Influenza Hemagglutination-inhibition Antibody Titer as a Mediator of Vaccine-induced Protection for Influenza B

Cowling, Benjamin J.; Lim, Wey Wen; Perera, Ranawaka A.P.M.; Fang, Vicky J.; Leung, Gabriel M.; Peiris, J. S. Malik; Tchetgen, Eric J. Tchetgen

doi:10.1093/cid/ciy759

Cited by 54 publications

(29 citation statements)

References 16 publications

(29 reference statements)

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“…In comparison, hemagglutination inhibition titer against B/Victoria influenza virus mediated an estimated 57% of inactivated influenza vaccine efficacy against virologically confirmed B/Victoria influenza illness. 44 As hemagglutination inhibition titer has been used to guide vaccine strain selection and approval, this defines a benchmark for a potential level of mediation relevant for supporting vaccine approval decisions. 45 The very high overall vaccine efficacy and the small number of vaccine recipients with negative/undetectable antibody levels in COVE limited the ability to identify a high percentage of neutralization-mediated vaccine efficacy.…”

Section: Discussionmentioning

confidence: 99%

Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial

Gilbert

Montefiori

McDermott

et al. 2021

Preprint

151

192

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Background: In the Coronavirus Efficacy (COVE) trial, estimated mRNA-1273 vaccine efficacy against coronavirus disease-19 (COVID-19) was 94%. SARS-CoV-2 antibody measurements were assessed as correlates of COVID-19 risk and as correlates of protection. Methods: Through case-cohort sampling, participants were selected for measurement of four serum antibody markers at Day 1 (first dose), Day 29 (second dose), and Day 57: IgG binding antibodies (bAbs) to Spike, bAbs to Spike receptor-binding domain (RBD), and 50% and 80% inhibitory dilution pseudovirus neutralizing antibody titers calibrated to the WHO International Standard (cID50 and cID80). Participants with no evidence of previous SARS-CoV-2 infection were included. Cox regression assessed in vaccine recipients the association of each Day 29 or 57 serologic marker with COVID-19 through 126 or 100 days of follow-up, respectively, adjusting for risk factors. Results: Day 57 Spike IgG, RBD IgG, cID50, and cID80 neutralization levels were each inversely correlated with risk of COVID-19: hazard ratios 0.66 (95% CI 0.50, 0.88; p=0.005); 0.57 (0.40, 0.82; p=0.002); 0.41 (0.26, 0.65; p<0.001); 0.35 (0.20, 0.60; p<0.001) per 10-fold increase in marker level, respectively, multiplicity adjusted P-values 0.003-0.010. Results were similar for Day 29 markers (multiplicity adjusted P-values <0.001-0.003). For vaccine recipients with Day 57 reciprocal cID50 neutralization titers that were undetectable (<2.42), 100, or 1000, respectively, cumulative incidence of COVID-19 through 100 days post Day 57 was 0.030 (0.010, 0.093), 0.0056 (0.0039, 0.0080), and 0.0023 (0.0013, 0.0036). For vaccine recipients at these titer levels, respectively, vaccine efficacy was 50.8% (-51.2, 83.0%), 90.7% (86.7, 93.6%), and 96.1% (94.0, 97.8%). Causal mediation analysis estimated that the proportion of vaccine efficacy mediated through Day 29 cID50 titer was 68.5% (58.5, 78.4%). Conclusions: Binding and neutralizing antibodies correlated with COVID-19 risk and vaccine efficacy and likely have utility in predicting mRNA-1273 vaccine efficacy against COVID-19. Trial registration number: COVE ClinicalTrials.gov number, NCT04470427

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Section: Discussionmentioning

confidence: 99%

Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial

Gilbert

Montefiori

McDermott

et al. 2021

Preprint

151

192

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“…These results raise at least two obvious questions: (1) whether conventional haemagglutination inhibition antibody titres, despite their longstanding use as predictors of post-vaccination efficacy against both influenza A and B,15, 26 are truly an appropriate surrogate for an effective humoral response in therapeutic studies against influenza A, and hence whether better markers of antibody-mediated activity might exist that should be substituted, and (2) whether the overall host immune response to infection with influenza B might differ in some fundamental way from that against influenza A. It is known, for example, that acute influenza infection is also associated with pronounced impairment of the cellular immune response, including defective T-cell responses and a sometimes lethal unbridling of the proinflammatory cytokine cascade 27, 28.…”

Section: Discussionmentioning

confidence: 99%

Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial

Davey¹,

Fernández‐Cruz²,

Markowitz³

et al. 2019

The Lancet Respiratory Medicine

110

143

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SummaryBackgroundSince the 1918 influenza pandemic, non-randomised studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit for patients with influenza infection, but definitive data do not exist. We aimed to evaluate the safety and efficacy of hIVIG in a randomised controlled trial.MethodsThis randomised, double-blind, placebo-controlled trial was planned for 45 hospitals in Argentina, Australia, Denmark, Greece, Mexico, Spain, Thailand, UK, and the USA over five influenza seasons from 2013–14 to 2017–18. Adults (≥18 years of age) were admitted for hospital treatment with laboratory-confirmed influenza A or B infection and were randomly assigned (1:1) to receive standard care plus either a single 500-mL infusion of high-titre hIVIG (0·25 g/kg bodyweight, 24·75 g maximum; hIVIG group) or saline placebo (placebo group). Eligible patients had a National Early Warning score of 2 points or greater at the time of screening and their symptoms began no more than 7 days before randomisation. Pregnant and breastfeeding women were excluded, as well as any patients for whom the treatment would present a health risk. Separate randomisation schedules were generated for each participating clinical site using permuted block randomisation. Treatment assignments were obtained using a web-based application by the site pharmacist who then masked the solution for infusion. Patients and investigators were masked to study treatment. The primary endpoint was a six-category ordinal outcome of clinical status at day 7, ranging in severity from death to resumption of normal activities after discharge. The choice of day 7 was based on haemagglutination inhibition titres from a pilot study. It was analysed with a proportional odds model, using all six categories to estimate a common odds ratio (OR). An OR greater than 1 indicated that, for a given category, patients in the hIVIG group were more likely to be in a better category than those in the placebo group. Prespecified primary analyses for safety and efficacy were based on patients who received an infusion and for whom eligibility could be confirmed. This trial is registered with ClinicalTrials.gov, NCT02287467.Findings313 patients were enrolled in 34 sites between Dec 11, 2014, and May 28, 2018. We also used data from 16 patients enrolled at seven of the 34 sites during the pilot study between Jan 15, 2014, and April 10, 2014. 168 patients were randomly assigned to the hIVIG group and 161 to the placebo group. 21 patients were excluded (12 from the hIVIG group and 9 from the placebo group) because they did not receive an infusion or their eligibility could not be confirmed. Thus, 308 were included in the primary analysis. hIVIG treatment produced a robust rise in haemagglutination inhibition titres against influenza A and smaller rises in influenza B titres. Based on the proportional odds model, the OR on day 7 was 1·25 (95% CI 0·79–1·97; p=0·33). In subgroup analyses for the pr...

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“…The HAI assay is a well-established approach to evaluate the ability of inactivated influenza vaccine in clinical protection 13 . Clinical data demonstrated that the magnitude of the HAI titer 4 weeks after vaccination correlated with TLR5 expression upregulation in human subjects 4 .…”

Section: Resultsmentioning

confidence: 99%

“…To the best of our knowledge, EGCG3”Me is the first orally delivered exogenous compound to upregulate TLR5 expression. EGCG3”Me enhanced the split-virus vaccine-induced HAI titer, a criterion used to evaluate protective effects of vaccines 13 .…”

Section: Discussionmentioning

confidence: 99%

Methylated (−)-epigallocatechin 3-O-gallate potentiates the effect of split vaccine accompanied with upregulation of Toll-like receptor 5

Kumazoe

Takamatsu

Horie

et al. 2021

Sci Rep

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Split-virus vaccine serves as a major countermeasure against influenza virus, but its effectiveness and protective action are not complete. We previously demonstrated the effect of Benifuuki, a green tea cultivar in Japan, on enhancing the split-virus vaccine–elicited immune response. However, little is known about the detail mechanisms. Here, we show that EGCG3”Me intake significantly potentiated the vaccine-elicited hemagglutination inhibition titer increase. Flow cytometry analysis revealed the increased Toll-like receptor 5 (TLR5) expression after EGCG3”Me treatment in lamina propria dendritic cells (LPDCs) and macrophages, which play crucial roles in the humoral immune system. TLR5 expression correlated with the level of interleukin-6 (IL-6)/C–C chemokine type receptor 5, which are important mediators of the humoral immunity. Taken together, In vivo and ex vivo studies showed that EGCG3”Me potentiated the split-virus vaccine–elicited immune response accompanied with the upregulation of TLR5 in intestine and splenocyte macrophages.

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Influenza Hemagglutination-inhibition Antibody Titer as a Mediator of Vaccine-induced Protection for Influenza B

Cited by 54 publications

References 16 publications

Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial

Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial

Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial

Methylated (−)-epigallocatechin 3-O-gallate potentiates the effect of split vaccine accompanied with upregulation of Toll-like receptor 5

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