Hemagglutination Inhibition Antibody Titers as a Correlate of Protection Against Seasonal A/H3N2 Influenza Disease (original) (raw)
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Vaccine, 2009
The hemagglutination-inhibition (HI) assay is the main tool used by epidemiologists to quantify antigenic differences between circulating influenza virus strains, with the goal of selecting suitable vaccine strains. However, such quantitative measures of antigenic difference were recently shown to have poor predictive accuracy with respect to influenza vaccine effectiveness (VE) in healthy adults. Here, we re-examine those results using a more rigorous criterion for predictive accuracy -considering only cases when the vaccine (V) and dominant (D) circulating strains are antigenically different -and greater numbers of HI titers. We find that the Archetti-Horsfall measure of antigenic difference, which is based on both the normalized HI titer (NHI) of D relative to antisera raised against V and the NHI of V relative to D, predicts VE very well (R 2 = 0.62, p = 4.1 × 10 −3 ). In contrast, the predictive accuracies of the NHI of D relative to V alone (R 2 = 0.01), and two other measures of antigenic difference based on the amino acid sequence of influenza virus hemagglutinin (R 2 = 0.03 for both measures) are relatively poor. Furthermore, while VE in the elderly is generally high in cases when D and V are antigenically identical (VE = 35%, S.E. = 5%), in other cases VE appears to increase with the antigenic difference between D and V (R 2 = 0.90, p = 2.5 × 10 −5 ). This paradoxical observation could reflect the confounding effects of prior immunity on estimates of VE in the elderly. Together, our results underscore the need for consistently accurate selection of suitable vaccine strains. We suggest directions for further studies aimed at improving vaccine-strain selection and present a large collection of HI titers that will be useful to such studies.
Open Forum Infectious Diseases, 2021
Background Data from a randomized, controlled efficacy trial of an inactivated quadrivalent influenza vaccine in children 6−35 months of age were used to determine whether hemagglutination inhibition (HI) antibody titer against A/H1N1 and A/H3N2 is a statistical correlate of protection (CoP) for the risk of RT-PCR-confirmed influenza associated with the corresponding strain. Methods The Prentice criteria were used to statistically validate strain-specific HI antibody titer as a CoP. The probability of protection was identified using Dunning's model corresponding to a pre-specified probability of protection at an individual level. The group level protective threshold was identified using Siber's approach, leading to unbiased predicted vaccine efficacy (VE). A case-cohort sub-sample was used for this exploratory analysis. Results Prentice criteria confirmed that HI titer is a statistical CoP for RT-PCR-confirmed influenza. Dunning's model predicted a probability of protect...
Vaccine, 2012
Vaccination against influenza induces homologous as well as cross-specific hemagglutination inhibiting (HI) responses. Induction of cross-specific HI responses may be essential when the influenza strain does not match the vaccine strain, or even to confer a basic immune response against a pandemic influenza virus. We carried out a clinical study to evaluate the immunological responses after seasonal vaccination in healthy adults 18-60 years of age, receiving the yearly voluntary vaccination during the influenza season 2006/2007. Vaccinees of different age groups were followed for laboratory confirmed influenza (LCI) and homologous HI responses as well as cross-specific HI responses against the seasonal H1N1 strain of 2008 and pandemic H1N1 virus of 2009 (H1N1pdm09) were determined. Homologous HI titers that are generally associated with protection (i.e. seroprotective HI titers ≥40) were found in more than 70% of vaccinees. In contrast, low HI titers before and after vaccination were significantly associated with seasonal LCI. Cross-specific HI titers ≥40 against drifted seasonal H1N1 were found in 69% of vaccinees. Cross-specific HI titers ≥40 against H1N1pdm09 were also significantly induced, especially in the youngest age group. More specifically, cross-specific HI titers ≥40 against H1N1pdm09 were inversely correlated with age. We did not find a correlation between the subtype of influenza which was circulating at the age of birth of the vaccinees and cross-specific HI response against H1N1pdm09. These data indicate that the HI titers before and after vaccination determine the vaccination efficacy. In addition, in healthy adults between 18 and 60 years of age, young adults appear to be best able to mount a cross-protective HI response against H1N1pdm09 or drifted seasonal influenza after seasonal vaccination.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2014
Recent studies suggest that influenza vaccination in the previous season may influence the effectiveness of current-season vaccination, but this has not been assessed in a single population over multiple years. Patients presenting with acute respiratory illness were prospectively enrolled during the 2004-2005 through 2012-2013 influenza seasons. Respiratory swabs were tested for influenza and vaccination dates obtained from a validated registry. Vaccination status was determined for the current, previous, and prior 5 seasons. Vaccine effectiveness (VE) was calculated for participants aged ≥9 years using logistic regression models with an interaction term for vaccination history. There were 7315 enrollments during 8 seasons; 1056 (14%) and 650 (9%) were positive for influenza A(H3N2) and B, respectively. Vaccination during current only, previous only, or both seasons yielded similar protection against H3N2 (adjusted VE range, 31%-36%) and B (52%-66%). In the analysis using 5 years of...
Vaccine, 2017
The influenza vaccine is less immunogenic in older than younger adults, and the duration of protection is unclear. Determining if protection persists beyond a typical seasonal epidemic is important for climates where influenza virus activity is year-round. A systematic review protocol was developed and registered with PROSPERO [CRD42015023847]. Electronic databases were searched systematically for studies reporting haemagglutination-inhibition (HI) titres 180-360days following vaccination with inactivated trivalent seasonal influenza vaccine, in adults aged ⩾65years. Geometric mean titre (GMT) and seroprotection (HI titre ⩾1:40) at each time point was extracted. A Bayesian model was developed of titre trajectories from pre-vaccination to Day 360. In the meta-analysis, studies were aggregated using a random-effects model to compare pre-vaccination with post-vaccination HI titres at Day 21-42 ('seroconversion'), Day 180 and Day 360. Potential sources of bias were systematicall...
Human vaccines & immunotherapeutics, 2016
In this study we describe the immunogenicity results from a subset of older people (N = 5187) who participated in a Phase 3 randomized, observer-blinded trial of AS03-TIV versus TIV (Fluarix™) (ClinicalTrials.gov, NCT00753272). Participants received one dose of AS03-TIV or TIV in each study year and antibody titers against the vaccine strains were assessed using hemagglutination-inhibition (HI) assay at 21 days and 180 days post-vaccination in each vaccine group in the 2008/09 (Year 1) and 2009/10 (Year 2) influenza seasons. Manufacturing consistency of three lots of AS03-TIV for HI antibody responses in Year 1 was a co-primary objective. In a post-hoc analysis, a statistical regression model included 4830 subjects in whom immunogenicity and laboratory-confirmed attack rate data were available; the analysis was performed to assess HI antibody titers against A/H3N2 as a correlate of protection for laboratory-confirmed A/H3N2 influenza. AS03-TIV and TIV elicited strong HI antibody res...
Vaccine, 1996
The immunogenicity of the trivalent split-virus influenza vaccine was investigated among 70 healthy adults (mean age: 48.5, range. 36-68). The vaccine antigens were. Al Yamagatai32189 (HI Nl); AIBeijingl3.52/89 (H3N2); and BIBangkokll63l90. Regarding the entire sample, the vaccine induced a tenfold or more rise on the average in the hemagglutination inhibition (HAI) antibody to each antigen. The response rates (greater than or equal to a fourfold rise) were about 90% or more among those with a prevaccination titer 11.64 (equivalent to il:16 on the Western scale: in Japan, the HAI titers are expressed by the@nal, and not the initial, dilution of the serum; from hereon our findings will be expressed using the Japanese scale), whereas they were O-50% at 2 1:128. Thus, the prevaccination titer was negatively associated with antibody induction. The achievement rates (postvaccination titer 2 1:128) among those with a prevaccination titer cl.16 remained at 4868%. Regarding the analysis of variance, a significant efiect on antibody induction was indicated for the prevaccination titer (P 10.002), but not for age (P 2 0.425). Th e interaction between the prevaccination titer and age was signtj?cant for AlYamagata (P=O.O30), while it was also suggestive for AlBeijing (PzO.054): as age increased, those with no preexisting antibody (<1:16) showed greater titer rises, in contrast to the smaller rises among those with a titer 2 I:16 Based on the attack survey conducted separately, the vaccine eficacy on influenza-like illnesses with fever 2 3 7°C and 237.5"C was calculated to be 16% (95% confidence interval:-66% to 57%) and 37% (-55% to 74%), respectively.
Biologicals, 2009
For many vaccines the amount of antibodies induced has a positive correlation with the likelihood of clinical protection from disease. Mean antibody level is therefore frequently used as a serological surrogate endpoint for vaccine efficacy. In addition, a dichotomous surrogate endpoint is often defined: seroprotection. We explore the relationship between mean antibody level, seroprotection and clinical protection from influenza, using a simple statistical model. The model reveals that the relationship depends not only on the mean but also on the dispersion of the antibody levels, the threshold for clinical protection and the clinical protection curve. The consequences for the interpretation of mean antibody levels and seroprotection rates in terms of clinical protection from influenza are discussed.