Fabrice Bailleux

Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model

BackgroundAntibodies directed against haemagglutinin, measured by the haemagglutination inhibition (HI) assay are essential to protective immunity against influenza infection. An HI titre of 1:40 is generally accepted to correspond to a 50% reduction in the risk of contracting influenza in a susceptible population, but limited attempts have been made to further quantify the association between HI titre and protective efficacy.MethodsWe present a model, using a meta-analytical approach, that estimates the level of clinical protection against influenza at any HI titre level. Source data were derived from a systematic literature review that identified 15 studies, representing a total of 5899 adult subjects and 1304 influenza cases with interval-censored information on HI titre. The parameters of the relationship between HI titre and clinical protection were estimated using Bayesian inference with a consideration of random effects and censorship in the available information.ResultsA significant and positive relationship between HI titre and clinical protection against influenza was observed in all tested models. This relationship was found to be similar irrespective of the type of viral strain (A or B) and the vaccination status of the individuals.ConclusionAlthough limitations in the data used should not be overlooked, the relationship derived in this analysis provides a means to predict the efficacy of inactivated influenza vaccines when only immunogenicity data are available. This relationship can also be useful for comparing the efficacy of different influenza vaccines based on their immunological profile.

Vaccination of immunocompetent elderly subjects with a live attenuated Oka strain of varicella zoster virus : a randomized, controlled, dose-response trial

After primary infection in childhood, varicella zoster virus (VZV) remains latent in the dorsal route ganglia. Its reactivation later in life can lead to a zoster episode. VZV-specific, T-cell-mediated immunity (VZV-CMI) is likely to be important in preventing symptomatic reactivation. As CMI declines with age, a vaccine enhancing VZV-CMI might be effective in decreasing the incidence or severity of zoster in elderly subjects. A randomized, double blind controlled trial assessing CMI responses of elderly subjects immunized with a live attenuated, VZV-Oka vaccine was conducted. Two hundred healthy volunteers (55-75 years of age) received either a single injection of the VZV vaccine (PMC), containing 3200 (Oka 3200), 8500 (Oka 8500), or 41,650 (Oka 41650) PFU of live VZV, or a pneumococcus vaccine control group (Pneumo 23((R)). The immune response to VZV was assessed by measuring the T-cell response to VZV antigens, i.e. proliferation (stimulation index, SI), precursor cell frequency (PCF), cytokine secretion, and antibody titers. Six weeks post-vaccination, VZV-specific SI (adjusted mean values) was significantly greater (P<0.0001) in the 3 vaccine groups (with SI=5. 6 for Oka 3200; SI=5.0 for Oka 8500, and SI=7.2 for Oka 41,650) than in the control group (SI=2.9). The increase in PCF was striking, with 72.4, 91.2 and 85.1 precursors per million cells respectively in these 3 vaccine groups, vs 26.3 in the control group. No significant IL-4 secretion was observed in any subject, whereas the presence of IFN-gamma secretion was found to correlate with good responder status. The increase of these CMI parameters did not depend upon the titer of virus injected. Geometric mean titers of VZV antibodies increased in all vaccine groups and remained unchanged in the control group. Nevertheless, no correlation between the antibody response and the cell-mediated response was found. Live attenuated VZV vaccine caused a significant increase in VZV-CMI in a healthy, elderly population. No relationship between vaccine dose and the intensity of the specific response was found.

Avidity and Subclasses of IgG after Immunization of Infants with an 11-Valent Pneumococcal Conjugate Vaccine with or without Aluminum Adjuvant

Finnish and Israeli infants received an 11-valent mixed-carrier pneumococcal conjugate vaccine with or without aluminum adjuvant at 2, 4, 6, and 12 months of age. The relative avidity of serotype 1-, 5-, 6B-, 14-, 19F-, and 23F-specific IgG antibodies in serum obtained at 7, 12, and 13 months of age was measured by EIA, using thiocyanate as a chaotropic agent. For all serotypes, except 14, avidity increased between the ages of 7 and 12 months. After boosting at 12 months, avidity further increased for all serotypes. The adjuvant improved antibody avidity against serotype 5. The IgG antibodies produced were mainly IgG1 subclass, although some infants also produced IgG2 after boosting. In conclusion, the immunization of infants with this 11-valent pneumococcal conjugate vaccine increased avidity of IgG, suggesting successful immunologic priming.

Tolerability and immunogenicity of an eleven valent mixed carrier Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid or tetanus protein conjugate vaccine in Finnish and Israeli infants.

Background. To have wide global coverage of pneumococcal serotypes, the number of serotypes covered by the current 7-valent pneumococcal conjugate vaccine must be increased. We have studied the safety and immunogenicity of an 11-valent mixed carrier vaccine (PncDT11) in infants. Methods. The study vaccine contained polysaccharide antigens of serotypes 1, 4, 5, 7F, 9V, 19F and 23F conjugated to tetanus protein and serotypes 3, 6B, 14 and 18C conjugated to diphtheria toxoid. The vaccine was administered to Finnish (n = 117) and Israeli (n = 135) infants at ages 2, 4, 6 and 12 months concomitantly with other vaccines used in national vaccination programs. IgG antibodies to polysaccharides were determined by enzyme immunoassay from serum samples taken at ages 2, 7, 12 and 13 months. After each injection the infants were followed for 30 min to detect any immediate adverse reactions, and parents were given a diary card to report any adverse events during the next 5 days. Results. No severe adverse reactions occurred, and immediate adverse reactions were rare. After each dose ∼30% of the vaccinees experienced local reactions of which pain was the most common. Fever of >38°C was reported in 33 to 53% of the vaccinees and high fever (>40°C) was reported 6 times. The PncDT11 vaccine was immunogenic. The antibody concentrations after primary immunization series were higher in Israeli than in Finnish infants, but the differences were not significant for most serotypes. The difference was most marked at 13 months, a time point at which the difference was significant in 10 of 11 serotypes. Conclusion. PncDT11 is safe and immunogenic in infants. The use of 11-valent pneumococcal vaccine would increase the serotype coverage beyond the currently available 7-valent vaccine.

Predicted long-term persistence of pertussis antibodies in adolescents after an adolescent and adult formulation combined tetanus, diphtheria, and 5-component acellular pertussis vaccine, based on mathematical modeling and 5-year observed data.

In a clinical trial, adolescents who had received a booster dose of reduced dose diphtheria-tetanus-5-component acellular pertussis vaccine (Adacel, Tdap) 5 years earlier maintained increased antibody concentrations to all antigens compared with pre-vaccination values. Observed data were applied to several mathematical models designed to predict further antibody decay for pertussis antigens. A linear mixed model including a random-intercept term provided the best fit for the observed data and was used for predictions. The predicted times for sufficient antibody decay to reach pre-vaccination levels were 15.3 years (95% CI: 7.0-28.0) for pertactin, 11.0 years (5.7-18.9) for fimbriae types 2 and 3, 10.5 years (3.6-24.7) for pertussis toxoid and 9.5 years (4.2-24.6) for filamentous hemagglutinin. For at least 87% of subjects, the 10-year predicted antibody concentration was higher than the limit of quantitation (LOQ) for each pertussis antigen measured. These results support Tdap booster doses every 10 years, following the current schedule for Td vaccination.

A dose-response study of a live attenuated varicella-zoster virus (Oka strain) vaccine administered to adults 55 years of age and older

Decreased cell-mediated immune (CMI) response to varicella-zoster virus (VZV) is correlated with an increased risk of reactivation of latent virus from dorsal root sites, leading to herpes zoster. The cell-mediated and humoral immunogenicity of three concentrations (3200, 8500, and 41,650 pfu/dose) of a live attenuated VZV vaccine (Oka strain; VZV/Oka) was compared with a control pneumococcal polysaccharide vaccine in 200 healthy adults who were > or = 55 years old. Six weeks after vaccination, the VZV-specific CMI response (as measured by stimulation index values and precursor cell frequencies) was enhanced in all VZV/Oka vaccine groups compared with the control group (for all VZV/Oka groups combined vs. controls, tested with VZV crude antigen: stimulation index, P < .001; precursor cell frequency, P < .001). Geometric mean titers of anti-VZV antibodies increased in all VZV/Oka vaccine groups but remained unchanged in the control vaccine group. No dose effect of VZV/Oka vaccine was observed for CMI or humoral responses.

A new approach to estimate vaccine efficacy based on immunogenicity data applied to influenza vaccines administered by the intradermal or intramuscular routes

Background Despite their pivotal role in the assessment of influenza vaccines, limited attempts have been made to use hemagglutination inhibition (HI) titers for predicting vaccine efficacy against laboratory-confirmed influenza. We present here the second step of a two-step approach allowing performing such predictions and use it to compare a new trivalent inactivated influenza vaccine administered by the intradermal (ID) route (INTANZA®/IDFlU®) with the vaccine administered by the classical intramuscular (IM) route. Results Pooling all available immunogenicity data, the predicted vaccine efficacy was 63.3% [CI: 58.1; 68.7] for ID route and 54.4% [CI: 49.4; 59.2] for IM route. The corresponding relative increase in efficacy was 16.5% [CI: 12.7; 20.1]. Predicted vaccine efficacies decreased with age for both vaccines, but the decrease was less marked by ID route: the relative increase in efficacy for subjects aged 70 years and above is of 18.0% [CI:12;24]: Methods The first step corresponding to the estimation of the level of protection against laboratory-confirmed influenza that can be linked to each HI titer, referred to as the HI protection curve, was achieved by using a meta-analytical approach based on published information. Vaccine efficacy and differences in vaccine efficacy are predicted in a second step using this HI protection curve alongside the results of two randomized clinical trials providing comparative information on the immunogenicity of trivalent inactivated influenza vaccines administered ID or IM in 3,503 & 1,645 elderly participants, respectively. Conclusion The analysis performed confirmed that the superior immune response provided by the vaccine using the ID route should translate into a higher vaccine efficacy against laboratory-confirmed influenza.

Some extensions in continuous models for immunological correlates of protection

BackgroundA scaled logit model has previously been proposed to quantify the relationship between an immunological assay and protection from disease, and has been applied in a number of settings. The probability of disease was modelled as a function of the probability of exposure, which was assumed to be fixed, and of protection, which was assumed to increase smoothly with the value of the assay.MethodsSome extensions are here investigated. Alternative functions to represent the protection curve are explored, applications to case-cohort designs are evaluated, and approaches to variance estimation compared. The steepness of the protection curve must sometimes be bounded to achieve convergence and methods for doing so are outlined. Criteria for evaluating the fit of models are proposed and approaches to assessing the utility of results suggested. Models are evaluated by application to sixteen datasets from vaccine clinical trials.ResultsAlternative protection curve functions improved model evaluation criteria for every dataset. Standard errors based on the observed information were found to be unreliable; bootstrap estimates of precision were to be preferred. In most instances, case-cohort designs resulted in little loss of precision. Some results achieved suggested measures for utility.ConclusionsThe original scaled logit model can be improved upon. Evaluation criteria permit well-fitting models and useful results to be identified. The proposed methods provide a comprehensive set of tools for quantifying the relationship between immunological assays and protection from disease.

Modeling the long-term persistence of neutralizing antibody in children and toddlers after vaccination with live attenuated Japanese encephalitis chimeric virus vaccine

ABSTRACT The live-attenuated Japanese encephalitis chimeric virus vaccine JE-CV (IMOJEV®, Sanofi Pasteur) elicits a robust antibody response in children, which wanes over time. Clinical efficacy is based on a correlate of protection against JE infection defined as neutralizing antibody levels equal to or greater than the threshold of 10 (1/dil). Information on the duration of persistence of the JE antibody response above this threshold is needed. We constructed statistical models using 5-year persistence data from a randomised clinical trial (NCT00621764) in children (2–5 years old) primed with inactivated JE vaccine who received a booster dose of JE-CV, and in JE-naïve toddlers (12–24 months) who received a JE-CV single dose primary vaccination. Models were constructed using a Bayesian Monte-Carlo Markov Chain approach and implemented with OpenBugs V3.2.1. Antibody persistence was predicted for up to 10 years following JE-CV vaccination. Findings from a piecewise model with 2 phases (children) and a classic linear model (toddlers) are presented. For children, predicted median antibody titers (77 [2.5th–97.5th percentile range 41–144] 1/dil) remained above the threshold for seroprotection over the 10 years following booster JE-CV vaccination; the predicted median duration of protection was 19.5 years. For toddlers, 10 years after JE-CV primary vaccination median antibody titers were predicted to wane to around the level required for seroprotection (10.8 [5.8–20.1] 1/dil). A booster dose of JE-CV in children is predicted to provide long-term protection against JE. Such data are useful to facilitate decisions on implementation of and recommendations for future vaccination strategies.

Erratum to: A threshold method for immunological correlates of protection

Background: Immunological correlates of protection are biological markers such as disease-specific antibodies which correlate with protection against disease and which are measurable with immunological assays. It is common in vaccine research and in setting immunization policy to rely on threshold values for the correlate where the accepted threshold differentiates between individuals who are considered to be protected against disease and those who are susceptible. Examples where thresholds are used include development of a new generation 13-valent pneumococcal conjugate vaccine which was required in clinical trials to meet accepted thresholds for the older 7-valent vaccine, and public health decision making on vaccination policy based on long-term maintenance of protective thresholds for Hepatitis A, rubella, measles, Japanese encephalitis and others. Despite widespread use of such thresholds in vaccine policy and research, few statistical approaches have been formally developed which specifically incorporate a threshold parameter in order to estimate the value of the protective threshold from data. Methods: We propose a 3-parameter statistical model called the a:b model which incorporates parameters for a threshold and constant but different infection probabilities below and above the threshold estimated using profile likelihood or least squares methods. Evaluation of the estimated threshold can be performed by a significance test for the existence of a threshold using a modified likelihood ratio test which follows a chi-squared distribution with 3 degrees of freedom, and confidence intervals for the threshold can be obtained by bootstrapping. The model also permits assessment of relative risk of infection in patients achieving the threshold or not. Goodness-of-fit of the a:b model may be assessed using the Hosmer-Lemeshow approach. The model is applied to 15 datasets from published clinical trials on pertussis, respiratory syncytial virus and varicella. Results: Highly significant thresholds with p-values less than 0.01 were found for 13 of the 15 datasets. Considerable variability was seen in the widths of confidence intervals. Relative risks indicated around 70% or better protection in 11 datasets and relevance of the estimated threshold to imply strong protection. Goodness-of-fit was generally acceptable. Conclusions: The a:b model offers a formal statistical method of estimation of thresholds differentiating susceptible from protected individuals which has previously depended on putative statements based on visual inspection of data.