Peripheral blood monocyte-to-lymphocyte ratio at study enrollment predicts efficacy of the RTS,S malaria vaccine: analysis of pooled phase II clinical trial data.

BACKGROUND: RTS,S is the most advanced candidate malaria vaccine but it is only partially protective and the causes of inter-individual variation in efficacy are poorly understood. Here, we investigated whether peripheral blood monocyte-to-lymphocyte ratios (ML ratio), previously shown to correlate with clinical malaria risk, could account for differences in RTS,S efficacy among phase II trial participants in Africa. METHODS: Of 11 geographical sites where RTS,S has been evaluated, pre-vaccination ML ratios were only available for trial participants in Kilifi, Kenya (N = 421) and Lambarene, Gabon (N = 189). Using time to first clinical malaria episode as the primary endpoint we evaluated the effect of accounting for ML ratio on RTS,S vaccine efficacy against clinical malaria by Cox regression modeling. RESULTS: The unadjusted efficacy of RTS,S in this combined dataset was 47% (95% confidence interval (CI) 26% to 62%, P <0.001). However, RTS,S efficacy decreased with increasing ML ratio, ranging from 67% (95% CI 64% to 70%) at an ML ratio of 0.1 to 5% (95% CI -3% to 13%) at an ML ratio of 0.6. The statistical interaction between RTS,S vaccination and ML ratio was still evident after adjustment for covariates associated with clinical malaria risk in this dataset. CONCLUSION: The results suggest that stratification of study participants by ML ratio, easily measured from full differential blood counts before vaccination, might help identify children who are highly protected and those that are refractory to protection with the RTS,S vaccine. Identifying causes of low vaccine efficacy among individuals with high ML ratio could inform strategies to improve overall RTS,S vaccine efficacy. TRIAL REGISTRATION: ClinicalTrials.Gov numbers NCT00380393 and NCT00436007

Quantifying previous SARS-CoV-2 infection through mixture modelling of antibody levels.

As countries decide on vaccination strategies and how to ease movement restrictions, estimating the proportion of the population previously infected with SARS-CoV-2 is important for predicting the future burden of COVID-19. This proportion is usually estimated from serosurvey data in two steps: first the proportion above a threshold antibody level is calculated, then the crude estimate is adjusted using external estimates of sensitivity and specificity. A drawback of this approach is that the PCR-confirmed cases used to estimate the sensitivity of the threshold may not be representative of cases in the wider population-e.g., they may be more recently infected and more severely symptomatic. Mixture modelling offers an alternative approach that does not require external data from PCR-confirmed cases. Here we illustrate the bias in the standard threshold-based approach by comparing both approaches using data from several Kenyan serosurveys. We show that the mixture model analysis produces estimates of previous infection that are often substantially higher than the standard threshold analysis

Children with cerebral malaria or severe malarial anaemia lack immunity to distinct variant surface antigen subsets

Abstract Variant surface antigens (VSAs) play a critical role in severe malaria pathogenesis. Defining gaps, or “lacunae”, in immunity to these Plasmodium falciparum antigens in children with severe malaria would improve our understanding of vulnerability to severe malaria and how protective immunity develops. Using a protein microarray with 179 antigen variants from three VSA families as well as more than 300 variants of three other blood stage P. falciparum antigens, reactivity was measured in sera from Malian children with cerebral malaria or severe malarial anaemia and age-matched controls. Sera from children with severe malaria recognized fewer extracellular PfEMP1 fragments and were less reactive to specific fragments compared to controls. Following recovery from severe malaria, convalescent sera had increased reactivity to certain non-CD36 binding PfEMP1s, but not other malaria antigens. Sera from children with severe malarial anaemia reacted to fewer VSAs than did sera from children with cerebral malaria, and both of these groups had lacunae in their seroreactivity profiles in common with children who had both cerebral malaria and severe malarial anaemia. This microarray-based approach may identify a subset of VSAs that could inform the development of a vaccine to prevent severe disease or a diagnostic test to predict at-risk children

A Plasma Survey Using 38 PfEMP1 Domains Reveals Frequent Recognition of the Plasmodium falciparum Antigen VAR2CSA among Young Tanzanian Children

PfEMP1 proteins comprise a family of variant antigens that appear on the surface of P. falciparum-infected erythrocytes and bind to multiple host receptors. Using a mammalian expression system and BioPlex technology, we developed an array of 24 protein constructs representing 38 PfEMP1 domains for high throughput analyses of receptor binding as well as total and functional antibody responses. We analyzed the reactivity of 561 plasma samples from 378 young Tanzanian children followed up to maximum 192 weeks of life in a longitudinal birth cohort. Surprisingly, reactivity to the DBL5 domain of VAR2CSA, a pregnancy malaria vaccine candidate, was most common, and the prevalence of reactivity was stable throughout early childhood. Reactivity to all other PfEMP1 constructs increased with age. Antibodies to the DBL2βC2PF11_0521 domain, measured as plasma reactivity or plasma inhibition of ICAM1 binding, predicted reduced risk of hospitalization for severe or moderately severe malaria. These data suggest a role for VAR2CSA in childhood malaria and implicate DBL2βC2PF11_0521 in protective immunity

Ape parasite origins of human malaria virulence genes

Antigens encoded by the var gene family are major virulence factors of the human malaria parasite Plasmodium falciparum, exhibiting enormous intra- and interstrain diversity. Here we use network analysis to show that var architecture and mosaicism are conserved at multiple levels across the Laverania subgenus, based on var-like sequences from eight single-species and three multi-species Plasmodium infections of wild-living or sanctuary African apes. Using select whole-genome amplification, we also find evidence of multi-domain var structure and synteny in Plasmodium gaboni, one of the ape Laverania species most distantly related to P. falciparum, as well as a new class of Duffy-binding-like domains. These findings indicate that the modular genetic architecture and sequence diversity underlying var-mediated host-parasite interactions evolved before the radiation of the Laverania subgenus, long before the emergence of P. falciparum