Synergy in anti-malarial pre-erythrocytic and transmission-blocking antibodies is achieved by reducing parasite density.

Ellie Sherrard-Smith,Katarzyna A Sala,Andrew M Blagborough,Azra C Ghani,Fiona Angrisano,Thomas S Churcher,Leanna M Upton,Merribeth J Morin,Michael Betancourt

doi:10.7554/elife.35213

Ellie Sherrard-Smith, Katarzyna A Sala + Show 7 more

Open Access

https://doi.org/10.7554/elife.35213

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Abstract

Anti-malarial pre-erythrocytic vaccines (PEV) target transmission by inhibiting human infection but are currently partially protective. It has been posited, but never demonstrated, that co-administering transmission-blocking vaccines (TBV) would enhance malaria control. We hypothesized a mechanism that TBV could reduce parasite density in the mosquito salivary glands, thereby enhancing PEV efficacy. This was tested using a multigenerational population assay, passaging Plasmodium berghei to Anopheles stephensi mosquitoes. A combined efficacy of 90.8% (86.7-94.2%) was observed in the PEV +TBV antibody group, higher than the estimated efficacy of 83.3% (95% CrI 79.1-87.0%) if the two antibodies acted independently. Higher PEV efficacy at lower mosquito parasite loads was observed, comprising the first direct evidence that co-administering anti-sporozoite and anti-transmission interventions act synergistically, enhancing PEV efficacy across a range of TBV doses and transmission intensities. Combining partially effective vaccines of differing anti-parasitic classes is a pragmatic, powerful way to accelerate malaria elimination efforts.

Highlights

Malaria remains a major global health challenge with an estimated 216 million new cases and 445,000 deaths in 2016 (World Health Organization, 2017)
Using statistical methods that explicitly capture parasite density and account for the impact of the interventions on both the prevalence and density of infection (Sherrard-Smith et al, 2017), we estimated pre-erythrocytic stage vaccine (PEV) antibody alone to reduce the prevalence of infection by 48.0% (95% credible interval, CrI, 36.6–58.0%)
The efficacy of multiple PEV and transmission-blocking vaccines (TBV) candidates against rodent and human parasites have been shown to depend on parasite density; TBV efficacy decreases with increased parasite dose (Churcher et al, 2012; Miura et al, 2016) and a representative PEV (RTS,S) only provides sterilizing immunity in volunteers against lightly infected mosquitoes (Churcher et al, 2017)

Summary

Introduction

Malaria remains a major global health challenge with an estimated 216 million new cases and 445,000 deaths in 2016 (World Health Organization, 2017). Whilst current tools have substantially reduced the global burden of disease, new tools will be needed to achieve malaria elimination (Walker et al, 2016). Development of malaria vaccines focused on either the pre-erythrocytic stage vaccine (PEV) – eliciting an immune response to prevent incoming sporozoites from establishing patent infection – or blood-stage – boosting natural responses to surface proteins on the infected erythrocytes (Schwartz et al, 2012). The first malaria vaccine RTS,S/AS01 to complete Phase III trials is a PEV vaccine and has been demonstrated to be partially effective, reducing clinical incidence in 5 – 17-month-old children by 36.3% (95%CI: 31.8 – 40.5%) over 40 months follow-up (RTSS Clinical Trials Partnership, 2015). A range of vaccines that target human-to-mosquito transmission by attacking sexual, sporogonic, and/or mosquito antigens

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