Antibody interference by a non-neutralizing antibody abrogates humoral protection against Plasmodium yoelii liver stage

Vijayan, Kamalakannan; Visweswaran, Ganesh Ram R.; Chandrasekaran, Ramyavardhanee; Trakhimets, Olesya; Brown, Samantha; Watson, Alexander; Zuck, Meghan; Dambrauskas, Nicholas; Raappana, Andrew; Carbonetti, Sara; Kelnhofer-Millevolte, Laurel; Glennon, Elizabeth K.K.; Postiglione, Rachel; Sather, D. Noah; Kaushansky, Alexis

doi:10.1016/j.celrep.2021.109489

Cited by 18 publications

(25 citation statements)

References 61 publications

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“…2C). The known inhibitory anti-PyCSP mAb 2F6 38,39 reduced both inhibition and traversal in this assay, as expected (Fig. 2B and C).…”

Section: Pytrap Polyclonal Antibodies Can Prevent Parasite Infection ...supporting

confidence: 87%

“…Studies examining CSP-elicited antibody responses have shown that within a polyclonal antibody population only a subset are highly potent antibody clones, and their distinguishing binding properties can be quite nuanced 39,44,45,[54][55][56][57][58] . Understanding the characteristics associated with protection is crucial for the development of superior mAb products and vaccine immunogens, yet such studies have not been previously performed for TRAP or other non-CSP pre-erythrocytic antibody targets.…”

Section: Discussionmentioning

confidence: 99%

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Anti-TRAP/SSP2 monoclonal antibodies can inhibit sporozoite infection and enhance protection of anti-CSP monoclonal antibodies

Wilder

Вигдорович

Carbonetti

et al. 2021

Preprint

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Vaccine-induced sterilizing protection from infection with the Plasmodium parasite, the pathogen that causes malaria, will be an essential tool in the fight against malaria as it would prevent both malaria-related disease and transmission. Stopping the relatively small number of parasites injected by the mosquito before they can migrate from the skin to the liver is an attractive goal. Antibody-eliciting vaccines have been used to pursue this objective by targeting the major parasite surface protein present during this stage, the circumsporozoite protein (CSP). While CSP-based vaccines have recently had encouraging success in disease reduction, this was only achieved with extremely high antibody titers and appeared less effective for a complete block of infection. While such disease reduction is important, these results also indicate that further improvements to vaccines based solely on CSP will likely yield diminishing benefits towards the goal of durable, infection-blocking immunity. Here, we show that monoclonal antibodies (mAbs) recognizing the sporozoite protein TRAP/SSP2 across the major protein domains exhibit a range of inhibitory capacity and that these mAbs can augment CSP-based protection despite delivering no sterile protection on their own. Therefore, pursuing a multivalent subunit vaccine immunization is a promising strategy for improving infection-blocking malaria vaccines.

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“…2C). The known inhibitory anti-PyCSP mAb 2F6 38,39 reduced both inhibition and traversal in this assay, as expected (Fig. 2B and C).…”

Section: Pytrap Polyclonal Antibodies Can Prevent Parasite Infection ...supporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Anti-TRAP/SSP2 monoclonal antibodies can inhibit sporozoite infection and enhance protection of anti-CSP monoclonal antibodies

Wilder

Вигдорович

Carbonetti

et al. 2021

Preprint

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“…We may therefore need to optimize cadence and epitope context for presenting these two short epitopes in tandem 70 . At the parasite level, Vijayan et al 71 have shown possible interference when monoclonal antibodies to the major and minor repeats of P. yoelii CSP are bound simultaneously; likewise, there is no evidence that P. falciparum mAb 317 and CIS43 can synergize in vitro (unpublished data). Therefore, immune-broadening using multiple short inhibitory epitopes on a single vaccine construct was complex and, in this instance, was found detrimental to vaccine efficacy.…”

Section: Discussionmentioning

confidence: 99%

Restricted valency (NPNA)n repeats and junctional epitope-based circumsporozoite protein vaccines against Plasmodium falciparum

et al. 2022

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The Circumsporozoite Protein (CSP) of Plasmodium falciparum contains an N-terminal region, a conserved Region I (RI), a junctional region, 25–42 copies of major (NPNA) and minor repeats followed by a C-terminal domain. The recently approved malaria vaccine, RTS,S/AS01 contains NPNAx19 and the C-terminal region of CSP. The efficacy of RTS,S against natural infection is low and short-lived, and mapping epitopes of inhibitory monoclonal antibodies may allow for rational improvement of CSP vaccines. Tobacco Mosaic Virus (TMV) was used here to display the junctional epitope (mAb CIS43), Region I (mAb 5D5), NPNAx5, and NPNAx20 epitope of CSP (mAbs 317 and 580). Protection studies in mice revealed that Region I did not elicit protective antibodies, and polyclonal antibodies against the junctional epitope showed equivalent protection to NPNAx5. Combining the junctional and NPNAx5 epitopes reduced immunogenicity and efficacy, and increasing the repeat valency to NPNAx20 did not improve upon NPNAx5. TMV was confirmed as a versatile vaccine platform for displaying small epitopes defined by neutralizing mAbs. We show that polyclonal antibodies against engineered VLPs can recapitulate the binding specificity of the mAbs and immune-focusing by reducing the structural complexity of an epitope may be superior to immune-broadening as a vaccine design approach. Most importantly the junctional and restricted valency NPNA epitopes can be the basis for developing highly effective second-generation malaria vaccine candidates.

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“…The repeat region in Py CSP contains two general motifs that make up the longer, N -terminal major repeat region and the shorter, more C-terminal minor repeats ( Fig 2B ). The minor repeat region is the target of potent α- Py CSP neutralizing activity of mAb 2F6 [ 29 – 31 ] but neutralization by mAbs targeting the major repeat region has not been reported. At week 3, the strains had equivalent IgG titers to the major repeat peptide, but BALB/cJ mice had significantly higher titers to the minor repeat peptide ( Fig 2D ).…”

Section: Resultsmentioning

confidence: 99%

“…To evaluate this possibility, we investigated whether the major repeat also could be a target for NAbs, or whether neutralization is solely mediated through the minor repeat motif as observed for mAb 2F6. We previously characterized a non-neutralizing antibody (nNAb), RAM1, which binds to the major repeat with relatively low affinity, does not induce the CSP reaction, nor protects in vitro or in vivo [ 31 ]. In this study, we isolated a mAb RAM2, which also binds to an epitope in the major repeat motif like RAM1 (Figs 3A and S4A ).…”

Section: Resultsmentioning

confidence: 99%

Germinal center activity and B cell maturation are associated with protective antibody responses against Plasmodium pre-erythrocytic infection

Visweswaran¹,

Vijayan²,

Chandrasekaran³

et al. 2022

PLoS Pathog

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Blocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. However, the lack of well-defined features within vaccine-elicited antibody responses that correlate with protection represents a major roadblock to improving on current generation vaccines. We vaccinated mice (BALB/cJ and C57BL/6J) with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated vaccine-elicited humoral immunity and identified immunological factors associated with protection after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice. In contrast, all C57BL/6J mice were infected similar to controls. Protection was mediated by antibodies and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer CSP-specific germinal center experienced B cells and class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that the development of protective antibody responses in BALB/cJ mice in response to vaccination with PyCSP was associated with increased germinal center activity and somatic mutation compared to C57BL/6J mice, highlighting the key role B cell maturation may have in the development of vaccine-elicited protective antibodies against CSP.

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Antibody interference by a non-neutralizing antibody abrogates humoral protection against Plasmodium yoelii liver stage

Cited by 18 publications

References 61 publications

Anti-TRAP/SSP2 monoclonal antibodies can inhibit sporozoite infection and enhance protection of anti-CSP monoclonal antibodies

Anti-TRAP/SSP2 monoclonal antibodies can inhibit sporozoite infection and enhance protection of anti-CSP monoclonal antibodies

Restricted valency (NPNA)n repeats and junctional epitope-based circumsporozoite protein vaccines against Plasmodium falciparum

Germinal center activity and B cell maturation are associated with protective antibody responses against Plasmodium pre-erythrocytic infection

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