Immunogenicity Of Vaccine Research Articles

Safety and immunogenicity of the yellow fever vaccine for patients with end-stage renal disease

Resumo Introdução: Em dezembro de 2016, houve um surto de febre amarela (FA) silvestre em áreas não endêmicas da região sudeste do Brasil. A resposta imunológica à vacina contra FA e sua segurança em indivíduos com doença renal crônica (DRC) que vivem em regiões endêmicas de febre amarela não são totalmente compreendidas. O objetivo deste estudo foi avaliar a incidência de eventos adversos e a resposta sorológica após vacinação primária com a vacina 17DD-YF em pacientes com DRC submetidos à diálise. Métodos: Este foi um estudo de coorte retrospectivo e multicêntrico envolvendo 223 indivíduos com DRC que estavam em diálise após vacinação primária contra FA. Foram coletadas características clínicas, epidemiológicas e avaliados os eventos adversos da vacina (EAV). Cerca de 35 meses após a vacinação, a resposta sorológica foi avaliada em 71 (32%) pacientes usando testes de neutralização. Resultados: Não houve EAV grave em nenhum paciente. Reações locais foram relatadas em 13 indivíduos (5,8%), enquanto 6 (2,7%) relataram reações sistêmicas generalizadas e 205 (91,9%) não apresentaram nenhum EAV. Nenhuma característica clínica ou epidemiológica predisse a ocorrência de EAV. Uma resposta sorológica adequada foi encontrada em 38% dos participantes e nenhuma das características clínicas ou epidemiológicas foi associada à imunogenicidade. Conclusão: Os desfechos de nosso estudo sugerem que a vacina contra FA é bem tolerada em pacientes com DRC em diálise, mas não induz uma resposta imunológica adequada. Pesquisas futuras devem se concentrar na avaliação das respostas imunes tanto celulares quanto humorais após a administração de várias doses da vacina contra FA.

A substitution at the cytoplasmic tail of the spike protein enhances SARS-CoV-2 infectivity and immunogenicity

Global dissemination of SARS-CoV-2 Omicron sublineages has provided a sufficient opportunity for natural selection, thus enabling beneficial mutations to emerge. Characterisation of these mutations uncovers the underlying machinery responsible for the fast transmission of Omicron variants and guides vaccine development for combating the COVID-19 pandemic. Through systematic bioinformatics analysis of 496,606 sequences of Omicron variants, we obtained 40amino acid substitutions that occurred with high frequency in the S protein. Utilising pseudoviruses and a trans-complementation system of SARS-CoV-2, we identified the effect of high-frequency mutations on viral infectivity and elucidated the molecular mechanisms. Finally, we evaluated the impact of a key emerging mutation on the immune protection induced by the SARS-CoV-2 VLP mRNA vaccine in a murine model. We identified a proline-to-leucine substitution at the 1263rd residue of the Spike protein, and upon investigating the relative frequencies across multiple Omicron sublineages, we found a trend of increasing frequency for P1263L. The substitution significantly enhances the capacity for S-mediated viral entry and improves the immunogenicity of a virus-like particle mRNA vaccine. Mechanistic studies showed that this mutation is located in the FERM binding motif of the cytoplasmic tail and impairs the interaction between the Sprotein and the Ezrin/Radixin/Moesin proteins. Additionally, this mutation facilitates the incorporation of Sproteins into SARS-CoV-2 virions. This study offers mechanistic insight into the constantly increasing transmissibility of SARS-CoV-2 Omicron variants and provides a meaningful optimisation strategy for vaccine development against SARS-CoV-2. This study was supported by grants from the National Key Research and Development Plan of China (2021YFC2302405, 2022YFC2303200, 2021YFC2300200 and 2022YFC2303400), the National Natural Science Foundation of China (32188101, 32200772, 82422049, 82241082, 32270182, 82372254, 82271872, 82341046, 32100755 and 82102389), Shenzhen Medical Research Fund (B2404002, A2303036), the Shenzhen Bay Laboratory Startup Fund (21330111), Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseases (SZSM202211023), Yunnan Provincial Science and Technology Project at Southwest United Graduate School (202302AO370010). The New Cornerstone Science Foundation through the New Cornerstone Investigator Program, and the Xplorer Prize from Tencent Foundation.

Safety and immunogenicity of the yellow fever vaccine for patients with end-stage renal disease.

In December 2016, an outbreak of sylvatic yellow fever (YF) occurred in the non-endemic areas of the south-eastern region of Brazil. The immune response to the yellow fever vaccine and its safety in individuals with chronic kidney disease (CKD) living in YF-endemic regions are not thoroughly understood. The objective of this study is to assess the incidence of adverse events and the serological response after primary vaccination with the 17DD-YF vaccine in CKD patients undergoing dialysis. This was a multicenter, retrospective cohort study involving 223 individuals with CKD who were on dialysis after primary vaccination against YF. Clinical and epidemiologic characteristics were collected and the vaccine adverse event (VAE) were assessed. Around 35 months after vaccination, the serological response was evaluated in 71 (32%) patients using neutralization tests. No serious VAE occurred in any patient. Local reactions were reported in 13 individuals (5.8%), while 6 (2.7%) reported generalized systemic reactions and 205 (91.9%) did not display any VAE. No clinical or epidemiologic characteristic predicted the occurrence of VAE. Adequate serological response was found in 38% of participants and none of the clinical or epidemiological characteristics were associated with immunogenicity. The outcomes of our study suggest that the yellow YF vaccine is well-tolerated in CKD patients undergoing dialysis, but it does not induce adequate immune response. Future research should focus on evaluating both cellular and humoral immune responses following administration of various doses of the YF vaccine.

Safety and immunogenicity of mRNA-1345 RSV vaccine coadministered with an influenza or COVID-19 vaccine in adults aged 50 years or older: an observer-blinded, placebo-controlled, randomised, phase 3 trial

Coadministration of a respiratory syncytial virus (RSV) vaccine with seasonal influenza or SARS-CoV-2 vaccines could reduce health-care visits and increase vaccination uptake in older adults who are at high risk for severe respiratory disease. The RSV mRNA-1345 vaccine demonstrated efficacy against RSV disease with acceptable safety in the ConquerRSV trial in adults aged 60 years and older. We aimed to evaluate the safety and immunogenicity of mRNA-1345 coadministered with a seasonal influenza vaccine or SARS-CoV-2 mRNA vaccine. We conducted a two-part, phase 3, observer-blinded, placebo-controlled, randomised trial in medically stable adults aged 50 years or older in the USA. In part A, participants were randomly assigned in a 7:10:10 ratio to receive 50 μg mRNA-1345 plus placebo (0·9% sodium chloride) or coadministered with 60 μg of a standard-dose quadrivalent inactivated influenza vaccine (SIIV4), or SIIV4 plus placebo. In part B, participants were randomly assigned in a 1:1:1 ratio to receive 50 μg mRNA-1345 plus placebo or coadministered with 50 μg SARS-CoV-2 mRNA-1273.214 (bivalent [Wuhan-Hu-1 plus omicron BA.1]), or mRNA-1273.214 plus placebo. Random allocation in both parts was stratified by age group (50-59 years, 60-74 years, and ≥75 years) and used interactive response technology. The coprimary objectives in each part were safety in the safety set throughout the study and non-inferiority for six immunogenicity endpoints in the per-protocol set comparing coadministered versus individual vaccines on day 29. Immunogenicity endpoints were geometric mean titre (GMT) ratios (GMRs) of RSV-A neutralising antibodies (nAbs; in parts A and B), GMRs of haemagglutination inhibition (HAI) titres to each of the four influenza strains in SIIV4 (A/Victoria/2570/2019 [H1N1]pdm09-like virus [A/H1N1], A/Cambodia/e0826360/2020 [H3N2]-like virus [A/H3N2], B/Washington/02/2019-like virus [B/Victoria], and B/Phuket/3073/2013-like virus [B/Yamagata]; in part A), GMRs of nAbs against SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B), and differences in seroresponse rates for nAbs against RSV-A (parts A and B) and SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B). Non-inferiority was declared when the lower bound of the 95% CI for GMRs was greater than 0·667 and for seroresponse rate differences was greater than -10%. This trial is registered with ClinicalTrials.gov (NCT05330975) and is ongoing. Between April 1 and June 9, 2022, 1631 participants were randomly allocated in part A and 1623 received vaccinations on day 1 (685 [42%] received mRNA-1345 plus SIIV4, 249 [15%] mRNA-1345 plus placebo, and 689 [42%] SIIV4 plus placebo). Due to an interactive response technology error, the mRNA-1345 plus placebo group was smaller than planned (249 vs 420 participants). Of the 1623 participants in the safety set, 877 (54%) were female and 746 (46%) were male. Between July 27 and Sept 28, 2022, 1691 participants were randomly allocated in part B and 1681 received vaccinations on day 1 (564 [34%] received mRNA-1345 plus mRNA-1273.214, 558 [33%] mRNA-1345 plus placebo, and 559 [33%] mRNA-1273.214 plus placebo). Among the 1681 participants in the safety set, 924 (55%) were female and 757 (45%) were male. The reactogenicity profiles of the coadministered regimens were generally similar to the profiles when the vaccines were administered alone. As of the 6-month and 7-month follow-up times for parts A and B, respectively, no serious adverse events, adverse events of special interest, discontinuations due to adverse events, or fatal events considered related to study vaccination were reported. In part A, the GMR of nAbs against RSV-A in the mRNA-1345 plus SIIV4 group versus the mRNA-1345 alone group was 0·81 (95% CI 0·67 to 0·97), and the seroresponse rate difference in nAbs against RSV-A between the groups was -11·2% (95% CI -17·9 to -4·1). GMRs of anti-HAI titres in the mRNA-1345 plus SIIV4 versus SIIV4 alone groups were 0·89 (0·77 to 1·03) for A/H1N1, 0·97 (0·86 to 1·09) for A/H3N2, 0·93 (0·82 to 1·05) for B/Victoria, and 0·91 (0·81 to 1·02) for B/Yamagata. In part B, the GMR of nAbs against RSV-A in the mRNA-1345 plus mRNA-1273.214 versus the mRNA-1345 alone groups was 0·80 (95% CI 0·70 to 0·90), and the seroresponse rate difference was -4·4% (95% CI -9·9 to 1·0). Comparing the mRNA-1345 plus mRNA-1273.214 group with the mRNA-1273.214 alone group, the GMR of nAbs was 0·96 (0·87 to 1·06) for the ancestral (D614G) virus and 1·00 (0·89 to 1·14) for omicron BA.1; seroresponse rate differences were 0·2% (95% CI -6·0 to 6·3) for SARS-CoV-2 ancestral and -0·9% (-6·6 to 4·7) for omicron BA.1. Coadministered mRNA-1345 plus SIIV4 or mRNA-1273.214 vaccines had acceptable safety profiles and elicited mostly non-inferior immune responses compared to individual vaccines in adults aged 50 years or older; only the seroresponse rate difference in nAbs against RSV-A in part A did not meet the non-inferiority criterion. Overall, these data support coadministration of mRNA-1345 with these vaccines in this population; longer-term evaluation continues in this study. Moderna.

A randomized trial comparing safety, immunogenicity and efficacy of self-amplifying mRNA and adenovirus-vector COVID-19 vaccines

This phase 3 trial compared safety, tolerability, immunogenicity and efficacy of the self-amplifying mRNA COVID-19 vaccine, ARCT-154, with ChAdOx1-S adenovirus-vector vaccine. In four centers in Vietnam adult participants aged 18‒85 years were randomly assigned to receive two doses, 28 days apart, of either ARCT-154 (n = 1186) or ChAdOx1-S (n = 1180). Both vaccines were well tolerated with similar safety and reactogenicity profiles consisting of mainly mild-to-moderate solicited adverse events and few related serious adverse events. Higher neutralizing antibody responses persisting to one-year post-vaccination after ARCT-154 compared with ChAdOx1-S were associated with a generally higher efficacy against COVID-19. In an exploratory analysis relative vaccine efficacy of ARCT-154 vs. ChAdOx1-S against any COVID-19 from Day 36 to Day 394 was 19.8% (95% CI: 4.0–33.0). Self-amplifying mRNA vaccine offers potential immunological advantages in terms of immunogenicity and efficacy over adenovirus-vector vaccine without compromising safety.

Immunosuppressants in dermatology on vaccine immunogenicity: a prospective cohort study of pemphigus patients in the pandemic

Immunosuppressants in dermatology on vaccine immunogenicity: a prospective cohort study of pemphigus patients in the pandemic

MRNA compartmentalization via multimodule DNA nanostructure assembly augments the immunogenicity and efficacy of cancer mRNA vaccine.

Messenger RNA (mRNA) vaccine has fueled a great hope for cancer immunotherapy. However, low immunogenicity, caused by inefficient mRNA expression and weak immune stimulation, hampers the efficacy of mRNA vaccines. Here, we present an mRNA compartmentalization-based cancer vaccine, comprising a multimodule DNA nanostructure (MMDNS)-assembled compartment for efficient mRNA translation via in situ localizing mRNA concentration and relevant reaction molecules. The MMDNS is constructed via programmable DNA hybridization chain reaction (HCR)-based strategy, with integrating antigen-coded mRNA, CpG oligodeoxynucleotides (ODNs), acidic-responsive DNA sequence, and dendritic cells targeting aptamer. MMDNS undergoes in situ assembly in acidic lysosomes to form a micro-sized aggregate, inducing an enhanced CpG ODN adjuvant efficacy. Subsequently, the aggregates escape into cytoplasm, providing a moderate compartment which supports the efficient translation of spatially proximal mRNA transcripts via localizing relevant reaction molecules. The mRNA compartmentalization-based vaccine boosts a strong immune response and effectively inhibits tumor growth and metastasis, offering a robust strategy for cancer immunotherapy.

The Impact of Obesity on Influenza Vaccine Immunogenicity and Antibody Transfer to the Infant During Pregnancy

The Impact of Obesity on Influenza Vaccine Immunogenicity and Antibody Transfer to the Infant During Pregnancy

Modular Display of Plasmodium yoelii Circumsporozoite Surface Protein and Merozoite Surface Protein-1 on Norovirus-like Particles.

Recently, virus-like particles have been regarded as a promising platform for displaying foreign peptides or proteins on their surface. In this study, a dual-protein-displaying platform based on the norovirus-like particle (NoV-LP) was developed using SpyTag (SpT)/SpyCatcher (SpC) protein bioconjugation. A short 14-amino-acid SpT peptide was added to the C-terminus of VP1, with a rigid "EAAAK" spacer in between. Antigenic proteins from a rodent malaria parasite, Plasmodium yoelii, specifically the circumsporozoite protein (PyCSP) and the 19 kDa C-terminal region of merozoite surface protein 1 (PyMSP119), were displayed on the surface of NoV-LPs in both monovalent and bivalent formats. The immunogenicity of these VLP-based vaccines was assessed, and they were found to induce antigen-specific IgG responses against both PyCSP and PyMSP119 in BALB/c mice in the absence of an adjuvant, at levels comparable to those induced by subunit antigenic proteins with an alum adjuvant added. Interestingly, the bivalent vaccine raised IgG responses at a similar titer to the monovalent vaccine. This finding hints that the NoV-LP possesses an inherent adjuvanted property in the presence of a foreign antigen. The measured anti-PyCSP and anti-PyMSP119 antibodies through ELISA indicate that surface display of PyCSP and PyMSP119 on SpTagged-NoV-LP has the potential for further development as a bivalent vaccine against two different life-cycle stages of malaria.

A Modified Novel Validated High-Throughput Hemagglutinin Inhibition Assay Using Recombinant Virus-like Particles and Human Red Blood Cells for the Objective Evaluation of Recombinant Hemagglutinin Nanoparticle Seasonal Influenza Vaccine.

Currently available seasonal influenza vaccines confer variable protection due to antigenic changes resulting from the accumulation of diverse mutations. The analysis of new seasonal influenza vaccines is challenging in part due to the limitations of the traditional hemagglutination inhibition (HAI) assay with A/H3N2 strains. An improved and objective novel HAI assay was developed with recombinant virus-like particles (VLPs) and an egg-derived virus as agglutinins, the oseltamivir treatment of VLPs, human red blood cells, and using an automated image reader-based analysis of hemagglutination. HAI validation was demonstrated using four VLPs and egg-derived strains, with 46-56 serum samples tested 12 times in duplicate per strain. The validated HAI assay was precise as indicated by the percent geometric coefficient of variation for intra-, inter-, and total assay precision, as well as accurate as evidenced by percent bias measurements. The assay exhibited linearity, specificity for homologous type/subtype strains, and sensitivity with a starting dilution of 1:10. Assay robustness and sample stability were demonstrated as a percentage difference compared to reference condition. Validated HAI results were equivalent for the single and duplicate sample testing and correlated well with a qualified live wild-type influenza microneutralization assay. These findings demonstrate the suitability of this high-throughput novel modified validated HAI assay for evaluating vaccine immunogenicity and efficacy.

Immunogenicity and safety of COVID-19 vaccines in patients with lung cancer : results of a systematic review and meta-analysis.

COVID-19 has emerged as a significant worldwide health crisis in recent years, characterized by elevated morbidity and mortality rates. COVID-19 vaccinations can diminish transmission and safeguard people. The evaluation of immunogenicity and safety in high-risk populations, such as lung cancer patients, continues to provide a problem. This evaluation seeks to evaluate the safety and immunogenicity of COVID-19 vaccinations in patients with lung cancer. A search was conducted in PubMed, EMBASE, and Web of Science from January 2021 to November 2022 utilizing the keywords: COVID-19 OR SARS-CoV-2 AND COVID-19 vaccination AND lung cancer OR lung carcinoma. The subsequent requirements must be satisfied for inclusion: (1) Research involving at least 30 lung cancer patients undergoing active anti-tumor therapy alongside healthy controls; (2) COVID-19 vaccination; (3) Observational studies (either prospective or retrospective) and clinical trials featuring healthy controls; (4) The primary outcome measured was anti-SARS-CoV-2 spike IgG titers following the second dose of the COVID-19 vaccine in lung cancer patients. Secondary results included local and systemic adverse responses following the first and second doses. Antibody titers (mean ± standard deviation) were assessed for each study individually. The occurrence of adverse events following the first and second dosages was recorded Results: Eight studies were included, comprising 1,220 lung cancer patients and 599 healthy persons. IgG titers against the SARS-CoV-2 spike protein were markedly reduced in lung cancer patients compared to healthy controls, with a statistically significant difference (p=0.002). The safety profiles of lung cancer patients and healthy individuals were comparable: local reaction after the first vaccine: RR=0.90, 95% CI: 0.68-1.19; systemic reaction after the first vaccine: RR=0.92, 95% CI: 0.51-1.66; local reaction after the second vaccine: RR=0.81, 95% CI: 0.54-1.19; systemic reaction after the second vaccine: RR=1.20, 95% CI: 0.65-2.21. The antibody titer in lung cancer patients is markedly lower than that in the healthy group. Consequently, fatalities from COVID-19 may transpire in these people notwithstanding vaccination. Consequently, comprehensive protective measures must continue to be implemented to safeguard lung cancer patients who have received two doses of the COVID-19 vaccination against COVID-19.

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

Obesity is a recognized factor influencing immune function and infectious disease outcomes. Characterization of the influence of obesity on SARS-CoV-2 humoral vaccine immunogenicity is required to properly tailor vaccine type (mRNA, viral-vector, protein subunit vaccines) and dosing schedule. Data from a prospective cohort study collected over 34 months was used to evaluate the slope of antibody production and decay and neutralizing capacity following SARS-CoV-2 vaccination in individuals with and without obesity at baseline. Most participants were female (65.4%), white (92.4%), and received mRNA vaccines. 210 were obese and 697 non-obese. Sex and infection-acquired immunity were identified as effect modifiers for the relationship between obesity and COVID-19 vaccine humoral immunogenicity. No consistent influence of obesity on peak titres, titre retention, antibody isotype (IgG, IgM, IgA), or neutralization was identified when controlling for other key variables. It may not be necessary to consider this variable when developing SARS-CoV-2 vaccine dosing strategies.

IL-7 promotes mRNA vaccine-induced long-term immunity

Messenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, improving the immunogenicity and durability of mRNA vaccines remains a challenge. To elicit optimal immune responses, integrating antigen-encoded mRNA and immunostimulatory adjuvants into a single formulation is a promising approach to enhancing the efficacy of mRNA vaccines. Here, we report an adjuvant strategy to enhance the efficacy of mRNA vaccines by co-loading mRNA encoding the antigen (rabies virus glycoprotein, RABV-G) and mRNA encoding IL-7 into lipid nanoparticles, achieving co-delivery to the same antigen-presenting cells. A single immunization with G&IL-7 mRNA vaccine elicited robust humoral immune responses in mice and conferred complete protection against RABV challenge. Notably, the high levels of neutralizing antibody induced by the G&IL-7 mRNA vaccine were maintained for at least 6 months, providing mice with long-term significant and complete protection against RABV. Additionally, IL-7 also enhanced antibody responses against the SARS-CoV-2. These data demonstrate that IL-7 is a potent mRNA vaccine adjuvant that can provide the required immune stimulation in various mRNA vaccine formulations.Graphical

Harmonization of Vaccine Ligand Binding Assays Validation.

The urgency and importance of organizing a global effort to harmonize clinical assay validation specific to the vaccine industry was identified during the drafting of the 2020 White Paper in Bioanalysis due to the lack of clarity and regulatory guidance/guidelines in vaccine immunoassay validation. Indeed, the Workshop on Recent Issues in Bioanalysis (WRIB) issues the White Paper in Bioanalysis yearly, which is one of the high-profile articles of the Bioanalysis Journal focused on detailed discussions and recommendations on vaccine assay validation. Since 2017, participation in the WRIB working groups by vaccine assay validation experts and regulators has rapidly increased due to its unique format where industry leaders and regulators can meet and exchange ideas on topics of interest to both groups. In early 2021, Vaccine manufacturers approached WRIB for sponsoring/supporting the authorship and publication of an overarching vaccine assay validation document based on the 2017-2020 discussions and consensus starting from immunogenicity assays first and followed by future papers on molecular and cell-based assay validation. Using industry and WRIB vaccine network, a vaccine immunogenicity assay validation working group was assembled consisting of 16 companies. The work on the first white paper started officially in April 2021 focusing on Vaccine LBA Validation (Part 1), and the drafting of Vaccine LBA Development (Part 2) and Vaccine LBA Monitoring & Transfer (Part 3) are presently ongoing and expected to be published shortly after this paper. Moreover, recommendations on Vaccine Cell-Based Assays Validation (ELISpot and Flow cytometry) and Vaccine Molecular Assays Validation (PCR, NGS, NanoString) are also on the WRIB publications agenda and the drafting is planned to start in mid-2024. For too long, vaccine scientists have not had a clear validation guidance for clinical vaccine immunogenicity assays. We hope that this common effort will help close this regulatory gap.

Safety and immunogenicity of freeze-dried human rabies vaccines: A phase 3 clinical trial of Zagreb and Essen regimes

ABSTRACT Recently optimized freeze-dried rabies vaccines (Vero cell) are promising for rabies prevention; however, comparisons of Essen 5-dose and Zagreb 4-dose regimens are needed for clinical applications. This phase III clinical trial aimed to assess the safety and immunogenicity of candidate freeze-dried rabies vaccines developed for human use by Shandong Yeedo Biotechnology (Registration No.: CTR20182016, http://www.chinadrugtrials.org.cn/index.html). In total, 40 participants in stage I and 1797 subjects in stage II with an age range of 10–60 years were recruited. Both 4-dose and 5-dose experimental vaccines were well-tolerated in stage 1, with similar overall adverse event (AE) rates. In stage 2, systemic fever (35.39%) and local pain (48.91%) were common, and the rate of Grade 3 AEs was approximately 2.5%. Rates of local reactions and unsolicited AEs differed among groups (p = .045 and 0.011). Immunogenicity analyses showed higher antibody levels, seroconversion rates, and pre-immune seroconversion rates in the 4-dose experimental group versus the 5-dose group (p < .001) on day 7 post-first dose, with similar GMCs (geometric mean concentrations) by day 14. Pre-immune negative subjects had comparable antibody levels in the 4-dose and 5-dose experimental groups, outperforming the 5-dose control group (p = .039). The rate difference (95% CI) for first-dose seroconversion at 14 days post-vaccination among pre-immune antibody-negative subjects indicated non-inferiority between the 5-dose experimental and control groups. Overall, the Shandong Yeedo rabies vaccine demonstrated satisfactory safety and efficacy, offering a new option for rabies prevention.

H9 Consensus Hemagglutinin Subunit Vaccine with Adjuvants Induces Robust Mucosal and Systemic Immune Responses in Mice by Intranasal Administration.

The H9N2 subtype avian influenza viruses mainly cause respiratory symptoms, reduce the egg production and fertility of poultry, and result in secondary infections, posing a great threat to the poultry industry and human health. Currently, all H9N2 avian influenza commercial vaccines are inactivated vaccines, which provide protection for immunized animals but cannot inhibit the spread of the virus and make it difficult to distinguish between the infected animals and vaccinated animals. In this study, a trimeric consensus H9 hemagglutinin (HA) subunit vaccine for the H9N2 subtype avian influenza virus based on a baculovirus expression system was first generated, and then the effects of three molecular adjuvants on the H9 HA subunit vaccine, Cholera toxin subunit B (CTB), flagellin, and granulocyte-macrophage colony-stimulating factor (GM-CSF) fused with H9 HA, and one synthetic compound, a polyinosinic-polycytidylic acid (PolyI:C) adjuvant, were evaluated in mice by intranasal administration. The results showed that these four adjuvants enhanced the immunogenicity of the H9 HA subunit vaccine for avian influenza viruses, and that GM-CSF and PolyI:C present better mucosal adjuvant activity for the H9 HA subunit vaccine. These results demonstrate that we have developed a potential universal H9 HA mucosal subunit vaccine with adjuvants in a baculovirus system that would be helpful for the prevention and control of H9N2 subtype avian influenza viruses.

Disease-associated B cells and immune endotypes shape adaptive immune responses to SARS-CoV-2 mRNA vaccination in human SLE.

Severe acute respiratory syndrome coronavirus 2 mRNA vaccination has reduced effectiveness in certain immunocompromised individuals. However, the cellular mechanisms underlying these defects, as well as the contribution of disease-induced cellular abnormalities, remain largely unexplored. In this study, we conducted a comprehensive serological and cellular analysis of patients with autoimmune systemic lupus erythematosus (SLE) who received the Wuhan-Hu-1 monovalent mRNA coronavirus disease 2019 vaccine. Our findings revealed that patients with SLE exhibited reduced avidity of anti-receptor-binding domain antibodies, leading to decreased neutralization potency and breadth. We also observed a sustained anti-spike response in IgD-CD27- 'double-negative (DN)' DN2/DN3 B cell populations persisting during memory responses and with greater representation in the SLE cohort. Additionally, patients with SLE displayed compromised anti-spike T cell immunity. Notably, low vaccine efficacy strongly correlated with higher values of a newly developed extrafollicular B and T cell score, supporting the importance of distinct B cell endotypes. Finally, we found that anti-BAFF blockade through belimumab treatment was associated with poor vaccine immunogenicity due to inhibition of naive B cell priming and an unexpected impact on circulating T follicular helper cells.

Assessment of Single-Cycle M-Protein Mutated Vesicular Stomatitis Virus as a Safe and Immunogenic Mucosal Vaccine Platform for SARS-CoV-2 Immunogen Delivery.

The goal of the next-generation COVID-19 vaccine is to provide rapid respiratory tract protection with a single dose. Circulating antibodies do not protect the olfactory mucosa from viral infection, necessitating localized mucosal immunization. Live attenuated vesicular stomatitis virus (VSVMT)-based COVID-19 vaccines effectively stimulate mucosal immunity in animals, though safety concerns remain, particularly in immunocompromised populations. A viral vector capable of single-cycle replication may face less stringent regulatory requirements. A replication-defective VSVMT is developed with its G protein replaced by a SARS-CoV-2 spike protein (S) mutant, where residues K986 and V987 are substituted by prolines (S2P). This studies show that single-cycle VSVMT encoding Omicron subvariant S2P (VSVMT-S2P) is safe in both healthy and immunocompromised animals treated with cyclophosphamide (CP). Significant antibody and T-cell responses against the spike protein are observed in VSVMT-S2P vaccinated healthy animals. Intramuscular VSVMT-S2P administration induces neutralizing antibody responses comparable to those from replication-competent VSVMT-S. In immunocompromised animals, lower and delayed immune responses are observed. Thus, single-cycle M-protein mutated VSV offers a safe and effective platform for SARS-CoV-2 immunogen delivery. Remarkably, replication-competent VSVMT-S caused no pathogenicity and elicited potent mucosal immunity via intranasal administration, highlighting its potential as a mucosal COVID-19 vaccine.

Immunogenicity of intraperitoneal and intranasal liposome adjuvanted VLP vaccines against SARS-CoV-2 infection

Humans get SARS-CoV-2 infection mainly through inhalation; thus, vaccine that induces protective immunity at the virus entry site is important for early control of the infection. In this study, two anionic liposome (L)-adjuvanted VLP vaccines against SARS-CoV-2 were formulated. Baculovirus-Sf21 insect cell system was used for production of VLPs made of full-length S, M and E proteins. S protein of one vaccine (L-SME-VLPs) contained furin cleavage site at the S1/S2 junction, while that of another vaccine (L-S′ME-VLPs) did not. Both vaccines were innocuous and immunogenic when administered IP and IN to mice. Mice immunized IP with L-SME-VLPs/L-S′ME-VLPs (three doses, two-weeks intervals) had serum virus neutralizing (VN) antibodies (in falling order of isotype frequency): IgG3, IgA and IgG2a/IgG3, IgA and IgM, respectively. The L-S′ME VLPs vaccine induced significantly higher serum VN antibody titers than the L-SME-VLPs vaccine. All mice immunized IN with both vaccines had significant rise of VN antibodies in their bronchoalveolar lavage fluids (BALF). The VN antibodies in 67% of immunized mice were Th1- isotypes (IgG2a and/or IgG2b); the immunized mice had also other antibody isotypes in BALF. The intranasal L-S′ME-VLPs should be tested further step-by-step towards the clinical use as effective and safe vaccine against SARS-CoV-2.

A therapeutic HBV vaccine containing a checkpoint modifier enhances CD8+ T cell and antiviral responses.

In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that augments CD8+ T cell responses. The vaccine is based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, which targets conserved and highly immunogenic regions of the viral polymerase and core antigens fused to HSV gD. The vaccine was tested with and without gD in mice for immunogenicity, and in an AAV8-1.3HBV vector model of antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular injection achieved pronounced and sustained declines of circulating HBV DNA copies and HBV surface antigen; both inversely correlated with HBV-specific CD8+ T cell frequencies in spleen and liver.