PlacMalVac

Clinical development of a var2CSA-based placental malaria vaccine candidate

Background

Women, who have acquired immunity against malaria during childhood, nevertheless become susceptible to malaria again during their first pregnancies.  Parasites accumulate in the placenta, where a combination of altered blood flow and expression of chondroitin sulphate A (CSA) provides a new niche for parasites to sequester.  Fortunately, women can acquire immunity against placental malaria (PM) and in malaria endemic areas the average birth weight is significantly higher among second and third- compared to first-born babies1,2.  This relatively fast development of protection has raised the hope that a vaccine for PM can be developed.

In 2003, var2CSA was identified at Centre for Medical Parasitology (CMP), University of Copenhagen (UCPH) as the parasite protein which enable parasite accumulation in the placenta3.  The aim of a var2CSA based PM vaccine is to induce antibodies that can hinder adhesion in the placenta followed by destruction of infected red blood cells in the spleen.

Through different supports and collaboration, Ali Salanti’s group (CMP, UCPH) has identified subunits of the var2CSA protein that induce highly inhibitory and cross-inhibitory IgGs which have been successfully produced in small scale in S2 cells at ExpreS2ion Biotechnologies.  The PAMCPH project is supporting the selection of the optimal antigen adjuvant var2CSA vaccine formulation and its production under cGood Manufacturing Practice allowing its use in clinical trials.

Objectives

One objective of the project is to conduct a phase I clinical trial with the PM vaccine from PAMCPH.  Another objective is the implementation of a field site and a protocol for a phase II clinical trial in African women.  Under the proposed project an Small and  Medium Enterprises, ExpreS2ion Biotechnologies will optimise production and purification of the vaccine antigen, a complex protein not compatible with traditional vaccine production platforms.  The academic partners are researchers at UCPH collaborating with Institut de Recherche pour le Développement (IRD), Université d'Abomey-Calavi (UAC) to optimise vaccine antigens and to prepare sites for phase II clinical testing and with University of Tübingen for the phase I clinical trial.  EVI will provide product management and coordinate execution of the phase I clinical trial.

The project is organised in six work package groups:

1. Management of the project

2. Formulation development and selection of adjuvant and analytical development

3. Upstream and downstream process development

4. Process up-scaling, manufacturing, and optimisation

5. Clinical trial phase Ia/Ib

6. Preparation for phase II clinical trial

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Major Milestones

  • Definition of protein adjuvant formulation for the clinical trials
  • Optimisation of the production of the vaccine antigen
  • Protocol of the phase I clinical trial
  • Phase I clinical trial approval by regulatory authorities and independent ethic committees
  • Definition of the end-points of efficacy and the number of subjects required for the phase II clinical trial.

References:

  1. Brabin BJ. An analysis of malaria in pregnancy in Africa. Bull World Health 1983;61(6):1005-16.
  2. McGregor IA, Wilson ME, Billewicz WZ. Malaria Infection of the Placenta in the Gambia, West-Africa - Its Incidence and Relationship to Stillbirth, Birth-Weight and Placental Weight. Transactions of the Royal Society of Tropical Medicine and Hygiene 1983;77(2):232-44.
  3. Salanti A, Staalsoe T, Lavstsen T, Jensen AT, Sowa MP, Arnot DE, et al. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol Microbiol. 2003 Jul;49(1):179-91.

Publications

Malar J (2016) 15:476 DOI 10.1186/s12936-016-1527-8