Immunogenicity In Humans Research Articles

Obesity does not influence SARS-CoV-2 humoral vaccine immunogenicity

Obesity does not influence SARS-CoV-2 humoral vaccine immunogenicity

Safety and Humoral Immunogenicity of Different Dose Levels of Ad26.COV2.S as a 2-Dose Regimen in COVID-19 Vaccine-Naïve Healthy Adults: A Phase 3 Randomized Clinical Trial.

This study aimed to support the end-of-shelf life specification (2.5 × 1010 virus particles [vp]) for the standard Ad26.COV2.S dose (5 × 1010 vp). This randomized, double-blind Phase 3 study evaluated immunogenicity, reactogenicity, and safety of several Ad26.COV2.S dose levels (range 1.25 to 9 × 1010 vp) in 1593 adults between June 2021 and July 2023. Spike-binding antibody responses 28 days post-dose 1 were non-inferior for the 9 × 1010 vp, but not the 2.5 × 1010 vp group when compared with the standard dose. Non-inferiority was demonstrated in terms of spike-binding antibody responses 14 days post-dose 2 for each dose level, including the lowest dose level of 1.25 × 1010 vp, compared to 28 days after one dose and 14 days after two doses of the standard dose. Spike-binding antibody levels correlated well with virus neutralizing titers. There was no impact of pre-existing Ad26.COV2.S neutralizing titers on immunogenicity at any dose level. All dose levels were well tolerated. This study highlights the challenges associated with conducting clinical studies in a rapidly evolving environment and underscores the importance of platform data that can guide initial vaccine specifications such as shelf life during accelerated vaccine development. The present study supports the end-of-shelf life specifications for the approved Ad26.COV2.S dose, and could provide useful information in future vaccine developments using adenovirus vector vaccines.

Safety, immunogenicity, and optimal dosing of a modified vaccinia Ankara-based vaccine against MERS-CoV in healthy adults: a phase 1b, double-blind, randomised placebo-controlled clinical trial.

MERS-CoV is a respiratory pathogen with a case-fatality rate of 36%, and for which no vaccines are currently licensed. MVA-MERS-S is a candidate vaccine based on recombinant modified vaccinia virus Ankara (MVA). In this study, the safety, immunogenicity, and optimal dose schedule of MVA-MERS-S was assessed in individuals with previous exposure to SARS-CoV-2 infections and vaccines. We conducted a multicentre, double-blind, randomised controlled phase 1b clinical trial at two university medical centres in Germany and the Netherlands. Healthy volunteers aged 18-55 years were assigned by computer randomisation to receive three intramuscular injections of 107 or 108 plaque-forming units (PFU) of MVA-MERS-S, with two treatment groups each of either 28-day or 56-day intervals between the initial two doses, and one control arm that received only placebo, at a ratio of 2:2:2:2:1. The third dose was given after 224 days. The sponsor, clinical and laboratory staff, and participants were masked to both vaccine dose and dosing interval. The primary outcome was safety, assessed in the all participants who had received at least one injection; daily solicited vaccine reactions were recorded after each dose for 7 days, unsolicited adverse events for 28 days, and serious adverse events throughout the study. The secondary outcome was humoral immunogenicity, measured with vaccine-induced geometric mean antibody concentrations and seroconversion rates, analysed in all participants who received at least three allocated treatments. This study is registered at ClinicalTrials.gov (NCT04119440) and is completed. Between 26 July, 2021, and 3 March, 2022, 244 volunteers were screened, 177 of whom were eligible and 140 were randomly assigned either to the 28-day 107 PFU group (n=32), 56-day 107 PFU group (n=31), 28-day 108 PFU group (n=31), 56-day 108 PFU group (n=30), or placebo group (n=16). In total, 178 doses were administered of 107 PFU of MVA-MERS-S, 174 of 108 PFU, and 164 doses of placebo, and 139 participants received at least one injection. 73 (53%) were female and 66 (48%) were male. No serious vaccine-related adverse events occurred. Solicited local reactions were mild in 288 (93%, 95% CI 90-96) of 309 reports and consisted primarily of pain or tenderness. Pain or tenderness (of any severity) occurred after 69 (39%, 32-46) of 178 107 PFU injections, 138 (79%; 73-85) of 174 108 PFU injections, and 18 (11%; 7-11) of 164 placebo injections. Of 595 reported solicited systemic reactions, 479 (81%, 77-83) were graded as mild. Systemic reactions of any grade occurred after 77 (43%; 36-51) 107 PFU injections, 102 (59%; 51-66) 108 PFU injections, and 67 (41%; 34-49) of 164 placebo injections. At 28 days after the second dose, MERS-CoV neutralising antibodies were highest for participants assigned to 56-day 108 PFU, with geometric mean ratios of 7·2 (95% CI 3·9-13·3) for the 56-day 108 PFU group versus the 28-day 108 PFU group (p<0·0001), 3·9 (2·1-7·2) for the 56-day 108 PFU group versus the 56-day 107 PFU group (p=0·0031), and 5·4 (2·9-10·0) for the 56-day 108 PFU group versus the 28-day 107 PFU group (p=0·0003). MVA-MERS-S was safe and immunogenic in individuals with previous and concurrent SARS-CoV-2 exposure. The second vaccination with the 108 PFU dose of MVA-MERS-S elicited a stronger humoral immune response when administered 56 days after the first dose than a 28-day interval. Further studies are needed to verify these findings in groups at risk for MERS-CoV exposure, and at risk of severe disease, including older individuals and those with relevant comorbidities. Coalition for Epidemic Preparedness Innovations, the German Centre for Infection Research, and the German Research Foundation.

A Lipid Nanoparticle-Formulated Self-Amplifying RNA Rift Valley Fever Vaccine Induces a Robust Humoral Immune Response in Mice.

Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that causes high fetal and neonatal mortality rates in ruminants and sometimes severe to fatal complications like encephalitis and hemorrhagic fever in humans. There is no licensed RVF vaccine for human use while approved livestock vaccines have suboptimal safety or efficacy. We designed self-amplifying RNA (saRNA) RVF vaccines and assessed their humoral immunogenicity in mice. Plasmid DNA encoding the Rift Valley fever virus (RVFV) medium (M) segment consensus sequence (WT consensus) and its derivatives mutated to enhance cell membrane expression of the viral surface glycoproteins n (Gn) and c (Gc) were assessed for in vitro expression. The WT consensus and best-expressing derivative (furin-T2A) were cloned into a Venezuelan equine encephalitis virus (VEEV) plasmid DNA replicon and in vitro transcribed into saRNA. The saRNA was formulated in lipid nanoparticles and its humoral immunogenicity in BALB/c mice was assessed. High quantities of dose-dependent RVFV Gn IgG antibodies were detected in the serum of all mice immunized with either WT consensus or furin-T2A saRNA RVF vaccines. Significant RVFV pseudovirus-neutralizing activity was induced in mice immunized with 1 µg or 10 µg of the WT consensus saRNA vaccine. The WT consensus saRNA RVF vaccine warrants further development.

Safety and Immunogenicity of a Carbohydrate Fatty Acid Monosulphate Ester Adjuvant Combined with a Low-Dose Quadrivalent Split-Virion Inactivated Influenza Vaccine: A Randomised, Observer-Blind, Active-Controlled, First-in-Human, Phase 1 Study.

Seasonal influenza vaccine effectiveness is low. Carbohydrate fatty acid monosulphate ester (CMS), a new oil-in-water adjuvant, has proven potency in animal models with suggested capacity for dose-sparing. The objective was to evaluate safety and immunogenicity of CMS when added to a low-dose influenza vaccine (QIV) in humans. In a randomised, double-blind, active-controlled, first-in-human study, sixty participants (18-50 years) received either 0.5 mg CMS or 2 mg CMS with 1/5th dose QIV, or a full dose QIV without CMS. Adverse events (AE) were monitored until 7 days post-vaccination. Haemagglutinin inhibition (HI) titres in serum and CD4+ T cells in PBMCs were determined at day 0, 7, 28, and 180. Mean age was 37.6 (±10.1) years and 42/60 (70.0%) were female. Pain at injection site (42/60, 86.7%) and headache (34/60, 56.7%) were reported most and more frequently in the 2 mg CMS group. HI titres and the frequency of influenza specific CD4+ T cells were equal across strains for the three cohorts on all visits, increased until day 28 and decreased at day 180 to values higher than baseline. CMS was safe in humans. Humoral and cell-mediated immunogenicity was similar across vaccines, even with 1/5th antigen dose. CMS can have beneficial implications in low-resource settings or in a pandemic context.

Safety and immunogenicity of mRNA-based seasonal influenza vaccines formulated to include multiple A/H3N2 strains with or without the B/Yamagata strain in US adults aged 50–75 years: a phase 1/2, open-label, randomised trial

Inclusion of additional influenza A/H3N2 strains in seasonal influenza vaccines could expand coverage against multiple, antigenically distinct, cocirculating A/H3N2 clades and potentially replace the no longer circulating B/Yamagata strain. We aimed to evaluate the safety and immunogenicity of three next-generation seasonal influenza mRNA vaccines with different compositions that encode for haemagglutinins of multiple A/H3N2 strains, with or without the B/Yamagata strain, in adults. This randomised, open-label, phase 1/2 trial enrolled healthy adults aged 50-75 years across 22 sites in the USA. Participants were randomly assigned (1:1:1:1:1:1:1) via interactive response technology to receive a single dose of mRNA-1011.1 (pentavalent; containing one additional A/H3N2 strain [Newcastle]), mRNA-1011.2 (quadrivalent; B/Yamagata replaced with one additional A/H3N2 strain [Newcastle]), mRNA-1012 at one of two dose levels (pentavalent; B/Yamagata replaced with two additional A/H3N2 strains [Newcastle and Hong Kong]), or one of three quadrivalent mRNA-1010 controls each encoding one of the A/H3N2 study strains. The primary outcomes were safety, evaluated in all randomly assigned participants who received a study vaccination (safety population), and reactogenicity, evaluated in all participants from the safety population who contributed any solicited adverse reaction data (solicited safety population). The secondary outcome was humoral immunogenicity of investigational mRNA vaccines at day 29 versus mRNA-1010 control vaccines based on haemagglutination inhibition antibody (HAI) assay in the per-protocol population. Here, we summarise findings from the planned interim analysis after participants had completed day 29. The study is registered with ClinicalTrials.gov, NCT05827068, and is ongoing. Between March 27 and May 9, 2023, 1183 participants were screened for eligibility, 699 (59·1%) were randomly assigned, and 696 (58·8%) received vaccination (safety population, n=696; solicited safety population, n=694; per-protocol population, n=646). 382 (55%) of the 696 participants in the safety population self-reported as female and 314 (45%) as male. Frequencies of solicited adverse reactions were similar across vaccine groups; 551 (79%) of 694 participants reported at least one solicited adverse reaction within 7 days after vaccination and 83 (12%) of 696 participants reported at least one unsolicited adverse event within 28 days after vaccination. No vaccine-related serious adverse events or deaths were reported. All three next-generation influenza vaccines elicited robust antibody responses against vaccine-matched influenza A and B strains at day 29 that were generally similar to mRNA-1010 controls, and higher responses against additional A/H3N2 strains that were not included within respective mRNA-1010 controls. Day 29 geometric mean fold rises in HAI titres from day 1 against vaccine-matched A/H3N2 strains were 3·0 (95% CI 2·6-3·6; Darwin) and 3·1 (2·6-3·8; Newcastle) for mRNA-1011.1; 3·3 (2·7-4·1; Darwin) and 4·2 (3·4-5·2; Newcastle) for mRNA-1011.2; 3·4 (2·9-4·0; Darwin), 4·5 (3·6-5·5; Newcastle), and 5·1 (4·2-6·2; Hong Kong) for mRNA-1012 50·0 μg; and 2·6 (2·2-3·1; Darwin), 3·7 (3·0-4·6; Newcastle), and 4·1 (3·3-5·1; Hong Kong) for mRNA-1012 62·5 μg. Inclusion of additional A/H3N2 strains did not reduce responses against influenza A/H1N1 or influenza B strains, and removal of B/Yamagata did not affect responses to B/Victoria. These data support the continued clinical development of mRNA-based next-generation seasonal influenza vaccines with broadened influenza A/H3N2 strain coverage. Moderna.

52061 The effects of immunomodulators on humoral and cellular vaccine immunogenicity of pemphigus patients: A prospective cohort study

52061 The effects of immunomodulators on humoral and cellular vaccine immunogenicity of pemphigus patients: A prospective cohort study

Immunogenicity, clinical efficacy, and safety of the sinopharm (BBIBP-CorV) SARS-CoV-2 vaccine among people with multiple sclerosis receiving disease-modifying therapies: a prospective cohort study

BackgroundTo investigate the safety (adverse events [AEs] and post-vaccination multiple sclerosis [MS] activity within 6 weeks), clinical efficacy (protection against coronavirus disease 2019 [COVID-19]), and vaccine-induced humoral immunogenicity (SARS-CoV-2 neutralizing antibody, anti-nucleocapsid IgG, and anti-spike IgG) of the Sinopharm (BBIBP-CorV) vaccine among people with MS (PwMS) receiving different disease-modifying therapies (DMTs).MethodsThis prospective cohort study was conducted between November 2021 and May 2022. PwMS were followed for six months after the 2nd dose of vaccination. Antibody responses were measured 2–16 weeks after the 2nd dose injection. Multivariate logistic regression was employed to assess the impact of each DMT on dichotomous antibody responses, adjusting for age, sex, MS phenotype, expanded disability status scale, disease duration, and vaccination-antibody titration interval.ResultsAmong the 261 screened PwMS, 209 (aged 38.23 ± 9.73 years, female: 70.8%; relapsing-remitting MS: 80.4%) were included. The frequencies of experiencing non-serious AEs and post-vaccination MS activity were 66.0% and 4.8%, respectively. Breakthrough COVID-19 infection was observed in 14.8% of the PwMS. A subcohort of 125 PwMS was assessed for antibody responses. Positive neutralizing antibodies, anti-nucleocapsid IgG, and anti-spike IgG were detected in 36.8%, 35.2%, and 52.0% of the PwMS, respectively. Multivariate regression indicated a 96% (OR: 0.04 [95% CI: 0.00, 0.51], P = 0.013), 93% (OR: 0.07 [0.01, 0.64], P = 0.019), and 89% (OR: 0.11 [0.01, 0.96], P = 0.045) reduced odds of positive neutralizing antibody, anti-nucleocapsid IgG, and anti-spike IgG, respectively, among fingolimod-receivers. Additionally, anti-CD20s-receivers had 88% (OR: 0.12 [0.02, 0.85], P = 0.034) lower odds of being positive for anti-nucleocapsid IgG.ConclusionsBBIBP-CorV appeared to be well tolerated in PwMS, with promising clinical efficacy. However, a suboptimal humoral response was observed in PwMS receiving fingolimod and anti-CD20s. Future research should investigate the relationship between humoral responses and the frequency and severity of COVID-19 infection across various DMTs.

Comparison of long-term anti-RBD SARS-CoV-2 antibody response following different vaccination schemes in Tunisia.

The study aimed to compare long-term vaccine-induced humoral immunity following different vaccines regimens. Anti-S-RBD total antibody levels were measured in blood samples of 167 participants nearly 6 months post-vaccination. Participants had received one; two or four doses of Pfizer vaccine or who received a third dose of mRNA vaccine (Pfizer) and primed with mRNA (Pfizer/Moderna), adenoviral (AstraZeneca/Jonson & Jonson) or inactivated (CoronaVac/Sinopharm) vaccine. Among all vaccination regimens, fourth dose of Pfizer achieved the highest S-RBD antibody titers. Nevertheless, the third dose of mRNA vaccine primed with adenoviral vaccine achieved the lowest titers of S-RBD antibody. Notably, the group that received a third dose of mRNA primed with two doses of mRNA vaccine exhibited higher S-RBD antibody compared to groups inoculated with a third dose of mRNA and primed with inactivated or adenovirus vaccine. Our data showed the superiority of three mRNA vaccinations compared to third heterologous vaccine (inactivated of adenoviral) including mRNA as booster in terms of humoral immunogenicity. Our findings supporting the use of additional booster shot from a more potent vaccine type such as mRNA vaccines. Nevertheless, due to the limited number of subjects, it is difficult to extrapolate the results of our study to the whole of Tunisian population. Future studies should investigate a larger cohort and other potential correlates of protection, such as cellular immunity and how it is affected by different vaccination schemes after long-term post-vaccination.

Omicron XBB.1.16-Adapted Vaccine for COVID-19: Interim Immunogenicity and Safety Clinical Trial Results.

(1) Background: The global coronavirus disease 2019 vaccination adapts to protect populations from emerging variants. This communication presents interim findings from the new Omicron XBB.1.16-adapted PHH-1V81 protein-based vaccine compared to an XBB.1.5-adapted mRNA vaccine against various acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains. (2) Methods: In a Phase IIb/III pivotal trial, adults previously vaccinated with a primary scheme and at least one booster dose of an EU-approved mRNA vaccine randomly received either the PHH-1V81 or BNT162b2 XBB.1.5 vaccine booster as a single dose. The primary efficacy endpoint assessed neutralization titers against the Omicron XBB.1.16 variant at day 14. Secondary endpoints evaluated neutralization titers and cellular immunity against different variants. Safety endpoints comprised solicited reactions up to day 7 post-vaccination and serious adverse events until the cut-off date of the interim analysis. Changes in humoral responses were assessed by pseudovirion-based or virus neutralization assays. (3) Results: At the cut-off date, immunogenicity assessments included 599 participants. Both boosters elicited neutralizing antibodies against XBB.1.16, XBB.1.5, and JN.1, with PHH-1V81 inducing a higher response for all variants. The PHH-1V8 booster triggers a superior neutralizing antibody response against XBB variants compared to the mRNA vaccine. A subgroup analysis consistently revealed higher neutralizing antibody responses with PHH-1V81 across age groups, SARS-CoV-2 infection history, and the number of prior vaccination shots. A safety analysis (n = 607) at the day 14 visit revealed favorable safety profiles without any serious vaccine-related adverse events. (4) Conclusions: PHH-1V81 demonstrates superiority on humoral immunogenicity compared to the mRNA vaccine against XBB variants and non-inferiority against JN.1 with a favorable safety profile and lower reactogenicity, confirming its potential as a vaccine candidate.

Allogeneic HLA Humoral Immunogenicity and the Prediction of Donor-Specific HLA Antibody Development.

The development of de novo donor-specific HLA antibodies (dnDSAs) following solid organ transplantation is considered a major risk factor for poor long-term allograft outcomes. The prediction of dnDSA development is a boon to transplant recipients, yet the assessment of allo-HLA immunogenicity remains imprecise. Despite the recent technological advances, a comprehensive evaluation of allo-HLA immunogenicity, which includes both B and T cell allorecognition, is still warranted. Recent studies have proposed using mismatched HLA epitopes (antibody and T cell) as a prognostic biomarker for humoral alloimmunity. However, the identification of immunogenic HLA mismatches has not progressed despite significant improvements in the identification of permissible mismatches. Certainly, the prediction of dnDSA development may benefit permissible HLA mismatched organ transplantations, personalized immunosuppression, and clinical trial design. However, characteristics that go beyond the listing of mismatched HLA antibody epitopes and T cell epitopes, such as the generation of HLA T cell epitope repertoires, recipient's HLA class II phenotype, and immunosuppressive regiments, are required for the precise assessment of allo-HLA immunogenicity.

Innate and cellular immune response to the Ebola vaccine Ad26.ZEBOV, MVA-BN-Filo: an ancillary study of the EBL2001 phase II trial.

The EBL2001 phase 2 trial tested the two-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine in Europe. Safety and humoral immunogenicity assessments led to EU market authorization in 2020. Complementary analyses of immune responses are warranted to better characterize vaccine effects. We conducted an ancillary study to analyze changes in the serum and cellular responses. Serum biomarkers of activation/inflammation were evaluated using a Luminex assay. Vaccine-elicited T cell responses and functions were evaluated assessing their phenotype, cytokine production, proliferation and cytotoxic potential. Integrated data analysis was performed through correlation and principal component analysis of serum biomarkers and cellular immune responses. Forty-eight volunteers were included. The Ad26.ZEBOV, MVA-BN-Filo vaccine elicited: i) serum increase of inflammatory/activation markers mainly at 1 day after the Ad26.ZEBOV vaccine; ii) durable EBOV-specific T cell proliferation and CD8+ T cells exhibiting a cytotoxic phenotype after Ad26.ZEBOV prime, after MVA-BN-Filo boost and 6 months post vaccination. Integrated analysis revealed correlations between: i) EBOV-specific CD8+ T cell proliferation and cytotoxic phenotype; ii) high EBOV-specific CD8+ T cell cytotoxic phenotype and low inflammatory marker IL-8 at day 1 post vaccination. This study provides unique insights into the in vivo contribution of proliferation/cytotoxic CD8+ T cells and inflammation to the Ad26.ZEBOV, MVA-BN-Filo vaccine-induced potency.

Patterns of Diversity and Humoral Immunogenicity for HIV-1 Antisense Protein (ASP).

HIV-1 has an antisense gene overlapping env that encodes the ASP protein. ASP functions are still unknown, but it has been associated with gp120 in the viral envelope and membrane of infected cells, making it a potential target for immune response. Despite this, immune response patterns against ASP are poorly described and can be influenced by the high genetic variability of the env gene. To explore this, we analyzed 100k HIV-1 ASP sequences from the Los Alamos HIV sequence database using phylogenetic, Shannon entropy (Hs), and logo tools to study ASP variability in worldwide and Brazilian sequences from the most prevalent HIV-1 subtypes in Brazil (B, C, and F1). Data obtained in silico guided the design and synthesis of 15-mer overlapping peptides through spot synthesis on cellulose membranes. Peptide arrays were screened to assess IgG and IgM responses in pooled plasma samples from HIV controllers and individuals with acute or recent HIV infection. Excluding regions with low alignment accuracy, several sites with higher variability (Hs > 1.5) were identified among the datasets (25 for worldwide sequences, 20 for Brazilian sequences). Among sites with Hs < 1.5, sequence logos allowed the identification of 23 other sites with subtype-specific signatures. Altogether, amino acid variations with frequencies > 20% in the 48 variable sites identified were included in 92 peptides, divided into 15 sets, representing near full-length ASP. During the immune screening, the strongest responses were observed in three sets, one in the middle and one at the C-terminus of the protein. While some sets presented variations potentially associated with epitope displacement between IgG and IgM targets and subtype-specific signatures appeared to impact the level of response for some peptides, signals of cross-reactivity were observed for some sets despite the presence of B/C/F1 signatures. Our data provides a map of ASP regions preferentially targeted by IgG and IgM responses. Despite B/C/F1 subtype signatures in ASP, the amino acid variation in some areas preferentially targeted by IgM and IgG did not negatively impact the response against regions with higher immunogenicity.

Development and validation of enzyme-linked immunosorbent assay for anti-mouse pertussis immunoglobulin G using international reference anti-Bordetella pertussis mouse serum NIBSC 97/642.

In this study, an in-house enzyme-linked immunosorbent assay (ELISA) was developed and validated. The titer of ELISA was calculated using the reference line (RFL) method based on the standard curve drawn using the international reference anti-mouse serum NIBSC (National Institute for Biological Standards and Control) 97/642. In the development step, signal to noise was depicted to select the buffers that showed the most appropriate ratio. In the validation step, standard range, precision, dilution linearity, and specificity were confirmed, and RFL and parallel line (PLL) methods were compared in precision and dilution linearity. Coating concentration for plate was achieved at 0.1 µg/mL for pertussis toxin (PT), 0.15 µg/mL for filamentous hemagglutinin antigen (FHA), and 0.25 µg/mL for pertactin (PRN). The signal to noise ratio was 22.02 for PT, 14.93 for FHA, and 8.02 for PRN with 0.25% goat serum in phosphate-buffered saline (PBS) as a dilution buffer, and 2% skim milk in PBS as a blocking buffer. Based on the precision results, we assessed the lower limit of quantification by 1, 0.2, and 1.5 EU/mL concentration for PT, FHA, and PRN which met the ICH (International Council for Harmonization) M10 criteria of a 25% accuracy and total error of 40%. In specificity, homologous serum was spiked into heterologous serum and the accuracy met the criteria. There was no difference in the results between RFL and PLL calculations (p-value=0.3207 for PT, 0.7394 for FHA, 0.2109 for PRN). ELISA validated with RFL calculation method in this study is a relatively accurate assay for mouse humoral immunogenicity test.

Safety and Immunogenicity of mRNA-1010, an Investigational Seasonal Influenza Vaccine, in Healthy Adults: Final Results From a Phase 1/2 Randomized Trial.

Seasonal influenza remains a global public health concern. A messenger RNA (mRNA)-based quadrivalent seasonal influenza vaccine, mRNA-1010, was investigated in a 3-part, first-in-human, phase 1/2 clinical trial. In Parts 1-3 of this stratified, observer-blind study, adults aged ≥18 years old were randomly assigned to receive a single dose (6.25 µg to 200 µg) of mRNA-1010 or placebo (Part 1) or an active comparator (Afluria; Parts 2-3). Primary study objectives were assessment of safety, reactogenicity, and humoral immunogenicity of mRNA-1010, placebo (Part 1), or active comparator (Parts 2-3). Exploratory endpoints included assessment of cellular immunogenicity (Part 1) and antigenic breadth against vaccine heterologous (A/H3N2) strains (Parts 1-2). In all study parts, solicited adverse reactions were reported more frequently for mRNA-1010 than placebo or Afluria and most were grade 1 or 2 in severity. No vaccine-related serious adverse events or deaths were reported. In Parts 1-2, a single dose of mRNA-1010 (25 µg to 200 µg) elicited robust Day 29 hemagglutination inhibition (HAI) titers that persisted through 6 months. In Part 3, lower doses of mRNA-1010 (6.25 µg to 25 µg) elicited Day 29 HAI titers that were higher or comparable to Afluria for influenza A strains. Compared with Afluria, mRNA-1010 (50 µg) elicited broader A/H3N2 antibody responses (Part 2). mRNA-1010 induced greater T-cell responses than placebo at Day 8 that were sustained or stronger at Day 29 (Part 1). Data support the continued development of mRNA-1010 as a seasonal influenza vaccine. NCT04956575 (https://clinicaltrials.gov/study/NCT04956575).

Humoral Immunogenicity of mRNA-1345 RSV Vaccine in Older Adults.

The mRNA-1345 vaccine demonstrated efficacy against RSV disease with acceptable safety in adults ≥60 years in the ConquerRSV trial. Here, humoral immunogenicity results from the trial are presented. This phase 2/3 trial randomly assigned adults (≥60 years) to mRNA-1345 50-µg encoding prefusion F (preF) glycoprotein (n = 17,793) vaccine or placebo (n = 17,748). RSV-A and RSV-B neutralizing antibody (nAb) and preF binding antibody (bAb) levels at baseline and day 29 post-vaccination were assessed in a per-protocol immunogenicity subset ([PPIS]; mRNA-1345, n = 1515; placebo, n = 333). Day 29 nAb geometric mean titers (GMTs) increased 8.4-fold against RSV-A and 5.1-fold against RSV-B from baseline. Seroresponses (4-fold rise from baseline) in the mRNA-1345 groups were 74.2% and 56.5% for RSV-A and RSV-B, respectively. Baseline GMTs were lower among participants who met the seroresponse criteria than those who did not. mRNA-1345 induced preF bAbs at day 29, with a pattern similar to nAbs. Day 29 antibody responses across demographic and risk subgroups were generally consistent with the overall PPIS. mRNA-1345 enhanced RSV-A and RSV-B nAbs and preF bAbs in adults (≥60 years) across various subgroups, including those at risk for severe disease, consistent with its demonstrated efficacy in the prevention of RSV disease.

Effectiveness and Safety of the COVID-19 Vaccine in Patients with Rheumatoid Arthritis in a Real-World Setting.

Novel mechanisms of COVID-19 vaccines raised concern about their potential immunogenicity in patients with rheumatoid arthritis (RA) undergoing immunomodulatory treatments. We designed a retrospective single-center study to investigate their effectiveness and safety in this population, analyzing data from the first vaccination program (December 2020-October 2021). Inclusion criteria were availability of post-vaccination serology and a minimum subsequent follow-up of 6 months. Binding antibody units (BAU/mL) ≥ 7.1 defined an adequate serological response. Post-vaccine COVID-19 incidence and its timing since vaccination, adverse events (AEs), and RA flares were recorded. Adjusted logistic and linear multivariate regression analyses were carried out to identify factors associated with vaccine response. We included 118 patients (87.2% women, age 65.4 ± 11.6 years, evolution 12.0 ± 9.6 years), of whom 95.8% had a complete vaccination schedule. Adequate humoral immunogenicity was achieved in 88.1% of patients and was associated with previous COVID-19 and mRNA vaccines, whereas smoking, aCCP, age, and DMARDs exerted a negative impact. Post-vaccine COVID-19 occurred in 18.6% of patients, a median of 6.5 months after vaccination. Vaccine AE (19.5%) and RA flares (1.7%) were mostly mild and inversely associated with age. Our results suggest that COVID-19 vaccines induce adequate humoral immunogenicity, with an acceptable safety profile in RA patients.

Cellular and humoral immunogenicity against SARS-CoV-2 vaccination or infection is associated with the memory phenotype of T- and B-lymphocytes in adult allogeneic hematopoietic cell transplant recipients

We conducted a cross-sectional study to evaluate cellular and humoral immunogenicity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination or infection and examine how lymphocyte subpopulations in peripheral blood correlate with cellular and humoral immunogenicity in adult allogeneic hematopoietic cell transplantation (HCT) recipients. The median period from SARS-CoV-2 vaccination or infection to sample collection was 110.5 days (range, 6–345 days). The median SARS-CoV-2 spike-specific antibody level was 1761 binding antibody units (BAU)/ml (range, 0 to > 11,360 BAU/ml). Enzyme-linked immunosorbent spot (ELISpot) assay of T cells stimulated with SARS-CoV-2 spike antigens showed that interferon-gamma (IFN-γ)-, interleukin-2 (IL-2)-, and IFN-γ + IL-2-producing T cells were present in 68.9%, 62.0%, and 56.8% of patients, respectively. The antibody level was significantly correlated with frequency of IL-2-producing T cells (P = 0.001) and IFN-γ + IL-2-producing T cells (P = 0.006) but not IFN-γ-producing T cells (P = 0.970). Absolute counts of CD8+ and CD4+ central memory T cells were higher in both IL-2- and IFN-γ + IL-2-producing cellular responders compared with non-responders. These data suggest that cellular and humoral immunogenicity against SARS-CoV-2 vaccination or infection is associated with the memory phenotype of T cells and B cells in adult allogeneic HCT recipients.

Interim results from the ELiPSE-1 study: A phase 1, multicenter, open-label study of CNTY-101 in subjects with relapsed or refractory CD19-positive B-cell malignancies.

7023 Background: CNTY-101 is an allogeneic, iPSC-derived anti-CD19 Chimeric Antigen Receptor NK (CAR-iNK) cell product with Allo-Evasion edits to avoid host rejection. Potential benefits of CNTY-101 include immediate availability for treatment, repeat dosing without the need for lymphodepletion, and the potential for improved safety over T-cell based therapies. The first-in-human Phase 1 clinical trial of CNTY-101, ELiPSE-1 (NCT05336409), evaluates safety, preliminary efficacy, PK, and translational biomarkers in patients with CD19-positive B-cell malignancies. Methods: Subjects with R/R aggressive and indolent B-cell NHL received lymphodepletion (LDC) followed by assignment to 100e6, 300e6 or 1e9 cells at either Day 1 (Schedule A) or Days 1, 8 and 15 (Schedule B). Eligible subjects (ie, achieved SD or better at Day 28 by PET/CT) can receive additional cycles, with or without one additional regimen of LDC. Subjects also receive daily subcutaneous injections of IL-2 for 8 days (A) or 4 days (B) following each infusion. Results: At time of abstract submission, 10 subjects have been treated (n=4 DL1A; n=3 DL2A; n=2 DL3A; n=1 DL2B). Three subjects (1 at DL1A, 2 at DL2A) received additional cycle(s) of CNTY-101. Three subjects have not yet been evaluated for full safety and efficacy within the DLT window. Seven subjects (n=5 DLBCL; n=1 FL; n=1 MZL) had data available as of the data cut (Nov 30, 2023). All had stage 4 disease, 6/7 were refractory to last line of therapy, with a median of 4 (2-5) prior lines of therapy including CAR T (3/7). No DLTs, GvHD or ICANs were observed. Two subjects had cytokine release syndrome (n=1 Gr 1, n=1 Gr 2), all responding promptly to treatment. ORR/CRR was 25%/25% for 100e6 cells (DL1A) and 67%/33% for 300e6 cells (DL2A). Dose escalation is ongoing. In subjects from all three dose levels, CNTY-101 rapidly traffics out of circulation after infusion and is observed via cell-free DNA on Day 3 and detected up to 28 days. CNTY-101 persistence was not adversely impacted when given without lymphodepletion in two subjects who received additional cycles of CNTY-101. Induction of functional humoral immunogenicity against CNTY-101 was not observed at any of the dose levels, regardless of single or multiple cycles of CNTY-101. Adaptive immune responses were observed in the tumor microenvironment on Day 8. Conclusions: CNTY-101 administered as a single dose in multiple cycles has demonstrated a manageable safety profile and preliminary evidence of efficacy. Allo-Evasion edits may allow for repeat dosing for multiple cycles without allorejection in the absence of lymphodepletion. Preliminary efficacy supports dosing at higher dose levels and with more dose-intense regimens. Updated safety, efficacy, PK, and CNTY-101's impact on tumor for DL3A and DL2B will be provided. Clinical trial information: NCT05336409 .

The Impact of Time between Booster Doses on Humoral Immune Response in Solid Organ Transplant Recipients Vaccinated with BNT162b2 Vaccines.

As solid organ transplant (SOT) recipients remain at risk of severe outcomes after SARS-CoV-2 infections, vaccination continues to be an important preventive measure. In SOT recipients previously vaccinated with at least three doses of BNT162b2, we investigated humoral responses to BNT162b2 booster doses. Anti-SARS-CoV-2 receptor binding domain (RBD) immunoglobulin G (IgG) was measured using an in-house ELISA. Linear mixed models were fitted to investigate the change in the geometric mean concentration (GMC) of anti-SARS-CoV-2 RBD IgG after vaccination in participants with intervals of more or less than six months between the last two doses of vaccine. We included 107 SOT recipients vaccinated with a BNT162b2 vaccine. In participants with an interval of more than six months between the last two vaccine doses, we found a 1.34-fold change in GMC per month (95% CI 1.25-1.44), while we found a 1.09-fold change in GMC per month (95% CI 0.89-1.34) in participants with an interval of less than six months between the last two vaccine doses, resulting in a rate ratio of 0.82 (95% CI 0.66 to 1.01, p = 0.063). In conclusion, the administration of identical COVID-19 mRNA vaccine boosters within six months to SOT recipients may result in limited humoral immunogenicity of the last dose.