Delayed fractional dosing with RTS,S/AS01 improves humoral immunity to malaria via a balance of polyfunctional NANP6- and Pf16-specific antibodies

Das, Jishnu; Fallon, Jonathan K.; Yu, Timothy C.; Michell, Ashlin; Suscovich, Todd J.; Linde, Caitlyn; Natarajan, Harini; Weiner, Joshua A.; Coccia, Margherita; Gregory, S; Ackerman, Margaret E.; Bergmann‐Leitner, Elke S.; Fontana, Laura; Dutta, Sandeep; Lauffenburger, Douglas A.; Jongert, Erik; Wille-Reece, Ulrike; Alter, Galit

doi:10.1016/j.medj.2021.10.003

Cited by 25 publications

(28 citation statements)

References 59 publications

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“…Modelling data indeed indicate that IgG concentration and avidity are regulated independently by separate biological processes (69). Other discrepancies are also found with recently published systems serology analyses of monthly versus Fx017M dosing (70) where different trends were observed with Fx017M to those reported here with DFx.…”

Section: Discussioncontrasting

confidence: 99%

Delayed booster dosing improves human antigen-specific Ig and B cell responses to the RH5.1/AS01_B malaria vaccine

Nielsen

Barrett

Davis

et al. 2022

Preprint

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BackgroundAntibodies are crucial for vaccine-mediated protection against many pathogens. Modifications to vaccine delivery that increase antibody magnitude, longevity, and/or quality are therefore of great interest for maximising efficacy. We have previously shown that a delayed fractional (DFx) dosing schedule (0-1-6mo) – using AS01B-adjuvanted RH5.1 malaria antigen – substantially improves serum IgG durability as compared to monthly dosing (0-1-2mo; NCT02927145). However, the underlying mechanism and whether there are wider immunological changes with DFx dosing was unclear.MethodsImmunokinetics of PfRH5-specific Ig across multiple isotypes were compared between DFx and monthly regimen vaccinees. Peak responses were characterised in-depth with a systems serology platform including biophysical and functional profiling. Computational modelling was used to define the humoral feature set associated with DFx dosing. PfRH5-specific B cells were quantified by flow cytometry and sorted for single cell RNA sequencing (scRNA-seq). Differential gene expression between DFx and monthly dosing regimens was explored with Seurat, DESeq2 and gene set enrichment analysis.ResultsDFx dosing increases the frequency of circulating PfRH5-specific B cells and longevity of PfRH5-specific IgG1, as well as other isotypes and subclasses. At the peak antibody response, DFx dosing was distinguished by a systems serology feature set comprising increased FcRn-binding, IgG avidity, and proportion of G2B and G2S2F IgG Fc glycans, alongside decreased IgG3, antibody-dependent complement deposition, and proportion of G1S1F IgG Fc glycan. At the same time point, scRNA-seq of PfRH5-specific B cells revealed enriched plasma cell and Ig / protein export signals in the monthly dosing group as compared to DFx vaccinees.ConclusionsDFx dosing of the RH5.1/AS01B vaccine had a profound impact on the humoral response. Our data suggest plausible mechanisms relating to improved FcRn-binding (known to improve Ig longevity) and a potential shift from short-lived to long-lived plasma cells. Recent reports of the positive impact of delayed boosting on SARS-CoV-2 vaccine immunogenicity highlight the broad relevance of these data.

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Section: Discussioncontrasting

confidence: 99%

Delayed booster dosing improves human antigen-specific Ig and B cell responses to the RH5.1/AS01_B malaria vaccine

Nielsen

Barrett

Davis

et al. 2022

Preprint

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“…Furthermore, these antibodies induced antibody-dependent respiratory burst by neutrophils, which indicates activation of neutrophils and the potential for cellular cytotoxicity [34] (p=0.011 for M3 vs M0; Figure 2B). RTS,S vaccine-induced antibodies also promoted opsonic phagocytosis of CSP-coated beads by the THP-1 monocyte cell line, which is commonly used as a model of monocyte phagocytosis in vitro (Figure 2C) [19,20,23,33,35,36]. We confirmed that antibodies also effectively promoted phagocytosis with primary human 13 monocytes purified from peripheral blood (Figure 2D).…”

Section: Rtss Vaccine-induced Antibodies Mediate Cellular Immune Resp...supporting

confidence: 66%

“…While IgG responses to NANP-repeats have been a focus of vaccine development, our data suggest that improving responses to the CT regions, in addition to NANP-repeats, may be important for maximizing functional activity and possibly efficacy since antibodies to the CT region can promote phagocytosis of sporozoites. This is supported by recent analysis of a phase I/IIa infection challenge trial in malaria-naïve adults [20]. Glycosylation of IgG can influence FcγR binding activity [55].…”

Section: Discussionmentioning

confidence: 71%

“…An immunologic mechanism that is being increasingly recognised in immunity against pathogens is the ability of IgG to interact with Fcγ-receptors (FcγR) expressed on various cell types leading to opsonic phagocytosis and other effector mechanisms [18][19][20][21][22]. We recently, identified that neutrophils were the major cell type to mediate opsonic phagocytosis of P. falciparum sporozoites in blood, whereas monocytes contributed a minor role [23].…”

Section: Introductionmentioning

confidence: 99%

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Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children

Feng

Kurtovic

Agius

et al. 2022

Preprint

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BACKGROUND: RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody function is limited, especially among children. Antibodies that promote opsonic phagocytosis and other cellular functions appear to be important contributors to RTS,S immunity. METHODS: We studied a phase IIb trial of RTS,S/AS02 conducted young children in malaria endemic regions of Mozambique. We evaluated the induction of antibodies targeting the circumsporozoite protein (CSP, vaccine antigen) that interact with Fcγ-receptors (FcRγs) and promote phagocytosis (neutrophils, monocytes, THP-1 cells), antibody-dependent respiratory burst (ADRB) by neutrophils, and natural killer (NK) cell activity, as well as the temporal kinetics of responses over 5 years of follow-up (ClinicalTrials.gov registry number NCT00197041). RESULTS: RTS,S vaccination induced CSP-specific IgG with FcγRIIa and FcγRIII binding activity and promoted phagocytosis by neutrophils, THP-1 monocytes, and primary human monocytes, neutrophil ADRB activity, and NK cell activation. Responses were highly heterogenous among children, and the magnitude of neutrophil phagocytosis by antibodies was relatively modest, which may reflect modest vaccine efficacy. Induction of functional antibodies was lower among children with higher malaria exposure. Functional antibodies largely declined within a year post-vaccination, consistent with the decline in vaccine efficacy over that time. Biostatistical modelling suggested IgG1 and IgG3 contribute in promoting FcγR binding and phagocytosis, and IgG targeting the NANP-repeat and C-terminal regions CSP were similarly important for functional activities. CONCLUSION: Results provide new insights to understand the modest and time-limited efficacy of RTS,S in children, and the induction of antibody functional activities. Improving the induction and maintenance of antibodies that promote phagocytosis and cellular functions, and combating the negative effect of malaria exposure on vaccine responses are potential strategies for improving RTS,S efficacy and longevity.

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“…RTS,S vaccine-induced antibodies also promoted opsonic phagocytosis of CSP-coated beads by the THP-1 monocyte cell line, which is commonly used as a model of monocyte phagocytosis in vitro (Fig. 2 C) [ 19 , 20 , 23 , 33 , 35 , 36 ]. We confirmed that antibodies also effectively promoted phagocytosis with primary human monocytes purified from peripheral blood (Fig.…”

Section: Resultsmentioning

confidence: 99%

Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children

Feng

Kurtovic

Agius

et al. 2022

BMC Med

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Background RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody function is limited, especially among children. Antibodies that promote opsonic phagocytosis and other cellular functions appear to be important contributors to RTS,S immunity. Methods We studied a phase IIb trial of RTS,S/AS02 conducted in young children in malaria-endemic regions of Mozambique. We evaluated the induction of antibodies targeting the circumsporozoite protein (CSP, vaccine antigen) that interact with Fcγ-receptors (FcRγs) and promote phagocytosis (neutrophils, monocytes, THP-1 cells), antibody-dependent respiratory burst (ADRB) by neutrophils, and natural killer (NK) cell activity, as well as the temporal kinetics of responses over 5 years of follow-up (ClinicalTrials.gov registry number NCT00197041). Results RTS,S vaccination induced CSP-specific IgG with FcγRIIa and FcγRIII binding activity and promoted phagocytosis by neutrophils, THP-1 monocytes, and primary human monocytes, neutrophil ADRB activity, and NK cell activation. Responses were highly heterogenous among children, and the magnitude of neutrophil phagocytosis by antibodies was relatively modest, which may reflect modest vaccine efficacy. Induction of functional antibodies was lower among children with higher malaria exposure. Functional antibody magnitude and the functional activity of antibodies largely declined within a year post-vaccination, and decay were highest in the first 6 months, consistent with the decline in vaccine efficacy over that time. Decay rates varied for different antibody parameters and decay was slower for neutrophil phagocytosis. Biostatistical modelling suggested IgG1 and IgG3 contribute in promoting FcγR binding and phagocytosis, and IgG targeting the NANP-repeat and C-terminal regions CSP were similarly important for functional activities. Conclusions Results provide new insights to understand the modest and time-limited efficacy of RTS,S in children and the induction of antibody functional activities. Improving the induction and maintenance of antibodies that promote phagocytosis and cellular functions, and combating the negative effect of malaria exposure on vaccine responses are potential strategies for improving RTS,S efficacy and longevity.

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Delayed fractional dosing with RTS,S/AS01 improves humoral immunity to malaria via a balance of polyfunctional NANP6- and Pf16-specific antibodies

Cited by 25 publications

References 59 publications

Delayed booster dosing improves human antigen-specific Ig and B cell responses to the RH5.1/AS01_B malaria vaccine

Delayed booster dosing improves human antigen-specific Ig and B cell responses to the RH5.1/AS01_B malaria vaccine

Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children

Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children

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Delayed fractional dosing with RTS,S/AS01 improves humoral immunity to malaria via a balance of polyfunctional NANP6- and Pf16-specific antibodies

Cited by 25 publications

References 59 publications

Delayed booster dosing improves human antigen-specific Ig and B cell responses to the RH5.1/AS01B malaria vaccine

Delayed booster dosing improves human antigen-specific Ig and B cell responses to the RH5.1/AS01B malaria vaccine

Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children

Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children

Contact Info

Product

Resources

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Delayed booster dosing improves human antigen-specific Ig and B cell responses to the RH5.1/AS01_B malaria vaccine

Delayed booster dosing improves human antigen-specific Ig and B cell responses to the RH5.1/AS01_B malaria vaccine