A proof-of-concept study for the design of a VLP-based combinatorial HPV and placental malaria vaccine

Christoph M Janitzek,Susan Thrane,Bryce Chackerian,Ali Salanti,Philip H R Carlsen,Adam F Sander,Morten A Nielsen,Julianne Peabody,Thor G Theander

doi:10.1038/s41598-019-41522-5

Christoph M Janitzek, Susan Thrane + Show 7 more

Open Access

https://doi.org/10.1038/s41598-019-41522-5

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Abstract

In Africa, cervical cancer and placental malaria (PM) are a major public health concern. There is currently no available PM vaccine and the marketed Human Papillomavirus (HPV) vaccines are prohibitively expensive. The idea of a combinatorial HPV and PM vaccine is attractive because the target population for vaccination against both diseases, adolescent girls, would be overlapping in Sub-Saharan Africa. Here we demonstrate proof-of-concept for a combinatorial vaccine utilizing the AP205 capsid-based virus-like particle (VLP) designed to simultaneously display two clinically relevant antigens (the HPV RG1 epitope and the VAR2CSA PM antigen). Three distinct combinatorial VLPs were produced displaying one, two or five concatenated RG1 epitopes without obstructing the VLP’s capacity to form. Co-display of VAR2CSA was achieved through a split-protein Tag/Catcher interaction without hampering the vaccine stability. Vaccination with the combinatorial vaccine(s) was able to reduce HPV infection in vivo and induce anti-VAR2CSA IgG antibodies, which inhibited binding between native VAR2CSA expressed on infected red blood cells and chondroitin sulfate A in an in vitro binding-inhibition assay. These results show that the Tag/Catcher AP205 VLP system can be exploited to make a combinatorial vaccine capable of eliciting antibodies with dual specificity.

Highlights

In Africa, cervical cancer and placental malaria (PM) are a major public health concern
To produce virus-like particle (VLP) which simultaneously display the L2-Human Papillomavirus (HPV) and the VAR2CSA-P. falciparum protein, the SpyCatcher sequence and L2-HPV coding sequences were genetically fused to the 5′ and 3′ ends of the gene coding for AP205 capsid protein, respectively (Fig. 1a)
The final yield of each VLPs was in the range of 25–100 mg/L culture and the VLPs were stable in 4 C for 14 days and in −80 °C for at least 12 months (Supplementary Fig. S1)

Summary

Introduction

In Africa, cervical cancer and placental malaria (PM) are a major public health concern. Cervical cancer is caused by a sexually acquired infection with certain types of Human Papillomavirus (HPV)[1], and causes more than 60,000 deaths annually in sub-Saharan Africa alone[2] This region accounts for 86% of global malaria cases (219 million), including 435,000 malaria related deaths per year[3]. Women are vulnerable to malaria during pregnancy when P. falciparum infections cause placental malaria (PM) (reviewed by[4] and[5]) Both cervical cancer and PM constitute major public health challenges in Sub-Saharan Africa, where people often have limited access to health care (e.g. for regular HPV screening or malaria testing), or the affected individuals may be incapable of paying for expensive vaccines or treatment[2,6]. An effective VAR2CSA-based PM vaccine may need to elicit antibodies that inhibit the binding between placental CSA and VAR2CSA expressed on the surface of infected erythrocytes (iE)[22,23,24]

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