Understanding the role of polymorphisms in vaccine escape to guide malaria vaccine development and implementation

The leading RTS,S malaria vaccine candidate confers higher protective efficacy against vaccine-like strains than dissimilar strains. Polymorphisms in the target CSP antigen (found within the CT region) may facilitate immune evasion of RTS,S-induced antibodies and contribute to strain-specific vaccine efficacy. Therefore, it is important to investigate polymorphisms in different geographic populations to understand how this may influence vaccine immunogenicity and efficacy.

We will perform sequence analysis of PfCSP-CT polymorphisms using available data from a large open-access global database (MalariaGen Pf3k). We will also include sequences from PNG and 10 other sites being generated by Alyssa’s group. We will evaluate nucleotide and haplotype diversity across sequences, define major allelic groups, and identify sequences that show the most divergence from the RTS,S vaccine strain (NF54/3D7). We will also quantify the prevalence of major allelic groups across populations in the Asia-Pacific region and compare these to those in Africa.

We will select sequences from 3-5 major PfCSP-CT allelic groups (or the most prevalent alleles) in the Asia-Pacific region identified and express these as recombinant proteins. This will be performed using the HEK-293 expression system that is well-established at Burnet Institute. Using this system, we have already expressed full-length PfCSP and PfCSP-CT region of the 3D7 strain5,6. Newly expressed PfCSP-CT variants will be assessed for protein purity and integrity by Western Blot.

We will evaluate whether RTS,S-induced antibodies are cross-reactive against polymorphic PfCSP-CT alleles prevalent in the Asia-Pacific. This will be performed using plasma samples collected from African children vaccinated with RTS,S in a phase 2b clinical trial (samples currently available at Burnet Institute, N=300).

Product Development
Vaccines (Immune Correlates)

Aug 2020 — Oct 2023

$15,000

Australia

Australian Centre for Research Excellence in Malaria Elimination (ACREME)