49 years and 140 aged ≥50 years). Neutralising antibody titres were analysed in 326 (74%) of 441 participants (235 [79%] of 299 aged 18-49 years and 91 [64%] of 142 aged ≥50 years). There were no vaccine-related unsolicited immediate adverse events, serious adverse events, medically attended adverse events classified as severe, or adverse events of special interest. Among all study participants, solicited local and systemic reactions of any grade after two vaccine doses were reported in 81% (95% CI 61-93; 21 of 26) of participants in the low-dose plus AF03 group, 93% (84-97; 74 of 80) in the low-dose plus AS03 group, 89% (70-98; 23 of 26) in the high-dose plus AF03 group, 95% (88-99; 81 of 85) in the high-dose plus AS03 group, 29% (10-56; five of 17) in the unadjuvanted high-dose group, and 21% (8-40; six of 29) in the placebo group. A single vaccine dose did not generate neutralising antibody titres above placebo levels in any group at days 22 or 36. Among participants aged 18-49 years, neutralising antibody titres after two vaccine doses were 13·1 (95% CI 6·40-26·9) in the low-dose plus AF03 group, 20·5 (13·1-32·1) in the low-dose plus AS03 group, 43·2 (20·6-90·4) in the high-dose plus AF03 group, 75·1 (50·5-112·0) in the high-dose plus AS03 group, 5·00 (not calculated) in the unadjuvanted high-dose group, and 5·00 (not calculated) in the placebo group. Among participants aged 50 years or older, neutralising antibody titres after two vaccine doses were 8·62 (1·90-39·0) in the low-dose plus AF03 group, 12·9 (7·09-23·4) in the low-dose plus AS03 group, 12·3 (4·35-35·0) in the high-dose plus AF03 group, 52·3 (25·3-108·0) in the high-dose plus AS03 group, and 5·00 (not calculated) in the placebo group. INTERPRETATION: The lower than expected immune responses, especially in the older age groups, and the high reactogenicity after dose two were probably due to higher than anticipated host-cell protein content and lower than planned antigen doses in the formulations tested, which was discovered during characterisation studies on the final bulk drug substance. Further development of the AS03-adjuvanted candidate vaccine will focus on identifying the optimal antigen formulation and dose. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Synbiotics-supplemented amino acid-based formula supports adequate growth in cow's milk allergic infants.

BACKGROUND: Children with cow's milk allergy (CMA) are at risk for inadequate nutritional intake and growth. Dietary management of CMA, therefore, requires diets that are not only hypoallergenic but also support adequate growth in this population. This study assessed growth of CMA infants when using a new amino acid-based formula (AAF) with prebiotics and probiotics (synbiotics) and evaluated its safety in the intended population. METHODS: In a prospective, randomized, double-blind controlled study, full-term infants with diagnosed CMA received either an AAF (control; n = 56) or AAF with synbiotics (oligofructose, long-chain inulin, acidic oligosaccharides, Bifidobacterium breve M-16V) (test; n = 54) for 16 wk. Primary outcome was growth, measured as weight, length and head circumference. Secondary outcomes included allergic symptoms and stool characteristics. RESULTS: Average age (±SD) of infants at inclusion was 4.5 ± 2.4 months. Both formulas equally supported growth according to WHO 2006 growth charts and resulted in similar increases of weight, length and head circumference. At week 16, differences (90% CI) in Z-scores (test-control) were as follows: weight 0.147 (-0.10; 0.39, p = 0.32), length -0.299 (-0.69; 0.09, p = 0.21) and head circumference 0.152 (-0.15; 0.45, p = 0.40). Weight-for-age and length-for-age Z-scores were not significantly different between the test and control groups. Both formulas were well tolerated and reduced allergic symptoms; the number of adverse events was not different between the groups. CONCLUSIONS: This is the first study that shows that an AAF with a specific synbiotic blend, suitable for CMA infants, supports normal growth and growth similar to the AAF without synbiotics. This clinical trial is registered as NCT00664768.