Immunogenicity Of Influenza Vaccine Research Articles

Conserved linear B-cell peptides among the influenza A viral neuraminidases enhance the cross-protective potential of inactivated whole-virion influenza vaccine

Introduction. Influenza is a disease caused by a widespread virus with pandemic potential. Frequently, individuals vaccinated against seasonal influenza virus are still susceptible to the disease, indicating the need to improve the immunogenic potential of existing vaccines. To assess the efficacy of influenza virus vaccines, immune response only to a single viral antigen — hemagglutinin molecule, is taken into consideration. However, according to preclinical and clinical studies, neuraminidase (NA) stimulates cross-protective immunity, which is effective against not only homologous but also drifted variants of influenza A virus. Materials and methods. In the present study, we investigated the ability of previously selected conserved linear B-cell NA epitopes (SGYSGK, SWPDGK, EECSCYPK, VELIRGRK) to enhance the immunogenicity of an inactivated whole-virion influenza vaccine based on the model strain PR8 (iPR8). BALB/c mice were injected with iPR8 in combination with one of the peptides intramuscularly three times at two-week intervals. Blood samples were collected 14 days after the last immunization, after which the mice were challenged with heterosubtypic influenza viruses H1N1pdm09 and H3N2. Results. All immunized mice showed induction of H1N1 (PR8)-specific IgG antibodies two weeks after the third immunization. The group of mice immunized with the iPR8 vaccine preparation in combination with VELIRGRK peptide showed the most pronounced induction of IgG antibodies to the H6N1 reassortant strain, the NA of which corresponds to the iPR8 virus, indicating the ability of the NA peptide to stimulate the production of NA-specific antibodies. However, the antibodies produced after immunization were not capable to inhibit the NA enzymatic activity. Despite this, mice immunized with iPR8 in combination with anti-NA peptides showed a higher survival rate after infection with heterologous virulent influenza viruses: A/California/07/09 (H1N1pdm09) and A/Philippines/2/82 (H3N2) compared to the PBS and iPR8 groups. Conclusion. Thus, the study demonstrated the immune-potentiating effect of individual peptides corresponding to conservative linear epitopes of the NA molecule in combination with a standard inactivated influenza vaccine, which made it possible to improve the protective effect of the vaccine against heterosubtypic influenza viruses.

The Relationship between Immunogenicity and Reactogenicity of Seasonal Influenza Vaccine Using Different Delivery Methods.

Vaccine immunogenicity and reactogenicity depend on recipient and vaccine characteristics. We hypothesized that healthy adults reporting higher reactogenicity from seasonal inactivated influenza vaccine (IIV) developed higher antibody titers compared with those reporting lower reactogenicity. We performed a secondary analysis of a randomized phase 1 trial of a trivalent IIV delivered by microneedle patch (MNP) or intramuscular (IM) injection. We created composite reactogenicity scores as exposure variables and used hemagglutination inhibition (HAI) titers as outcome variables. We used mixed-model analysis of variance to estimate geometric mean titers (GMTs) and titer fold change and modified Poisson generalized estimating equations to estimate risk ratios of seroprotection and seroconversion. Estimates of H3N2 GMTs were associated with the Systemic and Local scores among the IM group. Within the IM group, those with high reaction scores had lower baseline H3N2 GMTs and twice the titer fold change by day 28. Those with high Local scores had a greater probability of seroconversion. These results suggest that heightened reactogenicity to IM IIV is related to low baseline humoral immunity to an included antigen. Participants with greater reactogenicity developed greater titer fold change after 4 weeks, although the response magnitude was similar or lower compared with low-reactogenicity participants.

Preliminary results on novel adjuvant combinations suggest enhanced immunogenicity of whole inactivated pandemic influenza vaccines

Due to the inherent risk of a further pandemic influenza outbreak, there is a need and growing interest in investigating combinations of prophylactic vaccines and novel adjuvants, particularly to achieve antigen dose sparing and improved immunogenicity. Influenza is a highly variable virus, where the specific vaccine target is constantly changing, representing a major challenge to influenza vaccine development. Currently, commercial inactivated influenza vaccines have a poor CD8+ T response, which impacts cross-reactivity and the duration of response. Adjuvanted influenza vaccines can increase immune responses, thereby achieving better protection and cross-reactivity to help contain the spread of the disease. An early exploration of a hybrid cholesterol-PLGA nanoparticle delivery system containing the saponin tomatine and a NOD2 (nucleotide-binding oligomerization domain 2) agonist called SG101 was conducted. This combination was preliminarily evaluated for its ability to induce cellular immunity when combined with whole inactivated virus (WIV) influenza vaccine. After the adjuvants were manufactured using a single emulsion process, two formulations with different drug loadings were selected and physico-chemically characterized, showing sizes between 224 ± 32 and 309 ± 45 nm and different morphologies. After ensuring the lack of in vitro toxicity and hemolytic activity, a pilot in vivo assay evaluated the hybrid nanoparticle formulation for its ability to induce humoral and cellular immunity when combined with whole inactivated virus (WIV) H5N1 influenza vaccine by intramuscular administration in mice. Hemagglutinin inhibition (HAI) titers for adjuvanted groups showed no significant difference compared to the group vaccinated with the antigen alone. It was similar for CD4+ and CD8+ T cell responses, although the high drug loading formulation induced higher titers of IFNγ-positive CD8+ T cells. These proof-of-concept results encourage further investigations to develop the hybrid formulation with increased or different loading ratios, to investigate manufacturing optimization, and to evaluate the role of the individual immunostimulatory compounds in immune responses.

Safety and immunogenicity of the intranasal H3N2 M2-deficient single-replication influenza vaccine alone or coadministered with an inactivated influenza vaccine (Fluzone High-Dose Quadrivalent) in adults aged 65–85 years in the USA: a multicentre, randomised, double-blind, double-dummy, phase 1b trial

Older adults (aged ≥65 years) show increased susceptibility to severe disease with influenza virus infection, accounting for 70-85% of annual influenza-related fatalities in the USA. Stimulating mucosal antibodies and T cells might enhance the low vaccine effectiveness seen in older adults for currently licensed inactivated influenza vaccines, which induce mainly serum antibodies. We aimed to evaluate the safety and immunogenicity of the intranasal H3N2 M2-deficient single-replication (M2SR) vaccine, alone or coadministered with a licensed inactivated influenza vaccine (Fluzone High-Dose Quadrivalent; hereafter referred to as Fluzone HD), in older adults. In this multicentre, randomised, double-blind, double-dummy, phase 1b trial, individuals aged 65-85 years who were considered healthy or with stable chronic conditions with no recent (<6 months) influenza vaccinations were recruited from five clinical trial sites in the USA and randomly assigned (3:3:3:1) using a permuted block design to receive the H3N2 M2SR vaccine and Fluzone HD, the H3N2 M2SR vaccine and placebo, Fluzone HD and placebo, or placebo alone. All participants received a single intranasal spray and a single intramuscular injection, whether active or placebo, to maintain masking. The primary outcome was to assess the safety of H3N2 M2SR, administered alone or with Fluzone HD, in the safety analysis set, which included all participants who were randomly assigned and received treatment. Serum and mucosal antibodies were assessed as a secondary endpoint, and cell-mediated immunity as an exploratory endpoint, in participants in the per-protocol population, which included individuals in the safety analysis set without major protocol deviations. This trial is registered with ClinicalTrials.gov, NCT05163847. Between June 14 and Sept 15, 2022, 305 participants were enrolled and randomly assigned to receive the H3N2 M2SR vaccine plus placebo (n=89), H3N2 M2SR vaccine plus Fluzone HD (n=94), Fluzone HD plus placebo (n=92), or placebo alone (n=30). All randomly assigned participants were included in the safety analysis set. The most frequently reported local symptoms up to day 8 in groups that received M2SR were rhinorrhoea (43% [38 of 89] in the H3N2 M2SR plus placebo group and 38% [36 of 94] in the H3N2 M2SR plus Fluzone HD group), nasal congestion (51% [45 of 89] and 35% [33 of 94]), and injection-site pain (8% [seven of 89] and 49% [46 of 94]), and the most frequently reported solicited systemic symptoms were sore throat (28% [25 of 89]) for M2SR and decreased activity (26% [24 of 94]) for the M2SR plus Fluzone HD group. In the Fluzone HD plus placebo group, the most frequently reported local symptom was injection-site pain (48% [44 of 92]) and systemic symptom was muscle aches (22% [20 of 92]). The frequency of participants with any treatment-emergent adverse event related to vaccination was low across all groups (2-5%). One serious adverse event was reported, in a participant in the Fluzone HD plus placebo group. M2SR with Fluzone HD induced seroconversion (≥four-fold increase in haemagglutination inhibition antibodies from baseline to day 29) in 44 (48%) of 91 participants, compared with 28 (31%) of 90 participants who seroconverted in the Fluzone HD plus placebo group (p=0·023). M2SR with Fluzone HD also induced mucosal and cellular immune responses. The H3N2 M2SR vaccine coadministered with Fluzone HD in older adults was well tolerated and provided enhanced immunogenicity compared with Fluzone HD administered alone, suggesting potential for improved efficacy of influenza vaccination in this age group. Additional studies are planned to assess efficacy. US Department of Defense.

Sex Differences in the Immunogenicity and Efficacy of Seasonal Influenza Vaccines: A Meta-analysis of Randomized Controlled Trials.

Sex impacts individuals' response to vaccination. However, most vaccine studies do not report these differences disaggregated by sex. The aim of this study was to assess sex differences in the immunogenicity and efficacy of influenza vaccine. We performed a meta-analysis using phase 3 randomized controlled trial data conducted between 2010 and 2018. Using hemagglutination inhibition antibody titers for each strain, differences in geometric mean ratios (GMRs) were calculated by sex. Risk ratios (RRs) comparing seroconversion proportions were pooled for females and males using random-effects models. Vaccine efficacy (VE) was assessed. Data were analyzed by age group (18-64 vs ≥65 years). A total of 33 092 healthy adults from 19 studies were included for immunogenicity analysis, and 6740 from 1 study for VE. Whereas no sex differences in immunogenicity were found in adults <65 years old, older females had a significantly greater chance to seroconvert compared to older males for all strains: RRH1N1 = 1.17 [95% confidence interval {CI}, 1.12-1.23]; RRH3N2 = 1.09 [95% CI, 1.05-1.14]; RRVictoria = 1.23 [95% CI, 1.14-1.31]; RRYamagata = 1.22 [95% CI, 1.14-1.30]. GMRs were also higher in older females for all strains compared to older males. VE in preventing laboratory-confirmed influenza was higher in older females compared to older males with VEs of 27.32% (95% CI, 1.15%-46.56%) and 6.06% (95% CI, -37.68% to 35.90%), respectively. Our results suggest a higher immunogenicity and VE in females compared to males in older adults. These differences in immunogenicity and VE support the disaggregation of vaccine data by sex in clinical trials and observational studies. CRD42018112260.

Diet switch pre-vaccination improves immune response and metabolic status in formerly obese mice.

Metabolic disease is epidemiologically linked to severe complications upon influenza virus infection, thus vaccination is a priority in this high-risk population. Yet, vaccine responses are less effective in these same hosts. Here we examined how the timing of diet switching from a high-fat diet to a control diet affected influenza vaccine efficacy in diet-induced obese mice. Our results demonstrate that the systemic meta-inflammation generated by high-fat diet exposure limited T cell maturation to the memory compartment at the time of vaccination, impacting the recall of effector memory T cells upon viral challenge. This was not improved with a diet switch post-vaccination. However, the metabolic dysfunction of T cells was reversed if weight loss occurred 4 weeks before vaccination, restoring a functional recall response. This corresponded with changes in the systemic obesity-related biomarkers leptin and adiponectin, highlighting the systemic and specific effects of diet on influenza vaccine immunogenicity.

Exploratory Study of the Phase IV Immunization Schedule of Quadrivalent Influenza Split-Virion Vaccine in Children Aged 3-8 Years.

This study explored the optimum immunization schedule for the quadrivalent influenza split-virion vaccine containing influenza A strains (H1N1 and H3N2) and B lineage strains (Yamagata and Victoria) in children aged 3-8 years. The 652 participants enrolled were divided into two groups based on a history of influenza immunization (IH group) or no history of influenza immunization (NH group). The groups were administered a two-dose immunization schedule on days 0 and 30. In the NH group, on day 30 after the first dose, the positive rates of influenza hemagglutination-inhibition antibodies of strains H1N1, H3N2, BV, and BY were 85.85%, 71.70%, 65.27% and 60.45%, respectively. The positive rates of BV and BY failed to meet the absolute criteria for evaluating the immunogenicity of influenza vaccine in the population aged 3-60 years (for each strain antibody). On day 30 after the second dose, HI antibodies to strains H1N1, H3N2, BV, and BY met the immunogenicity acceptable criteria. In the IH group, on day 30 after the first dose, HI antibodies to strains H1N1, H3N2, BV, and BY met the acceptable criteria for immunogenicity. The incidence rates of adverse reactions (vaccine-related adverse events) from the first dose up until 30 days after the second dose were 20.80% in the IH group and 19.50% in the NH group. Only two Grade 3 adverse reactions (fever: temperature ≥ 39.5 °C, swelling: area ≥ 50% of the injection site area) occurred in the IH group, and no Grade 3 adverse reactions occurred in the NH group. No serious adverse reactions occurred in either group. We conclude that for the NH group, two doses of quadrivalent influenza vaccine should be administered, and for the IH group, a one-dose regimen is acceptable.

Evaluation of Vaccine Immunogenicity-Correlates to Real-World Protection: Influenza.

Recent events highlighted that, despite decades of studying vaccine immunogenicity and efforts toward finding correlates of protection, evaluating real-world vaccine efficacy as well as establishing meaningful licensing criteria still represents a significant challenge. In this paper, we review all aspects of influenza vaccine immunogenicity, including animal and human challenge studies, humoral and cellular immunity parameters, and their potential correlation with real-life protection from disease.

Immunophenotypic predictors of influenza vaccine immunogenicity in pediatric hematopoietic cell transplant recipients

AbstractPediatric hematopoietic cell transplant (HCT) recipients exhibit poor serologic responses to influenza vaccination early after transplant. To facilitate the optimization of influenza vaccination timing, we sought to identify B- and T-cell subpopulations associated with influenza vaccine immunogenicity in this population. We used mass cytometry to phenotype peripheral blood mononuclear cells collected from pediatric HCT recipients enrolled in a multicenter influenza vaccine trial comparing high- and standard-dose formulations over 3 influenza seasons (2016-2019). We fit linear regression models to estimate relationships between immune cell subpopulation numbers before vaccination and prevaccination to postvaccination geometric mean fold rises in antigen-specific (A/H3N2, A/H1N1, and B/Victoria) serum hemagglutination inhibition antibody titers (28-42 days, and ∼6 months after 2 doses). For cell subpopulations identified as predictive of a response to all 3 antigens, we conducted a sensitivity analysis including time after transplant as an additional covariate. Among 156 HCT recipients, we identified 33 distinct immune cell subpopulations; 7 significantly predicted responses to all 3 antigens 28 to 42 days after a 2-dose vaccine series, irrespective of vaccine dose. We also found evidence that baseline absolute numbers of naïve B cells, naïve CD4+ T cells, and circulating T follicular helper cells predicted peak and sustained vaccine-induced titers irrespective of dose or timing of posttransplant vaccine administration. In conclusion, several B- and T-cell subpopulations predicted influenza vaccine immunogenicity in pediatric HCT recipients. This study provides insights into the immune determinants of vaccine responses and may help guide the development of tailored vaccination strategies for this vulnerable population.

Immunogenicity, Safety, and Efficacy of Influenza Vaccine in T2DM and T2DM with Chronic Kidney Disease.

Patients with Type 2 diabetes mellitus (T2DM) and Chronic Kidney Disease (CKD) face an increased risk of morbidity and mortality after influenza infection. Several studies have shown that the influenza vaccine effectively prevents morbidity and mortality in T2DM patients. However, there has been limited research aimed at assessing the effectiveness of the trivalent influenza vaccine in T2DM-CKD patients. This study aimed to identify Geometric Mean Titers (GMTs), seroprotection, seroconversion, safety, and efficacy. This open-label clinical trial was conducted at AMC Hospital in Bandung, West Java, Indonesia between June 2021 and July 2022. The study subjects consisted of 41 T2DM and 26 T2DM-CKD patients who were administered the trivalent influenza vaccine. There was a significant difference in the average age, with the T2DM-CKD patients being older. Median titers post-vaccination for the B/Washington virus were higher in the T2DM patients compared to the T2DM-CKD patients, and this difference was statistically significant. A majority, comprising 75.6% of the T2DM and 80.8% of the T2DM-CKD patients monitored post-influenza-vaccination, did not experience any adverse reactions. The most common reaction was the sensation of fever, with incidence rates of 12.2% in the T2DM patients and 15.4% in the T2DM-CKD patients. Furthermore, we observed that the incidence of Influenza-like Illness was highest at 7.3% in the T2DM patients and 7.7% in the T2DM-CKD patients. The trivalent influenza vaccine demonstrated equivalent safety and effectiveness in both groups.

Immunogenicity and safety of concomitant bivalent COVID-19 and quadrivalent influenza vaccination: implications of immune imprinting and interference

ObjectivesConcomitant COVID-19 and influenza vaccination would be an efficient strategy. Although the co-administration of monovalent COVID-19 and influenza vaccinations showed acceptable immunogenicity, it remains unknown whether the bivalent COVID-19 vaccine could intensify immune interference. We aimed to evaluate the immunogenicity and safety of concomitant BA.5-based bivalent COVID-19 and influenza vaccination. MethodsAn open-label, nonrandomized clinical trial was conducted for 154 age-matched and sex-matched healthy adults between October 2022 and December 2022. Participants received either a concomitant bivalent COVID-19 mRNA booster and quadrivalent influenza vaccination (group C) or separate vaccinations (group S) at least 4 weeks apart. Solicited and unsolicited adverse events were reported up to 6 months postvaccination. Immunogenicity was evaluated by anti-spike (S) IgG electrochemiluminescence immunoassay, focus reduction neutralization test, and hemagglutination inhibition assay. ResultsGroup C did not meet the noninferiority criteria for the seroconversion rates of anti-S IgG and neutralizing antibodies against the wild-type SARS-CoV-2 strain compared with group S (44.2% vs. 46.8%, difference of −2.6% [95% CI, −18 to 13.4]; 44.2% vs. 57.1%, difference of −13.0% [95% CI to −28.9 to 2.9]). However, group C showed a stronger postvaccination neutralizing antibody response against Omicron BA.5 (72.7% vs. 64.9%). Postvaccination geometric mean titers for SARS-CoV-2 and influenza strains were similar between groups, except for influenza B/Victoria. Most adverse events were mild and comparable between the study groups. DiscussionConcomitant administration of bivalent COVID-19 mRNA and quadrivalent influenza vaccines showed tolerable safety profiles and sufficient immunogenicity, particularly attenuating immune imprinting induced by previous ancestral vaccine strains.

Estimand for non-inferiority influenza vaccine immunogenicity trials

According to recent regulatory guidance, clinical trial objectives should be translated into estimands, i.e., precise descriptions of that what is to be estimated. Hence, estimands are to be formulated for influenza vaccine immunogenicity (IVI) trials, notably for one of the most popular immunogenicity trials, the non-inferiority trial. In this paper an estimand for this trial design is proposed.An estimand should state how intercurrent events are handled. Intercurrent events are events that occur after the start of the trial and that affect the endpoint’s measurement or interpretation or prevent its observation. In IVI trials the intercurrent events of interest are immunological intercurrent events (IIEs). Major IIEs are identified, i.e., protocol deviations occurring during the trial that affect immunogenicity endpoints, and the consequences for the trial data collection are discussed.In the statistical analysis endpoint values that are missing or excluded from the analysis due to IIEs are to be substituted by plausible values, by means of multiple imputing. Replacing values are based on predictors of the endpoint. A distinction is made between mandatory and non-mandatory predictors. Mandatory predictors are predictors necessary to prevent biased prediction. Non-mandatory predictors are predictors that limit the additional variance due to the imputing. The four steps of the multiple imputing are explained, and available software is listed.

A Multi-Season Randomised Controlled Trial of Advax-Adjuvanted Seasonal Influenza Vaccine in Participants with Chronic Disease or Older Age.

The aim of this study was to determine the safety and immunogenicity of trivalent inactivated influenza vaccine (TIV) alone or formulated with Advax™ delta inulin adjuvant in those of older age (> 60 years) or with chronic disease. Over four consecutive years from 2008-2011, adult participants with chronic disease or over 60 years were recruited into a randomised controlled study to assess the safety, tolerability and immunogenicity of Advax-adjuvanted versus standard TIV. The per protocol (PP) population with at least one post-baseline measurement of influenza antibodies comprised 1297 participants: 447 in the TIV, and 850 in the Advax-adjuvanted TIV, groups. No safety issues were identified. Variables negatively affecting vaccine responses included obesity and diabetes mellitus. Advax adjuvant had a positive impact on anti-influenza IgM responses and on H3N2 and B strain seropositivity as assessed by hemagglutination inhibition. Advax-adjuvanted TIV was safe and well tolerated in individuals with chronic disease. There is an ongoing need for research into improved influenza vaccines for high-risk populations. Australia New Zealand Clinical Trial Registry: ACTRN 12608000364370.

1639. A Review of Clinical Safety, Reactogenicity, and Immunogenicity of an mRNA-Based Seasonal Influenza Vaccine (mRNA-1010) in Adults

Abstract Background Seasonal influenza remains a public health threat with approximately 1 billion global infections annually. Vaccines based on messenger RNA (mRNA) technology are currently under investigation and have the potential to address limitations of current seasonal influenza vaccine platforms. Here, we review recent phase 1-3 randomized clinical trials evaluating an mRNA-based, quadrivalent seasonal influenza vaccine (mRNA-1010) in adults. Methods Safety, reactogenicity, and immunogenicity of a single dose of mRNA-1010 were assessed in adults aged ≥18 years in phase 1/2 (NCT04956575) and ongoing phase 3 immunogenicity (NCT05415462) trials and aged ≥50 years in an ongoing phase 3 efficacy (NCT05566639) trial. Safety endpoints were solicited local and systemic adverse reactions (ARs) up to 7 days after vaccination, unsolicited adverse events (AEs) up to 28 days after vaccination, and serious AEs (SAEs), AEs of special interest (AESIs), medically attended AEs (MAAEs), and AEs leading to study discontinuation. Immunogenicity was measured by hemagglutination inhibition assay. Available safety and immunogenicity data up to 6 months (phase 1/2) and up to 3 months (phase 3) after vaccination are summarized here. Results Approximately 14,400 participants received mRNA-1010 at the 50-µg dose level across trials. No safety concerns for mRNA-1010 have been identified for any trial. Overall, pain and axillary swelling/tenderness were the most common solicited local ARs while myalgia, headache, and fatigue were the most common systemic ARs. In the phase 1/2 and phase 3 immunogenicity trials, solicited ARs were more frequent after vaccination with mRNA-1010 than after an active comparator (licensed quadrivalent seasonal influenza vaccine). No vaccine-related SAEs were observed through 6 months after vaccination in the phase 1/2 trial; SAEs, AESIs, and MAAEs up to 3 months after vaccination were similar between mRNA-1010 and an active comparator group in the 2 phase 3 trials. A single dose of mRNA-1010 induced immune responses against influenza A and B strains included in the vaccine. Conclusion mRNA-1010 has demonstrated an acceptable safety and tolerability profile in phase 1-3 studies. These data support continued investigation of mRNA-based vaccines against seasonal influenza. Disclosures Mieke Soens, MD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Boris Kandinov, MD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Daniela Ramirez- Schrempp, MD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Jignesh Vakil, MD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Alicia Pucci, BSN, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Wenmei Huang, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Jia Guo, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Evelyn Du, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Andrei Avanesov, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Sinead Rudden, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Bryony Hicks, BSc, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Greg Livermore, BS, MBA, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Kristi Schaefers, BIS, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Mary Lau, BS, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Raffael Nachbagauer, MD, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds Jintanat Ananworanich, MD, PhD, Moderna, Inc.: Employee|Moderna, Inc.: Stocks/Bonds

280. A cross-sectional pilot study on the relationship of gut microbiota pattern to immunogenicity of influenza vaccine in lupus patients

Abstract Background Immunosuppressive therapy, the nature of the autoimmune disease, and different gut microbiome patterns may affect influenza vaccination responses of lupus patients. Thus far, the gut microbiome patterns in this population in response to influenza vaccination have yet to be studied extensively. So, this study aims to evaluate the gut microbiome pattern associated with influenza vaccination response and assess the associated factors that may affect different gut microbiome patterns among lupus patients. The bar plot shows relative abundances of gut microbiome at the phylum level in lupus patients and healthy controls. Methods The cross-sectional pilot study was conducted at Ramathibodi Hospital during 2021-2022. This study is a substudy of another cohort study investigating influenza vaccination response to different dosing regimens, randomly into the high-dose (HD) and standard-dose (SD) quadrivalent influenza vaccination. The patient’s demographics and other relevant information were retrieved. Fecal samples were collected at enrollment for microbiota study. Immunogenicity to vaccination was determined via seroprotection and seroconversion rates. Results A total of 62 participants were enrolled. Most patients were female (93.55%). The median (IQR) ages among SD and HD groups were 35.5 (28-42.5) and 34 (25-43) (P=0.878) years old. 18 (29.03%) were taking high-level immunosuppressive treatment (HI) received SD, and 18 (29.03%) were taking low-level immunosuppressive treatment (LI) received SD. There was no significant difference in gut microbiota patterns among all patient groups. Firmicutes were the most abundant phylum, and Bacteroides were the most abundant genera in all patient groups. The alpha diversity was more prominent in the seroconversion groups but no statistical differences (P=0.260 in Shannon indexes). Multivariate logistic regression analysis revealed the LI group (AOR: 7.39, 95% CI 1.11 to 49.36; P=0.039), presence of Bacteroides (AOR 1.16, 95% CI 1.01 to 1.33; P=0.031) were associated with seroconversion of influenza vaccine. Conclusion The gut microbiota patterns of lupus patients were not different from healthy controls nor vaccination response. Therefore, the immunosuppressive therapy did not affect the gut microbiota patterns in lupus patients, and an HD of influenza vaccine may not be necessary. Disclosures All Authors: No reported disclosures

1100. Cellular Immunophenotypic Predictors of Influenza Vaccine Immunogenicity in Pediatric Hematopoietic Cell Transplant Recipients

Abstract Background Pediatric hematopoietic cell transplant recipients (PHCTRs) have poor serologic responses to influenza vaccination. While absolute numbers of circulating B and T cells are important predictors of response, our goal was to identify B and T cell subpopulations associated with vaccine immunogenicity. Methods We conducted a secondary analysis of PHCTRs enrolled in a multicenter randomized controlled influenza vaccine trial spanning three influenza seasons (2016–2019). Peripheral blood mononuclear cells were collected before vaccination and 28–42 days after the second dose, and they were analyzed using mass cytometry (CyTOF). We fit linear regression models to estimate relationships between strain-specific (A/H3N2, A/H1N1, and B/Victoria) pre- to post-vaccination (28–42 days) serum hemagglutination-inhibition antibody titers vs. log-transformed cell counts, including vaccine dose as a covariate. We used the Benjamini–Yekutieli method to adjust for multiplicity. We conducted a subsequent sensitivity analysis, including time from transplant as an additional covariate, for cell populations identified as predictive of response to all three antigens. Results We included 156 PHCTRs. The median age at first vaccination was 11.8 years (IQR, 6.8–14.3 years), and the median time from transplantation was 7.9 months (IQR, 4.3–13.6 months). High-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine was administered to 79 (50.6%) and 77 (49.4%) PHCTRs, respectively. Mass cytometry revealed 33 distinct cell subpopulations, seven of which were significant predictors of geometric mean titer ratio for all three antigens after two vaccine doses, irrespective of dose (Table 1). We found evidence that subpopulations 1 and 18 (related B cell subpopulations differing by BTLA and CCR6 expression), 8 (CD8+ naïve T cells), and 19 (CD4+ T follicular helper cells) predicted titers irrespective of dose and time from transplantation. Table 1 Figure 1 UMAP from a 32-parameter CyTOF antibody panel generated from 156 PHCTRs at the time of vaccination. Major islands of CD4+ T cells, CD8+ T cells, and B cells are demarcated. Figure 2 Heat map of cell subpopulations identified by CyTOF. The frequency of several cell subpopulations predicted subsequent serological responses to multiple vaccine immunogens, including 1 and 18 (B cells), 5 and 7 (naïve CD4+ T cells), 19 (memory cTfh cells), and 23 (CD8+ memory T cells). Conclusion We identified distinct B and T cell subpopulations predictive of influenza vaccine immunogenicity in PHCTRs. Our findings may improve the identification of PHCTRs at high-risk for influenza due to impaired influenza vaccine immunogenicity and aid in the development of effective vaccine strategies in this population. Disclosures Daniel Dulek, MD, Eurofins Viracor: Research supplies Natasha B. Halasa, MD, MPH, Merck: Grant/Research Support|Quidell: Grant/Research Support|Quidell: donation of kits|Sanofi: Grant/Research Support|Sanofi: vaccine support

Influenza A(H3N2) Antibody Responses to Standard-Dose Versus Enhanced Influenza Vaccine Immunogenicity in Older Adults and Prior Season's Vaccine Status.

Annual influenza vaccination is recommended for older adults but repeated vaccination with standard-dose influenza vaccine has been linked to reduced immunogenicity and effectiveness, especially against A(H3N2) viruses. Community-dwelling Hong Kong adults aged 65-82 years were randomly allocated to receive 2017-2018 standard-dose quadrivalent, MF59-adjuvanted trivalent, high-dose trivalent, and recombinant-HA quadrivalent vaccination. Antibody response to unchanged A(H3N2) vaccine antigen was compared among participants with and without self-reported prior year (2016-2017) standard-dose vaccination. Mean fold rise (MFR) in antibody titers from day 0 to day 30 by hemagglutination inhibition and virus microneutralization assays were lower among 2017-2018 standard-dose and enhanced vaccine recipients with (range, 1.7-3.0) versus without (range, 4.3-14.3) prior 2016-2017 vaccination. MFR was significantly reduced by about one-half to four-fifths for previously vaccinated recipients of standard-dose and all 3 enhanced vaccines (β range, .21-.48). Among prior-year vaccinated older adults, enhanced vaccines induced higher 1.43 to 2.39-fold geometric mean titers and 1.28 to 1.74-fold MFR versus standard-dose vaccine by microneutralization assay. In the context of unchanged A(H3N2) vaccine strain, prior-year vaccination was associated with reduced antibody response among both standard-dose and enhanced influenza vaccine recipients. Enhanced vaccines improved antibody response among older adults with prior-year standard-dose vaccination.

Immunogenicity and Safety of MF59-Adjuvanted Quadrivalent Influenza Vaccine Compared with a Nonadjuvanted, Quadrivalent Influenza Vaccine in Adults 50-64 Years of Age.

Adults aged 50-64 years have a high incidence of symptomatic influenza associated with substantial disease and economic burden each year. We conducted a randomized, controlled trial to compare the immunogenicity and safety of an adjuvanted quadrivalent inactivated influenza vaccine (aIIV4; n = 1027) with a nonadjuvanted standard dose IIV4 (n = 1017) in this population. Immunogenicity was evaluated on Days 22, 181, and 271. On Day 22, upper limits (UL) of 95% confidence intervals (CI) for geometric mean titer (GMT) ratios (IIV4/aIIV4) were <1.5 and 95% CI ULs for the difference in seroconversion rate (SCR IIV4 - aIIV4) were <10% for all four vaccine strains, meeting primary endpoint noninferiority criteria. Protocol-defined superiority criteria (95% CI ULs < 1.0) were also met for A(H1N1) and A(H3N2). Immune responses following aIIV4 vaccination were more pronounced in persons with medical comorbidities and those not recently vaccinated against influenza. Safety data were consistent with previous studies of MF59 adjuvanted seasonal and pandemic influenza vaccines. These findings support the immunological benefit of aIIV4 for persons aged 50-64 years, especially those with comorbidities.

Trivalent inactivated influenza vaccine response and immunogenicity assessment after one week and three months in repeatedly vaccinated adults

ABSTRACTBackgroundThe influenza vaccine administrated every year is a recommended infection control procedure for individuals above the age of six months. However, the effectiveness of repeated annual vaccination is still an active research topic. Therefore, we investigated the vaccine immunogenicity in two independent groups: previously vaccinated versus non-vaccinated individuals at three time points; prior vaccination, one week and three months post vaccination. The assessment enabled us to evaluate the elicited immune responses and the durability of the induced protection in both groups.Research Design and MethodsA research study was conducted to assess the immunogenicity of a single dose of Trivalent Inactivated Influenza Vaccine (A/H1N1, A/H3N2, and B) in 278 healthy adults aged between 32 and 66 years. Almost half of the participants, 140 (50·36%), received influenza vaccination at least once precursor to past influenza seasons. One blood sample was taken prior to vaccination for complete blood analysis and baseline immunogenicity assessment. The selected study participants received a single vaccine dose on the first day, and then followed up for three months. Two blood samples were taken after one week and three months post vaccination, respectively, for vaccine immunogenicity assessment.ResultsBefore vaccination, the seroprotection, defined as a hemagglutination-inhibiting titer of =>1:40, was detected for the three vaccine virus strains in 20 previously vaccinated participants (14·29%) [8·95%, 21·2%]. We compared the overall vaccine response for the three virus strains using a normalized response score calculated from linearly transformed titer measurements; the score before vaccination was 84% higher in the previously vaccinated group and the mean difference between the two groups was statistically significant. Three months post-vaccination, we didn’t find a significant difference in vaccine responses; the number of fully seroprotected individuals became 48 (34·29%) [26·48%, 42·77%] in the previously vaccinated group and 59 (42·75%) [34·37%, 51·45%] in the non-vaccinated group. The calculated response score was almost equal in both groups and the mean difference was no longer statistically significant.ConclusionOur findings suggest that a single dose of influenza vaccine is equally protective after three months for annually vaccinated adults and first-time vaccine receivers.

Immunogenicity and safety of inactivated quadrivalent influenza vaccine compared with the trivalent vaccine for influenza infection: an overview of systematic reviews

BackgroundInfluenza infection is a highly preventable transmissible viral disease associated with mild upper respiratory symptoms and more severe conditions such as lethal pneumonia. Studies have shown that a broader spectrum influenza vaccine could reduce influenza’s burden of disease in low- and middle-income countries. A considerable number of systematic reviews reported that quadrivalent influenza vaccines are considered more effective compared to trivalent vaccines, hence, there is a need for an overview in order to synthesize the current evidence pertaining to the comparison between quadrivalent and trivalent inactivated influenza vaccines. Objective: The aim was to summarize the evidence from systematic reviews that investigated the immunogenicity and safety of the Influenza’s inactivated quadrivalent vaccine (QIV) compared to the trivalent vaccine (TIV), in the general population.MethodsWe searched articles up to December 2022 at: Web of Science, EMBASE, MEDLINE, Cochrane Library, and SCOPUS. The search strategy was conducted following the PICO model. We included systematic reviews comparing the primary outcomes of immunogenicity (seroprotection rate and seroconversion rate) and adverse events using risk ratios. The AMSTAR 2 and ROBIS were used for quality assessments, and GRADE was used for evidence certainty assessments.FindingsWe included five systematic reviews, totalling 47,740 participants. The Quadrivalent Inactivated Influenza Vaccine (QIV) exhibited enhanced immunogenicity in the context of B-lineage mismatch when compared to the Trivalent Inactivated Influenza Vaccine (TIV). While the safety profile of QIV was found to be comparable to that of TIV, the QIV showed a higher incidence of solicited local pain among children and adolescents, as well as an increased frequency of local adverse events within the adult population.ConclusionOur findings suggest that the QIV provides a superior immunogenicity response compared to the TIV in all age groups evaluated, especially when a lineage mismatch occurred. The safety of QIV was considered similar to the TIV, with no serious or systemic solicited or unsolicited adverse events; tough pain at the injection site was greater for QIV. We recommend caution owing to the high risk of bias in the selection process and no protocol registration.