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Limited available evidence supports theoretical predictions of reduced vaccine efficacy at higher exposure dose.

ABSTRACT: Understanding the causes of vaccine failure is important for predicting disease dynamics in vaccinated populations and planning disease interventions. Pathogen exposure dose and heterogeneity in host susceptibility have both been implicated as important factors that may reduce overall vaccine efficacy and cause vaccine failure. Here, we explore the effect of pathogen dose and heterogeneity in host susceptibility in reducing efficacy of vaccines. Using simulation-based methods, we find that increases in pathogen exposure dose decrease vaccine efficacy, but this effect is modified by heterogeneity in host susceptibility. In populations where the mode of vaccine action is highly polarized, vaccine efficacy decreases more slowly with exposure dose than in populations with less variable protection. We compared these theoretical results to empirical estimates from a systematic literature review of vaccines tested over multiple exposure doses. We found that few studies (nine of 5,389) tested vaccine protection against infection over multiple pathogen challenge doses, with seven studies demonstrating a decrease in vaccine efficacy with increasing exposure dose. Our research demonstrates that pathogen dose has potential to be an important determinant of vaccine failure, although the limited empirical data highlight a need for additional studies to test theoretical predictions on the plausibility of reduced host susceptibility and high pathogen dose as mechanisms responsible for reduced vaccine efficacy in high transmission settings.

SUBMITTER: Langwig KE

PROVIDER: S-EPMC6397254 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Limited available evidence supports theoretical predictions of reduced vaccine efficacy at higher exposure dose.

Langwig Kate E KE Gomes M Gabriela M MGM Clark Mercedes D MD Kwitny Molly M Yamada Steffany S Wargo Andrew R AR Lipsitch Marc M

Scientific reports 20190301 1

Understanding the causes of vaccine failure is important for predicting disease dynamics in vaccinated populations and planning disease interventions. Pathogen exposure dose and heterogeneity in host susceptibility have both been implicated as important factors that may reduce overall vaccine efficacy and cause vaccine failure. Here, we explore the effect of pathogen dose and heterogeneity in host susceptibility in reducing efficacy of vaccines. Using simulation-based methods, we find that incre ...[more]

PMID: 30824732

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Project description:Background and objectivesOcrelizumab improved clinical and MRI measures of disease activity and progression in three phase 3 multiple sclerosis (MS) studies. Post hoc analyses demonstrated a correlation between the ocrelizumab serum concentration and the degree of blood B-cell depletion, and body weight was identified as the most influential covariate on ocrelizumab pharmacokinetics. The magnitude of ocrelizumab treatment benefit on disability progression was greater in lighter vs heavier patients. These observations suggest that higher ocrelizumab serum levels provide more complete B-cell depletion and a greater delay in disability progression. The current post hoc analyses assessed population exposure-efficacy/safety relationships of ocrelizumab in patients with relapsing and primary progressive MS.MethodsPatients in OPERA I/II and ORATORIO were grouped in exposure quartiles based on their observed individual serum ocrelizumab level over the treatment period. Exposure-response relationships were analyzed for clinical efficacy (24-week confirmed disability progression (CDP), annualized relapse rate [ARR], and MRI outcomes) and adverse events.ResultsOcrelizumab reduced new MRI lesion counts to nearly undetectable levels in patients with relapsing or primary progressive MS across all exposure subgroups, and reduced ARR in patients with relapsing MS to very low levels (0.13-0.18). A consistent trend of higher ocrelizumab exposure leading to lower rates of CDP was seen (0%-25% [lowest] to 75%-100% [highest] quartile hazard ratios and 95% confidence intervals; relapsing MS: 0.70 [0.41-1.19], 0.85 [0.52-1.39], 0.47 [0.25-0.87], and 0.34 [0.17-0.70] vs interferon β-1a; primary progressive MS: 0.88 [0.59-1.30], 0.86 [0.60-1.25], 0.77 [0.52-1.14], and 0.55 [0.36-0.83] vs placebo). Infusion-related reactions, serious adverse events, and serious infections were similar across exposure subgroups.DiscussionThe almost complete reduction of ARR and MRI activity already evident in the lowest quartile, and across all ocrelizumab-exposure groups, suggests a ceiling effect. A consistent trend of higher ocrelizumab exposure leading to greater reduction in risk of CDP was observed, particularly in the relapsing MS trials, and was not associated with a higher rate of adverse events. Higher ocrelizumab exposure may provide improved control of disability progression by reducing disease activity below that detectable by ARR and MRI, and/or by attenuating other B-cell-related pathologies responsible for tissue damage.Classification of evidenceThis analysis provides Class III evidence that higher ocrelizumab serum levels are related to greater reduction in risk of disability progression in patients with multiple sclerosis. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in the open-label extension.Trial registration informationClinicalTrials.gov Identifier: NCT01247324 (OPERA I), NCT01412333 (OPERA II), and NCT01194570 (ORATORIO).

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Limited available evidence supports theoretical predictions of reduced vaccine efficacy at higher exposure dose.

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Limited available evidence supports theoretical predictions of reduced vaccine efficacy at higher exposure dose.

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