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Individuals with antibody levels >1 AU and >0.2 OD were considered responsive to MSP-142 and TT, respectively.
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Clinical immunity to malaria declines in the absence of repeated parasite exposure. However, little is known about how B cell populations and antigen-specific memory B cells change in the absence of P. falciparum infection. A successful indoor residual insecticide spraying campaign in a highland area of western Kenya, led to an absence of blood-sta...
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Citations
... An expansion of PB CD21-/lowCD27-CD11c+, mainly IgG+, MBCs has been described in children persistently exposed to malaria [50] and individuals in malaria-endemic areas [51,52]. Post-treatment, as patients become A c c e p t e d M a n u s c r i p t free from parasites, they no longer present with high CD21-/low B-cell frequencies [53]. The immune response to P. falciparum infections is dynamic, as observed in acutely infected and previously exposed individuals, where mainly CD21-/low CD11c+ B cells are first expanded and then decrease as the infection resolves [54]. ...
Memory B cells (MBCs) are an essential part of our immunological memory. They respond fast upon re-encountering pathogens and can differentiate into plasma cells that secrete protective antibodies. The focus of this review is on MBCs that lack, or express low levels of, CD21, hereafter referred to as CD21-/low. These cells are expanded in peripheral blood with age and during chronic inflammatory conditions such as viral infections, malaria, common variable immunodeficiency, and autoimmune diseases. CD21-/low MBCs have gained significant attention; they produce disease-specific antibodies/autoantibodies, and associate with key disease manifestations in some conditions. However, these cells can be divided into subsets based on classical B-cell and other markers, e.g., CD11c, FcRL4 and Tbet that, over the years, have become hallmarks to identify these cells. This has resulted in different names including age-associated, autoimmune-associated, atypical, tissue-like, tissue-resident, tissue-restricted, exhausted or simply CD21-/low B cells. It is however unclear whether the expanded ‘CD21-/low’ cells in one condition are equivalent to those in another, whether they express an identical gene signature and whether they have a similar function. Here, we will discuss these issues with the goal to understand whether the CD21-/low B cells are comparable in the different conditions.
... The prevalence and magnitude of antibody responses against Pf merozoite antigens have been extensively studied [reviewed in (47,48)]. In addition, it is known that Pf exposure results in the development of long-lived MBCs against merozoite antigens that are maintained in the absence of re-infection (28,(49)(50)(51). However, much remains unknown about the molecular characteristics of anti-merozoite antibodies and the connections between the MBC and plasma cell compartments. ...
Memory B cells (MBCs) and plasma antibodies against Plasmodium falciparum ( Pf ) merozoite antigens are important components of the protective immune response against malaria. To gain understanding of how responses against Pf develop in these two arms of the humoral immune system, we evaluated MBC and antibody responses against the most abundant merozoite antigen, full-length Pf merozoite surface protein 1 (PfMSP1 FL ), in individuals from a region in Uganda with high Pf transmission. Our results showed that PfMSP1 FL -specific B cells in adults with immunological protection against malaria were predominantly IgG ⁺ classical MBCs, while children with incomplete protection mainly harbored IgM ⁺ PfMSP1 FL -specific classical MBCs. In contrast, anti-PfMSP1 FL plasma IgM reactivity was minimal in both children and adults. Instead, both groups showed high plasma IgG reactivity against PfMSP1 FL , with broadening of the response against non-3D7 strains in adults. The B cell receptors encoded by PfMSP1 FL -specific IgG ⁺ MBCs carried high levels of amino acid substitutions and recognized relatively conserved epitopes on the highly variable PfMSP1 protein. Proteomics analysis of PfMSP1 19 -specific IgG in plasma of an adult revealed a limited repertoire of anti-MSP1 antibodies, most of which were IgG 1 or IgG 3 . Similar to B cell receptors of PfMSP1 FL -specific MBCs, anti-PfMSP1 19 IgGs had high levels of amino acid substitutions and their sequences were predominantly found in classical MBCs, not atypical MBCs. Collectively, these results showed evolution of the PfMSP1-specific humoral immune response with cumulative Pf exposure, with a shift from IgM ⁺ to IgG ⁺ B cell memory, diversification of B cells from germline, and stronger recognition of PfMSP1 variants by the plasma IgG repertoire.
... Here, we have used this multiplexed FluoroSpot assay to measure the frequencies of MBCs specific for six well known P. falciparum antigens [merozoite surface protein 1 (19) (MSP-1 19 ), MSP-2 (3D7), MSP-2 (FC27), MSP-3, apical membrane antigen 1 (AMA-1) and circumsporozoite protein (CSP)] in children living in an endemic region of Kenya. Circulating antibody responses to these antigens have previously been identified as possible markers of immunity against malaria (25,(31)(32)(33)(34). We compared antigen-specific MBCs against their cognate circulating antibodies in their ability to predict immunity to malaria, as well as previous exposure. ...
Identifying the mechanism of naturally acquired immunity against Plasmodium falciparum malaria could contribute to the design of effective malaria vaccines. Using a recently developed multiplexed FluoroSpot assay, we assessed cross-sectional pre-existing memory B-cells (MBCs) and antibody responses against six well known P. falciparum antigens (MSP-119, MSP-2 (3D7), MSP-2 (FC27), MSP-3, AMA-1 and CSP) and measured their associations with previous infections and time to clinical malaria in the ensuing malaria season in Kenyan children. These children were under active weekly surveillance for malaria as part of a long-term longitudinal malaria immunology cohort study, where they are recruited from birth. After performing Cox regression analysis, we found that children with a breadth of three or more antigen-specific MBC or antibody responses at the baseline had a reduced risk for malaria in the ensuing P. falciparum transmission season. Specifically, MBC responses against AMA-1, MSP-2 (3D7) and MSP-3, as well as antibody responses to MSP-2 (3D7) and MSP-3 were prospectively associated with a reduced risk for malaria. The magnitude or breadth of MBC responses were however not correlated with the cumulative number of malaria episodes since birth. We conclude that increased breadth for merozoite antigen-specific MBC and antibody responses is associated with protection against malaria.
... In the context of malaria, atMBCs also express inhibitory receptors, including FcRL5 (10)(11)(12). Upon P. falciparum infection, atMBCs show a peak in expansion around 10 days after malaria diagnosis and this cell population gradually contracts to background levels following clearance of infection (13,14). ...
Malaria, caused by Plasmodium parasites, still contributes to a high global burden of disease, mainly in children under 5 years of age. Chronic and recurrent Plasmodium infections affect the development of B cell memory against the parasite and promote the accumulation of atypical memory B cells (atMBCs), which have an unclear function in the immune response.
... Following peak levels of atMBCs during natural P. falciparum infection, the compartment gradually contracted to background levels with an estimated half-life of 295 days (Sundling et al., 2019). Similarly, Ayieko et al. (2013) showed that in the absence of infection, the percentage of class-switched atMBCs in malaria-exposed adults in Kenya decreased from an average of 7.7% to 2.8% over the course of 1 year (Ayieko et al., 2013). However, despite the gradual decline of atMBC numbers over time, elevated fractions of atMBCs following natural P. vivax infection have been observed 3 years postinfection (Changrob et al., 2018). ...
... Following peak levels of atMBCs during natural P. falciparum infection, the compartment gradually contracted to background levels with an estimated half-life of 295 days (Sundling et al., 2019). Similarly, Ayieko et al. (2013) showed that in the absence of infection, the percentage of class-switched atMBCs in malaria-exposed adults in Kenya decreased from an average of 7.7% to 2.8% over the course of 1 year (Ayieko et al., 2013). However, despite the gradual decline of atMBC numbers over time, elevated fractions of atMBCs following natural P. vivax infection have been observed 3 years postinfection (Changrob et al., 2018). ...
Protective immunity against clinical malaria is slow to develop, taking years of repeated exposure to parasites to acquire sufficiently broad and potent antibody responses. Increasing evidence suggests that Plasmodium infection and the resulting immune stimulation contribute to changes in the B cell compartment. In particular, accumulation of atypical memory B cells (atMBCs) is common in Plasmodium-exposed individuals. Similarities to cell subsets present in other acute and chronic disease settings have provided insight into the development and potential function of these cells; however, their contribution to protective immunity against malaria is still poorly understood. Here, we discuss recent findings that have increased our understanding of atMBCs and outline outstanding questions related to their function and development in the protective immune response to malaria.
... These cells, originally described as an exhausted subset of memory B cells in HIV infection (Moir and Fauci, 2009;Moir et al., 2008), have been found in the circulation of Plasmodium-infected individuals from endemic countries (Ly and Hansen, 2019). A role for aMBC in malaria immunity has been suggested on the basis of the accumulation of this sub-population in situations of parasitemia or shorter exposure history (Weiss et al., 2009;Changrob et al., 2018) in children and adults from malaria endemic areas (Weiss et al., 2009;Changrob et al., 2018;Portugal et al., 2015); importantly, aMBC were maintained in situations of persistent parasite exposure (Ayieko et al., 2013) with a decline over 12 months in the absence of transmission. The functional significance of vaccine-induced aMBC expansion and the role of these cells in the development of immunity to malaria needs further investigation. ...
Malaria-071, a controlled human malaria infection trial, demonstrated that administration of three doses of RTS,S/AS01 malaria vaccine given at one month intervals was inferior to a delayed fractional dose (DFD) schedule (62.5% vs 86.7% protection respectively). To investigate the underlying immunologic mechanism, we analyzed the B and T peripheral follicular helper cell (pTfh) responses. Here we show that protection in both study arms was associated with early induction of functional IL-21-secreting circumsporozoite (CSP)-specific pTfh cells together with induction of CSP-specific memory B cell responses after the 2nd dose that persisted after the 3rd dose. Data integration of key immunologic measures identified a subset of non-protected individuals in the standard (STD) vaccine arm who lost prior protective B cell responses after receiving the 3rd vaccine dose. We conclude that the DFD regimen favors persistence of functional B cells post 3rd dose.
... These cells, originally described as an exhausted subset of memory B cells in HIV infection (Moir and Fauci, 2009;Moir et al., 2008), have been found in the circulation of Plasmodium-infected individuals from endemic countries (Ly and Hansen, 2019). A role for aMBC in malaria immunity has been suggested on the basis of the accumulation of this sub-population in situations of parasitemia or shorter exposure history (Weiss et al., 2009;Changrob et al., 2018) in children and adults from malaria endemic areas (Weiss et al., 2009;Changrob et al., 2018;Portugal et al., 2015); importantly, aMBC were maintained in situations of persistent parasite exposure (Ayieko et al., 2013) with a decline over 12 months in the absence of transmission. The functional significance of vaccine-induced aMBC expansion and the role of these cells in the development of immunity to malaria needs further investigation. ...
Malaria-071, a controlled human malaria infection trial, demonstrated that administration of three doses of RTS,S/AS01 malaria vaccine given at one-month intervals was inferior to a delayed fractional dose (DFD) schedule (62.5% vs 86.7% protection, respectively). To investigate the underlying immunologic mechanism, we analyzed the B and T peripheral follicular helper cell (pTfh) responses. Here, we show that protection in both study arms was associated with early induction of functional IL-21-secreting circumsporozoite (CSP)-specific pTfh cells, together with induction of CSP-specific memory B cell responses after the second dose that persisted after the third dose. Data integration of key immunologic measures identified a subset of non-protected individuals in the standard (STD) vaccine arm who lost prior protective B cell responses after receiving the third vaccine dose. We conclude that the DFD regimen favors persistence of functional B cells after the third dose.
... These cells, originally described as an exhausted subset of memory B cells in HIV infection (Moir and Fauci, 2009;Moir et al., 2008), have been found in the circulation of Plasmodium-infected individuals from endemic countries (Ly and Hansen, 2019). A role for aMBC in malaria immunity has been suggested on the basis of the accumulation of this sub-population in situations of parasitemia or shorter exposure history (Weiss et al., 2009;Changrob et al., 2018) in children and adults from malaria endemic areas (Weiss et al., 2009;Changrob et al., 2018;Portugal et al., 2015); importantly, aMBC were maintained in situations of persistent parasite exposure (Ayieko et al., 2013) with a decline over 12 months in the absence of transmission. The functional significance of vaccine-induced aMBC expansion and the role of these cells in the development of immunity to malaria needs further investigation. ...
Malaria-071, a controlled human malaria infection trial, demonstrated that administration of three doses of RTS,S/AS01 malaria vaccine given at one-month intervals was inferior to a delayed fractional dose (DFD) schedule (62.5% vs 86.7% protection, respectively). To investigate the underlying immunologic mechanism, we analyzed the B and T peripheral follicular helper cell (pTfh) responses. Here, we show that protection in both study arms was associated with early induction of functional IL-21-secreting circumsporozoite (CSP)-specific pTfh cells, together with induction of CSP-specific memory B cell responses after the second dose that persisted after the third dose. Data integration of key immunologic measures identified a subset of non-protected individuals in the standard (STD) vaccine arm who lost prior protective B cell responses after receiving the third vaccine dose. We conclude that the DFD regimen favors persistence of functional B cells after the third dose.
... Some studies, which were conducted in P falciparum-and P vivax-endemic areas, have demonstrated that children and adults develop MBCs in response to recombinant antigens derived from blood-stage protein of malaria parasites that are able to persist for years, even in the absence of reinfection. [14][15][16][17][18][19] Other studies suggest that this cellular subtype is only maintained by persistent antigenic stimulation. 20 In the same way, while specific antibodies are rapidly lost from the serum of children when the infection is cleared, [21][22][23][24] it appears to persist for far longer in adults. ...
... These findings are similar to those observed in studies which used different recombinant proteins of P vivax. [17][18][19] Our data, which are consistent with the observed P falciparum infections in areas of low and instable transmission worldwide, 14,15,27,58 suggest that the biological behaviour of these parasites does not influence the dynamics It has long been known that continual exposure to malaria parasites is a critical factor to development of natural immunity. Besides this, levels of antibodies and/or occurrence of MBC combined with both clinical score and parasitaemia data can be important indicators of immunity degree. ...
... We were also able to determine that P vivax-specific antibodies can be observed for both B-cell epitopes in the absence of MBCs and vice versa what also was previously noted for others recombinant proteins of P falciparum and P vivax. [14][15][16][17][18][19] Finally, it is essential to emphasize that the use of peptides may offer many advantages over recombinant protein being considered an important strategy for vaccine design. 79 ...
Although antibodies are considered critical for malaria protection, little is known about the mechanisms/factors that maintain humoral immunity, especially regarding the induction and maintenance of memory B cells over time. In Brazilian endemic areas, this is the first time that the profile of antibody responses and the occurrence of antigen‐specific memory B‐cells (MBC) against P. vivax were investigated during acute malaria and up to six months after parasite clearance. For this, we selected two peptides, PvAMA‐1(S290‐K307) and PvMSP‐9(E795‐A808), which represent the Apical Membrane Antigen‐1 and Merozoite Surface Protein‐9 of P. vivax, respectively. Both peptides were previously described as containing linear B‐cell epitopes. Our findings were: 1‐ both peptides were recognized by IgG antibodies at a high frequency (between 24 to 81%) in all study groups; 2‐in the absence of infection, the IgG levels remained stable throughout 6 months of follow up; 3‐ PvAMA‐1(S290‐K307) and PvMSP‐9(E795‐A808)‐specific MBCs were detected in all individual groups in the absence of reinfection throughout the follow up period, suggesting long‐lived MBC. However, no positive association was observed between malaria‐specific antibody levels and frequency of MBCs over time. Taken together, these results suggest that peptides can be, in the future, an alternative strategy to polypeptidic vaccine formulation.
... An alteration of circulating MBC populations was detected during malaria infection [40,68,69]. Here, activated and atypical MBCs were identified as the MBC sub-sets that played major roles in the responses to rhoptry proteins during acute vivax episodes. ...
... A full understanding of these relationships would be useful for the context of immunity to malaria infection and vaccine development, since generation of pre-existing antibody from longlived plasma cells could help to kill parasites. In accordance with the previous studies, the temporary changes in MBC sub-sets was previously reported from an area with seasonal malaria transmission [40,68,69]. There, malaria-specific antibodies and MBCs were sustained whereas the cumulative exposure to malaria gradually altered the delicate balance between circulating classical MBCs and functionally impaired atypical MBCs [69]. ...
... Despite a negative impact of atypical MBCs on the efficacy of malaria vaccines, a rare study did detect malaria-specific atypical MBCs and observed their function in natural exposure [70]. Most of MBC sub-set studies reported total populations which phenotyped as CD19 + CD21 − CD27 − (atypical MBCs) or CD19 + CD27 + (classical MBCs), without any malaria specificity [40,68,69]. Further studies are needed to generate a high sensitivity technique for detecting the rare populations of each malaria-specific MBC sub-set, and to study the function of atypical MBCs and their relationship to classical MBCs in circulating blood. ...
Background:
Rhoptries are the large, paired, secretory organelles located at the apical tip of the malaria merozoite that are considered important for parasite invasion processes. Plasmodium vivax rhoptry proteins have been shown to induce humoral immunity during natural infections. Therefore, these proteins may be potential novel vaccine candidates. However, there is a lack of data on the duration of antibody and memory B cell (MBC) responses. Here, the longitudinal analysis of antibody and MBC responses to the P. vivax rhoptry proteins PvRALP1-Ecto and PvRhopH2 were monitored and analysed in individuals to determine their persistence.
Methods:
Thirty-nine samples from P. vivax-infected subjects (age 18-60 years) were recruited to explore the frequency and persistence of antibody and MBC responses against rhoptry proteins (PvRALP1-Ecto and PvRhopH2) using both cross-sectional and longitudinal cohort study designs. Antibody levels were determined by ELISA during clinical malaria, and at 3, 9 and 12 months post-infection. The frequency of MBC sub-sets and presence of rhoptry-specific MBCs in subjects 18 months after treatment were detected by flow cytometry and ELISPOT assay.
Results:
The seroprevalence of antibodies against PvRALP1-Ecto and PvRhopH2 proteins was found to be high during acute infection, with IgG1, IgG2 and IgG3 sub-classes predominant. However, these anti-rhoptry responses were short-lived and significantly decreased at 9 months post-infection. To relate the durability of these antibody responses to MBC persistence at post-infection, 18-month post-infection peripheral blood mononuclear cells (PBMCs) samples were taken to detect rhoptry-specific MBCs and frequency of MBC sub-sets, and correlate with antibody responses. These late post-infection samples revealed that rhoptry-specific MBCs were present in about 70% of total subjects. However, the persistence of specific MBCs was not correlated with antibody responses as the majority of malaria subjects who were positive for PvRALP1-Ecto- or PvRhopH2-specific MBCs were seronegative for the rhoptry antigens. The frequencies of classical MBCs were increased after infection, whereas those of activated and atypical MBCs were decreased, indicating that MBC responses could switch from activated or atypical MBCs to classical MBCs after parasite clearance, and were maintained in blood circulating at post-infection.
Conclusion:
The study showed that rhoptry antigens induced the development and persistence of MBC responses in P. vivax-infected subjects who lived in a region of low malaria transmission, which were not related to the longevity of antibody responses.
