scholarly journals Safety and Immunogenicity of M2-Deficient, Single Replication, Live Influenza Vaccine (M2SR) in Adults

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1388
Author(s):  
Joseph Eiden ◽  
Gilad Gordon ◽  
Carlos Fierro ◽  
Renee Herber ◽  
Roger Aitchison ◽  
...  
Keyword(s):  
Influenza A ◽  
Phase 1 ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Controlled Study ◽  
High Dose ◽  
Severe Reaction ◽  
Infectious Dose ◽  
Mucosal Antibody ◽  
H3n2 Influenza

M2SR (M2-deficient single replication) is an investigational live intranasal vaccine that protects against multiple influenza A subtypes in influenza-naïve and previously infected ferrets. We conducted a phase 1, first-in-human, randomized, dose-escalation, placebo-controlled study of M2SR safety and immunogenicity. Adult subjects received a single intranasal administration with either placebo or one of three M2SR dose levels (106, 107 or 108 tissue culture infectious dose (TCID50)) expressing hemagglutinin and neuraminidase from A/Brisbane/10/2007 (H3N2) (24 subjects per group). Subjects were evaluated for virus replication, local and systemic reactions, adverse events (AE), and immune responses post-vaccination. Infectious virus was not detected in nasal swabs from vaccinated subjects. At least one AE (most commonly mild nasal rhinorrhea/congestion) was reported among 29%, 58%, and 83% of M2SR subjects administered a low, medium or high dose, respectively, and among 46% of placebo subjects. No subject had fever or a severe reaction to the vaccine. Influenza-specific serum and mucosal antibody responses and B- and T-cell responses were significantly more frequent among vaccinated subjects vs. placebo recipients. The M2SR vaccine was safe and well tolerated and generated dose-dependent durable serum antibody responses against diverse H3N2 influenza strains. M2SR demonstrated a multi-faceted immune response in seronegative and seropositive subjects.

scholarly journals Efficacy of Heterologous Prime-Boost Vaccination with H3N2 Influenza Viruses in Pre-Immune Individuals: Studies in the Pig Model

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 968
Author(s):  
Sharon Chepkwony ◽  
Anna Parys ◽  
Elien Vandoorn ◽  
Koen Chiers ◽  
Kristien Van Reeth
Keyword(s):  
Lymph Nodes ◽  
Influenza A ◽  
Serum Antibody ◽  
Swine Influenza ◽  
Cross Reactivity ◽  
Influenza Viruses ◽  
Antibody Responses ◽  
Pig Model ◽  
Boost Vaccination ◽  
H3n2 Influenza

In a previous study in influenza-naïve pigs, heterologous prime-boost vaccination with monovalent, adjuvanted whole inactivated vaccines (WIV) based on the European swine influenza A virus (SwIAV) strain, A/swine/Gent/172/2008 (G08), followed by the US SwIAV strain, A/swine/Pennsylvania/A01076777/2010 (PA10), was shown to induce broadly cross-reactive hemagglutination inhibition (HI) antibodies against 12 out of 15 antigenically distinct H3N2 influenza strains. Here, we used the pig model to examine the efficacy of that particular heterologous prime-boost vaccination regimen, in individuals with pre-existing infection-immunity. Pigs were first inoculated intranasally with the human H3N2 strain, A/Nanchang/933/1995. Seven weeks later, they were vaccinated intramuscularly with G08 followed by PA10 or vice versa. We examined serum antibody responses against the hemagglutinin and neuraminidase, and antibody-secreting cell (ASC) responses in peripheral blood, draining lymph nodes, and nasal mucosa (NMC), in ELISPOT assays. Vaccination induced up to 10-fold higher HI antibody titers than in naïve pigs, with broader cross-reactivity, and protection against challenge with an antigenically distant H3N2 strain. It also boosted ASC responses in lymph nodes and NMC. Our results show that intramuscular administration of WIV can lead to enhanced antibody responses and cross-reactivity in pre-immune subjects, and recall of ASC responses in lymph nodes and NMC.

scholarly journals Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial

2017 ◽  
Vol 4 (4) ◽  
pp. e367 ◽  
Author(s):  
Christopher LaGanke ◽  
Lawrence Samkoff ◽  
Keith Edwards ◽  
Lily Jung Henson ◽  
Pavle Repovic ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Controlled Study ◽  
Antibody Treatment ◽  
Double Blind ◽  
Semaphorin 4D

Objective:To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS.Methods:Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation.Results:VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment–related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer ≥100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations ≤0.3 μg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for ≥155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance.Conclusions:These results support the continued investigation of VX15/2503 in neurodegenerative diseases.ClinicalTrials.gov identifier:NCT01764737.Classification of evidence:This study provides Class III evidence that anti-semaphorin 4D antibody VX15/2503 at various doses was safe and well tolerated vs placebo, although an increase in treatment-emergent adverse events in the treatment group could not be excluded (risk difference −0.7%, 95% CI −28.0% to 32.7%).

scholarly journals Frailty Is Associated With Increased Hemagglutination-Inhibition Titers in a 4-Year Randomized Trial Comparing Standard- and High-Dose Influenza Vaccination

2020 ◽  
Vol 7 (5) ◽  
Author(s):  
Nathalie Loeb ◽  
Melissa K Andrew ◽  
Mark Loeb ◽  
George A Kuchel ◽  
Laura Haynes ◽  
...  
Keyword(s):  
Influenza Vaccination ◽  
Hemagglutination Inhibition ◽  
Influenza A ◽  
Standard Dose ◽  
Geometric Mean ◽  
Frailty Index ◽  
Antibody Responses ◽  
High Dose ◽  
Antibody Titers ◽  
The Impact

Abstract Background Although high-dose (HD) vaccines have been reported to stimulate higher antibody responses compared with standard-dose (SD) influenza vaccines, there have been limited studies on the impact of frailty on such responses. Methods We conducted a randomized, double-blind trial (2014/2015 to 2017/2018) of SD versus HD trivalent split-virus vaccine (Fluzone) in 612 study participants aged 65+ over 4 influenza seasons. Hemagglutination inhibition antibody titers for influenza H1N1, H3N2, and B vaccine subtypes were measured at baseline and at 4, 10, and 20 weeks postvaccination and frailty was measured using a validated frailty index. Results Geometric mean antibody titers were significantly higher in HD compared with SD vaccine recipients for all influenza subtypes at all time points postvaccination. However, frailty was positively correlated with 4-week titers and was associated with increased odds of being a vaccine responder. For influenza A subtypes, this was mostly limited to HD recipients. Conclusions Frailty was associated with higher titers and increased antibody responses at 4 weeks after influenza vaccination, which was partially dependent on vaccine dosage. Chronic inflammation or dysregulated immunity, both of which are commonly observed with frailty, may be responsible, but it requires further investigation.

scholarly journals Key Determinants of Cell-Mediated Immune Responses: A Randomized Trial of High Dose Vs. Standard Dose Split-Virus Influenza Vaccine in Older Adults

2021 ◽  
Vol 2 ◽  
Author(s):  
Chris P. Verschoor ◽  
Laura Haynes ◽  
Graham Pawelec ◽  
Mark Loeb ◽  
Melissa K. Andrew ◽  
...  
Keyword(s):  
Older Adults ◽  
Immune Responses ◽  
Influenza Vaccine ◽  
Influenza A ◽  
Standard Dose ◽  
Serum Antibody ◽  
High Dose ◽  
Post Vaccination ◽  
Antibody Titers ◽  
Virus Influenza

Background: Efforts to improve influenza vaccine effectiveness in older adults have resulted in some successes, such as the introduction of high-dose split-virus influenza vaccine (HD-SVV), yet studies of cell-mediated immune responses to these vaccines remain limited. We have shown that granzyme B (GrB) activity in influenza A/H3N2 challenged peripheral blood mononuclear cells (PBMC) correlates with protection against influenza following standard dose vaccination (SD-SVV) in older adults. Further, the interferon-γ (IFNγ) to interleukin-10 (IL-10) ratio can be a correlate of protection.Methods: In a double-blind trial (ClinicalTrials.gov NCT02297542) older adults (≥65 years, n = 582) were randomized to receive SD-SVV or HD-SVV (Fluzone®) from 2014/15 to 2017/18. Young adults (20–40 years, n = 79) received SD-SVV. At 0, 4, 10, and 20 weeks post-vaccination, serum antibody titers, IFNγ, IL-10, and inducible GrB (iGrB) were measured in ex vivo influenza-challenged PBMC. iGrB is defined as the fold change in GrB activity from baseline levels (bGrB) in circulating T cells. Responses of older adults were compared to younger controls, and in older adults, we analyzed effects of age, sex, cytomegalovirus (CMV) serostatus, frailty, and vaccine dose.Results: Prior to vaccination, younger compared to older adults produced significantly higher IFNγ, IL-10, and iGrB levels. Relative to SD-SVV recipients, older HD-SVV recipients exhibited significantly lower IFNγ:IL-10 ratios at 4 weeks post-vaccination. In contrast, IFNγ and iGrB levels were higher in younger SD vs. older SD or HD recipients; only the HD group showed a significant IFNγ response to vaccination compared to the SD groups; all three groups showed a significant iGrB response to vaccination. In a regression analysis, frailty was associated with lower IFNγ levels, whereas female sex and HD-SVV with higher IL-10 levels. Age and SD-SVV were associated with lower iGrB levels. The effect of prior season influenza vaccination was decreased iGrB levels, and increased IFNγ and IL-10 levels, which correlated with influenza A/H3N2 hemagglutination inhibition antibody titers.Conclusion: Overall, HD-SVV amplified the IL-10 response consistent with enhanced antibody responses, with little effect on the iGrB response relative to SD-SVV in either younger or older adults. These results suggest that enhanced protection with HD-SVV is largely antibody-mediated.Clinical Trial Registration: ClinicalTrials.gov (NCT02297542).

Use of the enzyme-linked immunosorbent assay to detect serum antibody responses of volunteers who received attenuated influenza A virus vaccines

1980 ◽  
Vol 29 (2) ◽  
pp. 342-347 ◽  
Author(s):  
B R Murphy ◽  
E L Tierney ◽  
B A Barbour ◽  
R H Yolken ◽  
D W Alling ◽  
...  
Keyword(s):  
Immunosorbent Assay ◽  
Recombinant Virus ◽  
Influenza A ◽  
Serum Antibody ◽  
Immunological Response ◽  
Virus Antigen ◽  
Enzyme Linked Immunosorbent Assay ◽  
Infectious Dose ◽  
The Difference ◽  
Attenuated Viruses

Sera from volunteers who received live influenza A wild-type or ts recombinant virus were tested by hemagglutination inhibition (HI) assay, neuraminidase inhibition (NI) assay, and the enzyme-linked immunosorbent assay (ELISA) to determine which assay system was the most sensitive in detecting an immunological response to infection. The ELISA was performed with inactivated whole virus antigen, and the optical density at each of five serial twofold dilutions of pre- and postimmunization sera was measured. The difference in the amount of ELISA antibody in pre- and postinoculation serum specimens was taken to be proportional to the area between the respective titration curves. The ELISA was more sensitive than the HI or NI test in detecting a seroresponse in volunteers infected with A/Hong Kong/123/77 (H1N1), A/New Jersey/8/76 (Hswine N1), or A/Alaska/6/77 (H3N2) ts recombinant virus. These results suggest that the ELISA should be used to determine the frequency of infection with attenuated viruses as well as the 50% human infectious dose of candidate live influenza A vaccine viruses.

scholarly journals Antibody responses to porcine reproductive and respiratory syndrome virus, influenza A virus, and Mycoplasma hyopneumoniae from weaning to the end of the finisher stage in fourteen groups of pigs in Ontario, Canada

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Elana Raaphorst ◽  
Abdolvahab Farzan ◽  
Robert M. Friendship ◽  
Brandon N. Lillie
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Serum Antibody ◽  
Mycoplasma Hyopneumoniae ◽  
Low Complexity ◽  
Antibody Responses ◽  
Respiratory Syndrome Virus ◽  
Factors Affecting ◽  
Farm Productivity ◽  
Virus Influenza

Abstract Background Respiratory diseases are among the most important factors affecting swine farm productivity in Canada. The objectives of this study were to investigate antibody responses to porcine reproductive and respiratory syndrome virus (PRRSV), influenza A virus (IAV), and Mycoplasma hyopneumoniae (M. hyopneumoniae) from weaning to the end of the finisher stage on a subset of commercial swine farms in Ontario, Canada, and to examine the association between nursery diet and antibody responses. Results Overall, older pigs were more likely to test seropositive for PRRSV and less likely to test seropositive for M. hyopneumoniae (p <  0.001). Pigs were more likely to test seropositive for IAV at weaning and the end of the grower and finisher stages compared to the end of nursery (p <  0.001). Pigs that were seropositive for IAV were more likely to test seropositive for both PRRSV and M. hyopneumoniae (p <  0.001). Two, 9, and 4 groups that had more than 20% of pigs seropositive to PRRSV, IAV, and M. hyopneumoniae, respectively, from the end of nursery to the end of finisher were classified as seropositive. Pigs fed a plant-based (low complexity) diet during nursery were more likely to be seropositive for PRRSV (p <  0.001) but there were no significant differences in seropositivity to IAV or M. hyopneumoniae due to nursery diet complexity. Conclusions This study provides information regarding changes in serum antibody in pigs across different stages of production and highlights periods of vulnerability. Additionally, these findings may encourage further research into the effects of nursery diet complexity on disease susceptibility and immune response.

scholarly journals Oral immunization against hepatitis B using bile salt stabilized vesicles (bilosomes)

2008 ◽  
Vol 11 (1) ◽  
pp. 59 ◽  
Author(s):  
Anshuman Shukla ◽  
Kapil Khatri ◽  
Prem N Gupta ◽  
Amit K Goyal ◽  
Abhinav Mehta ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Fluorescence Microscopy ◽  
Bile Salt ◽  
Serum Antibody ◽  
Oral Immunization ◽  
Attractive Alternative ◽  
Lymphoid Tissues ◽  
High Dose ◽  
Mucosal Antibody ◽  
Mucosal Secretions

PURPOSE: Presently available hepatitis B vaccine is administered through parenteral route and fails to induce mucosal antibody response. Oral immunization appears to be an effective and attractive alternative to the parenteral immunization. However, the problem of degradation of antigen in harsh and hostile environment of the gastrointestinal tract consequently requires larger dose and more frequent dosing of antigen. Furthermore, much larger dose can induce systemic tolerance. In order to overcome these problems bile salt stabilized vesicles (bilosomes) can be used, which could provide both protection to antigen as well as transmucosal uptake and subsequent resultant systemic immunity. Another purpose of this study was to determine the dose that could produce comparable serum antibody titre against hepatitis B through oral route as obtained after intramuscular immunization. METHODS: In the present study bilosomes containing recombinant hepatitis B surface antigen were prepared by cast film method. HBsAg loaded bilosomes were characterized in vitro for their shape, size, percent entrapment and stability. The fluorescence microscopy was carried out to confirm the uptake of bilosomes by gut associated lymphoid tissues (GALT). The in vivo study was comprised of estimation of anti-HBsAg IgG response in serum and anti-HBsAg sIgA in various body secretions using specific ELISA techniques following oral immunization with low dose loaded bilosomes (BSSV1, 10 µg), intermediate dose loaded bilosomes (BSSV2, 20 µg) and high dose loaded bilosomes (BSSV3, 50 µg) in Balb/c mice. RESULTS: The fluorescence microscopy suggests that an increase in fluorescence intensity following the uptake of bilosomes entrapped FITC-BSA in gut associated lymphoid tissues. The high dose HBsAg bilosomes (BSSV3, 50 µg) produced comparable anti-HBsAg IgG levels in serum to those observed in the case of intramuscular administration of alum adsorbed HBsAg (10 µg). However, alum adsorbed HBsAg was unable to produce sIgA in mucosal secretions, whilst, all bilosomal preparations could elicit measurable sIgA in mucosal secretions, where the highest responses were observed in high dose HBsAg bilosomes (BSSV3, 50µg). CONCLUSIONS: HBsAg loaded bilosomes produced both systemic as well as mucosal antibody responses upon oral administration. Thus bilosomes may emerge out to be potential carriers for non invasive mucosal immunization.

Time-course of antibody responses againstCoxiella burnetiifollowing acute Q fever

2012 ◽  
Vol 141 (1) ◽  
pp. 62-73 ◽  
Author(s):  
P. F. M. TEUNIS ◽  
B. SCHIMMER ◽  
D. W. NOTERMANS ◽  
A. C. A. P. LEENDERS ◽  
P. C. WEVER ◽  
...  
Keyword(s):  
Time Course ◽  
Mixed Model ◽  
Q Fever ◽  
Phase 1 ◽  
Serum Antibody ◽  
Immunofluorescence Assay ◽  
Antibody Responses ◽  
Mixture Analysis ◽  
Serum Samples ◽  
Model Framework

SUMMARYLarge outbreaks of Q fever in The Netherlands have provided a unique opportunity for studying longitudinal serum antibody responses in patients. Results are presented of a cohort of 344 patients with acute symptoms of Q fever with three or more serum samples per patient. In all these serum samples IgM and IgG against phase 1 and 2Coxiella burnetiiwere measured by an immunofluorescence assay. A mathematical model of the dynamic interaction of serum antibodies and pathogens was used in a mixed model framework to quantitatively analyse responses toC. burnetiiinfection. Responses show strong heterogeneity, with individual serum antibody responses widely different in magnitude and shape. Features of the response, peak titre and decay rate, are used to characterize the diversity of the observed responses. Binary mixture analysis of IgG peak levels (phases 1 and 2) reveals a class of patients with high IgG peak titres that decay slowly and may represent potential chronic cases. When combining the results of mixture analysis into an odds score, it is concluded that not only high IgG phase 1 may be predictive for chronic Q fever, but also that high IgG phase 2 may aid in detecting such putative chronic cases.

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