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A model to assess the efficacy of vaccines for control of liver fluke infection.

ABSTRACT: Fasciola hepatica, common liver fluke, infects cattle and sheep causing disease and production losses costing approximately $3 billion annually. Current control relies on drugs designed to kill the parasite. However, resistance is evident worldwide and widespread in some areas. Work towards a vaccine has identified several antigens of F. hepatica that show partial efficacy in terms of reducing worm burden and egg output. A critical question is what level of efficacy is required for such a vaccine to be useful? We have created the first mathematical model to assess the effectiveness of liver fluke vaccines under simulated field conditions. The model describes development of fluke within a group of animals and includes heterogeneity in host susceptibility, seasonal exposure to metacercariae and seasonal changes in temperature affecting metacercarial survival. Our analysis suggests that the potential vaccine candidates could reduce total fluke burden and egg output by up to 43% and 99%, respectively, on average under field conditions. It also suggests that for a vaccine to be effective, it must protect at least 90% of animals for the whole season. In conclusion, novel, partial, vaccines could contribute substantially towards fasciolosis control, reducing usage of anthelmintics and thus delaying the spread of anthelmintic resistance.

SUBMITTER: Turner J

PROVIDER: S-EPMC4806326 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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Project description:Predictions of vaccine efficacy against Neisseria meningitidis serogroup B (NmB) disease are hindered by antigenic variability, limiting the representativeness of individual NmB isolates. A qualitative human serum bactericidal assay using endogenous complements of individual subjects (enc-hSBA) enables large panels of NmB isolates to be tested. A 110-isolate panel was randomly selected from 442 invasive NmB isolates from United States cases reported to the Centers for Disease Control (CDC) from 2000 to 2008. Typing analyses confirmed the 110-isolate panel is representative of the 442 isolates. The genetic features of the 110-isolate panel were compared against over 4,200 invasive NmB isolates collected from 2000 to 2018 in the United States, Australia, Canada, and nine European countries. Clonal complexes in the 110-isolate panel are also present in each geographical region; cumulative percentages show that these account for around 81% of the clonal complexes found in NmB isolates in other panels. For the antigens (fHbp, NHBA, PorA1.4, NadA) included in the currently licensed meningococcal serogroup B (MenB) vaccines, specifically considering the presence of at least one antigen with a matched genotype, the 110-isolate panel represents approximately 89% of the NmB isolates circulating worldwide, ranging from 87% for the European isolates to 95% and 97% for NmB isolates in the United States and Australia, respectively. The 110-isolate panel includes the most prevalent clonal complexes and genetic variants of MenB vaccine antigens found in a multinational collection of invasive NmB isolates. This panel is useful for assessing the efficacy of MenB vaccines in clinical trials worldwide. IMPORTANCE Neisseria meningitidis serogroup B (NmB) is a major cause of invasive meningococcal disease (IMD). Predicting the effectiveness of vaccines against NmB is difficult because NmB is an uncommon disease and because antigens targeted by meningococcal serogroup B (MenB) vaccines have highly variable genetic features and expression levels. Therefore, a large number of NmB isolates from different regions would need to be tested to comprehensively assess vaccine effectiveness. We examined a panel of 110 isolates obtained from NmB IMD cases in the United States and compared the genetic features of this panel with those of panels from different countries around the world. We found the 110-isolate panel included the most common clonal complexes and genetic variants of MenB vaccine antigens that exist in the global collections of invasive NmB isolates. This confirms the value of the NmB 110-isolate panel in understanding the effectiveness of MenB vaccines in clinical trials worldwide.

Project description:BackgroundTyphoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge.Methods and findingsWe performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model.ConclusionsDespite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge.Trial registrationClinicalTrials.gov (NCT01405521) and EudraCT (number 2011-000381-35).

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A model to assess the efficacy of vaccines for control of liver fluke infection.

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