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. 2020 Nov 3;38(47):7498-7507.
doi: 10.1016/j.vaccine.2020年09月06日9. Epub 2020 Oct 9.

Modelling the roles of antibody titre and avidity in protection from Plasmodium falciparum malaria infection following RTS,S/AS01 vaccination

Affiliations

Modelling the roles of antibody titre and avidity in protection from Plasmodium falciparum malaria infection following RTS,S/AS01 vaccination

Hayley A Thompson et al. Vaccine. .

Abstract

Anti-circumsporozoite antibody titres have been established as an essential indicator for evaluating the immunogenicity and protective capacity of the RTS,S/AS01 malaria vaccine. However, a new delayed-fractional dose regime of the vaccine was recently shown to increase vaccine efficacy, from 62.5% (95% CI 29.4-80.1%) under the original dosing schedule to 86.7% (95% CI, 66.8-94.6%) without a corresponding increase in antibody titres. Here we reanalyse the antibody data from this challenge trial to determine whether IgG avidity may help to explain efficacy better than IgG titre alone by adapting a within-host mathematical model of sporozoite inoculation. We demonstrate that a model incorporating titre and avidity provides a substantially better fit to the data than titre alone. These results also suggest that in individuals with a high antibody titre response that also show high avidity (both metrics in the top tercile of observed values) delayed-fractional vaccination provided near perfect protection upon first challenge (98.2% [95% Credible Interval 91.6-99.7%]). This finding suggests that the quality of the vaccine induced antibody response is likely to be an important determinant in the development of highly efficacious pre-erythrocytic vaccines against malaria.

Keywords: Antibody response; Correlates of protection; Malaria; Mathematical modelling; Predictive vaccine efficacy; Sporozoites.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘ACG has a data-transfer agreement with GSK Vaccines to cover ongoing analysis of trial data related to the RTS,S vaccine. She does not receive any funding from GSK for this work. All other authors declare no competing interests.’.

Figures

Fig. 1
Fig. 1
Sporozoite Infection Model. The sporozoite infection model mathematically captures the parasite and immune dynamics following vaccination and challenge. This schematic conceptualises the model: following mosquito challenge with 5 infectious mosquitos, inoculated sporozoites (k) migrate to the liver, undergo intrahepatic development, and release an initial infectious dose of merozoites (Q). These merozoites cycle through blood stage development until they reach a threshold level for detection. Following vaccination with RTS,S the number of antibodies and the avidity of antibodies (x) will influence the survival probability of the inoculated sporozoites such that the probability that sporozoites will successfully initiate blood stage infection, Sk, will become reduced as function of the immune response: Sk(x). In addition, the antibody immune response will also influence the initial infectious dose of merozoites (Q), if the number of sporozoites that successfully initiate liver stage infection are reduced so too will the initial load of merozoites emerging from the liver which can be related back to longer delays in detection of parasitaemia. If an individual is protected, then we assume all infectious sporozoites will have been prevented from completing liver stage development.
Fig. 2
Fig. 2
Comparisons of model predicted vaccine efficacy resulting from the sporozoite-infection model when (A) anti-NANP IgG antibody titre and avidity are included as predictors of vaccine efficacy and (B) when only anti-NANP IgG antibody titre is included as a predictor of vaccine efficacy. The dashed black line represents equivalent predicted and observed efficacy. Pink points represent the Fx017M volunteers and blue points the 012 M volunteers. Black points represent all trial volunteers grouped into quintiles according to their model predicted vaccine efficacy. Vertical lines represent binomial 95% confidence intervals for observed efficacy in each subgroup. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Distribution of model predicted vaccine efficacy against infection for each volunteer (n46) in the challenge trial by vaccination schedule arm. This shows there is significant variation in predicted efficacy but with a large proportion of volunteers falling in the higher (>80%) vaccine efficacy. The heterogeneity in individual predicted vaccine efficacy results from the underlying heterogeneity in immune measurements between individuals. As there is no threshold of protection for immune measurements, we see this efficacy distribution of the delayed-fractional regime that is characteristic of a leaky vaccine.
Fig. 4
Fig. 4
Predicted efficacy against infection as a function of anti-NANP IgG antibody titre (ELISA Units) and avidity index. Vertical dashed lines represent the median and 90% ranges of the observed antibody titres. Horizontal dashed lines represent the median and 90% ranges of the observed avidity index measurements. Isoclines represent the 30%, 50%, 70% and 90% estimated vaccine efficacies for combinations of avidity and titre. Green represents infected volunteers and white protected volunteers, * the Fx017M arm and • the 012 M arm. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Fig. 5
Predicted vaccine efficacy against infection for (A) increasing IgG avidities predicted at the median levels of IgG antibody titre (ELISA Units) observed in the challenge study and (B) for increasing IgG antibody titre (ELISA Units) predicted at the median IgG avidity measurement from volunteers in the challenge study. Histogram showing the distribution of avidity indices and titres respectively from vaccinated volunteers across both vaccine schedule arms. Median levels from the study avidity index: 53.5 and titre: 29,459 ELISA Units. The shaded regions represent the 95% prediction intervals of the estimated vaccine efficacy.

References

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