THE ROLE OF LEUKOCYTE-ASSOCIATED IMMUNOGLOBULIN-LIKE RECEPTOR 1 (LAIR1)-BEARING ANTIBODIES IN

Abstract

Malaria, caused by parasites of the Plasmodium genus, was responsible for 241 million cases and over 600,000 deaths globally in 2020. This was an increase from 217 million cases in 2014 despite measures such as vector control using insecticide-treated nets, and insecticide residual spraying being applied. The deaths are high despite the availability of anti-malaria medication, partly due to the emergence of resistance to antimalarial drugs. To augment the control of malaria, several vaccines are in the development pathway. The challenge with vaccine development is the complex biology of the parasite such that in the blood stage, the parasite express variant surface antigens which are highly polymorphic and variant. Therefore, the development of vaccines to this stage requires either targeting conserved epitopes or generation of broadly reactive antibodies. Four studies recently characterised antibodies that contain leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) insert and are broadly reactive to the P. falciparum variant surface antigens (VSA). This study, nested in the Controlled Human Malaria Infection (CHMI) conducted at KWTRP, sought to establish the association between LAIR1-bearing antibodies (LBA) and immunity against malaria. 108 of 142 CHMI study participants came from a region with high malaria transmission and 34 from an area with low malaria transmission. The participants were classified as “treated” or “untreated” depending on whether they became symptomatic or not during follow-up. Pre-challenge (C-1) plasma samples was assayed using ELISA to screen for LBA. The aim was to establish a high throughput assay for LBA screening, to compare the seroprevalence of LBA at C-1 and C+14, to assess the association between LBA and anti-VSA antibody breadth and to evaluate the correlation between prior malaria exposure and LBA levels. Plasma samples from malaria un-exposed UK individuals were used as negative control and 3 standard deviations above their mean absorbance was defined as the positivity cut off. The median vi level of anti-VSA to six parasite isolates was used as proxy for anti-VSA breadth. Anti-schizont antibody response was used as proxy for prior malaria exposure. The seroprevalence of LBA in CHMI samples was 27% (39/142). There was no association between LBA status and malaria endemicity of participants’ residence (Chi-squared test, P= 0.6150). Additionally, although 64% of LBA positive samples were in the untreated group, there was no significant difference in the median LBA across CHMI outcomes (P=0.9610). There was a positive correlation between LBA levels and the number of parasite isolates recognised (Spearman correlation, rho = 0.1875. p-value = 0.02547). Additionally, there was a weak positive correlation between LBA levels and anti-schizont antibody levels (spearman correlation, rho = 0.260821, P-value = 0.001718). In conclusion, nearly a third of the CHMI study participants had LBA and prior malaria parasite exposure seems to drive LBA development. There was a positive correlation between LBA levels and the breadth of anti-VSA antibodies as well as prior malaria exposure. However, there was no association between LBA positivity with CHMI outcomes or the malaria endemicity of participants’ residence.