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    • Vaccination strategies designed to induce consistent

    2018-10-23

    Vaccination strategies designed to induce consistent production of bnAbs currently face a number of concerns, including the length of time required to develop the Abs, the amount of somatic hypermutations required to develop strong neutralizing activity, and the relative rarity of B cells capable of inducing bnAb progenitors. We, and others, have clearly demonstrated that ADCC activity can be measured within the first few months following HIV infection in humans, and as early as 3weeks in some NHP studies (Alpert et al., 2012; Dugast et al., 2014a; Chung et al., 2011b). Regarding QA255.157 and QA255.253, the amount of somatic hypermutation recorded for the two CD4i Abs was <10%, similar to that reported from ADCC-mediating Abs identified from RV144 recipients (Bonsignori et al., 2012), but significantly less than the 21% to 37% required for potent bnAbs such as the CD4bs-specific VRC and CH30-34 (Wu et al., 2011; Wu et al., 2010) and the complex V3 glycan-specific PGT families (Walker et al., 2011; Mouquet et al., 2012). Finally, both QA255.157 and QA255.253 were derived from VH1-69 genes but use distinct DH, JH and light chain genes, implying that each antibody originated from a unique B cell, rather than somatic variants of the same B cell. Taken together, these observations suggest that development of a strong ADCC-specific Ab response may be less affected by the challenges associated with development of a robust bnAb response.
    Funding
    Conflict of Interest
    Author Contributions
    Acknowledgments
    Introduction Malaria and iron deficiency (ID) are major public health problems for children living in sub-Saharan Africa. Malaria caused an estimated 437,000 deaths in young African children in 2013 (WHO, 2014) and >70% of children have asymptomatic malaria in some malaria-endemic areas (Houngbedji et al., 2015), while ID is thought to impair cognitive development (Black et al., 2011) and is the leading cause of years lived with disability in sub-Saharan Africa (Vos et al., 2012). Hepcidin, the iron-regulatory hormone, may provide a critical link between malaria and ID. Hepcidin controls the buy CM-272 and distribution of iron (Ganz, 2013) and is thought to play a role in the innate immune response by restricting iron availability for pathogen growth (Ganz, 2009; Drakesmith and Prentice, 2012). The synthesis of hepcidin is regulated by diverse, often competing, physiological processes, including iron stores, inflammation and erythropoietic drive (Ganz, 2011; Atkinson et al., 2014). Malaria also alters hepcidin concentrations. Febrile malaria is associated with increased plasma concentrations (Howard et al., 2007; de Mast et al., 2009; Casals-Pascual et al., 2012; Ayoya et al., 2009), while severe and complicated malaria is associated with reduced plasma levels in African children (Casals-Pascual et al., 2012; Burte et al., 2013). Asymptomatic malaria also increased plasma levels in Indonesian school-age children (de Mast et al., 2010). In turn, we hypothesized that hepcidin may mediate the risk of malaria and other infections by restricting iron availability (Ganz, 2009; Drakesmith and Prentice, 2012). Intriguing data from mouse models suggest that hepcidin may play a critical role in host defence against malaria (Wang et al., 2011), malaria superinfection (Portugal et al., 2011), and bacterial infection (Arezes et al., 2015), but how this may work in children is not known. In the current study, our objectives were to assess the effect of a range of factors including age, gender and malaria on hepcidin concentrations and in turn to assess the effect of hepcidin concentrations on subsequent infectious risk in a longitudinal surveillance study of Kenyan children intensively monitored for malaria and other febrile illnesses.
    Materials and Methods
    Discussion Both malaria and ID are important public health problems in African children. In the current study 12% of children were parasitaemic and 46% had ID. Hepcidin concentrations fell rapidly in infancy and then more slowly with increasing age, while female infants had higher concentrations than males. We found that asymptomatic malaria was associated with significantly elevated hepcidin concentrations, which were proportional to parasite density and modified by age, inflammation, and the presence of ID. Furthermore, hepcidin was positively associated with antibody titres to P. falciparum antigens. Concentrations fell rapidly and then slowly after treatment of clinical malaria, but were not altered by non-malarial febrile illnesses. Nevertheless, hepcidin concentrations did not predict the subsequent risk of malaria or other febrile illnesses.