Can incorporating genotyping data into efficacy estimators improve efficiency of early phase malaria vaccine trials?
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PROVIDER: S-EPMC10543529 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Project description:BackgroundEarly phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as VEHR = 1-hazard ratio or VERR = 1-risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: VEmolFOI, the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VEC, the vaccine-induced proportion reduction in mean number of infecting clones per exposure.MethodsPower of VEmolFOI and VEC was compared to that of VEHR and VERR by simulations and analytic derivations, and the four VE methods were applied to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion.ResultsIn the trial of RTS,S vaccine, a significantly reduced number of clones at first infection was observed, but this was not the case in trials of PfSPZ Vaccine or primaquine, although the PfSPZ trial lacked power to show a reduction. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VEC compared to VEHR for data like those from RTS,S, but VEC is less powerful than VEHR for trials in which the number of clones at first infection is not reduced. VEmolFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VEmolFOI. The primaquine VEmolFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VEmolFOI from improving power.ConclusionsThe power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, these estimators are not recommended as primary endpoints for small trials unless supported by targeted data analysis.Trial registrationsNCT00866619, NCT02663700, NCT02143934.
| S-EPMC10729369 | biostudies-literature
Project description:BACKGROUND:The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical malaria. METHODS:Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity (anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes. We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios. RESULTS:Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001), pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001). Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095). Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a second slower decay over the next three to four years. Antibody titres were significantly associated with protection, with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation rate (EIR)?= 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR?= 20 ibpy, we predict RTS,S will avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include an absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals. CONCLUSIONS:Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy.
| S-EPMC4227280 | biostudies-literature
Project description: Not available
| S-EPMC10258782 | biostudies-literature
Project description:Malaria is a life-threatening global epidemic disease and has caused more than 400,000 deaths in 2019. To control and prevent malaria, the development of a vaccine is a potential method. An effective malaria vaccine should either combine antigens from all stages of the malaria parasite's life cycle, or epitopes of multiple key antigens due to the complexity of the Plasmodium parasite. Malaria's random constructed antigen-1 (M.RCAg-1) is one of the recombinant vaccines, which was selected from a DNA library containing thousands of diverse multi-epitope chimeric antigen genes. Moreover, besides selecting an antigen, using an adjuvant is another important procedure for most vaccine development procedures. Freund's adjuvant is considered an effective vaccine adjuvant for malaria vaccine, but it cannot be used in clinical settings because of its serious side effects. Traditional adjuvants, such as alum adjuvant, are limited by their unsatisfactory immune effects in malaria vaccines, hence there is an urgent need to develop a novel, safe and efficient adjuvant. In recent years, Pickering emulsions have attracted increasing attention as novel adjuvant. In contrast to classical emulsions, Pickering emulsions are stabilized by solid particles instead of surfactant, having pliability and lateral mobility. In this study, we selected aluminum hydroxide gel (termed as "alum") as a stabilizer to prepare alum-stabilized Pickering emulsions (ALPE) as a malaria vaccine adjuvant. In addition, monophosphoryl lipid A (MPLA) as an immunostimulant was incorporated into the Pickering emulsion (ALMPE) to further enhance the immune response. In vitro tests showed that, compared with alum, ALPE and ALMPE showed higher antigen load rates and could be effectively endocytosed by J774a.1 cells. In vivo studies indicated that ALMPE could induce as high antibody titers as Freund's adjuvant. The biocompatibility study also proved ALMPE with excellent biocompatibility. These results suggest that ALMPE is a potential adjuvant for a malaria vaccine.
| S-EPMC8624716 | biostudies-literature
Project description:BackgroundPhase III trials of the malaria vaccine, RTS, S, are now underway across multiple sites of varying transmission intensity in Africa. Heterogeneity in exposure, vaccine response and waning of efficacy may bias estimates of vaccine efficacy.MethodsTheoretical arguments are used to identify the expected effects of a) heterogeneity in exposure to infectious bites; b) heterogeneity in individual's response to the vaccine; and c) waning efficacy on measures of vaccine efficacy from clinical trials for an infection-blocking vaccine.ResultsHeterogeneity in exposure and vaccine response leads to a smaller proportion of trial participants becoming infected than one would expect in a homogeneous setting. This causes estimates of vaccine efficacy from clinical trials to be underestimated if transmission heterogeneity is ignored, and overestimated if heterogeneity in vaccine response is ignored. Waning of vaccine efficacy can bias estimates of vaccine efficacy in both directions.ConclusionsFailure to account for heterogeneities in exposure and response, and waning of efficacy in clinical trials can lead to biased estimates of malaria vaccine efficacy. Appropriate methods to reduce these biases need to be used to ensure accurate interpretation and comparability between trial sites of results from the upcoming Phase III clinical trials of RTS, S.
| S-EPMC2851701 | biostudies-literature
Project description:BackgroundIn a non-inferiority (NI) trial, analysis based on the intention-to-treat (ITT) principle is anti-conservative, so current guidelines recommend analysing on a per-protocol (PP) population in addition. However, PP analysis relies on the often implausible assumption of no confounders. Randomisation-based efficacy estimators (RBEEs) allow for treatment non-adherence while maintaining a comparison of randomised groups. Fischer et al. have developed an approach for estimating RBEEs in randomised trials with two active treatments, a common feature of NI trials. The aim of this paper was to demonstrate the use of RBEEs in NI trials using this approach, and to appraise the feasibility of these estimators as the primary analysis in NI trials.MethodsTwo NI trials were used. One comparing two different dosing regimens for the maintenance of remission in people with ulcerative colitis (CODA), and the other comparing an orally administered treatment to an intravenously administered treatment in preventing skeletal-related events in patients with bone metastases from breast cancer (ZICE). Variables that predicted adherence in each of the trial arms, and were also independent of outcome, were sought in each of the studies. Structural mean models (SMMs) were fitted that conditioned on these variables, and the point estimates and confidence intervals compared to that found in the corresponding ITT and PP analyses.ResultsIn the CODA study, no variables were found that differentially predicted treatment adherence while remaining independent of outcome. The SMM, using standard methodology, moved the point estimate closer to 0 (no difference between arms) compared to the ITT and PP analyses, but the confidence interval was still within the NI margin, indicating that the conclusions drawn would remain the same. In the ZICE study, cognitive functioning as measured by the corresponding domain of the QLQ-C30, and use of chemotherapy at baseline were both differentially associated with adherence while remaining independent of outcome. However, while the SMM again moved the point estimate closer to 0, the confidence interval was wide, overlapping with any NI margin that could be justified.ConclusionDeriving RBEEs in NI trials with two active treatments can provide a randomisation-respecting estimate of treatment efficacy that accounts for treatment adherence, is straightforward to implement, but requires thorough planning during the design stage of the study to ensure that strong baseline predictors of treatment are captured. Extension of the approach to handle nonlinear outcome variables is also required.Trial registrationThe CODA study: ClinicalTrials.gov, identifier: NCT00708656 . Registered on 8 April 2008. The ZICE study trial: ClinicalTrials.gov, identifier: NCT00326820 . Registered on 16 May 2006.
| S-EPMC5343391 | biostudies-literature
Project description:Vaccine clinical trials with active surveillance for infection often use the time to infection as the primary endpoint. A common method of analysis for such trials is to compare the times to infection between the vaccine and placebo groups using a Cox regression model. With new technology, we can sometimes additionally record the precise number of virions that cause infection rather than just the indicator that infection occurred. In this article, we develop a unified approach for vaccine trials that couples the time to infection with the number of infecting or founder viruses. We assume that the instantaneous risk of a potentially infectious exposure for individuals in the placebo and vaccine groups follows the same proportional intensity model. Following exposure, the number of founder viruses X* is assumed to be generated from some distribution on 0,1,…, which is allowed to be different for the two groups. Exposures that result in X*=0 are unobservable. We denote the placebo and vaccine means of X* by μ and μΔ so that 1-Δ measures the proportion reduction in the mean number of infecting virions due to vaccination per exposure. We develop different semi-parametric methods of estimating Δ. We allow the distribution of X* to be Poisson or unspecified, and discuss how to incorporate covariates that impact the time to exposure and/or X*. Interestingly Δ, which is a ratio of untruncated means, can be reliably estimated using truncated data (X*>0), even if the placebo and vaccine distributions of X* are completely unspecified. Simulations of vaccine clinical trials show that the method can reliably recover Δ in realistic settings. We apply our methods to an HIV vaccine trial conducted in injecting drug users.
| S-EPMC4729213 | biostudies-literature
Project description:Most randomized efficacy trials of interventions to prevent HIV or other infectious diseases have assessed intervention efficacy by a method that either does not incorporate baseline covariates, or that incorporates them in a non-robust or inefficient way. Yet, it has long been known that randomized treatment effects can be assessed with greater efficiency by incorporating baseline covariates that predict the response variable. Tsiatis et al. (2007) and Zhang et al. (2008) advocated a semiparametric efficient approach, based on the theory of Robins et al. (1994), for consistently estimating randomized treatment effects that optimally incorporates predictive baseline covariates, without any parametric assumptions. They stressed the objectivity of the approach, which is achieved by separating the modeling of baseline predictors from the estimation of the treatment effect. While their work adequately justifies implementation of the method for large Phase 3 trials (because its optimality is in terms of asymptotic properties), its performance for intermediate-sized screening Phase 2b efficacy trials, which are increasing in frequency, is unknown. Furthermore, the past work did not consider a right-censored time-to-event endpoint, which is the usual primary endpoint for a prevention trial. For Phase 2b HIV vaccine efficacy trials, we study finite-sample performance of Zhang et al.'s (2008) method for a dichotomous endpoint, and develop and study an adaptation of this method to a discrete right-censored time-to-event endpoint. We show that, given the predictive capacity of baseline covariates collected in real HIV prevention trials, the methods achieve 5-15% gains in efficiency compared to methods in current use. We apply the methods to the first HIV vaccine efficacy trial. This work supports implementation of the discrete failure time method for prevention trials.
| S-EPMC2997740 | biostudies-literature
Project description:Controlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events. To optimize power calculations for CHMI-based malaria vaccine trials, we developed a novel non-linear statistical model for parasite kinetics as measured by qPCR, using data from mosquito-based CHMI experiments in 57 individuals. We robustly account for important sources of variation between and within individuals using a Bayesian framework. Study power is most dependent on the number of individuals in each treatment arm; inter-individual variation in vaccine efficacy and the number of blood samples taken per day matter relatively little. Due to high inter-individual variation in the number of first-generation parasites, hepatic vaccine trials required significantly more study subjects than erythrocytic vaccine trials. We provide power calculations for hypothetical malaria vaccine trials of various designs and conclude that so far, power calculations have been overly optimistic. We further illustrate how upcoming techniques like needle-injected CHMI may reduce required sample sizes.
| S-EPMC5230743 | biostudies-literature
Project description:BackgroundA vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use.MethodsWe conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15 μg, 30 μg, or 60 μg respectively of VMP001, all formulated in 500 μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls.ResultsThe vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period.SignificanceThis trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.
| S-EPMC4769081 | biostudies-literature