Genetic diversity of human malaria parasites associated with continued malaria transmission in pre-elimination settings in South Africa

Abstract

South Africa is targeting malaria elimination (halting malaria transmission within the country’s border) by 2023. However, hotspots of stable residual malaria transmission pose a threat to this goal. Whilst several factors associated with continued residual malaria transmission have been investigated, the contribution of parasite genetic diversity in these hotspots and across the southern African region in sustaining transmission has not been critically evaluated. Approaches to eliminate malaria in the country therefore require adoption of novel tools and strategies such as parasite population genetics tools to support better surveillance of the disease in aid of reaching elimination. These tools have successfully been used in eradication programs of other diseases such as polio where it has been shown that genetic diversity influences transmission of these diseases, and their use is gaining momentum in understanding malaria transmission dynamics. Thus, this PhD project aimed to use such tools to evaluate the genetic diversity of Plasmodium falciparum parasites from malaria hotspots in South Africa compared to regionally transmitted parasites to identify contributing factors associated with sustained transmission.

To address the existing knowledge gaps around P. falciparum population genetics in South Africa, this thesis characterised the within-host and population level diversity of P. falciparum parasite populations from the Vhembe District, Limpopo Province, at different spatial and temporal scales (Chapter 2). Consistent with the Vhembe District’s classification as a stable 'high' transmission setting within South Africa, P. falciparum diversity was moderate to high and complex, with less pronounced population structure - all indicative of constant transmission at relatively moderate levels. Whilst this level of genetic diversity in Limpopo was attributed mostly to residual local transmission, in Kwa-Zulu Natal (KZN) Province, a significantly lower transmission setting, similar levels of parasite genetic diversity were attributed to imported infections as indicated in the comparative analysis in Chapter 3. This heterogeneity in transmission settings and parasite populations will therefore have significant implications for malaria control strategies in South Africa and will require differentiation in our approaches to reach our malaria elimination goals. This outcome therefore necessitated comparison of the South African parasite population to regional parasite genotypes to understand P. falciparum transmission dynamics in the southern African region.

As such, a meta-analysis on southern African parasite populations (Chapter 4) was conducted. A total of 5314 samples were analysed, with microsatellite genotyping data collected from studies conducted in Namibia, Eswatini, South Africa and Mozambique. Noteworthy, this thesis revealed that the parasite population was structured and that there was an endogenous circulation of parasites in each of these countries. From an elimination perspective, in a low-transmission elimination setting such as Eswatini, for example, this shows that although imported infections play a significant role in continued transmission, there is also a contribution of locally acquired/generated parasites (parasites of local/internal origin) circulating within the individual countries preventing those countries from "getting to zero" (local) infections. Furthermore, there was some evidence of genetic connectivity of parasites between the different endemic countries, likely due to human migration. This suggests that malaria transmission may be sustained in the region, thus hindering success of control measures and progress towards elimination.

Taken collectively, this thesis addresses relevant knowledge gaps in our understanding of the parasite's contribution to malaria transmission dynamics in South Africa and the southern Africa region on a population genetics level. The data presented here may contribute to better decision making on a national level and for southern Africa as a regional block on what interventions should be put in place, and concentrated in which areas, with the goal of achieving national and regional malaria elimination.