A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine

White, Michael; Bejon, Philip; Olotu, Ally; Griffin, Jamie T.; Bojang, Kalifa; Lusingu, John PA; Salim, Nahya; Abdulla, Salim; Otsyula, Nekoye; Agnandji, Selidji Todagbé; Lell, Bertrand; Asante, Kwaku Poku; Owusu‐Agyei, Seth; Mahama, Emmanuel; Agbenyega, Tsiri; Ansong, Daniel; Sacarlal, Jahit; Aponte, John J.; Ghani, Azra C

doi:10.1186/preaccept-5212460251240508

Cited by 26 publications

(34 citation statements)

References 32 publications

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“…In particular, biphasic models that model both short-term antibody decay and longer-term antibody decay with different exponential decay rates have been shown to work well in other systems, such as malaria 36 . The biphiasic form is captured by:

{Titer}_{normalt} = θ_{1} \cdot (θ_{2} \cdot exp (- θ_{3} t) + (1 - θ_{2}) \cdot exp (- θ_{4} t))

where θ 1 , θ 2 , θ 3 and θ 4 capture the decay of the titers.…”

Section: Methodsmentioning

confidence: 99%

Reconstruction of antibody dynamics and infection histories to evaluate dengue risk

Salje

Cummings

Rodríguez-Barraquer

et al. 2018

Nature

236

261

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As with many pathogens, most dengue infections are subclinical and therefore unobserved1. Coupled with limited understanding of the dynamical behavior of potential serological markers of infection, this observational problem has wide-ranging implications, including hampering our understanding of individual- and population-level correlates of infection and disease risk and how they change over time, assay interpretation and cohort design. We develop a framework that simultaneously characterizes antibody dynamics and identifies subclinical infections via Bayesian augmentation from detailed cohort data (3,451 individuals with blood draws every 91 days, 143,548 hemagglutination inhibition assay titer measurements)2,3. We identify 1,149 infections (95% CI: 1,135–1,163) that were not detected by active surveillance and estimate that 65% of infections are subclinical. Post infection, individuals develop a stable setpoint antibody load after 1y that places them within or outside a risk window. Individuals with pre-existing titers of ≤1:40 develop hemorrhagic fever 7.4 (95% CI: 2.5–8.2) times as often as naïve individuals compared to 0.0 times for individuals with titers >1:40 (95% CI: 0.0–1.3). PRNT titers ≤1:100 were similarly associated with severe disease. Across the population, variability in the force of infection results in large-scale temporal changes in infection and disease risk that correlate poorly with age.

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{Titer}_{normalt} = θ_{1} \cdot (θ_{2} \cdot exp (- θ_{3} t) + (1 - θ_{2}) \cdot exp (- θ_{4} t))

where θ 1 , θ 2 , θ 3 and θ 4 capture the decay of the titers.…”

Section: Methodsmentioning

confidence: 99%

Reconstruction of antibody dynamics and infection histories to evaluate dengue risk

Salje

Cummings

Rodríguez-Barraquer

et al. 2018

Nature

236

261

View full text Add to dashboard Cite

show abstract

“…However, during immunization regimes where sporozoites are used as live attenuated parasite vaccines, the large number of parasites arriving at the lymph node does elicit protective immune responses in mice [36,38]. Importantly, RTS,S, the only malaria vaccine candidate that has demonstrated any efficacy in Phase III trials, is a subunit vaccine based on CSP, and follow-up studies generally suggest that protection is correlated to antibody titers [39][40][41]. It is possible that these antibodies primarily target sporozoites in the skin, where they spend most of their time before invading hepatocytes.…”

mentioning

confidence: 97%

Active migration and passive transport of malaria parasites

Douglas

Amino

Sinnis

et al. 2015

Trends in Parasitology

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“…With respect to protective immune responses, much is still incompletely understood despite numerous recent analyses [36][37][38][39][40]. While antibody levels and to a lesser extend cell mediated immune responses, have been shown to associate with protection against malaria infection, a definitive correlate of protection remains elusive.…”

Section: Phase III Programmentioning

confidence: 98%

“…The indication is for active immunization of children aged 6 weeks up to 17 months against malaria caused by P. falciparum and against [1]) and completed in 2014 [34]. GSK submitted a regulatory application to the European Medicines Agency (EMA) for review under the Article 58 procedure in 2014 [39]. The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion in July 2015 [6].…”

Section: Introductionmentioning

confidence: 99%

RTS,S: Toward a first landmark on the Malaria Vaccine Technology Roadmap

Kaslow

Biernaux

2015

Vaccine

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The Malaria Vaccine Technology Roadmap calls for a 2015 landmark goal of a first-generation malaria vaccine that has protective efficacy against severe disease and death, lasting longer than one year. This review focuses on product development efforts over the last five years of RTS,S, a pre-erythrocytic, recombinant subunit, adjuvanted, candidate malaria vaccine designed with this goal of a first-generation malaria vaccine in mind. RTS,S recently completed a successful pivotal Phase III safety, efficacy and immunogenicity study. Although vaccine efficacy was found to be modest, a substantial number of cases of clinical malaria were averted over a 3-4 years period, particularly in settings of significant disease burden. European regulators have subsequently adopted a positive opinion under the Article 58 procedure for an indication of active immunization of children aged 6 weeks up to 17 months against malaria caused by Plasmodium falciparum and against hepatitis B. Further evaluations of the benefit, risk, feasibility and cost-effectiveness of RTS,S are now anticipated through policy and financing reviews at the global and national levels.

show abstract

A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine

Abstract: 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.

Cited by 26 publications

References 32 publications

Reconstruction of antibody dynamics and infection histories to evaluate dengue risk

Reconstruction of antibody dynamics and infection histories to evaluate dengue risk

Active migration and passive transport of malaria parasites

RTS,S: Toward a first landmark on the Malaria Vaccine Technology Roadmap

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